Pioneers in Neonatal/Perinatal Medicine: Perinatal Profiles from NeoReviews [1 ed.] 9781610020381, 9781610020374

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… Much of this collection has been written by the students of these pioneers who have gone on to become key NPM innovators themselves. They provide rare insight into the personalities of their mentors and the development of NPM. You’ll meet such luminaries as: • Alex Minkowski, MD, whose life’s work, including a conference on whether assisted ventilation did more harm than good, led French President Jacques Chirac in 2004 to call him “one of the consciences of the 20th century.” • Martin Couney, MD, who in 1896 began 40 years of organizing preterm baby “child hatchery ” sideshows to showcase the marvels of incubator technology at expositions, state fairs, traveling circuses—even Coney Island!—showing the public that even the most severely preterm infants had a chance for survival. • Elizabeth Blackwell, Marie Putnam Jacobi, Elizabeth Garret, and Madeleine Brès, the first female physicians caring for women and children at the end of the 19th century. All struggled for admission to medical school yet eventually managed to pierce the armor of sex bias. • Ignác Fülöp Semmelweis, the Hungarian pioneer of antisepsis who first demonstrated that most childbed fever cases could be prevented—one of the most important discoveries of 19th-century medicine—yet was ridiculed and released in disgrace from his Viennese hospital and medical school faculty posts.

Pioneers in Neonatal/Perinatal Medicine: Perinatal Profiles from NeoReviews

From the files of NeoReviews comes this collection of Perinatal Profiles, chosen to provide a glimpse into the lives of the “movers and shakers” in neonatal/perinatal medicine …

PIONEERS IN

NEONATAL/

PERINATAL

MEDICINE Perinatal Profiles from NeoReviews Dr. Martin Couney

• Cathy Cropley, the Seattle nurse who wove nurses into the fabric of neonatal resuscitation as team members and instructors, insisting that skill take precedence over title. This collection of 26 key columns was compiled and edited by NeoReviews Editor-in-Chief Alistair G.S. Philip, MD, FRCPE, FAAP, in honor of the 15th anniversary of NeoReviews, the American Academy of Pediatrics’ online journal of neonatology, available at http://www.neoreviews.org.

Dr. Virginia Apgar

The Hess Incubator

Production of this book was made possible thanks to a generous grant from the AAP Section on Neonatal-Perinatal Medicine, www.aap.org/perinatal, which offers resources for neonatologists, trainees, pediatricians and families.

Dr. Clem Smith

CONTENTS Introduction ................................................................................................................................................... 1 Perinatal Profiles: Dr Julius Hess and His Incubator Tonse N.K. Raju ........................................................................................................................................... 2 Perinatal Profiles: William Little and Cerebral Palsy Tonse N.K. Raju ........................................................................................................................................... 4 Perinatal Profiles: Ian Donald and Obstetric Diagnostic Ultrasound Alistair G.S. Philip ......................................................................................................................................... 6 Perinatal Profiles: Childbed Fever and Igna´c Fu¨lo¨p Semmelweis Istvan Seri.................................................................................................................................................... 10 Perinatal Profiles: Sir Joseph Barcroft: The 20th Century’s Renaissance Perinatal Physiologist Tonse N.K. Raju ......................................................................................................................................... 14 Perinatal Profiles: Geoffrey S. Dawes: A Neonatologist’s Appreciation Roderic H. Phibbs....................................................................................................................................... 16 Perinatal Profiles: Robert McCance and Elsie Widdowson: Pioneers in Neonatal Science Andrew Whitelaw ........................................................................................................................................ 19 Perinatal Profiles: Alexandre Minkowski: Founder of “Biology of the Neonate” Alistair G.S. Philip ....................................................................................................................................... 23 Perinatal Profiles: Clem Smith: A Gentle Gardener Nicholas M. Nelson..................................................................................................................................... 26 Perinatal Profiles: Roberto Caldeyro-Barcia: Obstetric Physiologist Extraordinary Peter M. Dunn............................................................................................................................................ 31 Perinatal Profiles: Professor John (Johnny) Lind, Neonatology Pioneer William Oh .................................................................................................................................................. 36 Perinatal Profiles: John William Ballantyne: Scottish Obstetrician and Prolific Writer Alistair G.S. Philip ....................................................................................................................................... 39 Perinatal Profiles: Pierre Budin: The Fight Against Maternal and Infant Mortality Paul L. Toubas ............................................................................................................................................ 42 Perinatal Profile: Jim Farquhar and Infants of Diabetic Mothers Alistair G.S. Philip ....................................................................................................................................... 47 Perinatal Profile: Bill Kitchen and Very Low-birthweight Infants Lex W. Doyle .............................................................................................................................................. 52 Perinatal Profiles: Dr Colette Dreyfus-Brisac: Development of Brain Electrocortical Activity Paul L. Toubas ............................................................................................................................................ 55

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Perinatal Profile: Arvo Ylppo¨: Little Big Man Kari O. Raivio ............................................................................................................................................. 59 Perinatal Profile: Klaus Riegel: A Swabian “Someone” Hans T. Versmold ....................................................................................................................................... 64 Perinatal Profiles: Bengt Robertson: A Pioneer of Surfactant Research Henry L. Halliday, Christian P. Speer......................................................................................................... 71 Perinatal Profiles: Bent Friis-Hansen: A Danish Pioneer of Neonatology Gorm Greisen.............................................................................................................................................. 74 Perinatal Profiles: Cathy Cropley, RN, MS: A Partner in Developing NRP Ron Bloom.................................................................................................................................................. 80 Perinatal Profiles: Martin Couney and Newborn Infant Sideshows Tonse N.K. Raju ......................................................................................................................................... 82 Pioneer Women in Neonatology: Part 1: 1870–1945 Paul-Louis Toubas....................................................................................................................................... 85 Pioneer Women in Neonatology: Part 2: 1945–1960 Paul-Louis Toubas....................................................................................................................................... 90 Pioneer Women in Neonatology: Part 3: The Roaring Sixties (1960–1980) Paul-Louis Toubas....................................................................................................................................... 96 Perinatal Profiles: E´lie Metchnikoff: Probiotic Pioneer Michael P. Sherman .................................................................................................................................. 103 Index .......................................................................................................................................................... 106

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Introduction In 2010, NeoReviews marked its 10th anniversary by collecting 36 of its Historical Perspectives columns into a book titled “Milestones in Neonatal/Perinatal Medicine,” highlighting many of the seminal articles (and their authors) that influenced the development of neonatology. The original series of Historical Perspectives also included a series which we labeled “Perinatal Profiles,” detailing the contributions of individuals who influenced the development of neonatal-perinatal medicine around the world. In addition to the USA, the countries represented included Australia, Denmark, England, Finland, France, Germany, Norway, Scotland, Sweden and Uruguay. Now, in 2015, thanks to a generous grant from the AAP Section on Neonatal-Perinatal Medicine, we celebrate the journal’s 15th anniversary by collecting 26 of these Perinatal Profiles (including one from the

Milestones book) into the present volume: “Pioneers of Neonatal/Perinatal Medicine.” Clearly, this is a highly select group of individuals about whom the profile authors had some particular knowledge, whether as colleagues, students or friends. While we think it is important to acknowledge the enormous contributions of these pioneers, we also acknowledge that there probably are hundreds of individuals from other countries who added their own knowledge and insights to influence the way that neonatal-perinatal medicine is practiced throughout the world. In summary, while many of these luminaries have reached the pinnacle of achievement, we should all practice medicine to the best of our ability. To do this, we need to “stand on the shoulders” of those who have gone before. This book is intended primarily to allow younger physicians to appreciate the contributions of some of the giants in our field. Alistair G.S. Philip, MD, FRCPE, FAAP Editor-in-Chief, NeoReviews Emeritus Professor of Pediatrics, Stanford University School of Medicine

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Perinatal Profiles: Dr Julius Hess and His Incubator Tonse N.K. Raju, MD, DCH*

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Raju did not disclose any financial relationships relevant to this article.

Historians trace the beginnings of incubator care to Johann Georg von Ruehl in 1835 at the Imperial Foundling Hospital in St Petersburg, Russia. However, the French obstetrician Ste´phane Tarnier (1828 –1897) is credited with having conceived the development of “incubators” for preterm infants similar to those used for “brooding hens” (couveuses). Collaborating with an engineer from Paris, he developed an ingenious “thermo-siphon” heating system that circulated hot water between a double-walled metallic cage that could hold two preterm infants comfortably. In 1880, the Tarnier incubators were installed at the Paris Maternity Hospital, which became the world’s first neonatal intensive care unit (ICU). In 1915, Dr Julius Hess (1876 – 1955) introduced an electric-heated water-jacketed infant incubator and bed at the Sarah Morris Hospital of Michael Reese Medical Center in Chicago. Because of electric heat and other characteristics, this incubator could maintain a constant internal temperature with a safe-maximum limit and a constant supply of fresh air with “normal average” humidity. Made of heavy sheet copper, the bed measured 30 inches in length, 17 inches in width, and 13 inches in depth. The floor and the sides were surrounded by a 1-inch thick “waterjacket,” and the walls were covered *Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md.

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by 1⁄4-inch thick cork to prevent radiant heat loss. A standard supplied with ballbearing casters allowed for transportation. Infants were placed in a “baby basket” (281481⁄2 inches), and the basket was kept on a 2-inch platform to allow for free circulation of air around it. This also prevented the infants from coming into direct contact with the heated incubator walls. A miniature version of this incubator was used for infant transportation, also developed by Hess in collaboration with the City of Chicago and the Chicago Yellow Cab Company. At the time of Hess’ publication about the incubator in 1915, three infants were cared for in the incubator bed. By May 1922, his unit had expanded and been given a formal name: the Premature Infant Station,

Figure. The Hess incubator on display at

the Spertus Museum of Jewish History in Chicago on loan from the International Museum of Surgical Science.

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arguably, the first “neonatal ICU” in the United States. Hundreds of Hess incubators were sold and used during the first half of the 20th century, but only a few have survived. One Hess incubator is in a private collection, a second is at the Smithsonian Institute, and the third (located by the author) is owned by the International Museum of Surgical Science in Chicago (Figure). Despite its drawbacks, the incubator became a powerful and enduring symbol of what machines can do to cure human problems—a tunnel vision prevalent even today. It is noteworthy that the Hess incubator had provisions for oxygen administration through a small porthole. However, because it was not air-tight, oxygen

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leaked, preventing a build-up of high oxygen concentrations inside the incubator. Perhaps because of this, despite high survival rates for preterm infants, the Michael Reese Hospital recorded one of the lowest incidences of retrolental fibroplasia (later renamed retinopathy of prematurity) in the 1940s through the early 1950s, when other neonatal ICUs in the United States that used “new and improved” incubators were encountering an epidemic of blinded infants. Such may be the unintended consequences of “medical progress.” Dr Hess was a prolific author, and his books, particularly in collaboration with Evelyn Lundeen (his nursing supervisor at the Sarah Morris Hospital Premature Infant Station),

had a profound influence on the delivery of neonatal care during the first half of the 20th century.

Suggested Reading Baker JP. The Machine in the Nursery: Incubator Technology and the Origins of Newborn Intensive Care. Baltimore, Md: The Johns Hopkins University Press; 1996 Hess JH. An electric-heated water-jacketed infant incubator and bed for use in the care of premature and poorly nourished infants. JAMA. 1915;64:1068 –1069 Hess JH. Premature and Congenitally Diseased Infants. Philadelphia, Pa: Lea & Febiger; 1922 Hess JH, Lundeen EC. The Premature Infant: Its Medical and Nursing Care. Philadelphia, Pa: JB Lippincott Company; 1941 Silverman WA. Incubator-baby side shows. Pediatrics. 1979;64:127–141

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Perinatal Profiles: William Little and Cerebral Palsy Tonse N.K. Raju, MD, DCH*

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Raju did not disclose any financial relationships relevant to this article.

William John Little (1810 –1894), an orthopedic surgeon in England, first described the condition later named cerebral palsy (CP) in a series of lectures he gave to medical students between 1843 and 1844. Having suffered from bilateral clubfoot (residual of poliomyelitis), Little had personal reasons to study and treat children’s deformities. He had helped found London’s Royal Orthopedic Hospital, where he gave these seminal talks, (1) and in 1853, published them in a monograph. (2) Today, about 163 years since Little’s classic description, an intellectual renaissance has occurred in the study of CP. A new definition and classification of CP have been proposed; (3) newer neuroimaging techniques are helping to assess the nature, evolution, and severity of neuronal injury in CP, speculate on its cause, and provide better prognostication; (4)(5) and advances in cytokine physiology, placental pathology, metabolic testing, and chromosomal evaluations are helping to determine multiple etiologic pathways that can injure the developing brain. (6) Such progress, however, did not take place in a smooth, step-by-step manner. Controversy began soon after Little had delivered his famous 1861 address to the Obstetric Society of London, in which he proposed a causal association between birth *Medical Officer/Program Scientist, Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md.

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events and later CP. (7) Obstetricians argued that Little’s theories were “interesting,” but remained skeptical. They asserted having seen cases of “apparent stillbirths” in which the child survived normally and having heard of children who had CP but no history of perinatal brain injury. Similar arguments, mostly along the lines of a clinician’s specialty, led to many theories on the cause of CP. Some experts agreed that prematurity and perinatal asphyxia were etiologically linked with CP. Others held that asphyxia was not a proximate cause for any CP because most cases were “congenital and inherited,” but unrelated to birthing events. A small number of experts argued that CP occurred from pathology in the spinal cord or was caused by other childhood conditions, such as infections, and even teething. (8) Almost 3 decades after Little’s lectures, William Osler christened the condition as “cerebral palsy.” Sigmund Freud, while dismissing “spinal pathology” as the cause of CP, agreed with Little about asphyxia being a potential cause of brain injury. Freud also made a profound observation that in many cases of CP, the brain itself may be developmentally abnormal long before the infant’s birth. (8) Posterity has proved that Little was, indeed, correct in his primary argument that serious adverse perinatal events can cause brain injury, and preterm infants are especially vulnerable. Evaluating the 63 cases Little described in 1861, Accardo (9) concluded that 57 (90%) suffered from CP, 34 (60%) had cerebral diplegia, NeoReviews Vol.7 No.11 November 2006 e567

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Some Reasons Why Little Was Misunderstood Table.

●

●

● ●

●

●

The neuronal doctrine of cerebral function was unknown in Little’s time, making it difficult to explain the complex and changing signs and symptoms of cerebral palsy (CP). Other crippling neurologic conditions, such as poliomyelitis, encephalitis, and meningitis, which were poorly understood at that time, also led to confusion. Statistical methods such as multivariate analyses, odds ratio, and relative risks had not evolved. Hospitals, nursing homes, and alms houses where Little saw crippled children did not maintain medical records. Thus, his work was retrospective, with all the associated limitations, such as recollection and ascertainment bias, lack of controls, and the limitations in making causal inferences from observations. Although birth asphyxia was common, such diagnoses were not based on uniform standards. Thus, it was difficult to appreciate the heterogeneity of asphyxia as the cause of CP. Little was an orthopedic surgeon, not an obstetrician; thus, he faced an uphill battle in convincing obstetricians that their practices were causing lifelong disabilities in their patients.

and 26 (46%) were preterm—a remarkable diagnostic accuracy. Yet, Little was profoundly misunderstood, and some reasons behind this historic misunderstanding are outlined in the Table. Although it is gratifying that at the threshold of the 21st century, we are beginning to understand the complexities of CP, today’s advances owe their debt to the pioneering

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works of Little, Osler, and Freud, among others. A study of the reasons why some of these scientists succeeded, erred, or were misunderstood also helps us to appreciate the complex nature of discovery.

References

1. Little WJ. Courses of lectures on the

deformities of the human frame. Lancet.

1843–1844;1:5–7, 38 – 44, 70 –74, 209 –212, 230 –233, 257–260, 290 –293, 318 –320, 346 –249, 350 –354 2. Little WJ. On the Nature and Course Treatment of Deformities of Human Frame. Being a Course of Lectures Delivered at the Royal Orthopedic Hospital in 1843 and 1844. London, England: Longman, Brown, Green, and Longmans; 1853 3. Bax M, Goldstein M, Rosenbaum P, et al, and the Executive Committee for the Definition of Cerebral Palsy. Proposed definition and classification of cerebral palsy, April 2005. Dev Med Child Neurol. 2005; 47:571–576 4. Miller SP, Ferriero DM, Leonard C, et al. Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome. J Pediatr. 2005;147: 609 – 616 5. Zimmerman RA, Bilaniuk LT. Neuroimaging evaluation of cerebral palsy. Clin Perinatol. 2006;33:517–543 6. Redline RW. Placental pathology and cerebral palsy. Clin Perinatol. 2006;33: 503–516 7. Little WJ. On the influence of abnormal parturition, difficult labours, premature births and asphyxia neonatorum on the mental and physical condition of the child, especially in relation to deformities. Transc Obstet Soc London. 1861;3:293 8. Raju TNK. Historical perspectives on the etiology of cerebral palsy. Clin Perinatol. 2006;33:233–250 9. Accardo P. William John Little and cerebral palsy in the nineteenth century. J History Med. 1989;44:56 –71

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Perinatal Profiles: Ian Donald and Obstetric Diagnostic Ultrasound Alistair G.S. Philip, MD, FRCPE*

Introduction

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Philip did not disclose any financial relationships relevant to this article.

One of the things that helps prospective parents to truly understand that they soon will become parents is an ultrasonography scan of the mother’s abdomen, which provides a visual image of the fetus – THEIR BABY. This moment of revelation is a comparatively recent development in obstetrics. Less than 50 years ago, the fetus was assessed largely by the palpating hands of the obstetrician.

Introduction of Ultrasonography Investigations

In 1958, Professor Ian Donald (Regius Professor of Midwifery at the University of Glasgow) and his colleagues John MacVicar (an obstetrician) and Tom Brown (an engineer) published a paper in The Lancet entitled “Investigation of Abdominal Masses by Pulsed Ultrasound.” This article described their experience with 100 patients and included 12 illustrations of various gynecologic disorders (eg, ovarian cysts, fibroids) as well as demonstration of obstetric findings such as the fetal skull at 34 weeks’ gestation, “hydramnios” (polyhydramnios), and twins in breech presentation. These “Bscope” images were somewhat “grainy” and indistinct compared with today’s images, but this was al-

*Emeritus Professor of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, Calif. 6     NeoReviews

most certainly the start of a revolution in obstetrics, even if it took many years before most obstetricians were persuaded of the usefulness of such imaging. It is worth noting that when a future Scottish Professor of Obstetrics visited the United States in 1964 and inquired about interest in ultrasonography diagnosis, he was told to forget it (!) and warned that it was “just a dream of a mad, redheaded Scotsman” that had no future. This characterization of Ian Donald was probably not limited to the United States. Recollections of another Scottish obstetrician indicate that even by the early 1970s, Glasgow was a “divided city.” There were two Professors of Obstetrics and Gynecology in two different institutions in Glasgow, and while Ian Donald was enthusiastically promoting the use of ultrasonography in obstetric diagnosis, his counterpart (“the other professor” in Glasgow) did not accept it.

Early History

Ian Donald was born in 1910 (variously reported to be in Paisley, Scotland or Cornwall, England), the son and grandson of Scottish doctors. He received most of his early education in Scotland, but obtained a BA from Cape Town University (South Africa) before graduating from St Thomas’s Hospital Medical School of the University of London in England in 1937. During the Second World War, he served as a medical officer in the Royal Air Force (RAF), and this allowed him to assimilate knowledge NeoReviews Vol.8 No.5 May 2007 e195

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about RADAR (radio detection and ranging) and SONAR (sound navigation and ranging). He realized that echo-sounding SONAR, his preferred term for diagnostic ultrasound for many years, had potential application to clinical obstetrics, but he did not pursue this aggressively until after his appointment as the Regius Professor of Midwifery at Glasgow University in 1954. Earlier (in 1951), he had been appointed as Reader (roughly equivalent to Associate Professor) in Obstetrics and Gynaecology at St Thomas’s Hospital in London. Donald apparently had an intense interest in machines of all kinds from childhood, which persisted during and after his time in the RAF. After World War II, many “bits and pieces” of equipment became available, some of which he acquired. Although his reputation is founded on his work with obstetric ultrasonography, his early research (which involved machines) is of particular interest to neonatologists. While at St Thomas’s Hospital, he collaborated with (Professor) Maureen Young of the Physiology Department and published a paper in the Journal of Physiology in 1952. This report was followed by two papers published in The Lancet; the first, in 1953, included a description of a negative-pressure respirator for neonates and the second, in 1954, concerned a positivepressure respirator, also for neonates, which was called locally “the puffer.” He later bequeathed this positivepressure ventilator to Dr Herbert Barrie (Consultant Pediatrician at Charing Cross Hospital, London), who recalled that it was a “formidable array of electronics,” much of which had been designed by Donald himself and built by his PhD engineers. Barrie later said that it was “basically an electronic finger” that e196 NeoReviews Vol.8 No.5 May 2007

occluded a hole in a tube through which gas was flowing to provide intermittent positive pressure. Professor Osmund Reynolds (University College Hospital, London) has referred to this device as “Ian Donald’s puffer ventilator.” (Comments from Barrie and Reynolds are both contained in the Wellcome Witnesses report “Origins of Neonatal Intensive Care in the UK.”)

Obstetric Ultrasonography

After moving to Glasgow, Donald was based initially at the Royal Maternity Hospital, where the obstetric patients were located, and the Western Infirmary, where the gynecology patients were located and where his ultrasonography equipment was based. In attempting to make gynecologic diagnoses, he relied heavily on collaboration with engineering colleagues, principally Tom Brown, who was “loaned out” by the firm of Kelvin and Hughes Scientific Instrument Company. The initial work was performed using a device that had been designed as a metal flaw detector. As noted in their 1958 article, one of the properties of ultrasound (vibrations whose frequency exceeds 20,000/sec, beyond the range of human hearing) is that it can be propagated as a beam. Reflections of the beam from abdominal interfaces in women being investigated allowed images to be created, which initially were recorded on Polaroid® film. Although he encountered considerable skepticism over the next few years, it is generally acknowledged (certainly by those with whom he worked in Glasgow) that he had not only vision, but enthusiasm and the courage of his convictions, which kept the entire research enterprise going. With the help of junior col-

leagues, to whom he gave considerable encouragement, he advanced the capability of ultrasonography in obstetric diagnosis, including diagnosis of placenta previa. Ian Donald, whose primary responsibilities were as a doctor and a teacher, delivered lectures “with care and enthusiasm.” He was the author of “Practical Obstetric Problems,” which ran to five editions and was extremely practical (somewhat unusual for the period). Professor Stuart Campbell, who subsequently became one of the foremost practitioners of obstetric diagnostic ultrasonography in the United Kingdom, found Donald to be intimidating when he (Campbell) was a junior doctor. He stated that Donald was “totally brilliant” and noted that although he had a quick temper, this was never directed at patients. For example, if a woman’s bladder was overdistended, blame was directed at the junior doctors, not at the patient. Campbell found that the best way to deal with it was “ to be quiet and he soon calmed down, because he was an extraordinarily generous man . . . . quite the most ethical and generous senior doctor I have ever [really] met.” It is evident that much of the early research investigation with ultrasonography was possible because Donald was greatly admired by his patients, and the era of written informed consent had not yet arrived. His patients were very willing to cooperate with the studies by Ian Donald and John MacVicar and later with those of James Willocks and Stuart Campbell, who were able to evaluate intrauterine growth using fetal cephalometry (biparietal diameter of the fetal skull) under Donald’s tutelage. Various commentators have noted that these studies with ultrasonography would not have been possible today because the unNeoReviews  7

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known effects of the imaging would have made obtaining informed consent difficult. However, it should be mentioned that Donald and his colleagues were very cognizant of the potential for damage from ultrasound and took pains to reassure themselves and others. A large section of their 1958 Lancet article was devoted to the “Possibility of Harmful Effects of Diagnostic Ultrasound,” with heat production and cavitation being major concerns. They reported on several experiments that had been performed either in vivo or in vitro by themselves or others. In particular, kittens “exposed to more than 30 times the dose of ultrasound necessary in its diagnostic use produced no detectable neuro-pathological change.” For approximately a decade, Donald split his time between two hospitals. In the early days, diagnostic ultrasonography studies on pregnant patients necessitated transporting the patients by private car to the ultrasound equipment, which was very bulky. In 1964, the new Queen Mother’s Hospital opened at Yorkhill in Glasgow, allowing Donald to see obstetric and gynecologic patients in the same hospital. Ultrasonography equipment also was evolving; the B-scope images that were presented in 1958 were followed by scan conversion (which converted to “peak memory” and allowed a photograph to be taken after looking at the image) and later by real-time scanners. Stuart Campbell saw the ADR linear array scanner in 1974 and called it “one of the most staggering innovations in ultrasound I had experienced in my life.”

Conclusion

Throughout his academic career, Ian Donald was recognized as one of the 8     NeoReviews

leaders in obstetrics and gynecology, who attracted attention from scholars around the world. He received many honors during his lifetime. His legacy is not confined to Scotland or the continued advances in obstetric ultrasonography. In 1981, the Ian Donald Inter-University School of Medical Ultrasound was founded in Dubrovnik, Croatia, by Professor Asim Kurjak. In addition, the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) awards the Ian Donald Gold Medal annually. He died in 1987, approximately 2 weeks after traveling to London to receive an Honorary Fellowship from the Royal College of Physicians, London. However, he apparently had been in ill health for almost half of his life, having had major cardiac surgery (for mitral valve stenosis) three times. During one of these hospitalizations, he self-diagnosed a retroperitoneal hematoma, which he was able to demonstrate to his doubting cardiac colleagues using ultrasonography! After the second operation, he published a “moving, yet wryly humorous essay” (in the words of John Fleming, one of his colleagues in Glasgow), which was published anonymously in the Lancet in 1969 (November 22 issue, pp 1129 – 1131), and apparently was very comforting to “many terrified patients about to undergo a similar ordeal.” After his third operation, he took careful notes and wrote an additional article that was published in the Scottish Medical Journal in 1976, entitled “At the Receiving End.” This article was intended to show others undergoing repeat cardiac surgery “that they need fear no worse than what they have survived previously; in fact, noticeably less.” Donald added, “Patients must not be lied to and

must be given every opportunity to face and stand up to the truth, as I was.” Today, we take for granted the remarkably clear images of the fetus that can be obtained with modern equipment. Such imaging allows for early detection of a wide variety of congenital abnormalities and for transfer of mother and baby to specialized centers for medical and surgical care. While this advance might have occurred eventually, the vision and unwavering dedication to the cause by Ian Donald undoubtedly contributed in large measure to where we are today.

Suggested Reading Selected Articles by Ian Donald Donald I, Young IM. An automatic respiratory amplifier. J Physiol. 1952,116:4P Donald I, Lord J. Augmented respiration: studies in atelectasis neonatorum. Lancet. 1953;1:9 –17 Donald I. Augmented respiration: an emergency positive-pressure patient-cycled respirator. Lancet. 1954;1:895– 899 Donald I, MacVicar J, Brown TG. Investigation of abdominal masses by pulsed ultrasound. Lancet. 1958;1:1188 –1195 Willocks J, Donald I, Campbell S, Dunsmore IR. Intrauterine growth assessed by ultrasonic fetal cephalometry. J Obstet Gynaecol Br Commonw. 1967;74:639 – 647 Donald I, Abdulla U. Placentography by sonar. J Obstet Gynaecol Brit Commonw. 1968;75:993–1006 Donald I. Sonar as a method of studying prenatal development. J Pediatr. 1969; 75:326 –333 Donald I. On launching a new diagnostic science. Am J Obstet Gynecol. 1969;103: 609 – 628 Donald I. At the receiving end: a doctor’s personal recollections of second time cardiac valve replacement. Scott Med J. 1976;21:49 –57 NeoReviews Vol.8 No.5 May 2007 e197

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Development of Ultrasonography in Obstetrics Christie DA, Tansey EM, eds. Looking at the Unborn: Historical Aspects of Obstetrical Ultrasonography. Wellcome Witness Seminar. March 10, 1998. Available at: http://www.

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ucl.ac.uk/histmed/ [Look under Publications and then go to Wellcome Witnesses to Twentieth Century Medicine, Volume 5] Additional detailed information about the development of obstetric ultrasonography is available at http: // www.ob-ultrasound.net/ history1. html

Donald’s Contribution to Neonatology For commentary about his role in development of assisted ventilation, see: http:// www.ucl.ac.uk/histmed/ [Look under Publications and then go to Wellcome Witnesses to Twentieth Century Medicine, Volume 9: Origins of Neonatal Intensive Care in the UK]

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Perinatal Profiles: Childbed Fever and Igna´c Fu¨lo¨p Semmelweis Istvan Seri, MD, PhD*

Introduction

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Seri did not disclose any financial relationships relevant to this article.

Despite existing infection-control measures, up to 10% of patients in acute-care hospitals acquire at least one nosocomial infection in the United States. According to recent data, this translates to nosocomial infections occurring in about 2 million patients in the United States every year, causing up to 90,000 deaths and resulting in $4.5 to 5.7 billion in additional patient care costs. (1) Hand washing before and after patient contact is the simplest and one of the most effective infection control measures. Interestingly, the first physician to prove the effectiveness of hand washing did so before the discovery of infectious agents. Igna´c Fu¨lo¨p Semmelweis, a Hungarian physician and the pioneer of antisepsis, was the first to demonstrate that most cases of childbed fever could be prevented. One would assume that the man who made one of the most important discoveries of the 19th century was honored by his peers and acknowledged by the medical establishment, and his methods were applied throughout the world. Instead, he was ridiculed, released in disgrace from the Viennese General Hospital and Medical School faculty, and never acknowledged by most of his contemporaries. His short and tragic life ended in a mental asylum in 1865 at the age of 47. (2)(3) Only after Pasteur, Koch, and Lister had

*USC Division of Neonatal Medicine, Women’s and Children’s Hospital and Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, Calif. 10     NeoReviews

produced more evidence of the “germ theory” and the use of antiseptic techniques was the value of hand washing appreciated and introduced into medical practice. Sadly, full compliance with this measure of infection control has not been reached even in the 21st century. Nevertheless, it is truly unfortunate that Semmelweis could not witness the transformation of medicine assisted by his discovery, when these changes occurred after the acceptance of the germ theory, years after his death. A complex but plausible explanation for the treatment of this medical pioneer emerges by closer examination of his life, medical training, and character; the state of medical knowledge; and the forces shaping the attitude and thinking of the traditional medical establishment in 19th century Europe. Another important consideration is the impact on Semmelweis’s life of the sweeping historical changes occurring in Europe in general and in Hungary and Austria in particular during this time.

Semmelweis’s Early Life

Igna´c Fu¨lo¨p Semmelweis was born on July 1, 1818, in Taban, a suburb of Buda, a city united with Pest in 1873 to form Budapest, now the capital of Hungary. His father was a well-to-do shopkeeper, who encouraged his son to become a government official in the Austrian empire to which Hungary belonged at that time. Semmelweis, the youngest of five children, initially studied at the Catholic Gymnasium of Buda. In 1835, he enrolled in the law school at NeoReviews Vol.8 No.6 June 2007 e235

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the University of Pest, graduating 2 years later and traveling to Vienna to apply to the law school in the capital of the Austrian Empire. However, instead of the law school, he enrolled in the Viennese Medical School. In 1839, Semmelweis returned to Pest and continued his studies in medicine at the University of Pest, which now bears his name. In 1841, he moved back to Vienna, where he finally was satisfied with the curriculum because it included teaching of both laboratory and bedside medicine. At the Viennese Medical School, Semmelweis studied under prominent teachers of his time, including Josef Skoda and Carl von Rokitansky. Rokitansky sought to transform traditional treatment methods by addressing difficult clinical problems with logic and mathematical precision, (3) and it is likely that this experience led Semmelweis to use data collection and statistics when establishing his hypothesis and to provide evidence for the effectiveness of his approach by tracking the changes in mortality.

Puerperal Fever

In 1844, Semmelweis completed his doctoral dissertation and graduated with a Magister degree. For the next 2 years, he continued to be trained in surgical techniques and different diagnostic approaches by Professor Skoda. In 1846, he was appointed as a surgical assistant at the Vienna General Hospital. Shortly thereafter, he noticed a significant discrepancy in childbed fever mortality between the medical school (13.1%) and the midwifery (2.03%) divisions of the hospital. Puerperal fever was believed to be a nonpreventable “epidemic disease” at that time and was known commonly as “the black death of the childbed.” (4) According to Semmelweis, “In the medical school division the mortality from puerperal e236 NeoReviews Vol.8 No.6 June 2007

fever was so terrifying that this division became notorious. There were heart rendering scenes when pregnant patients knelt down, wringing their hands, to beg for a transfer to the midwifery division.” More than five times as many women died at the hands of the medical students than at the hands of the midwifery students from puerperal fever. Semmelweis immediately tried to determine the reason for the discrepancy. The food and ventilation was the same in both divisions, and if anything, the surgical skills were better in the medical school and there was less overcrowding. He found the answer to his question in 1847, when his friend and colleague Jakob Kolletschka died from an infection after cutting his finger at a postmortem examination. Semmelweis performed the autopsy on his friend and discovered signs of infection “pathologically of the same changes” compared with that of the many women he had autopsied after they died of puerperal fever. He wrote, “if therefore, in the case of Professor Kolletschka . . . septic changes . . . arose from inoculation of cadaver particles, then puerperal fever must originate from the same source. . . .” Thus, Semmelweis made the connection between his observation of the high incidence of puerperal fever in the medical school division and the medical students coming from the autopsies before entering the ward when he wrote, “. . . the fingers and hands of students and doctors, soiled by recent dissections, carry those deathdealing cadavers’ poisons into the genital organs of women in childbirth.” His claim was shocking because the “germ theory” was not yet accepted, and most doctors believed that diseases manifested spontaneously. Semmelweis still had to prove his hypothesis that the cause of the high

prevalence of the disease in the medical school division was the students carrying infectious particles on their hands. Therefore, and despite resistance by his colleagues, Semmelweis made hand washing in chlorinated lime mandatory between examining corpses and live patients. Although he did not perform a randomized trial, he had the historical control data collected and was able to compare those to the data collected after the mandatory hand washing procedure was instituted. To his satisfaction, the high mortality rate in the medical school division decreased from 13.1% to only 2.38%, strongly suggesting that he was correct. He wanted to publish his findings, but he met with strong criticism because these observations indicated that the prevailing school of thought of the time was wrong. In 1848, Semmelweis expanded his “infection control measures” and had all medical instruments in his department cleaned in chlorinated solution prior to reuse. The incidence of puerperal fever plummeted to the point where Professor Josef Skoda, Semmelweis’s supervisor, proposed an investigation in 1849. However, the conservative university chairs denied the proposal. Instead, they made it impossible for Semmelweis to continue his work in Vienna.

Factors Working Against Semmelweis

Many factors, including Semmelweis’s personality traits and the historical background of central Europe in the 1840s, contributed to the harsh criticism of his theory and ultimately, his dismissal by the Austrian medical establishment. Semmelweis had signs of an inferiority complex and even may have had paranoid ideations during his stay in Vienna. Nonetheless, the situation must have been very difficult for a Hungarian NeoReviews  11

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physician lacking the pedigree lineage of an Austrian heritage and who spoke German with a Hungarian accent and perhaps without having a complete mastery of the German language. Partly due to centuries-old discrimination by the ruling Austrians against the defeated Hungarians, Semmelweis and his ideas may have been dismissed by most of his Austrian colleagues not only because of their novelty but because they came from a strange Hungarian. Austrian animosity toward Hungarians likely was enhanced by the growing Hungarian resistance to Austrian rule. Because of the uprisings against the monarchies spreading across Europe, Austrian control over Hungary appeared to be weakening in those years. In fact, a Hungarian uprising started on March 15, 1848, leading to the dethroning of the Austrian king and the formation of the independent Hungarian Republic. The ensuing Austrian military response resulted in an 18-month war between Hungary and Austria. The war ended when the Russian tsar came to the aid of the Austrian empire in the summer of 1849, and the combined Austrian and Russian armies crushed the Hungarians on the battlefield at Temesvar in Transylvania. Many Hungarian soldiers killed themselves after being taken as prisoners of war. Such historical events, combined with the implications of his theory, may explain most of the unrelenting hostility toward Semmelweis. Despite the evidence he presented in Vienna, his theory did not sit well with the medical establishment, who believed that physicians’ hands were meant to cure disease and, therefore, could not be the cause of the spread of disease. In response to Semmelweis’s claims, leaders of the Viennese medical university developed the idea that the excess mortality of preg12     NeoReviews

nant women cared for by the medical students was due to the emotional strain of being examined by male students in contrast to female midwives. Based on this hypothesis, the Medical Council of the University excluded all foreign medical students from the hospital because they were “rougher in their examination than the Viennese.” Unfortunately for the dying mothers, antidiscrimination laws did not exist, and death rates did not change.

After Vienna

It is no wonder that Semmelweis’s position at the Vienna General Hospital and Medical School was not renewed in 1850. He made numerous presentations before the Imperial and Royal Academy of Sciences in Vienna on the subject of sanitation in hospitals, receiving only criticism, dismissal, and no support. The final offer he received from the Viennese Medical School would have limited him to teaching midwives without using mannequins as teaching tools. Considering this offer the ultimate humiliation, he left Vienna the same night without telling anyone and moved back to Pest, Hungary. In Pest, at the St. Ro´kus (Rochus) Hospital, Semmelweis introduced disinfection policies in the obstetric division. Using his hand washing and instrument cleansing technique, he reduced the incidence of puerperal fever to 0.85% in a hospital operating under far more primitive conditions that the one he left in Vienna. At the same time, mortality rates from childbed fever in the Vienna General Hospital had returned to almost 20%. By this time, his results were so undeniable that hospitals throughout Hungary began adopting antiseptic procedures. Semmelweis’s method also was accepted in parts of Bavaria, and later the “sanitation concept” was devel-

oped more or less independently and embraced by Oliver Wendell Holmes in the Boston Lying-In Hospital. Interestingly, Holmes encountered similar hostility and opposition from the Boston medical establishment as had been experienced by Semmelweis in central Europe. In Pest, Semmelweis married, and he and his wife had five children during the 1850s. In 1855, he was appointed Chair of Theoretical and Practical Midwifery at the University of Pest, and in 1857, he opened his own private clinic. During his tenure at the University of Pest, he continued to isolate the causes of death systematically, autopsy the victims, set up control groups, and study the statistics. The death of two of his children added personal grief to his intensifying professional suffering as opposition to his ideas continued to spread throughout Europe. He became more obsessed and impatient with the world and did not understand why others could not see the truth in the numbers. Yet, he never gave up. Because his mental health may have started to deteriorate around the time, the book he finally and somewhat belatedly published in 1861 on his discoveries on the need for sanitation was verbose and difficult to read. Entitled “The Etiology, Concept, and Prophylaxis of Childbed Fever,” (5) it met much skepticism and hostility, not only in Austria, but in many other countries in Europe. Despite this, he continued to defend his theory for the rest of his life. In his continued frustration, however, he became his own worst enemy, writing open letters to obstetricians who did not believe in his theory, calling them murderers. Here is an excerpt from his letter written to Professor Friedrich Scanzoni, an influential physician leader and academic working at the UniverNeoReviews Vol.8 No.6 June 2007 e237

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sity of Wurtzburg: “If, Sir, without having refuted my doctrine, you continue to teach the students and midwives . . . that puerperal fever is an ordinary epidemic disease, I proclaim you before God and the world to be an assassin and the history of puerperal fever would not do you an injustice were it . . . to immortalize you as a medical Nero.” By the early summer of 1865, his mental health deteriorated to the point that he had taken to the streets of Pest, distributing open letters to startled pedestrians stating, “The peril of childbed fever menaces your life! Beware of doctors for they will kill you. Unless everything that touches you is washed with soap and water and then chlorine solution, you will die and your child will die with you.” Soon thereafter, in July of 1865, Semmelweis decompensated, began experiencing hallucinations and dementia, and developed episodes of violent behavior. His family and good friend Dr. von Hebra, a dermatologist, had no choice but to commit him to an insane asylum in Vienna. He died on August 13, 1865, only 13 days after his admission to the asylum. Although folklore and a Hungarian movie claim that he succumbed to sepsis from cutting himself at his last dissection before he was admitted to the asylum, some evidence suggests that he was killed when the guards tried to restrain him during one of his violent fits. According to The Bulletin of the History of Medicine, (6) his autopsy report

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states, “It is obvious that these horrible injuries were . . . the consequences of brutal beating, tying down, trampling underfoot.” Although most claim otherwise, it is important to note that Semmelweis was not the first to develop the concept that “specific contagions” may be the cause of puerperal fever. In 1795, Alexander Gordon argued in his “Treatise on the Puerperal Fever of Aberdeen” that “childbed fever was a specific contagion affecting only women who were visited or whose babies were delivered by someone who had previously attended patients affected with the same disease.” (7) However, Semmelweis was the first to make the observation, introduce a preventive measure, and collect data to follow up on the effectiveness of his intervention. It is truly unfortunate that Semmelweis could not enjoy the fruits of his pioneering work, see the transformation of medicine that occurred after the acceptance of germ theory, or hear Joseph Lister say, “Without Semmelweis, my achievements would be nothing.”

Conclusion

We all should remember as we wash our hands before and after each patient contact that it took so much for a few to convince so many of the importance and benefits of this simple process. Also, we should remember to wash our hands before and after each patient contact and feel comfortable about reminding our colleagues if infection control mea-

sures are not appropriately observed. Too many died in the past and may suffer in the future if we do not do so. NOTE. The author received his MD and PhD and part of his postgraduate training from the Semmelweis University School of Medicine, the medical school where Semmelweis had studied and later worked. The author also was trained and was a faculty member at the former Boston Lying-In Hospital (Brigham and Women’s Hospital) where Oliver Wendell Holmes introduced antisepsis. He has obsessively followed the teachings of these giants of medicine by washing his hands before and after every patient contact.

References

1. Burke JP. Infection control—a problem

for patient safety. N Engl J Med. 2003;348: 651– 656 2. Porter R. The Greatest Benefit to Mankind: A Medical History of Humanity From Antiquity to the Present. New York, NY: Harper Collins Publishers Ltd; 1998: 369 –370 3. Elek SD. Semmelweis commemoration. Semmelweis and the oath of Hippocrates. Proc R Soc Med. 1966;59:346 –352 4. Lamm RD. Marginal medicine. JAMA. 1998;280:931–933 5. Semmelweis I. The Etiology, Concept, and Prophylaxis of Childbed Fever. Carter KC, trans. Madison, Wisc: University of Wisconsin Press; 1983 6. Carter KS, Abbott S, Siebach JL. Five documents relating to the final illness and death of Ignaz Semmelweis. Bull History Med. 1995;69:255–270 7. Dunn PM. Dr. Alexander Gordon and the contagious puerperal fever. Arch Dis Child Fetal Neonatal Ed. 1998;78:232–233

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Perinatal Profiles: Sir Joseph Barcroft: The 20th Century’s Renaissance Perinatal Physiologist Tonse N.K. Raju, MD, DCH*

High-altitude Cardiopulmonary Physiology

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Raju did not disclose any financial relationships relevant to this article.

In 1932 when he turned 60, Sir Joseph Barcroft began a new line of research: the study of the physiology of the mammalian fetus. His work over the subsequent decade (1) was instrumental in establishing the evolving field of perinatal-neonatal medicine on a firm physiologic foundation. (2) Sir JB, as he was affectionately called, was born into a Quaker family on July 26, 1872 at the Glen, Newry, County Down, in today’s Northern Ireland. Schooling was at Bootham, York, and later at the Leys School in Cambridge. After earning a degree in Science from London in 1891, JB opted for a career in physiology, rather than medicine, and took up a job as a lecturer at Cambridge’s King’s College in 1900. He became a Fellow of the Royal College in 1911. During much of his professional life, Sir JB worked on high-altitude cardiopulmonary physiology. He was a quintessential “guinea pig scientist.” To study the effects of hypoxia, he made himself an experimental subject. In 1920, he built a glass chamber and lived in it for 6 days, Inside the chamber, the PO2 had been dropped to 84 mm Hg, a pressure lower than on top of Pikes Peak. There he studied the effects of exer*Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md.

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cise in hypoxic conditions by riding a bicycle in the chamber. He had his left radial artery cannulated for blood collection and measurement of blood gas tensions. In later years, he was amused when doctors and nurses fumbled to feel his nonexistent left radial pulse. Besides working in laboratories simulating high-altitude conditions, he led mountain expeditions, setting up portable laboratories on site to study cardiopulmonary adaptation to low oxygen. These expeditions took him to Tenerife and Monte Rose in Europe, and to Cerro de Pasco in Peruvian Andes. In 1914, he published a monograph, Respiratory Functions of Blood, that established him as the world’s foremost authority on oxygen physiology and acclimatization. He described the mechanisms of gas transport in the blood, the properties of hemoglobin, the distribution of cardiac output, organ blood flow, and their changes during exercise. (2)(3)(4)(5) These seminal contributions formed the scientific foundations of modern cardiovascular physiology. Sir JB also was widely praised for inventing the differential blood gas manometer—a forerunner of the blood gas acid-base measuring instrument.

Fetal Physiology

When he turned 60 in 1932, he decided to study fetal physiology because he was intrigued by how the fetus managed to survive and grow under conditions of intrauterine “hypoxia.” He famously compared the intervillous NeoReviews Vol.8 No.8 August 2007 e311

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oxygen supply to that of a man on a mountain and said that the fetus was “on Mount Everest in utero.” To study the fetus, Sir JB modified Huggett’s method of exteriorizing fetal sheep delivered into a saline bath, maintaining placental circulation and the temperature at 37°C. He also developed nonhuman primate, rabbit, rat, and guinea pig fetal models for physiologic studies. Even today, researchers around the world study fetal physiology using modifications of the animal models developed by Sir JB 75 years ago. With electronic, radiologic, and biochemical monitoring techniques, he made numerous fundamental discoveries in fetal physiology. Sir JB’s vast experience and knowledge from high-altitude physiologic studies helped him to gain deeper insights into fetal physiologic processes. Within a span of 7 years, he and his students described (many for the first time) fetal blood volume; changes in cardiovascular reflexes to hypoxia; fetal cardiac output and its distribution; the physiology of the ductus arteriosus; fetal utilization of glucose, fat, proteins, and amino acids; placental exchange of nutrients; oxygen- and carbon dioxidecarrying properties of fetal and adult hemoglobin; and the physiology of fetal breathing—and this is only a partial list. (6)(7)(8)(9)(10)(11)(12) (13) (14) (15) Throughout his work, Sir JB never lost sight of the fact that “one day, the call will come and the fetus will be born.” Thus, he sought to explain how the fetus managed to survive and grow in the intrauterine environment, adapt during labor and delivery, and adapt again to survive in the extrauterine environment, entirely different from that of the intra-

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uterine milieu. In the late 1930s, he began compiling his works into a monograph entitled Researches on Pre-Natal Life. (1) Beginning in 1939, his research stopped briefly during World War II, but not his writings. He said: “. . . during the days of the bomb . . . an hour or two each day to relax and write information concerning prenatal life. [Because] . . . if the bomb came my way, the information for which it was worth, would [still] remain.” No one who knew Sir JB was surprised at his humility. While London was being bombed, Sir JB continued to write his monograph. After the War, he began the second volume on fetal nervous system. However, on March 21, 1947, a few weeks after Volume I was published, he died in England. Sir JB received many awards and honors, including a mountain named in his honor. In 1954, the United States Board of Geographic named a 13,040-foot peak in California’s White Mountain Range as Mt. Barcroft, in recognition of Sir JB’s contributions to high-altitude physiology. On the eastern slope of Mt. Barcroft sits the White Mountain Research Station, renamed Nello Pace Laboratory in 1983, to honor Dr Nello Pace, who was instrumental in having the mountain peak named after Sir Barcroft. Perhaps Sir JB’s monumental contribution remains the large number of basic scientists he trained. Such renowned scientists as Geoffrey Dawes, Clement A. Smith, Donald Barron, and A.E. Barclay were his pupils, who continued work on fetal and neonatal physiology, inaugurating the modern era of investigative perinatal biology.

References

1. Barcroft JB. Researches on Pre-natal Life. Oxford, England: Blackwell Scientific Publications; 1946 2. Dunn PM. Sir Joseph Barcroft of Cambridge (1872–1947) and prenatal research. Arch Dis Child Fetal Neonatal Ed. 2000;82: F75–F76 3. Abeloos M, Barcroft J, Cordero N, Harrison TR, Sendroy J. The measurement of the oxygen capacity of haemoglobin. J Physiol. 1928;66:262–266 4. Barcroft J, Nagahashi M. The direct measurement of the partial pressure of oxygen in human blood. J Physiol. 1921;55: 339 –345 5. Barcroft J, Cooke A, Hartridge H, Parsons TR, Parsons W. The flow of oxygen through the pulmonary epithelium. J Physiol. 1920;53:450 – 472 6. Barcroft J, Karvonen MJ. The action of carbon dioxide and cyanide on foetal respiratory movements; the development of chemoreflex function in sheep. J Physiol. 1948; 107:153–161 7. Barclay AE, Barcroft J, Barron DH, Franklin KJ, Prichard MM. Pulmonary circulation times before and after functional closure of the ductus arteriosus. J Physiol. 1942;101:375–377 8. Barcroft J, Kennedy JA, Mason MF. Oxygen in the blood of the umbilical vessels of the sheep. J Physiol. 1940;97:347–356 9. Barcroft J, Barron DH, Cowie AT, Forsham PH. The oxygen supply of the foetal brain of the sheep and the effect of asphyxia on foetal respiratory movement. J Physiol. 1940;97:338 –346 10. Barcroft J, Kennedy JA, Mason MF. The direct determination of the oxygen consumption of the foetal sheep. J Physiol. 1939;95:269 –275 11. Barcroft J, Kennedy JA. The distribution of blood between the foetus and the placenta in sheep. J Physiol. 1939;95: 173–186 12. Barcroft J, Kennedy JA, Mason MF. The blood volume and kindred properties in pregnant sheep. J Physiol. 1939;95:159 –172 13. Barcroft J, Kramer K, Millikan GA. The oxygen in the carotid blood at birth. J Physiol. 1939;94:571–578 14. Barcroft J, Barron DH. Movements in mid-foetal life in the sheep embryo. J Physiol. 1937;91:329 –351 15. Barcroft J, Barron DH. The genesis of respiratory movements in the foetus of the sheep. J Physiol. 1936;88:56 – 61

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Perinatal Profiles: Geoffrey S. Dawes: A Neonatologist’s Appreciation Roderic H. Phibbs, MD*

Introduction

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Phibbs did not disclose any financial relationships relevant to this article.

When neonatology was emerging as a clinical discipline in the late 1950s and early 1960s, it had the advantage of a strong foundation of basic research in fetal and neonatal physiology. In particular, the new clinical enterprise (it was not yet a subspecialty) focused on cardiorespiratory pathophysiology. This foundation came from a few distinguished research laboratories studying fetal and neonatal physiology and the processes of the transition from fetal to neonatal life. The preeminent laboratory in the field was the Nuffield Institute for Medical Research at Oxford, directed by Geoffrey S. Dawes. Geoffrey Dawes became the director of the Institute in 1948. He received his medical degree in 1943, and in the following 5 years, he gained recognition as a prominent investigator in pharmacology and physiology. The very short interval between receiving his degree and being named director of an important research institute indicates how quickly the academic leadership recognized his exceptional qualities. As the new director, Dawes set the primary focus of research for the Nuffield Institute as developmental physiology. In this role, the Nuffield became the successor to the path of research started by Sir Joseph Barcroft at Cambridge early in the twentieth century. Dawes and his co-

*Department of Pediatrics and Cardiovascular Research Institute, University of California, San Francisco, Calif.

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investigators concentrated particularly on the preparations for and mechanisms of adaptation to extrauterine life. A central focus of the research was the adaptive mechanisms in the circulatory and respiratory systems, including placental function, establishment of lung function, and changes in the pulmonary and systemic circulations. Although most of the work examined cardiorespiratory physiology and its neurohumoral regulation, researchers also studied fetal growth and metabolism, and their studies included the responses to stresses such as hypoxia and hemorrhage. One of the hallmarks of the research of this highly productive group was the elegance of their experimental designs.

Responses to Stress

The clinical implications of this work were self-evident. What happened when the adaptive mechanisms for extrauterine life failed? What were the responses to stresses such as asphyxia? Beginning in 1958, Dawes and his associates had an ideal opportunity to expand this line of research. The United States National Institutes of Health were supporting studies on the mechanisms of brain injury in the fetus and newborn being performed in a primate laboratory in Puerto Rico, and various groups of investigators were invited to participate in the different aspects of the research. Dawes and the Nuffield team were among those invited to collaborate and made several extended visits over the next few years to conduct research with other investigators, particularly Stanley James and Karlis Adamsons. They made exNeoReviews Vol.8 No.9 September 2007 e365

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Fetal Physiology

Figure. The paradigm of the progression of cardiorespiratory changes during asphyxia.

Reprinted with permission from Dawes GS. Fetal and Neonatal Physiology. Chicago, Ill: Yearbook Medical Publishers, Inc; 1968.

tensive observations of the sequences of responses to progressive asphyxia. The resulting studies brought forth the paradigm of the progression of cardiorespiratory changes during asphyxia. The Figure from Dawes’ book that illustrates this paradigm has been reproduced both in its original form and with minor modifications in many clinical textbooks, usually as the starting point for a discussion of fetal asphyxia. (For exe366 NeoReviews Vol.8 No.9 September 2007

ample, see Figures 1.6 and 1.7 on page 1–7 of the Fourth Edition the American Academy of Pediatrics Textbook of Neonatal Resuscitation). They also started to study the responses to various components of resuscitation. For example, they demonstrated that when heart failure is due to acute asphyxia, correction of acidosis by an infusion of alkali quickly restores normal myocardial contractility.

During the formative era of “modern” neonatology, ie, neonatal care based on cardiopulmonary pathophysiology in the mid to late 1950s and early 1960s, many conferences dealt with the general topic of how to deploy a system of physiology-based care for newborns. Dawes was highly sought after for such conferences as much for his insightful, probing commentary on the work of others as for presentation of his own research. A good example of these times was the Ross Conference “Adaptations to Extrauterine Life,” held in Vancouver in November 1958. The Session Chairs were Dawes and McCance from Cambridge, and Harvard’s Clement Smith, the author of the text Physiology of the Newborn Infant, which was required reading for budding neonatologists. Mildred Stahlman, L. Stanley James, Thomas Oliver, Sidney Segal, and Jim Sutherland were among the attendees who were emerging as some of the early leaders in neonatology. In this program, Dawes’ presentation was effects of anoxia on newborn animals. The proceedings of the conference reflect the interests and intellectual energy of the formative years of neonatology. The program ended with a roundtable discussion on clinical applications in which McCance commented on “euthermia versus hypothermia” and Smith commented on “the effects of placental transfusion,” both subjects of research publications in 2006 and 2007. In 1967, Julius Comroe, the director of at the Cardiovascular Research Institute at the University of California, San Francisco (UCSF), invited Geoffrey Dawes to take a sabbatical at the Institute to write the book on fetal physiology. Dawes accepted and came to San Francisco for the latter half of 1967. Comroe provided Dawes with editorial staff, a NeoReviews  17

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medical illustrator, and an editorial advisory committee of physiologists who met with him weekly to critique his most recent chapter. Dawes clearly wanted the text to appeal to clinicians as well as physiologists, meeting frequently with Bill Tooley, the head of neonatology at UCSF, to discuss his strategy for upcoming chapters and regularly attending the weekly neonatal/perinatal clinical conferences, where he was an imposing presence. The product of the sabbatical was the superbly written and beautifully illustrated Fetal and Neonatal Physiology, published by Year Book Medical Publishers, Inc, in 1968. Although not a clinical text in the strict sense, most of the book is highly relevant to the practice of clinical neonatology. It quickly became required reading for serious students of neonatology. It remains highly relevant today and is so well written and illustrated that it probably still should be required reading for neonatologists in training. The original home for the Nuffield Institute for Medical Research was in an abandoned astronomical observatory in central Oxford. The building was designed by Christopher Wren, the great 17th century architect who designed many of the important buildings built after the great fire of London. However, this fine building of historic interest was not well suited for experimental physiology. When a new hospital of Obstetrics and Neonatal Pediatrics was built at Headington on the outskirts of Oxford, the Nuffield Institute moved into a large new facility immediately adjacent the clinical buildings, which was symbolic of Dawes’ close ties to clinical perinatology and neonatology. There was continuous exchange between the buildings, and Dawes regularly at-

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tended and participated actively in the weekly perinatal/neonatal clinical conferences. The proximity of the clinical units facilitated the Institute’s close collaboration with obstetricians and pediatricians. When Dawes began using the chronic in utero fetal lamb preparation, he noticed that fetal lambs made intermittent respiratory movements that occurred during rapid eye movement sleep. Moving to the human, his obstetrically trained research fellows could detect fetal breathing movements by ultrasonography that also were intermittent. These observations spawned a burst of clinical research in many centers as perinatologists studied the effects of various maternal states on fetal breathing. In time, fetal breathing movements became part of the biophysical profile of fetal well-being. As Dawes became familiar with the clinical methods of assessing fetal well-being, he was unhappy with the way fetal heart rate tracings were used to detect a fetus in distress because the system depended on expert recognition of particular patterns. He accumulated a very large database of digitized human fetal heart rate tracings and, with his strong background in mathematics, launched on a large-scale analysis. Ultimately, he developed a program that would allow automated detection of fetal distress. An instrument company produced a microprocessor that used his method to detect troublesome patterns of the fetal heart rate.

Developing Leaders

Another major contribution of Dawes was the development of leaders in academic neonatology and perinatology. There were three types of researchers at the Nuffield. The first were what might be considered the permanent scientists, some of

whom stayed on for many years and others of whom were there for several years, then moved to other academic positions, usually in physiology. The second group was the research fellows in training. Some of these were predoctorate, but in later years, many were postdoctorate pediatricians and obstetricians. The attraction of the Nuffield for physicians headed for careers in academic neonatology and perinatology were obvious, so talented young clinicians flocked to the Institute. They later filled many university faculty positions in neonatology and perinatology, particularly in the United Kingdom, Canada, the United States, Australia, and New Zealand. The third group of investigators was the established academicians, usually in perinatology, neonatology, or physiology, who spent a sabbatical leave (generally 6 months to 1 year) working in the Institute before returning to their home medical schools. The investigators who passed through the Nuffield became a sort of informal network that continued to communicate and often collaborate in research. Many of Geoffery Dawes’ long list of awards are related to neonatology and perinatology. Some of these include Fellow, Royal Collage of Obstetricians and Gynaecologists, the American Academy of Pediatrics, and American Collage of Obstetricians and Gynecologicts; the Apgar Award from the American Academy of Pediatrics; and the James Spence Award from the British Pediatric Association. Geoffrey Dawes stepped down as the director of the Nuffield Institute in 1985 and died in 1996. A more complete appreciation of him by Sir Graham Liggins appeared in Biographical Memoirs of Fellows of the Royal Society 1998.

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Perinatal Profiles: Robert McCance and Elsie Widdowson: Pioneers in Neonatal Science Andrew Whitelaw, MD, FRCPCH*

Introduction The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Whitelaw did not disclose any financial relationships relevant to this article.

Robert McCance and Elsie Widdowson have a special place in the history of neonatal science. Their use of experimentation and observation of human infants and many other species built much of the knowledge of perinatal physiology, particularly that related to nutrition and renal function, which underpins modern neonatology. Neither was a clinical pediatrician, but they had a major influence on the first wave of neonatologists trained in the United Kingdom in the 1960s and 1970s. Their stories show how the combination of intellectual curiosity and practical skill can lead to new knowledge in unexpected directions.

Robert McCance

Robert McCance was born in Northern Ireland in 1898. He joined the newly formed Royal Naval Air Service in the First World War and flew an observation aircraft launched from a gun turret on a battleship. After the war, he worked on a farm for 6 months before studying natural sciences at the University of Cambridge from 1919 to 1922. He joined the biochemistry laboratory of Fredrick Gowland Hopkins (1929 Nobel laureate in Medicine for his work on vitamins and beriberi) and obtained his PhD. In 1926, McCance moved to King’s College Hospital, London, to complete his *Professor of Neonatal Medicine, University of Bristol Medical School, Southmead Hospital, Bristol, United Kingdom.

clinical training in medicine and worked part-time in the biochemical and diabetic department. This was the era before insulin, and he worked on separating different carbohydrates in cooked fruits and vegetables. It was important to know which carbohydrates could be metabolized as fuel (eg, glucose, fructose, sucrose) and which could not (eg, polysaccharides now classed as fiber). He progressed to analyzing the content of meat and fish. In 1933, while sampling joints of meat in the hospital kitchens, he met Elsie Widdowson, a trainee dietitian, and their 60-year scientific partnership began.

Elsie Widdowson

Elsie Widdowson was born in 1906 in southeast London. She was inspired by her chemistry teacher at school to study chemistry at Imperial College, London. After graduating, she worked for 3 years on the chemistry and physiology of apples. Her first two papers were on carbohydrate analysis in apples. In 1932, her research grant ran out, and needing an income, she decided to train as a dietitian because she had heard that this was an emerging profession that would offer secure employment. She enrolled in the first postgraduate program offering a diploma in dietetics at King’s College Hospital and was sent to work in the main kitchen to learn large-scale cooking. There she met Robert McCance. They began conversing about carbohydrates in fruit, and she told him that his figures for fructose were wrong. Far NeoReviews Vol.8 No.11 November 2007 e455 NeoReviews   19

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from feeling threatened, McCance asked her to join his group and helped her obtain a grant from the Medical Research Council.

Chemical Composition of Foods

McCance and Widdowson realized the need for tables of the content of all types of food eaten in Britain. They set about analyzing not only the carbohydrate, but also the protein, fat, electrolyte, and mineral contents of fresh, cooked, and manufactured foods. The Chemical Composition of Foods was published in 1940 and has continued in numerous subsequent editions. Food was rationed during the Second World War, and their findings led to important experimental work on the minimum dietary requirements for the British population. The weekly ration was established as 120 g of fat, 150 g of sugar in all forms, one egg, 120 g of cheese, 480 g of meat and fish, and 1 L of milk. Bread and potatoes were not rationed. McCance, Widdowson, and colleagues tested the diet during long-distance walking in the mountains of the Lake District. One result was the addition of calcium to flour.

Change of Direction to Neonatal Science

After the war, McCance and Widdowson were sent by the Medical Research Council to Germany to study the nutritional needs of children, particularly orphans. Widdowson stayed for about 3 years, studying children in an orphanage outside Wuppertal. They showed that bread enriched with calcium, iron, and B vitamins could be the primary component of a healthy diet for growing children. Widdowson also observed that children who had been deprived of love and touch did not grow, even if the diet was adequate. 20      NeoReviews e456 NeoReviews Vol.8 No.11 November 2007

Body Composition

Growth and development became the main themes of Widdowson’s career. The analytical skills she had developed with apples and sausages led to analysis of the human body and other species at different phases from fetal life to adulthood. She analyzed the bodies of fetuses and stillborn babies at different gestations as well as children and adults. The bodies were dissected and the protein, fat, carbohydrate, electrolyte, and mineral content measured using the same techniques as for food. Eventually, she was able to analyze individual amino acids. Knowing the composition of the body at different gestational ages allowed her to calculate the increments in calcium, phosphorus, nitrogen, sodium, and other nutrients per week. This immensely important information laid the foundations for feeding of preterm infants both enterally and parenterally. Knowing the rate of accumulation of calcium and phosphate per week between 28 and 40 weeks’ gestation as well as the composition of human milk, Widdowson could determine that it was physically impossible for a preterm infant to accumulate the same amount of calcium and phosphate from human milk as would be obtained in utero. Her studies of accretion of individual amino acids provided vital information on which to base human milk supplementation and parenteral nutrition of preterm infants.

Renal Function

McCance had had an interest in renal function and fluid and electrolytes from his early work on diabetic ketoacidosis, and he and Widdowson conducted a number of studies testing the physiologic limits of their own kidneys. On one occasion, McCance depleted himself of salt for 14 days and then hyperventilated for

45 minutes to see if he could produce urine with zero sodium content. He had a respiratory arrest, but fortunately, was revived. On another occasion, the two researchers investigated excretion of strontium by injecting strontium lactate intravenously into each other. After 5 days of this, they developed fever, rigors, and headache. The cause was not the strontium but endotoxin in the solution. Stimulated by a young pediatric colleague, Winifred Young, McCance extended his renal studies to infants and found that newborns had a very limited capacity to excrete either a water or a sodium load, and the capacity was even more limited in preterm infants. Puzzling over how newborns managed to maintain normal plasma chemistry with such limited renal function, they realized the importance of mother’s milk being exactly and consistently the right composition and that growth in the newborn absorbed most of the nitrogen in the diet, unlike in adults.

Foundation of the Neonatal Society in the United Kingdom

In the 1950s, McCance and Widdowson concentrated on physiologic studies in newborn humans, guinea pigs, rats, dogs, and pigs. Increasing collaboration among neonatal pediatricians and scientists working on the perinatal period led in 1959 to the foundation of the Neonatal Society, with McCance as the founder president. The Society’s objective is to stimulate, evaluate, and disseminate neonatal science, and it has been an important vehicle for high-quality presentation and discussion of neonatal research, especially experimental work. Robert McCance and Elsie Widdowson were faithful supporters and discussants at all of the Society’s meetings for the rest of their lives.

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Long-term Programming of Growth

McCance and Widdowson were among the first to study long-term programming of growth. They varied the number of rats in a litter so a mother with only a few rat pups would have more milk available per pup than a mother with 16 to 20 rat pups. By weaning at 21 days, the pups in the small group were two to three times heavier than the rat pups in the large group. Despite being offered unlimited food after weaning, the rats in the larger litter group never caught up to the weight of the rats in the smaller group. A similar phenomenon was seen in pigs; pigs undernourished from 10 days of age never caught up to normal weight in adulthood.

Comparative Lactation

Widdowson was interested in comparative aspects of nutrition, and she noticed that human infants are unique in the high percentage of adipose tissue that is present at term (16%) compared with the 1% to 2% fat seen in most species. The guinea pig has 10% and the newborn seal 9% adipose tissue. She discovered that formula milk rich in linoleic acid changed the fatty acid composition of adipose tissue in infants and that maize oil in pregnancy changed the fatty acid composition of not only adipose tissue, but also of red cells, liver, and myelin in the neonatal brain. Her studies of hooded seals born onto pack ice, with Olav Oftedal of the Washington Zoo, showed that their milk was 60% fat, which enabled the newborn seals to double their body weight in 4 days. In her monograph on feeding the newborn mammal, Elsie described the chemical composition of milk from 40 different species, including the elephant. Her interest in comparative

biology extended even to blackbirds, thrushes, and bears.

Conclusion

McCance’s death in 1993 at age 95 ended the 60-year scientific partnership, surely one of the longest ever. Widowson continued to participate in research at Cambridge and attend meetings until shortly before her death in 2000, when she was almost 94 years old. Both became fellows of the Royal Society, Britain’s most prestigious body of scientists. Despite their international fame, McCance and Widdowson were both modest, and they were enthusiastic in supporting young investigators. I came face to face with Elsie Widdowson’s intellect in 1978 when she was principal examiner of my thesis at Cambridge. Although she asked very searching questions, she was generous with her encouragement. I well remember a complimentary remark from Robert McCance after my presentation to the Neonatal Society in 1980. When asked to give advice to a young scientist, they suggested the following principles: 1. Treasure your exceptions. Do not regard them as a nuisance because they increase your standard error. They may be the most interesting part of your study. 2. Vary your conditions. 3. Do not be afraid to own up to a mistake, even if your results have been published. 4. If you are using an animal as a model for human children, be careful to choose an appropriate species of the right age for your experiments. A newborn rat is like an extremely immature human neonate, whereas a newborn guinea pig corresponds to an infant several months old. 5. If your results do not make physiologic sense, think. You may

have made a mistake or you may have made a discovery. 6. Tender loving care of babies and careful handling of animals may make all the difference to the successful outcome of an experiment. Their approach was whole animal physiology rather than molecular reductionism, and their attitude to the interdependence of physiologic systems is reflected in the title of one of Widdowson’s invited lectures and monographs, “The Harmony of Growth.” Robert McCance and Elsie Widdowson deserve to be remembered because of the importance of some of the concepts they introduced to neonatologists and because of the elegance of their experiments, observations, thinking, and writing. ACKNOWLEDGMENT. I am grateful for the assistance of Margaret Atwell, editor of McCance and Widdowson, published by the British Nutrition Foundation in 1993.

Suggested Reading Cavell PA, Widdowson EM. Intakes and excretions of iron, copper and zinc in the neonatal period. Arch Dis Child. 1964; 39:496 –501 Dear RFA, McCance RA. Inulin, diodone, creatinine and urea clearances in newborn infants. J Physiol. 1947;106:431– 439 McCance RA, Naylor NJB, Widdowson EM. The response of infants to a large dose of water. Arch Dis Child. 1954;29: 104 –109 McCance RA, Young WF. The secretion of urine by newborn infants. J Physiol. 1941;99:265–282 Oftedal O, Bowen OD, Widdowson EM, Boness DS. Effects of suckling and the post-suckling fast on weight of the body and internal organs of harp and hooded seal pups. Biol Neonate. 1989;50:1–12 Widdowson EM. Changes in pigs due to undernutrition before birth and for one, two and three years afterwards and the effects of rehabilitation. Adv Exp Med Biol. 1974;49:165–181 Widdowson EM. Chemical composition of NeoReviews Vol.8 No.11 November 2007 e457 NeoReviews   21

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newly born mammals. Nature. 1950; 166:626 – 628 Widdowson EM. Harmony of growth. Lancet. 1970;i:901–905 Widdowson EM, Dauncey MJ, Gairdner DMT, Jonxis JHP, Pelikan-Filipova M. Body fat of British and Dutch infants. Br Med J. 1975;i:653– 655

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Widdowson EM, McCance RA. The effect of finite periods of undernutrition at different ages on the composition and subsequent development of the rat. Proc Roy Soc B. 1963;158:329 –342 Widdowson EM, Spray CM. Chemical development in utero. Arch Dis Child. 1951;26:205–214

For further information, including photographs, please go to: http://www. nature . com / nature / journal / v406 / n6798/full/406844a0.html (available for subscription); http://www.nares. net/mccance/robert_mccance_1898. htm; and http://www.royalsoc.ac.uk/ page.asp?id6678

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Perinatal Profiles: Alexandre Minkowski: Founder of “Biology of the Neonate” Alistair G.S. Philip, MD, FRCPE*

Introduction

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Philip did not disclose any financial relationships relevant to this article.

Almost every country boasts pioneers in the field of neonatology. Most neonatologists in the United States are familiar with the role that the French obstetricians Ste´phane Tarnier and Pierre Budin played in promulgating the use of incubators for preterm infants. In addition, Budin wrote about umbilical cord clamping and outlined many important principles of the care of newborn infants in his book “Le Nourisson” (The Nursling), which was published in French in 1900 and in English in 1907. However, the person in France who arguably exerted the greatest influence on neonatology in the 20th century is the pediatrician Alexandre Minkowski.

The Early Years

Minkowski was born in Paris in 1915 to two Jewish psychiatrists, Eugen`e and Franc¸oise Minkowski, who originally were from Poland. His secondary education was at L’Ecole Alsacienne, and he attended medical school at the University of Paris. During the Second World War he joined the resistance movement in Paris in 1941 and subsequently was awarded the Medaille de la Re´sistance as well as the Croix de Guerre 39 – 45 (1939 to 1945 War Cross). Immediately after the war, he was awarded a Rockefeller Foundation Bursary to study with Clement Smith at Harvard from 1946 through 1947. He was one of many interna*Emeritus Professor of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, Calif.

tional pediatricians who spent time with Clem Smith in Boston learning about fetal and neonatal physiology. He remained in the United States for some time after this, assimilating knowledge about clinical neonatology from pediatricians interested in the field such as Julius Hess in Chicago and Sam Levine in New York. He returned to Paris in 1950, where he supervised the nurseries at Hoˆpital Baudelocque.

Assembly of a Formidable Group

Starting in 1955, he became the Director of the Centre de Recherches Biologiques Ne´onatales at Hoˆpital Port Royal, which is immediately adjacent to Hoˆpital Baudelocque. This unit was under the auspices of INSERM (Institute National de la Sante´ et Recherche Medicale) from 1964 until the end of Minkowski’s tenure in 1985. Of interest, the clinical unit (neonatal intensive care unit) was on the 4th floor and the research unit on the 5th floor, in accord with Professor Minkowski’s desire that research activity be closely linked to clinical care. I was fortunate enough to spend some time with him in 1969, at which time he had managed to assemble a formidable array of talent, mostly women, sometimes referred to as his “harem.” Among this talented group were Suzanne Sainte Anne-Dargassies (who collaborated with the developmental neurologist Andre Thomas), Colette Dreyfus-Brisac and Nicole Monod (electroencephalography experts, who described the phases of sleep), JeanneNeoReviews Vol.9 No.1NeoReviews January 2008  23 e5

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Claudie Larroche (eminent perinatal pathologist), and the young Claudine Amiel-Tison (who trained with Sainte Anne–Dargassies, but emerged as an important developmental neurologist in her own right). Biochemistry and bacteriology were prominent and neonatal cardiology was represented by Michelle Monset-Couchard, recently returned from University of California Los Angeles (UCLA). Also on his team was a young neonatologist who had recently returned from the United States, where he worked both at UCLA and with Mildred Stahlman in Nashville, Tenn., Jean-Pierre Relier, who would succeed Alex Minkowski as Chief of the Neonatology Service at Port-Royal and also as Chief Editor of Biology of the Neonate.

Foundation of Journals and Recognition of Research Center

In 1969, Alex Minkowski already had had a substantial impact on European neonatology, having established a journal, Etudes Ne´onatales, in 1957, which was published in French, before becoming the founding editor of Biologia Neonatorum in 1959. Biologia Neonatorum was published in both French and English for a few years, but starting in 1962, the articles were published only in English, although summaries were provided in French, English, and German. Biologia Neonatorum was published by Karger and later (in 1983) changed its name to Biology of the Neonate and very recently (January 2007) became Neonatology: Fetal and Neonatal Research. Minkowski continued as Chief Editor until 1985. Minkowski’s Centre de Recherches Biologiques Ne´onatales attracted visitors from around the world, in much the same way that his mentor Clement Smith had attracted visitors to Boston. For example, during my 3-month visit, there were visitors from Brazil, Greece, 24    NeoReviews NeoReviews Vol.9 No.1 January 2008 e6

Spain, and Scandinavia. The year 1969 was something of a watershed in the development of assisted ventilation. Minkowski organized a conference in Paris on the subject, which attracted several prominent researchers in the field, including Mildred Stahlman (Nashville), Paul Swyer (Toronto), Leo Stern (Montreal), and Leonard Strang (London). The proceedings were published as a special issue of Biologia Neonatorum in 1970. The big question was whether we were doing more harm than good with ventilation because reports of bronchopulmonary dysplasia and other complications had been published recently and were uppermost in people’s minds at the time. Clearly, further progress in assisted ventilation was forthcoming.

Personality, Interests, and Beliefs

Much of the success of the center in Paris was due to the strength of Minkowski’s personality. He was a dynamic leader, who was able to accomplish things through the force of his personality. His life was not without controversy, however. He identified strongly with socialism and visited communist regimes in China, Cuba, and North Vietnam at a time when they were not on the itineraries of most Western physicians. He was close to such left-wing politicians as Pierre Mendes-France and Michel Rocard and advised “Medicins sans Frontie`res” (Doctors without Borders). He joined Bertrand Russell and Jean Paul Sartre at the International War Crimes Tribunal in Copenhagen in 1967, testifying “On Chemical and Biologic Warfare in Vietnam.” Jean-Pierre Relier has noted that he was “at odds with the greater part of the university world.”

He apparently had an exceptional memory and a wide range of interests, particularly music. His son Marc was a bassoonist who became a well-respected conductor of French baroque music and opera. In addition to editing Biology of the Neonate for many years, his indefatigable nature led him to travel extensively throughout the world and to write several books, both medical and nonmedical. These included “Un Juif pas tre`s Catholique” (A Jew not very Kosher, 1980), “L’Art de Naıˆtre” (The Art of Giving Birth, 1987), “Pour Les Enfants du Monde” (For the World’s Children, 1991) and his autobiography “Le Mandarin aux Pieds-Nus” (The Barefoot Mandarin, 1975) written in collaboration with Jean Lacouture. The first of these books includes an oft-quoted citation, which reads (my translation) “In France, it suffices to affirm something with authority, to have one’s word believed.” This kind of comment did not always endear him to his colleagues! According to Relier, “He ceaselessly questioned knowledge acquired and most of all that concerning the mother and child.” He fought to protect children in war zones from Vietnam to Palestine and, despite the fact that he was a Jew, he opposed Israel’s war against Lebanon in June 1982. He was a strong proponent of humanitarian aid for children of the developing world, as exemplified by the last (to my knowledge) medical article that he wrote, based on a lecture given in 1999 and published in Acta Pediatrica in 2000, whose title was “Protection of the young child’s brain: personal observations and thoughts in post-war stress syndrome and in natural catastrophes.” The diversity of his interests also

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is attested to by his election to the French parliament in 1992 at the age of 76 to represent the environment party “Ge´neration Ecologie,” although he resigned the following year, apparently because of lack of organization within the party.

Final Word

After his death in May 2004, at the age of 88, Jacques Chirac, the French president, called Alex Minkowski “one of

the consciences of the 20th century,” who was a “great doctor, scientist andfounder of French neonatal research.”

Suggested Reading Andrieu B. The research on the premature brain as a multidisciplinary model at the Baudelocque de Paris Clinic, 1942– 1962. [Published in French]. Hist Philos Life Sci. 2001;23:259 –277 Lagercrantz H. Presentation of Professor

Alexandre Minkowski. Acta Paediatr. 2000;89:1154 Minkowski A. Protection of the young child’s brain: personal observations and thoughts in post-war stress syndrome and in natural catastrophes. Acta Paediatr. 2000;89:378 –385 Relier J-P. Alexandre Minkowski, 1915– 2004. Biol Neonat. 2004;86:183 For books by and photographs of Professor Alexandre Minkowski, please go to: www.livrenpoche.com/auteur/MinkowskiAlexandre/9875.html. Books are in French.

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Perinatal Profiles: Clem Smith: A Gentle Gardener Nicholas M. Nelson, MD*

The Human Side

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Nelson did not disclose any financial relationships relevant to this article.

His beginnings (presciently) were in language, to the extent that he dropped out of medical school to study English and “Freshman Rhetoric” for a 2-year period. We in medicine can be grateful for Clem’s return to the fold, armed with the biblical background, articulate power, and insight to entitle a paper “The Valley of the Shadow of Birth.” His father, Shirley W. Smith, had been Professor of English at the University of Michigan and, after an interlude in the Philadelphia insurance business, returned to Ann Arbor as its VicePresident and a (sometime) screenwriter. Some of Clem’s continuing research funds were comprised of Shirley’s royalties from his delightful story for It Happens Every Spring, a 1949 movie about a magical baseball that repelled bats and allowed actor Ray Milland to become the winning pitcher of the World Series. Another funding source was the American Cancer Society because his Harvard colleague, Bill Castle (elucidator of intrinsic factor, vitamin B12, and megaloblastic anemia), had suggested to him that babies, as well as cancers, grow. Clem’s most faithful and lasting funding was from Leonard Mayo of the Association for the Aid of Crippled Children and, during his last active years, to the newly formed National Institute of Child Health and Human Development. *Professor of Pediatrics Emeritus, College of Medicine, The Pennsylvania State University, State College, Pa.

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Born in 1901, Clem was wholly educated through medical school at Ann Arbor. Following a 2-year pediatric residency at Michigan, he began his long association with Harvard as a Children’s Hospital resident in 1931 under Kenneth Blackfan, remaining there until 1943, when he briefly returned to Michigan as pediatric chair at Wayne State. Although I cannot delineate just when Clem’s interests gravitated across Longwood Avenue to the Boston Lying-in (“BLi”) from the Children’s Hospital, his first article on the newborn is dated 1939, and by 1941, the BLi was listed as his reprint address. He was, by this time, evidently and understandably fascinated with the differences between O2 and CO2 carriage in the blood of mother and fetus, as detailed by Barcroft in sheep. As a clinician, he recognized that cord blood was one fetal material ethically available for detailed study. His well-developed interest in the newborn brought him back in 1945 from his 2-year exercise in departmental administration to the BLi (now Brigham and Women’s) Hospital as Director of Research, where Duncan Reid (obstetrics), Stewart Clifford (pediatrics), Claude Villee (biochemistry), and Kurt Benirschke and Shirley Driscoll (pathology) became his frequent facilitators and occasional collaborators. Facilitators became necessary from time to time because the large private delivery service at BLi, although comprised of many pediatricians and obstetricians supportive of clinical research, also harbored some practitioners so protective of their infant charges that one occasionally NeoReviews Vol.9 No.4 April 2008 e137

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Figure 1. Clem in his beloved greenhouse.

could find a note pinned to a bassinet saying (paraphrased) “Under NO condition should Dr Smith, or any of his Fellows, examine this baby.” Clem married his first wife, Margaret Earhart, in 1926 and, except for the years 1932 to 1933 and 1943 to 1945, they lived in Cambridge with 4 children in a marvelous house on Brattle street, whose third floor in later years usually was occupied by a deserving, needy, and nonrelated student. Widowed in 1960, Clem was sustained by his greenhouse (Fig. 1), his children, friends (especially Alex Nadas, a founder of pediatric cardiology), and his Fellows, who began appearing at BLi in 1945. Because of Margaret’s long association as a trustee with Radcliffe College, Clem came to know Mary I. (“Polly”) Bunting, Radcliffe’s president (and previously my own father’s boss as Dean at Douglass College of Rutgers University), charged with the difficult task of enfolding Radcliffe within Harvard’s grasp. Their friendship ripened into marriage in 1975. Clem vastly enjoyed the fact that Polly’s prominence was much better established (hers was a Time magazine “cover story” in 1961) e138 NeoReviews Vol.9 No.4 April 2008

than his own, such that he barely was mentioned in newspaper accounts of their marriage. Somewhere in his late 60s, Clem had been assaulted by a severe case of rheumatoid arthritis that gradually was controlled by his talented rheumatologist and a program featuring supportive socks, bedrest, bourbon, and aspirin. As his wife and faithful nurse, Polly continued this program until Clem’s passing in 1988. Clem maintained a beloved summer and weekend home in Peacham, Vermont. At a service of remembrance in Harvard’s Memorial Church, Clem’s grandson fondly recalled him not as doctor, author, or educator, but as the man who had taught him how to run the Peacham tractor. This was in an earlier and more conservative Vermont that once was characterized for me by Clem’s faithful caretaker, Jim Quimby. “Up here,” said Jim, “if it’s gettin’ cold and your wood ain’t cut because your leg is broke, don’t worry—your neighbors’ll cut it for you. On the other hand, if your wood ain’t cut and your leg ain’t broke, you’re gonna freeze to death!” Clem’s correspondence and often his speech was graced by frequent and lengthy quotations of Shakespeare and the more minor poets. He knew the constellations, music, and a great deal about art— he was the definition of a Renaissance Man. At a dinner celebrating the retirements of Clem and his Harvard colleague, Lou Diamond (Lou went on to several more productive years at University of California–San Francisco, which evidently was pleased to continue benefitting from retired Harvard talent), Clem recalled with delight how a young woman from Tennessee was (many years earlier) in his Children’s Hospital office pleading for academic support for her striving Hungarian husband. With a twinkle Clem said, “I felt like Scar-

pia!,” a reference to Puccini’s archvillain in “Tosca.” Thus began the Nadas-Smith friendship. Clem became godfather to the young baseball fanatic, Johnny Nadas, who, during a summer’s break from college, tried Wall Street, loved it, and shared with Clem his unease at revealing this fact to his famously progressive father. It was Clem’s tradition to celebrate the departure of each Fellow with a bit of whimsical doggerel. For Klaus Reigel, who returned to Tu¨bingen to found German neonatology in 1965 after a Boston year of measuring blood oxygen content (in the Natelson microgasometer, which involved a lot of loud slamming of the machine against a metal stop), Clem composed “Eine Kleine ‘Knock’ Musik.” My own personal acquaintance with Clem began in 1956, when I spent 2 years in uniform defending French civilization at the 34th General United States Army Hospital (La Chapelle-St. Mesmin, Orle´ans, France). There I discovered Clem’s Physiology of the Newborn Infant, fell in love with same, and determined to finish my residency (begun at Bellevue under Emmett Holt) at Boston (under Charlie Janeway) and apply to Clem for a Fellowship (not quite known as such at the time) in neonatology (completely unknown at the time). I had applied to Clem’s program (but not yet met him) just before my first child was born at BLi. That birth in 1958 was a miserable experience. Husbands were discharged from mothers’ rooms with the first shot of oxytocin or scopolamine (whichever came first in the “House of Twilight Sleep”), and my wife developed mastitis (a very scary business for new parents in a day that lacked “lactation consultants”), relieved only by the attentions of our very skilled, but often elsewhere, obNeoReviews  27

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stetrician. One Sunday, at lunch in my white suit, I was complaining so loudly of this experience to my resident colleagues that I didn’t notice them kicking me under the table as an eminence grise approached, saying, “I understand that someone here doesn’t approve of BLi’s management of births.” I weakly raised my hand in admission, but my eyes were respectfully lowered too much to tell whether Clem had a twinkle in his eye as he said, “I just want you to know that . . . [personal sweat] . . . I agree with you!” Clem was a master of droll comic timing.

The Researcher and Educator

Over a period of 25 years, the Fellows passing through Clem’s small laboratory became involved in a distinctly eclectic range of clinical investigations, often taking advantage of the scientific intellectual ferment available across Longwood Avenue in Harvard Medical School’s Department of Physiology and the School of Public Health, particularly emphasizing the cardiopulmonary system. The clinical material available at the BLi was comprised of nearly 8,000 annual deliveries, most of which were private patients. Joslin Clinic diabetic pregnancies were followed and delivered at BLi, so infants of diabetic mothers as an “at-risk” population frequently served as “normal” infants for cardiopulmonary investigations as well as investigations of glucose metabolism, their approving parents often personally (and gratefully) observing these procedures of gas sampling and blood collecting. This was a much more gratifying and comfortable mode for clinical investigations than the heavily documented and legalistic environment of today’s “informed consent” (pace, Bill Silverman). Some investigations, particularly those involving water and acid-base balance, were driven 28     NeoReviews

by the clinical fashions of the day as these habits (eg, withholding feedings in the first few days of preterm life) began to come under question. Nearly none of Clem’s Fellows were supported by the National Institutes of Health, whose training programs did not begin until the early 1960s. Many of those from overseas brought their own support; most North Americans were supported by Clem. His Fellows also could be grouped by their previous involvement in clinical research. Overseas Fellows tended to arrive in Boston with their research ideas (and often techniques) well in hand, looking primarily for the opportunity for clinical investigation in the supportive environment created by Clem. The North American Fellows tended to arrive fresh out of their residencies, hoping to learn something of the world of clinical investigation and driven more by intellectual interest than by any need for academic career preparation, sub-Board certification being far in the future. Clem’s personal interest in nutrition and metabolism were among his earliest areas of investigation and were culminated by Dmitri Nicolopoulos’ demonstration that the denial of nutrition per os in the first days after birth “to protect the airway” was forcing negative nitrogen balance in preterm infants that exceeded that observed in Navy fliers shot down and surviving after 80 days of fasting on Pacific life rafts. The necessary intellectual and clinical corroboration of Dmitri’s observations soon came down to Boston from the North. Newborn care was essentially custodial in the late 1950s, but one had to take note of Bob Usher in Montreal, who had begun to offer intravenous glucose to preterm infants in the first hours after birth and was receiving much laudatory praise in the Canadian press for reversing

the “sine-wave EKG” (of hyperkalemia) with a simple infusion of glucose. It had not yet become apparent how well-deserved this praise was, and in the middle of tedious oxygen analyses with the micro-Scholander apparatus, Peter Auld and I grousingly agreed that it would be pleasant to see Bob’s approach fail, so we could rewrite “The Fall of the House of Usher.” We were too shortsighted to note that Bob’s approach had, in fact, converted the custodial preterm infant to an active patient, fully deserving of “intensive care.” The subsequent development of umbilical artery catheters, blood gas analyses, respirator support, and total parenteral nutrition mercifully closed the custodial era. Throughout all of these studies, Clem’s role was very much that of enthusiastic facilitator and scholarly interpreter rather than hands-on director, so the published output of his Fellows was distinctly more diverse in focus than that of most other programs. By 1959, those who had passed through Clem’s small BLi lab included Alex Minkowski (France); John Hansen (South Africa); Gerald Neligan and Jim Farquhar (United Kingdom); and Jim Sutherland, Jerry Lucey, and Jack Rudolph (United States). The focus on pulmonary function began in the early 1950s, with the arrival of Petter Karlberg from Sweden, working principally with Dav Cook and Donough O’Brien. They developed much of the knowledge of infant pulmonary function that stands today, taking advantage of the close proximity of the Harvard School of Public Health, which long had been a leader in adult pulmonary physiology. The later natural progression of such studies involved Peter Auld, Klaus Riegel, Sam Prod’hom, and Nick Nelson, particularly focusing on the development of technology that permitted the NeoReviews Vol.9 No.4 April 2008 e139

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measurement of blood gases and blood pressure, all of which contributed to the scientific bases for modern life support of the stressed newborn. Respirator support for infants, however, initially was developed in New York, Toronto, and Nashville, rather than Boston (which calls itself “the hub,” perhaps forgetting that the hub is that part of the wheel that merely rotates). As all these ideas were being developed by young investigators of infants in his lab, Clem could be frustratingly slow to achieve physiologic insight into some of the more abstruse concepts (eg, pulmonary transfer factor, pressure-volume hysteresis). However, once he grasped the concept under discussion, he could unerringly express it in plain English better than any of those who had tried to “educate” him. A steady presence in Clem’s lab was his associate of many years, Ruth Cherry (elder sister of the eminent James Cherry of UCLA). Ruth was very much the mother hen of Clem’s lab, both personally and professionally. One did not fully matriculate as a Fellow until mastering the calculation of standard deviations with the Monroe Hand(!) Calculator under Ruth’s tutelage. Three individuals bear special mention because although their interests were largely peripheral to the general thrust of investigations in Clem’s lab, their work was greatly facilitated by Clem’s cooperation, guidance, and encouragement. Mary Ellen (“Mel”) Avery arrived from Baltimore in the late 1950s, already determined to find (or not) that the lungs of preterm infants dying of “idiopathic respiratory distress syndrome” (RDS) were surfactantdeficient. Mel had formulated these ideas after her exposure at Johns Hopkins to the pathology observations and thinking of Peter Gruene140 NeoReviews Vol.9 No.4 April 2008

wald as well as the delineation of surfactant physiology and biochemistry by John Clements at nearby Fort Dietrich. She was advised by Richard Riley to seek out Boston, which contained a major intellectual resource (Jere Mead) at the School of Public Health, as well as a large population of preterm infants across Longwood Avenue at BLi. She spent most of her time at the Harvard School of Public Health, but occasionally returned to BLi to harvest the lungs of preterm infants who had succumbed to RDS (ne´e “hyaline membrane disease”). Present-day Fellows who have had their “breakthrough” research underappreciated can take heart from the decision of the pediatric Alte Herren of 1959 that Mel’s paper on the high surface tensions she found in these lungs was of insufficient interest for presentation at the spring pediatric meetings. Clem had been happy to lay out his welcome mat for Mel and vastly enjoyed the success of her mission. At about the same time, Abe Rudolph (as a Fellow in cardiology with Alex Nadas) was looking for evidence of anatomic shunts to explain the profound hypoxemia in RDS. He observed during cardiac catheterization of such infants at the BLi that the ductus arteriosus was wide open and carrying unoxygenated blood right-to-left. Thus began Abe’s long pursuit (often with Mike Heymann) of the ductus as key to the understanding and management of congenital heart malformations, culminating in the present control of the ductus with indomethacin and prostaglandin. In the late 1960s, Jeff Maisels arrived at the BLi from South Africa with no previous research experience and seized on the suggestion of David Nathan (Chief of Hematology at the Children’s Hospital) that there was considerable interest among he-

matologists in the rate of carbon monoxide production from the breakdown of hemoglobin. Since the release of carbon monoxide from hemoglobin leaves a residue of bilirubin and a surfeit of bilirubin produces jaundice, Jeff’s interest was immediately aroused. Moreover, there happened to be lying around in Clem’s lab the equipment required to permit the necessary infant rebreathing for serial measurements of blood carboxyhemoglobin. Thus began Jeff Maisels’ long and productive effort to understand bilirubin metabolism in the newborn.

The Editor

Clem greatly enjoyed his stewardship as Editor of Pediatrics, in which he was followed by Jerry Lucey. The single low point was when some poor author’s academic magnum opus was printed facing the particularly large proboscis of an orangutan, advertising some manufacturer’s nasal decongestant. Pediatrics’ editorial board examined the question of interspersed advertising (manufacturers’ preference) versus end-paper advertising (scholars’ preference). However, investigation demonstrated that not even the complaining academics were willing to sustain the estimated $5.00 increase in subscription price that noninterspersed advertising would have cost. Clem was disheartened, but still very proud of the “Karsh of Ottawa” photographic portrait of him with Pediatrics rolled up in his hand.

Conclusion

Hanging on the wall near Clem’s desk was a photograph of Sir Joseph Barcroft, by whose scholarship and eminence he had long been inspired. I’m not sure whether they had ever met, but the picture was accompanied by a letter fragment from Barcroft that said, “remember that the essence of the missionary enterNeoReviews  29

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Figure 2. The Clem Smith Academic Family Tree.

prise such as yours is to expel the people one by one. . . .” And he did. In my own case, I had been wondering whether I had made a late decision for medicine (I had foresworn a career in arachnidology) only to end up in a laboratory measuring oxygen contents and standard deviations by hand, so I was considering entering private practice. Knowing that Clem had briefly done the same in 1932 to 1933, I asked his advice and was not dissuaded, although he did express mild regret. Charlie Janeway said only, “Don’t get too used to the money!” ($25k as a full private partner—this was a long time ago!) 30     NeoReviews

Clem was gracious enough to accept me back at the BLi 3 years later, and the 20th-year reunion of his Fellows commemorated by his Academic Family Tree (Fig. 2) followed 1 year later. That happy occasion in 1965 was 3 years before his scheduled Harvard retirement, and with his customary mischievous twinkle, Clem remarked that the timing of the party was rather like “singing Christmas carols in September.” He also noted, in explanation of why 50-odd pediatricians had chosen to associate with him over the preceding 20 years, that, “If you were interested in babies and liked Boston, I was the only wheel in town!”

In addition to his many other honors, in 1975 Clem received the first annual Virginia Apgar Award (of the American Academy of Pediatrics) for “an individual whose career has had a continuing influence on the well-being of newborn infants.” Four of his Fellows have followed him in such recognition: Petter Karlberg (1990), Mel Avery (1991), Jerry Lucey (1993), and Jeff Maisels (2007). Res ipsa loquitur! What was the essence of Clement Andrew Smith: Scholar, educator, author, gentle humorist, gentle man? He was all of these. NeoReviews Vol.9 No.4 April 2008 e141

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Perinatal Profiles: Roberto Caldeyro-Barcia: Obstetric Physiologist Extraordinary Peter M. Dunn, MA, MD, FRCP, FRCOG, FRCPCH*

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Dunn has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

Introduction

Roberto Caldeyro-Barcia, MD, PhD, FRCOG (ad eundem), FACOG (hon), FACS (hon), was born in Montevideo, Uruguay on September 26, 1921. He was to become an outstanding obstetric physiologist, arguably the greatest of his day, if not of all time.

Early Days

Roberto’s father, Dr Joaquin Caldeyro, was a distinguished physician, and his mother, Elvira Barcia, was the daughter of a lawyer, Carlos Barcia, also with a medical family background. Roberto began his education at the English School in Montevideo. It was there that the headmistress, Mrs. Ivy Thomas, first called him “Bobby,” a name adopted by his family and close friends. While there, he also met Ofelia Stajano, later to become his wife. Moving on to the Elbro Fernandez School, Bobby confirmed his outstanding academic potential. He was very hard working and had an exceptional memory combined with an enquiring mind. At the same time, he enjoyed sport, including football, swimming, surfing, volleyball, and polo among his activities. From the age of 15, he began to court the beautiful and intelligent Ofelia. They were neighbors and went riding to*Emeritus Professor of Perinatal Medicine and Child Health, University of Bristol, Southmead Hospital, Bristol, United Kingdom.

gether, carefully chaperoned by his uncle. In 1938, at the age of 17, Roberto entered the University of Uruguay’s Faculty of Medicine. As before, he revealed himself to be a brilliant student, but he also found time for student affairs and was wellinformed about world events. Indeed, in 1940 during World War II, he took part in a march through Montevideo in support of the Allies. Roberto and Ofelia became engaged in 1945 and were married the following year. In 1947, Roberto qualified in medicine, winning the silver medal for his year. (1)

Academic Career

Upon graduation, Caldeyro-Barcia was appointed Assistant Professor of Physiology in the Institute of Physiology, Montevideo (Associate Professor, 1950). In parallel with his medical course, he had trained in physiology with Professor Bennati in Montevideo and abroad in Belgium with Professor Zenon Bacq (University of Liege) (1945). He received further physiologic training with Professor Corneille Heymans* of the University of Ghent (1948), Professor S.R.M. Reynolds of the University of Illinois (1950), and Professor Bernardo Houssay* of the University of Buenos Aires (*Nobel prize winners). Already by 1947, Caldeyro-Barcia had reported, with the Professor of Obstetrics, Hermogenes Alvarez, the first recording of amniotic (intrauterine) pressure in a pregnant woman. (2) This advance enabled them to study and analyze the intensity and NeoReviews Vol.9 No.5NeoReviews May 2008 e187   31

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frequency of uterine contractions as well as uterine tone and activity. In the 1950s, he and his team studied changes in fetal heart rate related to uterine contractions using a fetal scalp electrode. They classified “type I dips” in the fetal heart rate as due to head compression with a good prognosis, while the more severe late decelerations were called “type II dips” and were considered to be due to fetal hypoxia. In June 1952, Alvarez and Caldeyro-Barcia were invited to lecture on their work in England, including at the 13th British Congress of Obstetrics and Gynaecology. (3) They were given a warm welcome, and their new techniques had a great impact. Study of the influence of uterine contractions on the fetal heart rate soon became the basis for monitoring fetal well-being during labor in the United Kingdom and around the world. It subsequently formed the basis for the pregnancy “stress test.” Although some of his studies would be considered “brave” by today’s standards, CaldeyroBarcia always showed the deepest concern for the welfare of his patients, often spending all night with them while investigations were in progress. In recognition of his distinction, the University of Uruguay created a Service of Obstetrical Physiology in 1959 with Caldeyro-Barcia as professor and chairman. He rapidly built up a formidable team of scientists around him. His methods of monitoring the fetus also permitted study of various other factors influencing the progress and safety of labor, matters that increasingly occupied his attention in the years ahead. In particular, he became concerned about the effect of oxytocic hyperstimulation on the uterus and in 1969 warned of the misuse of such drugs at an important Pan American Health Organisation (PAHO)/World Health Orgae188 NeoReviews Vol.9 No.5 May 2008 32      NeoReviews

nization (WHO) conference that he had organized in Washington, DC, with the title “Perinatal Factors Affecting Human Development.” (4) The following year, the PAHO created the Latin American Centre of Perinatology and Human Development (CLAP) in Montevideo, with Caldeyro-Barcia as its director, to facilitate the work of his group. Obstetricians and physiologists from around the world flocked to Uruguay to study. He was not only an outstanding physiologist, but also a remarkable teacher, sought after to lecture at many international conferences. Among his innovations at CLAP was the creation of facilities for perinatal intensive care. A major interest was the use of uterine inhibitors to permit fetal recovery from distress in utero prior to delivery. Another development was the creation of a mother-infant rooming-in system, with the object of teaching mothers about infant care and development and to emphasize the importance of breastfeeding. During the 1970s, Caldeyro-Barcia studied and challenged many current routine obstetric practices, such as the common use of amniotomy, fasting during labor, use of the supine and lithotomy positions, restricted movement during labor and delivery, forced bearingdown efforts, and routine episiotomy. (5) In 1976, Caldeyro-Barcia was elected president of the International Federation of Gynecologists and Obstetricians (FIGO) (Fig. 1). It was a unique honor for a medical scientist rather than a practicing clinician. Under his presidency, the World Congress of Gynecology and Obstetrics was held in Tokyo in 1979. A particular emphasis was placed on primary perinatal care, especially in developing countries. (6)(7) Caldeyro-Barcia had become very

1. Roberto Caldeyro-Barcia, President of FIGO 1976 to 1979.

Figure

interested in the work of Professor Jose´ Galba Araujo of Brazil in training and making use of traditional birth attendants in areas without proper medical services. (8) Caldeyro-Barcia had himself, of course, made enormous contributions to the safety of childbirth and to the improvement of newborn care in the developing world, especially in Latin America. All his ideas were aired at an important international WHO/PAHO conference in Fortaleza, Brazil, in 1984, honoring the late Galba Araujo. (9) Not everyone welcomed his new approach. Steeped in interventionalist obstetrics, many of those who had regarded him previously as their leader felt betrayed by his warnings and criticisms. However, he was in no way daunted and continued to speak out about the hazards of iatrogenic obstetrics throughout the remainder of his life. On reaching the age of 60 in 1981, Caldeyro-Barcia retired as director of CLAP and was appointed chairman of the Department of Perinatology at the University of Uruguay. Not wishing to lose his wisdom and experience, the Ministry of Pub-

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Figure 2. Roberto and Ofelia Caldeyro-Barcia and their family in Montevideo at the time of their golden wedding anniversary, April

1996.

lic Health of Uruguay also appointed him director of the National Maternal-Child Health Program. On retiring from the University a few years later (1987), he was appointed director of the Basic Sciences Development Program (PEDECIBA) by the Ministry of Education and the University of Uruguay, with the aim of encouraging the return to Uruguay of scientists who had left during the troubled years and to provide a solid basis for the promotion of science in the country. He remained active, pushing forward his ideas and reforms, right up to his final illness from diabetes and heart disease. This brief summary of CaldeyroBarcia’s academic career has had to omit an account of the many posts he held on international societies, federations, and editorial boards. It also fails to mention the great range of his clinical and physiologic research published over the years in many books, chapters, and several hundred papers. Nor is it practical to describe in detail the many awards and honors he received throughout his career,

among which were honorary degrees from 11 universities and honorary fellowships from 38 academies and scientific societies. On no less than three occasions, he was nominated for a Nobel Prize. He received eight prizes and medals for his research, including the Abraham Horwitz Award of the Pan American Health and Education Foundation, given in recognition of his outstanding work concerning normal labor and the factors responsible for difficult labor and fetal distress. (1)

Family Memories

On January 19, 1946, Roberto married his beautiful fiance´e, Ofelia Stajano. Over the next 11 years they had six children – Ofelia, Lucia, Roberto, Carlos, Eduardo, and Martin. By 1996, when they celebrated their golden wedding anniversary, there were also 12 grandchildren and 8 great grandchildren (Fig. 2). Ofelia Stajano recently wrote to me, “Living with Bobby has been a continuum of exciting experiences and never-ending efforts pursuing his

ideals and research projects. Many a time he would say to me: ‘When I work on my experiments, I work with the greatest pleasure, being able to stay the whole day and night without eating or being tired’.” She continued, “Fortunately, we two had a good understanding of each other and happily survived our 50 years together. I thank God for having had the opportunity to share my life with him. I miss him all the time.” Ofelia also discussed in her letter Roberto’s efforts to improve obstetrics. Although acknowledging that great progress had been made over the years, he had regretted the many who were reluctant to change their habits, citing how many of his own grandchildren and great-grandchildren had been delivered by cesarean section or in the lithotomy position with anesthetics and episiotomy. Ofelia added: “Bobby was very proud of our family, but the children very much missed the presence of their father at home. And so, none of them were interested in medicine except Lucia who, in a tribute to her   33 NeoReviews Vol.9 No.5NeoReviews May 2008 e189

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Figure 3. Peter Dunn (left) with Roberto Caldeyro-Barcia (right) at the World Congress of Gynecology and Obstetrics in Rio de Janeiro, 1988.

father, stated that his memory was the great inspiration for everything she did.”

Personal Recollections

Although I had been aware of Caldeyro-Barcia’s work for many years, I first met him in 1977 when the WHO asked me to undertake two research projects in South America. Working closely with him in upcountry Uruguay and then in Ceara, Brazil, I got to know him well. We got on splendidly, and I was never more proud than when he told me I might almost be Spanish and made me an honorary member of his family. During the years that followed, I saw a great deal of Bobby in Montevideo, in Bristol, and at many conferences around the world, among which were some 15 organized by the FIGO Committee for Perinatal Mortality and Morbidity, of which we were both members (1979 to 1991) (Fig. 3). (10) One of the reasons why Bobby 34     NeoReviews e190 NeoReviews Vol.9 No.5 May 2008

and I got on so well was that from the outset we found we shared similar views over a wide range of obstetric matters. He confided to me that after many years of scientific study he had come to appreciate just how wonderful were nature’s mechanisms for delivering the baby. Modern technology (much of it, of course, pioneered by himself) had changed greatly, not always for the better, the management of pregnancy and labor when, in his view, the normal, physiologic processes were all that were needed in 80% or more of deliveries. In particular, he had come to appreciate the importance of mobility and the upright position during labor. (11) The latter was also important during delivery to open up the birth canal, increase the efficiency of the uterine contractions, reduce both pain and the problems arising from compression of the mother’s great vessels, and expedite delivery. He told me that he had also come to recognize the importance of the mother’s psychological state, if physiologic func-

tion was to be best achieved. Hence, the need for the woman in labor to be accompanied by her husband or a friend. He deplored the overuse of analgesics, sedatives, and anesthetics. Another obstetric practice that he considered ill-advised was that of instructing women in the second stage of labor to hold their breath and push and push, instead of continuing to take frequent short breaths. Roberto warned against the overuse of oxytocic drugs and the practice of rupturing the membranes early in labor or even before it had commenced. He was also critical of the overuse of episiotomy. However, when obstetric interventions were medically indicated, he was the first to agree that it was necessary to monitor carefully the well-being of the fetus, if possible without introducing adverse factors such as immobility and the lithotomy position. The Caldeyro-Barcia family originally hailed from Galicia in Spain. Indeed, Roberto had the air of a Spanish hidalgo. A very proud man, he was yet without a trace of pretension or pomposity. Of special pride to him were his wife, his family, and his country. He had great warmth and empathy and a deep compassion for people. All were treated with courtesy and patience. Although conscious of his prestige, he remained modest and humble. As a scientist, he was careful, deliberate, and accurate, paying meticulous attention to detail and to consideration of both patients and colleagues. He was always prepared to listen to others, however humble or uninformed they might be. Besides possessing wisdom and judgement, he had courage and integrity. A gracious host, he was widely respected and admired. He died following heart surgery on November 2, 1996. Many throughout the world mourned the

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loss of a dear friend. His death also deprived women in childbirth of their foremost champion. (12)(13)

References

1. Curi AB. Roberto Caldeyro-Barcia: el Mandato de Una Vocacio´n. Montevideo, Uruguay: Pedeciba; 2006:1–278 2. Alvarez H, Caldeyro R. Contractility of the human uterus recorded by new methods. Surg Gynecol Obstet. 1950;91:1–13 3. Caldeyro-Barcia R, Alvarez H. Abnormal uterine action during labour. J Obstet Gynaec Br Emp. 1952;59:646 – 656 4. Caldeyro-Barcia R, Magana JM, Castillo JB, et al. Perinatal factors affecting human development, 8th meeting. Advis Comm Med Res Sci Publ. 1969;185:248 5. Caldeyro-Barcia R. Physiological and psychological bases for the modern and humanized management of normal labor. In-

ternational Year of the Child Commemorative International Congress, Tokyo, Oct. 21–22, 1979. Scientific publication No. 858. Montevideo, Uruguay: PAHO/WHO, 1980 6. Caldeyro-Barcia R, Dunn, PM. Preface to Report of the FIGO/WHO Workshop on Innovative Approaches to Maternal and Perinatal Care as Part of Primary Care, Tokyo, 22–24th October, 1979. London, United Kingdom: FIGO; 1982 7. Caldeyro-Barcia R. Approaches to reducing maternal and perinatal mortality in Latin America. In: Philpott RH, ed. Maternity Services in the Developing World: What the Community Needs. Proceedings of the 7th RCOG Study Group, September 1979. London, United Kingdom: RCOG; 1980: 70 –90 8. Araujo G. The traditional birth attendant in Brazil. In: Philpott RH, ed. Maternity Services in the Developing World: What the Community Needs. Proceedings of the 7th

RCOG Study Group, September 1979. London, United Kingdom: RCOG; 1980: 293–310 9. World Health Organisation. Appropriate technology for birth. Lancet. 1985;ii: 436 – 437 10. Dunn PM. History of the FIGO Standing Committee on Perinatal Mortality and Morbidity, 1979 –1991. Int J Gynecol Obstet. 2007;96:131–137 11. Caldeyro-Barcia R, Dunn PM. Appropriate maternal posture during childbirth. In: Sabatino H, Dunn PM, Caldeyro-Barcia R, eds. Parto Humanizado: Formas Alternativas. Campinas, Brazil: Publ: Editora de Unicamp; 1992:17–25 12. Haire, D. In memory of Roberto Caldeyro-Barcia, MD, 1921–1996. Birth. 1997;24:211–212 13. Armas OR. In memoriam: professor Roberto Caldeyro-Barcia. Int J Gynecol Obstet. 1997;59:175–176

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Perinatal Profiles: Professor John (Johnny) Lind, Neonatology Pioneer William Oh, MD*

Introduction

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Oh has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

Professor John Lind was born and educated in Stockholm, Sweden. He received his medical degree from the Karolinska Institute with “Fetal and Neonatal Circulation” as his thesis. His interest in this area prompted him to establish a neonatal cardiovascular research laboratory at two sites, the Nortull Hospital and Southern Maternity Hospital, both affiliated with Karolinska. Over 3 decades, many of his overseas trainees conducted their research under his guidance at these sites. He was an astute, passionate, inspiring, and kind mentor to the visiting fellows who went back to their home countries to pursue research endeavors. His own achievements, as well as those of his former students, earned him international respect and accolades, including the Barclay Prize of the British Institute of Radiology in 1959, the Ylppo Gold Medal Award for Pediatric Research in Helsinki in 1967, and the Gold Medal of the Finnish Heart Association in 1976, among others. To quote the late Leo Stern’s introductory remarks during a Memorial Symposium in Professor Lind’s honor: “A person’s contribution to science and society is not only from his own works but the accomplishments of his students. In this regard, Professor Lind has indeed made a tremendous impact not only from his own scientific accomplishments but also the contributions of many of his former trainees from *Professor of Pediatrics, Warren Alpert Medical School of Brown University, Providence, RI.

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abroad who went on to establish their own research and academic programs in many countries.” (1) Professor Lind’s eminent international reputation also was evidenced by his multiple visiting lectureships in Scandinavian countries, Europe, and both North and South Americas. Professor Lind was an outstanding model of a great scientist, an inspiring mentor, and a kind man who loved the arts and reading (Figure).

The Scientist

During the embryonic stage of neonatology, several noted academicians began to work on its scientific foundations by studying the various aspects of perinatal biology. One of them was Johnny Lind, a pediatric cardiologist by training, who had a strong passion for understanding the genesis and physiology of the cardiovascular system of the developing fetus. He, in collaboration with Professor Carl Wegelius, a radiologist, painstakingly used the radiographs and cine-angiographies they had collected from fetuses and newborns of various gestational and postnatal ages to describe fetal and neonatal circulation. (2) The article they published in 1949 formed the basis for our understanding of cardiovascular adaptation from fetal to transitional and neonatal life. That publication also exemplified Professor Lind’s enormous contribution to the budding field of neonatal medicine. He subsequently focused his efforts on understanding the physiologic consequences of placental transfusion in newborns, (3) a subject that has seen recent resurgence of interest in both NeoReviews Vol.9 No.7 July 2008 e279

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The Mentor

term and preterm infants for potential reduction of the incidence of anemia during infancy in the former and reduction of acute or perhaps long-term complications in the latter group of infants, when placental transfusion is allowed by delayed cord clamping at birth. Johnny’s other important contribution to neonatology was his early strong advocacy for family-centered care. He insisted that the formation of an integral family begins in the delivery room. His favorite quotation was “With the birth of the child comes the birth of the family,” a commonsense concept that was not appreciated by everyone in those days. He strongly advocated the involvement of fathers in the delivery room at a time when they generally were barred from the delivery suites. He was also one of the first individuals who asserted the value of “singing to the fetus in the womb.” Later in his career, he had a strong passion for developing play therapy for the unfortunate children who needed to be in the hospital because of illness. His pioneering advocacy resulted in the establishment of play therapy programs in many children’s hospitals worldwide. e280 NeoReviews Vol.9 No.7 July 2008

One of Johnny’s unique attributes was the ability to stimulate and guide his fellows in doing research. He constantly asked questions, stimulated formation of hypotheses, and encouraged doing research to find the truth. I vividly remember an occasion during a sunny and crisp fall day in Stockholm, when Johnny went to the hospital’s formula room, grabbed two jars of baby food, and dragged me to sit on the front steps of Karolinska Barnkliniken (Swedish for Karolinska Children’s Hospital) to “brain storm.” The subject was the behavior of umbilical vessels at the time the infant takes the first breath. He theorized that when the infant takes the first breath and the oxygen saturation rises, the umbilical artery would constrict while the umbilical vein would remain patent with continuous blood flow to the fetus. To prove his point, he arranged to have audiovisual personnel join us at a delivery and take a movie of the intact umbilical cord during a normal vaginal term delivery. Lo and behold, the movie clearly showed the constriction of the umbilical arteries as the infant became pink with the first breath. This anecdote clearly demonstrates his original thought process and the ability to prove his point to his pupils. This episode also formed the basis for his thoughts on the occurrence of placental transfusion with delayed cord clamping at the time of birth. His provocative probing of scientific questions was always a stimulus for his fellows. It is not accidental that he trained so many noted academic neonatologists, including Mildred Stahlman, and the late Leo Stern and Bob Usher.

The Avid Art Lover and Reader

One of Johnny’s passions and hobbies was fine arts. When he visited big cities such as Chicago and New York, he would spend at least a day visiting

the Art Institute and the Metropolitan Museum of Fine Arts. The Impressionist paintings at the Met, in particular, excited him. When he came to Providence, Rhode Island, as a visiting professor, he insisted that a half day of his visit be set aside to visit an art museum. He spent that time at the Museum of Rhode Island School of Design, behaving like a happy kid in a candy store, really enjoying the exhibits of this small but quaint museum. He revisited this Museum a number of times just to enjoy the full length portrait of a lady by Manet. His other avid hobby was reading. He loved both fiction and nonfiction. He always had a book (usually a pocket book) with him. When taking a cab from one hospital to another making his daily rounds, he would read the book during the journey.

The Man

Despite his stature as the Professor of Pediatrics at Karolinska Institute, who by virtue of this position also served as the pediatrician for the Swedish Royal Family and as a member of the prestigious Nobel Prize Selection Committee, Johnny was a low-key, unassuming, kind-hearted, and somewhat shy person. In fact, he confided to me at one point that he always was intimidated by those who worked for him. He always put the interests of others ahead of his own. I fondly recall the summer of 1964 when I arrived at Stockholm to begin my Fellowship and found that Johnny had had a mild heart attack. In those days, patients who had myocardial infarcts were required to have 6 weeks of bed rest in the hospital. He insisted that I visit him frequently during the 6-week period to talk about my research plans. His devotion to his trainees was very evident. He was a man who never said no to a reasonable request from anyone. NeoReviews  37

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He was indeed a generous, kind, and very much loved and admired person. He was a hard worker, a classic workaholic; those who worked for him don’t recall his ever taking a vacation all his life. In summary, Professor John Lind was a man of vision. His career focused on understanding perinatal cardiovascular adaptation as well as pregnancy and childbirth as an opportunity to create a whole and integrated family. One statement clearly reflected his deep feeling for the unborn and the newborn: “Personally, I feel that one of the biggest discoveries in the field of pediatrics in my time is the concept that the newborn child is a small human being, with all its senses developed, open, and receptive.” His passion translated into a career highlighted by the acquisition

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of new knowledge of perinatal cardiovascular physiology, promulgation of the concept of an integrated family in the delivery room setting, and the importance of play therapy for sick children. His reputation as a great mentor and role model attracted countless trainees from all over the world, who, in turn, have made significant contributions to the science of perinatal medicine. This amazing, down-to-earth man of science, who also was an art and book lover, was well-loved by those who were fortunate to know and work for him. ACKNOWLEDGMENTS. The author appreciates and thanks Dr Alice C. Yao and Ms Ulla Fuhrer for their valuable input.

References

1. Monset-Couchard M. Cardiovascular and Respiratory Physiology of the Fetus and Newborn. Vol. 133. Montrouge, France; John Libbey Eurotext: 1986. (Editor’s note: The contents of this symposium are accessible on Google books at: http://books. google.com/books?idIshWs40WZgYC& pgPA11&lpgPA11&dqJohnLind andKarolinskaInstitute&sourceweb&ots zgamb8Eim2&sigF7We9JaMuje-j57vbyv JwSyBXjc&hlen. A photograph of John Lind is in the preface, an obituary “Stern L: John Lind 1909 –1983” is on pages 11 and 12, and “Walsh SZ: Fetal-neonatal circulation revisited” contains reminiscences of John Lind on pages 55 through 60. See also www.johnlind.org/English/english.html) 2. Lind J, Wegelius C. Angiocardiographic studies on the human foetal circulation; a preliminary report. Pediatrics. 1949;4: 391– 400 3. Yao AC, Lind J. Placental Transfusion: Clinical and Physiological Study. Springfield, Ill: C C Thomas, Publisher; 1982

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Perinatal Profiles: John William Ballantyne: Scottish Obstetrician and Prolific Writer Alistair G.S. Philip, MD, FRCPE*

Introduction The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Philip has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

Among obstetricians from other countries whose names are familiar to neonatologists in North America, perhaps the most familiar are Stephane Tarnier and Pierre Budin. These two Frenchmen undoubtedly were instrumental in emphasizing the importance of thermoregulation and documenting the beneficial effects of the incubator for preterm infants. Budin also is well recognized for his book Le Nourisson, published in French in 1902 and published in English as The Nursling in 1907. Less well known, but arguably as influential, is the Scotsman John William Ballantyne, who was a contemporary of Budin. In 1902, he published two extensive volumes under the title Antenatal Pathology and Hygiene. Volume 1 concerned The Fetus and Volume 2 dealt with The Embryo. These volumes, which contain a wealth of information, reflected the positions he held at that time. He was both lecturer in Midwifery and Gynecology at the Medical College for Women, Edinburgh, and lecturer on Antenatal Pathology and Teratology at the University of Edinburgh. He also was on the staff of the Royal Maternity Hospital, Edinburgh. Ballantyne was a prolific writer. In addition to the previously noted volumes, he wrote several other books, including An Introduction to the Diseases of Infancy: The Anatomy, Physi*Emeritus Professor of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, Calif.

ology and Hygiene of the Newborn Infant (1891) and The Diseases and Deformities of the Fetus, also in two volumes (1892 and 1895). He wrote more than 100 major articles between 1883 and 1901 as well as numerous (approximately 100) case reports. These articles are all catalogued in Antenatal Pathology and Hygiene.

Seminal Articles

Perhaps of greatest interest to neonatologists are two articles that Ballantyne wrote at about the same time as Antenatal Pathology and Hygiene, which were important contributions at the time. Both “The Problem of the Premature Infant” and “The Problem of the Post-mature Infant” were published in 1902. In these articles, published, respectively, in the British Medical Journal and the Journal of Obstetrics and Gynaecology of the British Empire, he made some astute observations, although he reflected some thoughts of that era about the chances of viability at various gestational ages. The preterm infant, he wrote, “is born with the skin and the skeleton and the organs of a seven-months fetus.” He stated that “neither fetal size nor weight can be regarded as sure indications of fetal age,” although he believed that survival was unlikely if the infant was born at less than 6½ calendar months of gestation. He was willing to speculate that the lower limit might decrease to “maybe 6 or 5 and a half months” within a decade. He did appreciate the importance of thermoregulation, and his article on the NeoReviews   39 NeoReviews Vol.9 No.11 November 2008 e503

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preterm infant contains the following delightful description of what it is like for the fetus at the moment of birth: “He is like some dweller in the hot plains of India who has been transported in a moment of time on some ‘magic carpet of Tangu’ to the chill summits of the ‘frosty Caucasus’, with no opportunity for acclimatization, such as gradual transit affords.” The article on the postmature infant is an extensive discussion of the topic directed primarily at obstetricians and draws attention to the difficulties that might be encountered when gestation is prolonged. He opened this paper with the following sentences: “The problem of the postmature infant differs in a very striking way from that of the preterm infant. The latter can with difficulty be kept alive after birth; the former can with difficulty be born alive.” After detailing some examples of prolonged gestation with large size of the baby, he indicated his belief that earlier delivery might be beneficial and stated “It is quite possible that the results of these investigations might justify us in bringing on labor even in the primipara.” Not only did he mention the association of anencephalus with prolonged gestation, but he described the absence of lanugo, the lack of vernix caseosa, and the presence of desquamation of the skin, with nails that “project beyond the tips of the digits.” He emphasized that it may be as difficult for a large head to pass through a normal pelvis as it is for a normal head to pass although a contracted pelvis. He demonstrated in some postmortem examinations that the liver was smaller, there was more meconium in the lower intestine (which might be “expelled into the uterine cavity”), and that both the foramen ovale and ductus arteriosus were virtually closed. These latter findings he considered to be the important features that “endan40      NeoReviews e504 NeoReviews Vol.9 No.11 November 2008

ger fetal life.” Because of advanced ossification, which was particularly evident in the cranium, he believed that molding could not occur and frequently observed fractures in these postmature infants, “especially of the cranium and the shoulder girdle.” He encouraged limiting the attempts to deliver with forceps, suggesting that too often the result was head crushing. He continued by saying, “. . . . it is quite likely that in five or ten years, the operation of choice will be Caesarean section.” Concerning postnatal management, he was much more circumspect, stating, “The management of the post-mature infant that survives his birth cannot be said to be well understood. . . actual knowledge of facts is small.”

Background

John William Ballantyne was born in Dalkeith, Scotland, in 1861 to a Scottish father, who was a seedsman and nursery gardener, and a Dutch mother, who died when he was only 1 year old. He was educated at George Watson’s College in Edinburgh, where he studied Latin and Greek, and traveled to both Holland and Germany from an early age, learning to speak both Dutch and German. He then attended medical school in Edinburgh (my alma mater) from 1877 to 1883 and was apparently an outstanding student. In addition to qualifying in Medicine with Distinction, he placed first of his year in Physiology, Pathology, Obstetrics, and Gynaecology. After serving as house surgeon to Professor AR Simpson (nephew of the great obstetrician James Young Simpson), he became Resident Medical Officer at the Royal Maternity Hospital in Edinburgh. In 1885, he visited medical schools in Gottingen, Berlin, and Munich and subsequently served as Assistant to Professor Simpson for 5 years before being appointed as assis-

tant physician to the Edinburgh Royal Infirmary in 1890 and chief physician in 1904. In 1889, he was awarded the MD degree with gold medal for his thesis “Some Anatomical and Pathological Conditions of the Newborn Infant in Relation to Obstetrics.” In 1891, he published his book Diseases of Infancy, which led to his election as Fellow of the Royal Society (still a prestigious honor) at the unusually early age of 30.

Prolific Writer and Literate Lecturer

As mentioned earlier, Ballantyne was a prolific writer. It is difficult to comprehend the breadth of his erudition, with his ability to read many texts from other countries in the original language. Apparently, he used to write from 6 AM to 10 AM every day, before beginning his daily duties of seeing patients and teaching students. In addition to writing about the mother, fetus, and newborn, he wrote extensively about gynecologic disorders as well as on general medical topics. In 1894, he founded a quarterly journal Teratologia, which was received enthusiastically initially, but was unable to continue publication for more than 2 years because of lack of subscribers. Clearly, he was ahead of his time. He lectured to both undergraduates and postgraduates at Edinburgh University from the late 1880s and at Surgeon’s Hall from about 1900. It is noteworthy that he admitted women to his lectures, although this was not generally the case at the University until 1916. It is hard to imagine that he had any time left over, but his hobby was literature, and he had a remarkable collection of books in his library.

Conclusion

Dr J.W Ballantyne died in 1923 from appendicitis and peritonitis at the age of 62. He gave his last public address

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to the Nottingham Medico-Chirurgical Society 3 weeks before his death. Throughout his life, he worked to improve understanding of the physiology and pathology of pregnancy as well as the prevention of fetal deaths and abnormalities. His concern for the neonate was perhaps typical of his generation of academic obstetricians and preceded that of most pediatricians. One of his last publications (also

in 1923) was very prescient. In an article entitled “The New Midwifery” he wrote the following: “There is need for specialization in neonatal medicine. This applies to doctors and nurses as well as teaching and construction of hospitals. The specialist in neonatal diseases and the nurse intensively trained and expert in the management of delicate newborns will be commonplace ere long.”

Suggested Reading Ballantyne JW. The problem of the premature infant. Br Med J. 1902;i:1196 – 1200 Ballantyne JW. The problem of the postmature infant. J Obstet Gynaecol Br Empire. 1902,2:521–554 Ballantyne JW. The new midwifery. Br Med J. 1923,i:617– 621 Reiss HE. Historical insights: John William Ballantyne 1861–1923. Hum Reprod Update. 1999,5:386 –389

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Perinatal Profiles: Pierre Budin: The Fight Against Maternal and Infant Mortality Paul L. Toubas, MD*

Introduction The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Toubas has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

The period between the FrancoPrussian War (1871) and the beginning of World War I (1914), rich in scientific discoveries and filled with artistic creation, opened a new era in medicine. A high infant mortality rate, which was fueled by lack of basic hygiene, curtailed population growth in various European countries. Governments were worried, especially in France, (1)(2)3) where industrialization and colonization were in progress. The “European Empires” needed men for industry, the military, and the colonies. Influential political men such as Dr Bourneville, a senator of the French Republic, (4) turned to obstetricians to solve the acute problem of infant mortality and address the depopulation issue. This powerful physician facilitated the creation of modern maternity units managed by certified obstetricians instead of surgeons.

Learning About Antisepsis

Maternal mortality had decreased markedly, starting in 1890, thanks to the introduction of antisepsis. A participant in this effort was the young doctor Pierre Budin, a senior resident of Stephane Tarnier, the leader of French obstetrics. (5) In 1874, he was sent to study with Joseph Lister in Edinburgh (6) to learn the preventive treatment of surgical infections. Puerperal fever had decimated ma*Professor of Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York. e60 NeoReviews Vol.10 No.2 February 2009 42     NeoReviews

ternity units to such an extent that some were closed intermittently. This serious issue absorbed so much of Dr Tarnier’s energy that he was forced to take a leave of absence to prevent his health from deteriorating. A friend of Budin, Lucas Championnie`re, (7) a young surgeon, had preceded him on this path by working for a few months with Lister at the Royal Infirmary in Edinburgh. In Paris, he already was applying the antiseptic method of Lister with extremely good results. (7) Shortly after Championnie`re, Budin made the trip to Scotland and learned all the details of the antiseptic method. He also benefited from the teaching of Duncan, the chief of obstetrics. Lister recommended to Budin that he visit Professor Karl Thiersh in Leipzig, Germany, (6) to see for himself the use and beneficial results of the antiseptic method, which consisted of hand washing and wound spraying with carbolic acid. Incidentally, Professor Thiersh switched later to salicylic acid. Budin returned to France with new knowledge in obstetrics and surgery. This astonishing fellowship would not have happened without the extraordinary development of the railroad, which facilitated the movements of many industrious men. A new international scientific and cultural dimension opened and allowed the formation and transmission of new ideas. The antisepsis concept had been demonstrated, but ignored by the medical community, by Ignaz Semmelweiss in 1847. (8) (Editors Note: See the Perinatal Profile by Istvan

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Seri in the June 2007 issue of NeoReviews.) Lister, convinced that the “germ theory” of Louis Pasteur was correct, had revived the concept. When Budin returned to Paris from his fellowship, he was convinced that antisepsis could be the first line of defense against puerperal fever. He did not anticipate that the introduction of antiseptic solutions in obstetrics would be an uphill battle due to the adamant opposition by some practitioners and surgeons. In 1879, Louis Pasteur identified the cause of the dreadful disease in the blood of postpartum infected women. The culprit was a bacterium, a coccus assembled in chains that was named Streptococcus by Rosenbach in 1884. Hand and vaginal washing with a modified mercury bichlorate antiseptic solution, (9) progressively decreased the rate of the deadly disease. This solution replaced carbolic acid, which was too irritating for hands and mucosae. Other antiseptic solutions were introduced later. High doses of mercury in solutions, as adopted by the French Academy of Medicine, also had significant, and sometimes lethal, toxicity effects when introduced into the vaginal or uterine cavity for disinfection purposes. Many midwives in France used it indiscriminately without serious supervision. (10)

A Life-changing Event

The continuing fear of surgeons was that the obstetricians would take over the field of gynecology, which the surgeons jealously guarded. The fight even reached the surveillance council of the Assistance Publique, where the surgeon’s lobby was too well established to be altered. Obstetrics remained under the auspices of surgery, but a serious incident pushed the balance in favor of the obstetricians. On Easter Monday 1881, the Director of St Antoine

Hospital searched in vain for one of the 13 on-call surgeons for the city of Paris to handle a difficult delivery. Desperate, the Director sent Budin a messenger. Luckily, he was not attending religious services that day; he had stayed home to finish an article. Like Bourneville, he endorsed republican ideals that were in conflict with those of the Catholic Church. He hailed a cab and asked the driver to rush him to St Antoine Hospital, located 30 minutes away. He had taken a set of forceps in his bag. When he arrived, he found a young mother in agony, with her eyes rolled up. Rapidly using the forceps, he extracted a dead infant. The mother died soon after. When he left the hospital, he was so upset that he had to stop behind a column to wipe away the tears. At the request of the Director of the hospital, Budin wrote a report that detailed the circumstances, timing, and story of this tragedy. Dubrisay, the Director of the Assistance Publique, made this event the starting point of a full restructuring of the maternity units of Paris hospitals and proposed an amendment for a “concours” (competitive examination) for the position of Obstetrician of the Paris Hospitals. The amendment was adopted in June 1881 by the Municipal Committee of the City of Paris. (10) Budin and his friend, Adolphe Pinard, became two of the first laureates. (6) The discipline of obstetrics finally was recognized. Budin was appointed Obstetrician-in-Chief of the Charity Hospital in Paris shortly thereafter.

Emergence of the Compassionate Obstetrician

Budin would remember the face of the young mother for the rest of his life, which influenced his care of women. He was not married at that time, had no children, and decided to

learn from his patients. Their lives became very important to him, and he devoted more time listening to their stories. He slowly emerged from his medical books like a butterfly from a cocoon. He became more polite, more helpful, and more understanding. He found the stories of the young mothers poignant. As French surgeons lost their grip on obstetrics, their hostility toward Budin grew. In 1885, in need of surgery for himself, Budin called on a British surgeon, Lawson Tait, to perform the laparotomy (6) to remove an echinococcal cyst from his abdominal cavity. This action, considered an insult by the influential Paris surgeons, delayed Budin’s appointment to the rank of full professor. By 1892, maternity units no longer needed to be closed because of puerperal fever of epidemic proportions. The fight against maternal mortality that had haunted his mentor, Tarnier, had been won. (6)

Fighting Infant Mortality

The fight against infant mortality was on the minds of the obstetricians, who also cared for infants until age 2 years. The solution to the problem came to Budin during maternal prenatal visits. Astute and acute observation skills, along with excellent data collection, led him to an original approach to infant mortality. He explained it in his book, The Nursling (11): “I took care of the newborns and was stricken by the response made by the women I had previously delivered when they came back for another pregnancy. I asked them what had happened to the previous infant they had given birth; I was told often: ‘He died!’ In fact, after discharge from the hospital, their only guide (to child care) was the vague experience of grandmothers, of the concierges, of herbalists (pharmacists). Filled with various biases, they NeoReviews Vol.10 No.2 February 2009    e61 NeoReviews 43

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had accumulated mistakes; their children became sick and died.” The causes of infant mortality at the end of the 19th century were well known and included primarily gastroenteritis, especially during the summer months. Another adverse factor was the growth of artificial feeding, replacing human milk with milk of poor quality frequently diluted by merchants and already infected by the long transport from the farms. Budin studied the basic rules of hygiene and nutrition of the newborn. “The high infant mortality was due to the lack of follow-up, good advice and special care.”

Encouraging Breastfeeding

In 1892, motivated by his initial observations and with the help of the Director of the Charity Hospital, he created one of the first well baby clinics in France. A previous attempt by Dr Herrgott from Nancy, who provided a stipend to mothers who breastfed, (12) may have attracted his attention. After attaining local success and because a crowd of mothers attended the clinics, he convinced the administration of the Paris hospitals to expand to other hospitals the concept of maternal education, promotion of infant nutrition with breastfeeding, use of sterilized milk in sterile bottles (Budin had also been a student of Louis Pasteur), and growth monitoring with scales for infants. He benefited from the enormous advantage of the Paris hospitals being under a single administration of the Ministry of the Interior. (13)(14)(15) Budin was supported in his work on the importance of human milk feeding by many colleagues, including Dr Gaston Variot, Chief of the Sick Children’s Hospital in Paris, (16) who expressed his feelings during a meeting of the League Against Infant Mortality, in 1902 at the Sorbonne: “If the mothers knew 44 e62     NeoReviews NeoReviews Vol.10 No.2 February 2009

the high fragility of the life of the newborn in the first few months of life, the difficulties and traps of bottle feeding, and the risk they impose on their baby, they would breastfeed immediately.” Budin, with the help of a dedicated pharmacist, Charles Michel, (17) continued to study the chemistry of milk and how to deliver it better. He invented a system for pumping human milk manually and described how to detect clinically infected human milk. He modified rubber feeding catheters (1886) for the nutrition of the smallest infants, using the technique of gavage employed on farms to produce liver hypertrophy in geese. The small apparatus included a graduated small glass container similar to the plasticized models currently used in nurseries. All the details of this succession on the improvement of infant feeding are well described in his manual of infant feeding published in 1906. (18)

Improving the Care of “Weaklings”

By 1895, Budin was in charge of the Port Royal Maternity and became full professor in 1897. (19) On his first visit, he was horrified by the unhygienic conditions to which the mothers and babies were subjected. The small pavilion that sheltered the incubators of Tarnier was poorly organized. He forced the Midwife-inChief, Mrs. Emilie Henry, to resign. This energetic woman had been directed by Tarnier to raise the money to build the pavilion in 1890. (20) Budin appointed one of his assistant physicians, Dr Perret, to take over the care of the “weaklings.” He then “medicalized” obstetric and neonatal care, placing the midwives under his control. Before his arrival, the Midwife-in-Chief was the equal of the Surgeon/Obstetrician. He took

over the teaching of obstetrics and renovated the maternity unit and the pavilion for the “weaklings.” Upon Tarnier’s death in 1898, (5) Budin took charge of the newly built Tarnier maternity unit. He continued the work of improving the use of infant incubators (21)(22) for preterm infants and weaklings and apparently inspired Martin Couney, (21)(22) a young German physician. Dr Couney, who had a taste for enterprise, helped Alexandre Lion, the engineer of the first servocontrolled incubator, to present and care for the preterm babies of the Charity Hospital maternity at the Berlin Industrial Show in 1896. Later, successful exhibits in fairs and amusement parks across the world, including the United States, led Couney to settle in 1903 at Luna Park. Despite controversy, (21)(22) the incubator show attracted the attention of Julius Hess (Editor’s Note: See the Perinatal Profile by Tonse Raju in the October 2006 issue of NeoReviews), a young pediatrician in Chicago, who corresponded with Couney. The design of the first American preterm newborn care unit received some discrete input from Couney. Although Couney was earning a good living with the incubator show and providing good specialized service to New York pediatricians, Budin wrote the first comprehensive book on the newborn in 1900. (11) This masterpiece was translated into English in 1907 as The Nursling. Both junior and senior neonatologists would find this book a rewarding read.

Continuing to Fight Infant Mortality

In 1902, with Paul Strauss and the help of the philanthropist Theophile Roussel, Budin founded the League Against Infant Mortality, (23) which concentrated all efforts to prevent threats to the health of infants. Vari-

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ous organizations working toward the same goals very quickly achieved extremely good results. In numerous French counties, infant mortality rates, which were as high as 288 per 1,000, fell to 112 per 1,000. (1)(2)(3) This was made possible by establishing infant clinics; training physicians, nurses, and midwives; and tracking results. This success story soon spread beyond France’s borders.

Other Contributions and Activities

Budin also contributed enormously to the field of obstetrics and assisted Tarnier in the production of the Manual of Obstetrics. (24) Budin’s doctoral thesis, “Of the Fetal Head,” (25) remains a classic of obstetrics. He had designed an ingenious artificial bronze pelvis to study the descent of cadaver fetal heads of different sizes. He was a member of the French Academy of Medicine as well as multiple European academies. He also was a member of the Bostonian Gynecological Society (6) and numerous philanthropic societies. (6) Certainly, Dr Budin was not the man at the origin of antisepsis; Semmelweiss and Lister preceded him. He did not invent the modern incubators for infants; Tarnier did. Herrgott from Nancy preceded him in the infant’s postnatal visits. However, he possessed the genius of grasping ideas and had the ability to pursue concrete projects with an intense tenacity until achieving success on a large scale. He was a link in the chain of great academicians who transformed medicine at the turn of the 20th century. A compassionate, very observant, and creative obstetrician and educator of mothers, Budin had the ability to convince, at the right time, administrative, medical, and political spheres to pursue a simple pilot project, the infant clinics, that

led to a marked decrease in infant mortality at the beginning of the 20th century. All his life, he worked with a group of young and extremely dedicated assistants such as Crouzat, Maygrier, Perret, and Bar. Despite his work load, he managed to travel throughout Europe, attending the first international medical meetings of the time. He was an avid reader, and his favorite authors included the philosopher and historian Hippolyte Taine and Russian novelist Ivan Tourgueneiv. (6) He attended the theater weekly. One of his patients was the famous actress Sarah Bernhardt. (6) Jean Richepin, the poet and playwright, was a very close friend.

Final Thoughts

While doing outreach teaching in Marseille in January 1907 (26) on the topic of infant mortality, Budin contracted a deadly pneumonia and died in a hotel room. Before his death, he dictated his last will to his colleagues who were attending at his bedside: “My dear friends, The fate of French children rests on you. I count on you to be the first to do the necessary propaganda to develop infant clinics and later to delegate this task to your students. Budin.” Professor Paul Bar succeeded Budin as head of the Tarnier maternity unit in Paris (27) and leader of French obstetrics. Pierre Budin did not see the final results of his work. Mothers were now better educated in infant healthcare, and increasing numbers of infants and children survived and reached adulthood. However, he would have been terribly saddened to see the loss of their precious lives to the cannons of World War I only a few years later. Although he was an

advocate of the availability of sterilized, controlled milk, he would have been greatly depressed by the progressive decline of breastfeeding in industrial countries over the next 75 years. In contrast, he would have been heartened by the remarkable decline in infant mortality that has been achieved in the 100 years since his death. Pierre Budin must be credited with the creation of the modern concepts of preventive pediatrics and obstetrics, promotion of primary care clinics for infants and young children, and recognition of the importance of promoting breastfeeding. All of these concepts are expressed and elaborated upon in his major book, The Nursling. (11) Marie Therese Budin, his wife of 14 years, continued the education of mothers started by her husband. The Foundation Pierre Budin (28) was created and later became the “Ecole de Puericulture.” A model infant clinic was opened to the public on May 24, 1909, by Emile Loubet (exFrench President). On March 5, 1923, Marie Therese Budin (29) received the high distinction of the Legion d’Honneur. In her response, she said, “Everything I did, I did for love of my husband; then for love of infants and their mothers, who are frequently admirable.”

References

1. Budin P. La Ville de Paris et la Mortalite´ Infantile. Paris, France: Masson; 1904 2. Budin P. La mortalite´ infantile dans les bouches du Rhoˆne. Obste´trique. 1900; 304 –345 3. Joseph A. Etude sur la Mortalite´ de la Premie`re Enfance dans la Population Urbaine de la France de 1892 a 1897. Paris, France: Doin; 1901 4. Poirier J, Signoret JL. De Bourneville a la Sclerose Tubereuse, La Spe´cialisation Des Medecins des Hopitaux. Paris, France: Flamarrion; 1991:91–92 NeoReviews Vol.10 No.2 February 2009    e63 NeoReviews 45

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5. Budin P. Le Professeur Tarnier. Paris, France: Progre`s Medical; 1898 6. Toubas P. Forgotten lessons of the past. Perinatal News. 1992;17(2) 7. Lucas Championnie`re J. The´orie et Pratique de la Chirurgie Antiseptique. Paris, France: Steinheil; 1908 8. Nuland SB. The Doctors’ Plague: Germs, Childbed Fever, and the Strange Story of Igna´c Semmelweis. New York, NY: W.W. Norton & Co; 2003 9. Shoemaker J. Practical Treatise Materia Medica and Therapeutics. 5th ed. Philadelphia, Pa: Davis Co Publishers; 1901 10. Minutes du Conseil de Surveillance des Hoˆpitaux de Paris 1890 –1900. Paris, France: Archives des Hoˆpitaux de l’Assistance Publique de Paris 11. Budin, P. Le Nourrisson: Alimentation et Hygie`ne. Enfants De´biles et Enfants Ne´s a Terme. Paris, France: Doin Ed; 1900 12. Herrgott A. L’æuvre de la Maternite´. Nancy, France: 1895 13. Budin P. Les consultations de nourrissons. Arch Ge´n Me´d. 1905;1:1234 –1257 14. Budin P. Les consultations de nourris-

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sons. Ann Med Chir Inf Paris. 1905: 618 – 645 15. Budin P. Des consultations de nourrissons, leurs re´sultats. Bull Acad Med Paris. 1905;11:289 –305 16. Variot G. Le Me´decin de l’Enfance. Paris, France: Boudet ed; 1892 17. Budin P, Michel Ch. Sur un Mode d’alimentation par les Produits de la Digestion Artificielle du Lait de Vache. Paris, France: French National Academy of Medicine; 1896 18. Budin P. Manuel Pratique d’allaitement. 2nd ed. Paris, France: Doin; 1906 19. Doin O. Banquet offert au professeur Budin par ses e´le`ves et ses amis a` l’occasion de sa nomination de Professeur. Paris 1897, Pierre Budin. Personal archives, American Academy of Pediatrics 20. Toubas PL, Nelson R. The role of the French midwives in establishing the first special care units for sick newborns. J Perinatol. 2002;22:75–77 21. Baker JP. The incubator controversy: pediatricians and the origins of premature infant technology in the United States,

1890 to 1910. Pediatrics. 1991;87:654 – 662 22. Silverman W. Incubator-baby side shows. Pediatrics. 1979;64:127–141 23. Houssay F. Le docteur The´ophile Roussel, Se´nateur, Membre de l’Institut, Pre´sident d’honneur de la Socie´te´ Protectrice de l’Enfance de Paris; sa vie et son Ouvre. Paris, France: Institut International de Bibliographie; 1904 24. Tarnier S. Traite´ de l’Art des Accouchements. Paris, France: Lauwereyns; 1882–1898 25. Budin P. De la Teˆte du Foetus au point de vue de l’Obstetrique [doctorate thesis]. Paris; 1876 26. Bonnaire A. Le Professeur Budin. Presse Me´dicale. 1907;8:8 27. Bar P. Pierre Budin. Chaire de Clinique Obste´tricale. Lec¸on Inaugurale. Paris, France: Capiomont; 1908 28. Bue V. L’Oeuvre de Budin en pue´riculture. Suisse Me´d. 1907;107:147–148 29. Reception de Marie The´re`se P. Budin dans l’ordre de la Legion d’Honneur, March 5, 1923. Paris, France: Calmette et G

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Perinatal Profile: Jim Farquhar and Infants of Diabetic Mothers Alistair G.S. Philip, MD, FRCPE*

Background

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Philip has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

James Watson Farquhar was born in Edinburgh, Scotland, in 1922; went to school at George Watson’s College, Edinburgh (where he played for the Rugby 1st XV); received his medical education at the University of Edinburgh; spent his entire academic career in the Department of Child Life and Health of Edinburgh University; and died in Edinburgh in 1998. If this suggests that Jim was a provincial, “stay at home” type, lacking a spirit of adventure, nothing could be further from the truth. Perhaps the phrase that captures him best is that he was “a peripatetic personality.” He was a cheerful, dynamic person, who always seemed to be “on the go.” I can see him still, marching briskly between the Royal Hospital for Sick Children (RHSC), where he was in charge of a children’s ward that specialized in metabolic problems, and the offices of the Department of Child Life and Health. Of course, he may have been walking briskly because of the climate in Edinburgh, which is not known for high temperatures, and Jim apparently reveled in higher temperatures. However, he could appreciate a cool, crisp, sunny day, too! As a result of his early research activity, he became a “world traveler” who had a profound interest in the pediatric problems of many different countries, but in particular

*Editor-in-Chief, NeoReviews; Emeritus Professor of Pediatrics, Stanford University School of Medicine, Division of Neonatal and Developmental Medicine, Palo Alto, Calif.

those of the developing world. This is exemplified by his volunteering in 1963 to lead the first batch of medical teachers in an exchange program between Edinburgh University and the University of Baroda in Gujarat state in India, which was sponsored by the World Health Organization. He took his wife and two children to live there for a year and made a very important contribution. Jim may have developed a taste for travel soon after finishing medical school. He entered medical school in Edinburgh in 1940, when Britain was already engaged in the Second World War. Because of his academic ability, he was selected to be enrolled in a compressed 4-year course. It should be mentioned that at that time (and later), young men (and women) could enter medical school in Britain directly from the equivalent of high school to embark on a 6-year course of study. The accelerated course into which Jim was enrolled meant less time for frivolity in the summer vacation, which most of us enjoyed, but a medical degree was granted much more quickly. He graduated MB, ChB (Bachelor of Medicine, Bachelor of Surgery) in 1944 and almost immediately received a commission in the Royal Army Medical Corps. He became a regimental medical officer with the Royal Ulster Rifles and the King’s African Rifles and soon traveled to India, Burma, Egypt, and Palestine. After the war, he returned to Edinburgh and progressed through the ranks of the RHSC and the Simpson Memorial Maternity Pavilion (SMMP) of the Royal Infirmary, NeoReviews Vol.10 No.5NeoReviews May 2009 e217   47

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Figure. Examples of the type of infant Jim Farquhar described in 1959. A. Typical

posture and appearing “full-faced and plethoric,” seen circa 1967. B. Infant seen circa 1972, weighing almost 6 kg at 37 weeks’ gestation, also demonstrating the typical posture and being “plump, sleek and liberally coated with vernix caseosa.”

Edinburgh, eventually being promoted in 1955 to Senior Lecturer in the Department of Child Life and Health, with consultant status at RHSC and SMMP. The 1950s were the years when he began his studies of diabetes mellitus, which included a particular interest in mothers who had diabetes and their infants. 48      NeoReviews e218 NeoReviews Vol.10 No.5 May 2009

Infants of Diabetic Mothers

Prior to the discovery of insulin, it was unusual for women who had diabetes mellitus to become pregnant. However, just as insulin dramatically changed the outlook for all who had diabetes, it meant that infertility became the exception rather than the rule for diabetic women. In the late

1950s, it became apparent that the birthweights of infants born to diabetic mothers were excessive for their gestational ages. (1) This year marks the 50th anniversary of the publication of an article by Jim Farquhar entitled “The Child of the Diabetic Woman.” (2) Although he wrote many articles about diabetes and particularly about fetuses and neonates of diabetic mothers, this was perhaps his magnum opus and undoubtedly was based on his thesis to become MD (awarded in 1958). The article occupies 20 journal pages and contains 20 figures and should be accessible in medical libraries that have electronic journals. His description of these neonates is eloquent and deserves to be savored again: “The infants are remarkable not only because, like fetal versions of Shadrach, Meshach and Abednego, they emerge at least alive from within the fiery furnace of diabetes mellitus, but because they resemble one another so closely that they might well be related. They are plump, sleek, liberally coated with vernix caseosa, full-faced and plethoric. The umbilical cord and the placenta share in the gigantism. During their first 24 or more extra-uterine hours they lie on their backs, bloated and flushed, their legs flexed and abducted, their lightly closed hands on each side of the head, the abdomen prominent and their respiration sighing. They convey a distinct impression of having had such a surfeit of food and fluid pressed on them by an insistent hostess that they desire only peace so they may recover from their excesses. And on the second day their resentment of the slightest noise improves the analogy, while their trembling anxiety seems to speak of intrauterine indiscretions of which we know nothing.” Immediately after this written description, he provided a figure showing three infants of diabetic mothers who looked remarkably similar phenotypically, with a quotation from

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Lewis Carroll (who wrote Alice in Wonderland): “. . . . For some of us are out of breath and all of us are fat.” A reminder of how such infants appear is shown in the Figure. Other pediatricians whose names were associated with infants of diabetic mothers at about that time are Marvin Cornblath, (3) whose monograph on Disorders of Carbohydrate Metabolism in Infancy, written with Bob Schwartz, is a classic, (4) and Sydney Gellis, (5) one of the giants of 20th century pediatrics in America. (6)

Personal Connection

When I was a medical student in Edinburgh, Jim Farquhar was one of a handful of consultant pediatricians, and he examined me in my Final Examinations in Child Life and Health (these “finals” would have been late in 1959). Somewhat later, in 1966, when I was a research fellow in neonatology at Boston City Hospital, Jim was invited as a Visiting Professor for a couple of weeks. Of course, he had no recollection that we had encountered each other before, but our interaction in Boston was much less stressful for me than our earlier encounter, and he was extremely cordial toward me. So much so, that he encouraged me to apply for a position as Registrar on the professorial unit at RHSC in Edinburgh, which he knew would be available the following year. For me, one of the highlights of his stay in Boston was a symposium on the infant of the diabetic mother, organized by my mentor David Ingall (who, like Jim, was a general pediatrician with a particular interest in the neonate). The participants in the symposium included not only Jim, but also Sydney Gellis and Guido Fanconi from Switzerland. Another recollection is that when I returned to RHSC the following

year, I came face to face with him across the net of a tennis court. There was a special ambience at the hospital in that era, and mixed doubles matches were arranged between the various units of the hospital, with an award for the winners. For some reason (I do not regard myself as a tennis player), I was picked to represent the professorial unit with one of the staff nurses who could play fairly well. Jim and his partner won!

Broader Involvement with Diabetes

Like most pediatricians in the United Kingdom, especially in that era, Jim did not confine his clinical activity to neonatology. Although he continued to supervise the care of neonates born at the SMMP, his primary responsibilities were at RHSC, where his ward (unit) dealt with a wide range of disorders, but with a particular focus on metabolic problems. His interest in diabetes mellitus extended far beyond infants of diabetic mothers, although he continued to write substantial articles on this topic for many years. (7)(8)(9) He started a diabetic clinic (the first specialized clinic at RHSC), was instrumental in establishing a residential hostel for troubled young diabetics, and developed camps and a “clinic-club” for young diabetics. He developed a detailed protocol for managing diabetic coma and a useful booklet to guide parents of diabetic children, and he maintained an epidemiologic register of children who had diabetes.

Other Contributions to Neonatology

Not long after joining the Department of Child Life and Health as Senior Lecturer, Jim Farquhar spent a year (1958 to 1959) in Boston with Clement Smith learning about fetal and neonatal physiology. This was an

era when many international visitors served as “fellows.” He can be found on one of the topmost branches of the “family tree” provided by Nick Nelson in his profile, which details Dr Smith’s worldwide reach. (10) While in Boston, Jim undoubtedly would have shared his ideas and experiences with Louis Diamond (who helped us to understand Rhesus incompatibility). (11) Both before and after visiting Boston, Jim was interested in exchange transfusion and was one of the pioneers of this technique. He reported on the technique in 1949, using the term “replacement transfusion” (also used by Dr Diamond) rather than “exchange transfusion.” (12) He made observations (mostly clinical) during the years 1948 to 1953 that stimulated him to perform more careful evaluations (both clinical and biochemical), which were published in 1958. (13) His interest in metabolic/ endocrine disorders resulted in his introduction of population screening for both phenylketonuria (PKU) (14) and congenital hypothyroidism in Edinburgh. As part of this interest, he later made a short film for parents, which included my elder daughter as a child who had PKU (not that she had PKU, but because she was fairskinned and had very blond hair, helping him to make a point). He always was striving for ways to educate families and teach students. He was a model neonatologist (although he did not restrict himself to our discipline) and mentor for dozens of senior house officers and registrars who worked with him at the SMMP. Many of them came from far afield and were influenced in their subsequent career choices. For example, Saroj Saigal, who went for a year to Edinburgh directly from India, was able to pursue a fellowship in neonatology with Bob Usher in NeoReviews Vol.10 No.5NeoReviews May 2009 e219   49

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Montreal as a result of Jim’s encouragement and strong recommendation. Later, she established herself at McMaster University (in Hamilton, Ontario) as one of the most important contributors to the literature on long-term follow-up of preterm neonates.

World Travels and Contacts

As a result of his publications on infants of diabetic mothers and other academic interests, Jim was sought after in many parts of the world as a Visiting Professor, Guest Lecturer, or Specialist Adviser. In addition to the United States and Canada (where he was once “piped in” to the Canadian Pediatric Society meeting in his kilt), he visited Pakistan, Indonesia, Ghana, Nigeria, South Africa, Zimbabwe, Swaziland, Uganda, Kenya, Abu Dhabi, Saudi Arabia, Kuwait, Egypt, Sri Lanka, the Caribbean Islands, and Japan. Did I happen to mention that he was not a “stay at home” type of person? He and his wife Betty were very generous in the provision of hospitality to postgraduate students from overseas, and he maintained contact with many of them long after they had returned to their own countries. I understand that each Christmas he used to give a party for the foreign house officers, which proved to be a very colorful occasion. Dr Saigal remembers that most of the guests were “shades of brown or black” and many dressed in multicolored outfits from their native countries— Africans, Indians, Middle-Easterners, Egyptians. They were also very welcoming of expatriates (such as me) who returned to Edinburgh at intervals. Jim had a great fund of stories, and it took very little to get him to regale his audience. I think that Betty did most of the work when people were invited to their home, while Jim 50      NeoReviews e220 NeoReviews Vol.10 No.5 May 2009

turned on the charm (of which he had plenty).

mother to offer advice about caring for her baby.

Teaching and Student Evaluation

Final Words

Jim Farquhar was a great teacher, who was heavily involved in the undergraduate and postgraduate teaching program at RHSC. He was articulate, both in the lecture theater and at the bedside, with a melodious speaking voice. In fact, one of Jim’s former students, who subsequently became a colleague, described him as “a charismatic lecturer.” His genuine caring for other people, his obvious sense of humor (he had a ready laugh), and his easy manner helped to put students at ease at all levels. Nevertheless, he was a comparatively strict disciplinarian. His ward rounds started promptly and he expected people to be there on time—which they were! One of the former head nurses on his unit has indicated that he used rather shrewd assessment methods to evaluate students. Apparently, although I was not privy to this information at the time, he would watch to see whether parents recognized the student, which would give him a good idea if they had spent time on the ward (or not). He also watched to see how adept they were at lowering the sides of the hospital infant cots (cribs). These took a little bit of practice to lower easily—another indication of time spent examining infants. The greatest test apparently was the student’s ability to undress the baby to listen to its chest without making it cry. He also insisted that each student could perform basic infant care— bathing, feeding, and dressing—and appreciate the inherent difficulties. It was his belief that no matter what field of medicine they eventually entered, at some point in the future they would be asked by a

This same head nurse also understood that Jim had a huge respect for nurses and nursing, recognizing the importance of a partnership of care for children and their families. He also had a great affinity for teenagers and was able to communicate with them much better than most. The camps he organized for diabetics attracted teenagers from all over Britain, and he arranged for them to meet with doctors, nurses, and dietitians to discuss their experiences. The stories they told often revealed a great deal about the attitudes of those who were supposed to be caring for them. Jim made sure that their comments got back to their own clinicians. Jim Farquhar served his local community and the Department with distinction and to the utmost of his ability. Indeed, his involvement with so many countries and committees meant that he served the national and international communities as well. For these services, he eventually was awarded a personal chair in 1978 and in 1982 was appointed head of the Department, before finally retiring in 1987. He was Chairman of the Edinburgh Medical Missionary Society for 6 years and for many years was an elder in the local parish church. By his love of life and his inquisitive mind, he affected many during his lifetime and influenced the management of countless neonates in many different countries—a true missionary. Best of all, parents, nurses, and medical colleagues had great affection for the man, so on his death many said “he was such a lovely man—always a perfect gentleman.”

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American Board of Pediatrics Neonatal-Perinatal Medicine Content Specification • Know the effects on the fetus and/or newborn infant of maternal diabetes 2 mellitus (including gestational diabetes) and their management.

References

1. Hsia DY, Gellis SS. Birth weight in in-

fants of diabetic mothers. Ann Hum Genet. 1957;22:80 –92 2. Farquhar JW. The child of the diabetic woman. Arch Dis Child. 1959;34:76 –96

3. Cornblath M. Infants of diabetic mothers. Pediatrics. 1961;28:1024 –1026 4. Cornblath M, Schwartz R. Disorders of Carbohydrate Metabolism in Infancy. Philadelphia, Pa: WB Saunders Co; 1966 (3rd edition published in 1991) 5. Gellis SS. The newborn infant of the diabetic mother. Clin Obstet Gynecol. 1962; 5:450 – 461 6. Bergman AB. Sydney S. Gellis, M.D. (1914 –2002). Arch Pediatr Adolesc Med. 2003;157:218 7. Farquhar JW. Metabolic changes in the infant of the diabetic mother. Pediatr Clin North Am. 1965;12:743–754 8. Farquhar JW. Prognosis for babies born to diabetic mothers in Edinburgh. Arch Dis Child. 1969;44:36 – 47 9. Farquhar JW. The infant of the diabetic

mother. Clin Endocrinol Metab. 1976;5: 237–264 10. Nelson NM. Historical perspectives: Perinatal profile: Clem Smith: a gentle gardener. NeoReviews. 2007;9:e137– e141 11. Philip AGS, Diamond LK, Pearson HA. Historical perspectives: the rise and fall of exchange transfusion. NeoReviews. 2003; 4:e169 – e174 12. Farquhar JW, Lewis IC. Replacement transfusion technique in the newborn. Lancet. 1949;i:953–955 13. Farquhar JW, Smith H. Clinical and biochemical changes during exchange transfusion. Arch Dis Child. 1958;33: 142–159 14. Farquhar JW, Kansas ET, Tait HP. Problems of routine screening for phenylketonuria. Lancet. 1962;ii:49 –500

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Perinatal Profile: Bill Kitchen and Very Low-birthweight Infants Lex W. Doyle, MD*

Introduction

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Doyle has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

Bill Kitchen (Fig. 1) was born in Sydney, Australia, in 1926; went to school at Scotch College in Melbourne from 1938 to 1942; and received his medical education at the University of Melbourne, graduating in 1949 with First Class Honors in Obstetrics and Gynecology. He subsequently trained in pediatrics at the Royal Children’s Hospital in Melbourne, obtaining both his MD and MRACP in 1954. After various positions, including a stint in private pediatric practice, Bill was appointed to the position of First Assistant in Neonatal Pediatrics at the Royal Women’s Hospital and the University of Melbourne in 1965, replacing Kate Campbell, who had been the first ever pediatrician appointed to the Royal Women’s Hospital. Prior to Kate Campbell’s appointment in the 1940s, all pediatric care in the Royal Women’s Hospital, from its founding in 1856, had been the responsibility of the obstetric staff.

The Introduction of Neonatal Intensive Care

In late 1965, “neonatal intensive care” was introduced to the Royal Women’s Hospital. Bill was concerned that any new treatments or changes in neonatal care needed to be evaluated thoroughly, including consideration of the health of any survivors long after they were discharged from the hospital. Consequently, he initiated a trial of “neonatal intensive care” in infants whose

*Professor of Neonatal Pediatrics, University of Melbourne, The Royal Women’s Hospital, Parkville, Victoria, Australia. 52     NeoReviews

birthweights were 1,000 to 1,500 g (infants whose birthweights were 1,000 g were considered “previable” at that time; although a few did manage to survive, they were not included in the trial). (1)(2) Eligible infants admitted to the nursery were allocated to either intensive care or routine care. The first baby’s treatment was decided by the toss of a coin, and subsequent babies were allocated alternately to either routine care or intensive care. Babies who had major malformations or hydrops fetalis, who required surgery, or who were not breathing regularly were excluded. “Neonatal intensive care” was very rudimentary by today’s standards and comprised the ability to insert an umbilical catheter, usually arterial, for blood gas and blood glucose measurement. The aim was to keep the arterial PO2 at 80 to 100 mm Hg. The umbilical catheter also was used for infusion of glucose and, in the latter half of the study, bicarbonate infusion in some babies. There was no assisted ventilation of any form, including continuous positive airway pressure, at that time at the Royal Women’s Hospital. The routine care group was provided no parenteral fluids for the first 72 hours after birth unless they had symptomatic hypoglycemia, although oral feedings began after 12 hours (sometimes delayed in babies who had respiratory distress). Oxygen was administered only to abolish central cyanosis. The trial of “neonatal intensive care” ran from February 1, 1966 until March 31, 1970 (50 months), and 238 infants were enrolled. Long-term survival rates were 70.6% (84/119) with intensive care NeoReviews Vol.10 No.12 December 2009 e587

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Figure 1. Dr Bill Kitchen in 2005.

and 61.3% (73/119) with routine care, a nonsignificant improvement. However, there was a significant improvement in survival to 28 days among infants who had respiratory distress and were given intensive care (82.2%) compared with routine care (61.2%) in the latter half of the study. In addition, a trade-off was seen for the gain in survival. At follow-up at 8 years of age, the rate of “profound or severe handicap” was higher in the “neonatal intensive care” group at 20.2% (17/84) compared with 8.2% (6/73) in the “routine care” group. (3) Following this study, Bill decided that the entire cohort should be followed longitudinally, including the 11 survivors who weighed less than 1,000 g but who were not part of the controlled trial. He was among the first of those involved in follow-up to recognize that he could not interpret the results of the very lowbirthweight (VLBW) cohort without having normal birthweight controls. Another problem Bill quickly identified was that large amounts of data would be generated per child with e588 NeoReviews Vol.10 No.12 December 2009

each assessment. Indeed, before he started at the Royal Women’s Hospital in 1965, he spent 3 months traveling the world to visit the then centers of excellence in follow-up. At one site, he estimated that the amount of data collected per child would reach the height of a two-story building. The solution to Bill was to computerize the data for retrieval and analysis. This was in an era of 80-column cards, and each card had to be punched and read into a computer the size of a whole room, nothing like the laptops and PCs that are ubiquitous today (and have much larger memories than the main-frame computers of that time). Because each column was expensive, his variable names were very short and started with the letter “A,” then after 80 columns with “B,” and so on. His other vital contribution was to recognize that high follow-up rates were essential. To this end, he was “forced” to travel from Australia to places like Spain and the Greek Islands to obtain data for some of the children in his studies. It would be difficult to convince funding agencies of the need for such travel today! Following the original controlled trial, Bill followed other hospitalonly cohorts of VLBW infants, but he soon realized that the babies cared for in one hospital were not necessarily representative of all VLBW infants born in the region. Therefore, he and his colleagues established the first geographically determined cohort of babies whose birthweights were 500 to 999 g born in the state of Victoria, Australia, in 1979 and 1980, of whom 25.4% (89/351) survived to 2 years of age. (4) This initial Victorian Infant Collaborative Study (VICS) cohort was followed longitudinally at intervals throughout childhood, and further VICS cohorts from the 1980s, early 1990s, late 1990s, and the 2000s also have been

followed longitudinally, allowing for comparisons between eras and for varying lengths of time, even into adulthood. Other researchers around the world have followed the example set by Bill Kitchen and the VICS team and now have their own geographically determined cohorts of very tiny or preterm children enrolled in long-term follow-up programs.

Personal Connection

I first met Bill as a fifth-year medical student in 1971 at the University of Melbourne, where he was the primary teacher of neonatal pediatrics during my 10-week rotation at the Royal Women’s Hospital. He looked the same then as he does now: rather short, tanned, and with a thick crop of gray hair. I returned to the hospital in 1975 for a 4-month stint as a house officer in neonatal pediatrics, just at a time when intubation and assisted ventilation for tiny babies was increasingly practiced, and Bill Kitchen was in charge of all ventilated babies. After another 12month rotation at the Royal Women’s Hospital in 1978, again under Bill’s leadership, I left for further neonatal training at McMaster University. I returned as Bill’s assistant in the University Department of Obstetrics and Gynaecology as a neonatal pediatrician and was fortunate to have him help guide my early career, until he retired in 1991. Survival rates for infants whose birthweights were less than 1,500 g at the Royal Women’s Hospital were low when Bill started in the mid-1960s, but they rose steadily over the time he worked at the hospital (Fig. 2).

Other Aspects

Bill Kitchen was an excellent teacher of medical undergraduates and postgraduates, and over his 26-year appointment at the Royal Women’s NeoReviews  53

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is satisfactory, and if not, to do something about it. This includes not only care for the individual child and the family, but also a search for causes that are subject to change and testing of such changes in randomized, controlled trials. As the survival rates for the tiniest and most immature babies have increased, the onus is even greater for today’s neonatal pediatricians to think of long-term outcomes for the babies in their care and how to improve those outcomes. Figure 2. Survival rates for babies whose birthweights were less than 1,500 g or less than 1,000 g born alive at the Royal Women’s Hospital, Melbourne, over time.

References

1. Kitchen WH, Campbell DG. Controlled

hospital, he guided the careers of hundreds of pediatricians. Of course, he needed help in this endeavor and was shrewd enough to build a team of allies to help him achieve his goals. By the time he left the hospital in 1991, the number of consultant and junior staff had increased enormously, even though the total number of babies being cared for in the intensive and special care nurseries actually had decreased over time. Bill’s other skills including being a silversmith as well as a cabinet maker. He always managed his time well;

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when not on call over a weekend, he would leave by 4 PM on a Friday for his house on the coast to get away from it all. He had a lathe in the garage, where he produced excellent homemade furniture. Fishing was also high on the weekend activity list.

Final Words

The legacy left by Bill Kitchen is the reminder that it is not good enough to ensure that the baby survives to leave the neonatal intensive care nursery. It is important to know that the long-term outcome for the child

trial of intensive care for very low birth weight infants. Pediatrics. 1971;48: 711–714 2. Kitchen WH, Ryan MM, Rickards A, et al. A longitudinal study of very lowbirthweight infants. I: Study design and mortality rates. Dev Med Child Neurol. 1978;20:605– 618 3. Kitchen WH, Richards A, Ryan MM, et al. A longitudinal study of very lowbirthweight infants. II: Results of controlled trial of intensive care and incidence of handicaps. Dev Med Child Neurol. 1979;21: 582–589 4. Kitchen W, Ford G, Orgill A, et al. Outcome in infants with birth weight 500 to 999 gm: a regional study of 1979 and 1980 births. J Pediatr. 1984;104:921–927

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Perinatal Profiles: Dr Colette Dreyfus-Brisac: Development of Brain Electrocortical Activity Paul L. Toubas, MD*

Important Participant in the Port Royal Team The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Toubas has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

The new Port Royal Hospital Maternity was built in the 1960s to replace the old 17th century Paris Maternity. Under the direction of Alexandre Minkowski, (1) it became one of the most important integrated European perinatal research centers of its time, attracting prolonged visits from world-famous foreign physicians. Studies were conducted there on the normal and pathologic developing neonatal brain. A team of neurophysiologists, directed by Dr Colette Dreyfus (1916 –2006), (2) worked in close contact with neonatologists and pediatric neurologists. Her first publication in 1947 with Dr Fischgold, her mentor, was signed Brisac, her maiden name. (3) By 1950, she had published a second paper under the name Dreyfus-Brisac. (4) Dr JeanClaude Dreyfus, a renowned biochemist, was her husband. To her coworkers, she was Madame Dreyfus. The laboratory in which they worked, located on the fifth floor of the maternity, was superbly equipped. From there, already in 1965, the neurophysiologists could observe with closed circuit television the behavior of any sick infant undergoing electroencephalography (EEG). Healthy babies were studied either at the mother’s bedside or in the laboratory, if follow-up was required. Dr Dreyfus worked quietly and came down every

*Professor of Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York.

morning from her fifth floor laboratory to the neonatal intensive care unit (NICU). After passing through the extraordinary infection control measures at the entrance and covered from head to foot with white hat, mask, gown, and white boots, she discussed the patient’s history with the NICU staff to determine the best candidates for an EEG study. She stood at the side of the incubator, with the discussion taking place above the Plexiglas hood. The preterm baby was undisturbed by our whispered conversation. Her very soft voice, combined with an acute observation of the patient and merry look, easily convinced the young residents to propose infants for study. She was the director of the group of physicians we called “the ladies of the fifth floor,” which was our way of referring to the powerful scientific team working in the rooms located on each side of a dark and deep corridor. In 1968, Dr Minkowski, my mentor, had assembled an important “think tank,” composed mostly of women, who occupied a complete wing of the maternity hospital and whose role, for the most part, was to study the normal or abnormal development of the neonatal brain. In the stressful environment of the NICU, in which we, the young residents, were suddenly immersed, Dr Dreyfus was a reassuring and calm presence who opened our minds to the mysteries of the irregular oscillations of multiple needles spitting rhythmic lines of blue ink on an immense moving sheet of paper. On one particular day, she was trying to convince me to have my very small patient, who NeoReviews Vol.11 No.2 February 2010    e51 NeoReviews 55

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weighed 750 g and had suffered intrauterine growth restriction, to be part of her study. I was very reluctant to disturb this defenseless infant and objected. She remained calm and patiently brought me to her point of view. Her skilled technician delicately placed very small electrodes. She pressed a button, calibrated the EEG recorder, and the brain of the infant became another marvelous marker of life. To me, a novice, interpretation looked more like deciphering tea leaves. Only much later did I search for the origin of all the knowledge that my young trainee mind had not questioned because I was too focused on filling the holes of my ignorance and trying to stay afloat in the NICU. Now that I know more, I realize that I and numerous friends and colleagues owe her a great debt.

Early Work

Dr Dreyfus started medical school in Paris and rapidly showed an interest in neurology. (2) The German occupation of France during World War II and the associated systematic antiSemitic pressures forced her family to flee Paris and move to Toulouse. She received her MD degree in 1942 after presentation of her thesis on “The Cutaneous Reactions to Histamine.” After the liberation of France, she returned to Paris to complete her residency in pediatrics and met Dr Samson, who introduced her to Professor Herman Fischgold (1899 – 1982), a pioneer of EEG in France. He was the father, stimulating thinker, and organizer of French neuroradiology. (5) During World War II, he lived undercover in Toulouse, like Dr Dreyfus. In 1946, he was appointed electroradiologist at the Pitie´ Hospital in Paris and became the chief of the Department of EEG and Neuroradiology. Dr Dreyfus was immersed in this wide field and assigned to the EEG department. Dr Fischgold, e52     NeoReviews NeoReviews Vol.11 No.2 February 2010 56

detecting her interest in the newborn, sent her to attend the consultations of Dr Andre Thomas and Dr Suzanne Saint-Anne Dargassies, the experts of neonatal neurologic development, at the Baudelocque Maternity. Beginning in 1949, she participated in the activities of the “Centre d’Etude Biologiques Neonatales” at the Baudelocque Maternity, directed by Dr Minkowski. In 1950, G. ArfelCapdevielle published her thesis entitled, “Electrical Activity of the Newborn,” focusing on ontogenic development and neuroanatomic correlations. (6) The studies involved Dr Samson-Dollfus, who presented in 1955, under the direction of Dr Dreyfus, her thesis on the EEG of the preterm and term infant younger than 3 years of age. (7) The future neonatal EEG team was taking shape, working in close contact with neurologists and pathologists (8, 9), in establishing the EEG patterns of the newborn. They studied extremely preterm infants, generally before their deaths because the treatment was limited to warmth, oxygen, and gavage feeding, under the most difficult conditions in a very modest laboratory with limited equipment.

Important Colleagues

It is impossible to talk of Dr Dreyfus without mentioning another member of her team who shared this difficult work. Dr Nicole Monod joined her in 1954, after Dr Samson-Dolfus went to Rouen to head the EEG laboratory. A new technology had to be developed to fit the very small and immature patients. Clinical and biologic studies were performed in correlation with neurologic and sometimes anatomic studies. Between 1953 and 1959, 12,000 EEG recordings were performed throughout the maternities and children’s hospitals of the city of Paris. (10) This remarkable achievement was fa-

cilitated by the solid organization of the Paris hospitals (Assistance Publique) and the will of its director to help this embryonic science. In 1957, during an international meeting in Geneva, Drs Dreyfus, Fischgold, and Samson coined the term sommeil alternant to describe quiet sleep in neonates. (2) Dr Dreyfus was promoted to research director at INSERM, Unit 129 (Port Royal Hospital) in 1958. She subsequently obtained multiple sources of funding in support of her work. She worked initially with an array of eminent electrophysiologists, including Nicole Monod, C. Blanc, and D. Samson-Dolfus. Dr J.C. Larroche contributed anatomic and pathologic documentation of neonatal development. Dr Saint-Anne Dargassies provided invaluable creative neurologic expertise and completed the trilogy of this research. The study of the ontogenesis of the electrocortical activity was a new field of research in animals as well as in humans. We must admire this group of meticulous women researchers working under the same roof for very modest salaries. From the first publication of C. Dreyfus-Brisac and N. Monod of work performed in a small laboratory emerged a strong tradition of precise work that was followed by the tremendous development of neonatal EEG. When the Port Royal NICU was built, it included an extremely modern laboratory for that time. It was visited by numerous international scholars, including Leonard Strang, Leo Stern, John Sinclair, Louis Gluck, Abraham Rudolph, Stanley James, and Alistair Philip, who lectured or spent their sabbatical years at Port Royal. The United States ambassador Sargent Schriver visited the laboratory. One day, a group of Japanese pediatricians photographed everything in sight. Another time, a team of Russian

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women physicians and their chaperone visited the unit, distributing medals from the Soviet Union. In the mid-1960s, other researchers joined the team: M.F. RadvanyiBouvet, L. Curzi-Dascalova, and F. Cukier-Hemeury, devoting their energies to bring the new field of brain development to a higher level. They began to study various aspects of neonatal pathology such as metabolic abnormalities and intraventricular hemorrhage. G. Vicente, a technician of electronics who maintained the EEG equipment initially, became an engineer and invented a device to record eye movements. Dr Dreyfus worked with several highly dedicated EEG technicians who had strong work ethics. The quality and precision of their work as well as their observational skills of babies met the highest standards. Some of them were invited by Dr A.H. Parmelee in Los Angeles to help him create his sleep laboratory. (11)

Accomplishments

Dr Dreyfus’ team synthesized the criteria of maturational state analysis and defined the normal and pathologic neonatal EEG pattern by 1962, (2) including descriptions already present in French as well as in English literature. Her team provided a complete description of neonatal EEG patterns according to the states of vigilance and to gestational age. Dr Dreyfus, however, did not work in isolation and took advantage of the collaborative spirit of the team at Port Royal to compare her data with the early pioneering work of Drs Andre Thomas and Saint-Anne Dargassies on cerebral maturation. Dr Dargassies had designed a scheme and organized the modifications of muscle tone and neonatal reflexes according to the age of gestation. By 1955, she had designed a grid for evaluation of the gestational age,

(12) analyzing the results of carefully performed evaluations of preterm infants. She had studied 100 preterm infants longitudinally from 28 weeks’ gestation to term. This method of evaluation of gestational age was transformed into a practical clinical tool by Claudine Amiel-Tison, a pupil of Saint-Anne Dargassies, who published the method in English in 1968 in the Archives of Diseases of Childhood. (13) By 1962, Dr J.C. Larroche had performed the study of the anatomic stages of brain development. Applying this maturation scheme to “small-for-dates” babies revealed that brain development during fetal life progresses independently of unfavorable gestational circumstances. By 1966, under Dr Minkowski’s direction, working on the same topic with different tools, the physicians of Port Royal synthesized the neurologic, anatomic, and EEG correlations. (14) They obtained impressive data on cerebral development before cerebral imaging techniques became available more than a decade later. Dr Dreyfus and her group contributed to the diagnostic and prognostic value of some striking EEG patterns: “paroxysmal EEG” in term babies who had hypoxic-ischemic encephalopathy and “positive rolandic spikes” in preterm infants who had intraventricular hemorrhage. (2) The polygraphic recording used by the team allowed for the additional observation of respiratory movement, ocular movements, and chin electromyography. Long recordings permitted studies of sleep cycling, disclosing that small neonates have shorter cycles than older infants. (2)

Subsequent Developments

Polygraphic recording became more complex and progressively allowed the simultaneous study of more variables, such as heart rate variability,

apneic and bradycardic episodes, gastroesophageal reflux, respiratory variables, and sleep states (2) and others that the creativity of international researchers in the field rapidly added. Dr Dreyfus also became extremely interested in sudden infant death, a field in which Dr Nicole Monod performed significant work. A large international network of correspondents visited Dr Dreyfus, and she visited many research centers, although she never was absent very long from her laboratory. Her insatiable curiosity led her to share information with physiologists, neurophysiologists, and biochemists who had similar areas of interest. Also, as a pediatric neurologist, despite her very focused field, she continued to see her population of older epileptic patients, using her humane qualities to listen to their difficulties and guide anguished families.

Completing the Portrait

Colette Dreyfus-Brisac was a woman of courage. She participated in the French Resistance and contributed as a military physician in February 1945. She opposed the Algerian war and oppression of all kinds and provided support to political refugees from different countries by founding an association to aid to fleeing physicians and health-care personnel. (2) She loved music, literature, and other forms of art and did not hesitate to mention it in the middle of the most serious scientific discussions. Her interest in any type of creativity had a great influence on her students and colleagues both in France and abroad. We owe her a great debt of gratitude as a role model and as a scientist. ACKNOWLEDGMENTS. I want to thank to Dr Marie-France RadvanyiBouvet for her valuable help in arranging the chronology of neonatal NeoReviews 57 NeoReviews Vol.11 No.2 February 2010    e53

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EEG discoveries and sharing cherished memories with me.

References

1. Philip AG. Historical perspectives: peri-

natal profiles: Alexandre Minkowski. NeoReviews. 2008;9:e5 2. Monod N, Radvanyi-Bouvet MF, Samson-Dollfus D. Colette Dreyfus Brisac (1916 –2006). Neurophysiol Clin. 2007;37: 297–298 3. Baudoin A, Fischgol H, Brisac C. Le role de l’electroencephalogramme dans les tumeurs cerebrales. Paris Med. 1947;37: 573–575 4. Puech P, Fischgold H, Lairy-Bounes GC, Dreyfus-Brisac C. Electroencephalographic signs of tumors of the hemispheres. Semaine des Hopitaux. 1950;26:2612–2622

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5. Wackenheim A, Metzger J. Hermann

Fischgold (1899 –1982). Neuroradiol. 1982;23:115–116 6. Bancaud J. Genevieve Arfel-Capdevielle 1922–1979. Rev d’Electroencephalograph Neurophysiol Clin. 1980;10:5–7 7. Samson-Dollfus D. L’EEG du pre´mature´ jusqu’a` l’age de trois mois et du nouveau ne´ a terme [thesis]. Foulon, Paris, 1955 8. Dreyfus-Brisac C, Samson D, Fischgold H. Method of recording the EEG of premature and newborn infants: Electroencephalogr Clin Neurophysiol. 1955;7: 429 – 432 9. Dreyfus Brisac C, Samson D, Blanc C, Monod N. The electroencephalogram of the normal infant under three years of age: bioelectrical functional aspects of nervous maturation [French]. Etudes Neonatales. 1958;7:143–75

10. Andrieu B. La conscience du nouveau ne. Crite`res e´lectrophysiologiques en me´decine ne´onatale. Philosophia Scientae. 2002; 6(1):3–32 11. Parmelee AH Jr, Minkowski A, SaintAnne Dargassies S, et al. Neurological evaluation of the premature infant. A follow-up study. Biol Neonate. 1970;15:65–78 12. Saint-Anne Dargassies S. La maturation neurologique du pre´mature´. Etudes Ne´onatales. 1955;4:71 13. Amiel-Tison C. Neurological evaluation of the maturity of the newborn infants. Arch Dis Child. 1968;43:89 14. Minkowski A, Vignaud J, DreyfusBrisac C, Larroche JC, Saint-Anne Dargassies S. Development of the nervous system in early life. In: Falkner F, ed. Human Development. Philadelphia, Pa: WB Saunders; 1966:254

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Perinatal Profile: Arvo Ylppo¨: Little Big Man Kari O. Raivio, MD*

Introduction

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Raivio has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

One hundred years ago, preterm birth was considered an unfortunate event that occurred for unknown reasons and led to loss of the child. The cause of death generally was ascribed to “weakness” (Lebensschwa¨che). Many obstetric textbooks considered babies born before 28 weeks’ gestation as unviable; others put this limit at birthweight less than 2,000 g. Midwives were taught that preterm birth occurs between 29 and 39 weeks’ gestation, and under favorable circumstances, the baby may survive, effectively leaving those below this range without care. In the late 1800s in France, Pierre Budin developed an incubator for keeping infants warm (see Toubas PL. NeoReviews. 2009;10:e60 – e64), but these were available in few obstetric or pediatric hospitals. Impressive results in treating preterm infants were obtained by Martin Couney, a disciple of Budin’s, who collected from delivery wards tiny infants otherwise doomed to die untreated. He put them in incubators, fed them with human milk, and put them on display at Coney Island in New York, as well as in fairs and exhibitions in the United States and in Europe between 1902 and 1940. The treatment of preterm infants could not progress until a change of attitudes was achieved and therapeutic nihilism abandoned. Enter Arvo Ylppo¨!

*Professor of Perinatal Medicine (Emeritus), University of Helsinki, Helsinki, Finland.

Early Career

Ylppo¨ was born in 1887 in a farmhouse in southwestern Finland. Birthweight was not recorded because no balance was available, but the mother’s estimate was 2,000 g. Catch-up growth took him up to an adult height of only 154 cm (5 ft), but small physical size was compensated by a keen intelligence and boundless energy. Ylppo¨ decided early in life to become a physician and started his medical studies at the University of Helsinki in 1906. When he entered the Children’s Hospital for the first time, toward the end of the clinical curriculum, he immediately felt at home and decided to specialize in pediatrics and obtain a doctoral degree. However, despite repeated requests, the professor refused to give him a research topic and supervise the work. Frustrated by the delay, Ylppo¨ sought another environment to learn pediatrics and research. Kaiserin Auguste Victoria Haus was a new institution, opened in 1909 in Berlin under the patronage of the last German empress, with the purpose of fighting infant mortality in Germany. Ylppo¨ wrote to the Director, Leo Langstein, for permission to study there for a summer. The permission was granted, and Ylppo¨ left for Berlin in the spring of 1912. Summer came and went, but Ylppo¨ stayed in Berlin until 1920. The research achievements and personal development that Arvo Ylppo¨ experienced during the Berlin years showed that the ingredients for scientific success were the same then as they are today: ambitious and in  59 NeoReviews Vol.11 No.4 NeoReviews April 2010 e169

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telligent student, stimulating environment, and encouraging supervisor. At their first meeting, Langstein proposed severe neonatal icterus as the theme for doctoral work. Before demonstration of Rh immunization as the primary cause of erythroblastosis fetalis in 1941, several theories for the cause of neonatal icterus had been presented: hepatic dysfunction caused by infection, unexplained hemolysis, or a combination of the two. Ylppo¨ studied the role of bacterial infection. The primary difficulty that Ylppo¨ encountered at the start was his lack of training in laboratory work. However, he learned quickly and received guidance from two prominent chemists. One was the head of the laboratory of his own hospital, Leonor Michaelis, whose claim to immortality is Km, or MichaelisMenten constant, familiar to all who have worked with enzymes. Another was Hans Fischer, who had developed methods for measuring the bile pigments bilirubin and biliverdin that Ylppo¨ soon needed for his studies. Fischer was awarded the Nobel Prize in chemistry in 1930. After some months of unsuccessfully trying to culture bacteria from the blood of infants who had severe icterus, Ylppo¨ realized that his lack of success was not related to his defective laboratory skills but by the fact that the samples were sterile. He decided to study the metabolism of bile pigments quantitatively in newborns, which required creating methods for measuring bilirubin and biliverdin in blood, urine, and feces. The spectrophotometer had been invented some decades earlier, allowing the measurement of colored substances in solution, but each sample had to be compared by eye against a standard in parallel cuvettes, using Nicol’s prism. Ylppo¨ extracted and purified bilirubin from gallstones, .

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converted some of it chemically to biliverdin, and made special cuvettes to accommodate small samples. To facilitate the separate collection of urine and feces samples, he devised a special bed for metabolic studies of newborns. His thesis, completed in 1913, was a monograph consisting of 118 pages and several novel findings. He showed that bilirubin was present in the blood of the fetus and increased toward term. Because maternal concentrations did not increase, Ylppo¨ drew the mistaken conclusion that the placenta is not a significant route of excretion for fetal bilirubin. After birth, he documented the regular increase of bilirubin concentrations over 3 to 10 days, followed by a decrease, which he ascribed to maturing liver function. The intestine was the primary route of excretion of bile pigments, with renal excretion playing a minor role. Although nucleated red cells were seen in the blood of some infants, Ylppo¨ failed to recognize the role of hemolysis in severe icterus. Instead, he considered the entire spectrum of hyperbilirubinemia to be explained by varying degrees of immaturity of liver function. After having his work printed, Ylppo¨ returned home to defend his thesis and obtain a doctoral degree at the University of Helsinki. He stayed some months to complete the clinical service required for graduation from the Faculty of Medicine. Again, he was disappointed at the lukewarm interest of the professor of pediatrics in his accomplishments and decided to return to Berlin. In 1914, Europe was sliding toward World War I, and Ylppo¨ was in an interesting situation. Finland was still part of the Russian Empire, as an autonomous Grand Duchy, and when war broke out between Germany and Russia, Ylppo¨ was techni-

cally an enemy citizen within Germany. However, “the little Russian,” as he was sometimes called, negotiated the diplomatic problems to keep working, although most other physicians were recruited to the army. There was little time for the laboratory, but his clinical activities and studies continued, as did his work as a pathologist, personally performing most of the autopsies at the hospital.

How the Preterm Infant Became a Patient

Arvo Ylppo¨ published his extensive observations on preterm infants in three monographs in 1919 for the 10th anniversary of the Kaiserin Auguste Victoria Haus. The first addressed pathologic findings; the second discussed physiologic, clinical, and follow-up studies; and the third addressed growth. He used the term “Fru¨hgeborenen” (preterms) throughout, but his patients actually consisted of low-birthweight infants, who weighed less than 2,500 g at birth. Ylppo¨ was aware of the importance of the degree of maturity and attempted to use available curves of birthweight as a function of gestational age. He realized that the length of gestation based on the last menstruation was too inaccurate and tried to improve the situation by exploiting World War I. He selected pregnancies in which the husband had only had a short leave from the front lines and the wife was considered faithful. Plotting gestational age and birthweight of these cases on the existing intrauterine growth curves, he found a very poor match. Either the curves were wrong or the wives were unfaithful! Ylppo¨, thus, had to contend with using birthweight alone to define his patient group. His suggested classification was prematurity (partus praematurus) for birthweights of 1,250 to 2,500 g, immaturity (partus

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immaturus) for birthweights of 600 to 1,250 g, and abortion (abortus) for birthweights less than 600 g. This was approved by the American Academy of Pediatrics and Royal College of Obstetricians and Gynaecologists in 1935, and the global statistics of the World Health Organization on low birthweight still are based on the 2,500-g limit. Later refinements of intrauterine growth curves and progress in intensive care have brought about the current classifications of appropriate for gestational age, small for gestational age, low birthweight, very low birthweight, and extremely low birthweight and removed the lower weight limit. The pathologic anatomic study was based on 175 autopsies that Ylppo¨ performed himself. Microscopic studies were included, as were clinical comparisons, and hemorrhagic tendency received special emphasis. The most interesting new findings were cerebral hemorrhages, which were more frequent in the smaller birthweight range, were localized near the motor tracts, and sometimes extended into the ventricles. Ylppo¨ concluded that they were not always due to mechanical birth trauma but could arise from lack of oxygen during the first hours and days after birth. He also postulated that they were not always fatal and could account for neurologic symptoms in the newborn, as well as cerebral palsy, then known as Little disease (see Raju TNK. NeoReviews. 2006;7: e567– e568). In his follow-up study of 598 infants until 8 years of age, the incidence of Little disease was 3.1% and of intellectual disability was 7.4%. These views brought him into open conflict with leading obstetricians, who denied the importance of hemorrhages and accused Ylppo¨ of blaming them for incompetence and harm to babies. The lungs of preterm infants who

died in the first postnatal days were known to be atelectatic, which had been ascribed to a primary failure to expand. Ylppo¨ combined serial radiographs with autopsy findings to show that the atelectasis usually was not primary; expanded lungs became airless after the first hours and days. He ascribed this to blood engorgement, and in a case of an infant whose birthweight was 1,070 g and who died at 14 hours of age, he described “fibrin masses” that filled the alveoli and prevented gas exchange. The term “hyaline membranes” was first suggested in 1925 by Johnson and Meyer, but there is little doubt that Ylppo¨ was describing the same phenomenon 6 years earlier. Ylppo¨ carefully recorded the clinical characteristics of preterm infants in relation to their birthweights. The babies were treated in special “couveuse rooms” that had elevated temperature and humidity. He documented the lability of thermoregulation and increased mortality of infants treated at low ambient temperatures. Respiratory distress was treated with oxygen administered through a thin catheter into the pharynx because endotracheal intubation was not developed before the mid-1930s. Lacking that option, Ylppo¨ studied gas exchange from the stomach. Because of the unpleasant setup, he had to experiment on himself. He concluded that 5% of human oxygen requirements could be satisfied by leading oxygen into the stomach but that a disturbing adverse effect was flatulence! Nevertheless, several infants were treated by “gastric breathing.” For the feeding of preterm infants, Ylppo¨ considered human milk as the only sensible alternative, although he believed its protein and calcium contents to be too low. Reindeer milk, which was used for infant feeding in Northern Scandina-

via, he considered dangerous because he measured four times higher fat and ten times higher protein content than in human milk. In follow-up studies, Ylppo¨ documented catch-up growth between 6 to 12 months, after which most preterm infants grew normally and, except for neurologic sequelae, were generally healthy. Head circumference grew normally even during the first 6 months, which Ylppo¨ interpreted as showing normal growth of the brain. He warned against mistaking the large head and prominent forehead of preterm infants as hydrocephalus and proposed the term “macrocephalus” instead.

Acid-base Balance

The conceptual framework and instrumentation for today’s acid-base balance studies were developed in the 1950s by Astrup and SiggardAndersen. When Ylppo¨ decided to study acidosis and its compensatory mechanisms in newborns and patients who had diarrhea, he used a calomel electrode to measure pH. Because he was aware that a tendency to acidosis could be masked by compensatory mechanisms, primarily exhalation of CO2, he measured pH in a fresh sample and in one from which CO2 had been removed, thus giving a parameter that he called “CO2 regulatory width,” which decreased with increasing respiratory compensation of acidosis. As another indicator of acidosis, he used the downward shift of the O2 dissociation curve of hemoglobin, for which he again had to create a methodology and establish normal values. Using this technological arsenal, Ylppo¨ showed that a compensated or even actual acidosis was common after birth, particularly in preterm infants. He also found that fasting provoked a tendency to acidosis, particularly in infants fed cow milk. In severe diarrhea, acidosis was comNeoReviews Vol.11 No.4 NeoReviews April 2010 e171   61

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mon and severe. The shift in the O2 dissociation curve of hemoglobin indicated that delivery of O2 to tissues was impaired in acidosis, which led to a vicious cycle.

Return to Finland

Despite being promoted to Assistant Chief Physician of Kaiserin Auguste Victoria Haus, Ylppo¨ had never given up his intention of returning to his home country, if and when conditions were favorable. In the midst of World War I and the Bolshevik revolution in Russia, Finland had declared independence in 1917, experienced a civil war in 1918, and gradually was establishing itself as a young republic. In 1919, the University of Helsinki made Ylppo¨ a Docent (assistant professor) and the following year gave him a teaching position. In the summer of 1920, Arvo Ylppo¨ returned to Finland, determined to use his skills and energy for fighting infant mortality. A momentous change in Ylppo¨’s career followed. Even though he kept publishing scientific articles, most of these were based on material from Berlin; setting up facilities and recruiting personnel for research in Finland were not at the top of his priority list. Instead, he began an extensive campaign to educate parents and health-care personnel in caring for children, which included writing popular books and articles, setting up the first well-baby clinics in Helsinki, and establishing the Mannerheim League for Child Welfare, together with the respected Commander-inChief of the Army, Gustaf Mannerheim. He was appointed Professor of Pediatrics of the University of Helsinki in 1925 and served until 1957, the last 3 years with special permission after the mandatory retirement age. During his tenure, he supervised the planning and building of two large hospitals, the Children’s Hose172 NeoReviews Vol.11 No.4 April 2010 62     NeoReviews

pital of the University of Helsinki and the Children’s Castle for chronically ill children. He served as the Chief of the latter hospital from 1920 to 1963. In one of his last publications, Ylppo¨ reacted against a therapeutic practice that he considered harmful. Based on the work of Clement Smith in Boston, the American Academy of Pediatrics in 1954 recommended a delay of up to 4 days before commencing feeding of a preterm infant because vomiting and edema were common and aspiration was feared. Ylppo¨ felt that a sudden break in placental nutrient and water supply followed by a total fast was poorly tolerated by the infant. His previous studies had shown that acidosis became worse, vomiting was common even in fasting infants, and in animal experiments that neonatal rats tolerated fasting much less than older pups. Thus, his advice was to start glucose by mouth or feeding tube on the first day, followed by human milk on the second day. Within a decade of this controversy, attention had been drawn to neonatal hypoglycemia and its potential sequelae, and controlled trials had established the advantages of early feeding. The controversy apparently left no hard feelings because in 1957, Clement Smith was the first recipient of the golden Arvo Ylppo¨ Medal, awarded every 5 years for outstanding research in neonatology. In 1977, Ylppo¨ himself gave the medal to Louis Gluck at the International Congress of Pediatrics in New Delhi on his 90th birthday.

Legacy

Arvo Ylppo¨ had a long, eventful, and rewarding life, and he never lost his physical agility or mental alertness. His tireless efforts on behalf of the well-being of children earned him the love and respect of the entire

nation. In 1952, the President of the Republic awarded him with the honorary title “Archiater,” carried for life by just one physician at a time in Finland. He has a park carrying his name as well as a statue in Helsinki, and for his 100th birthday, the government printed a postage stamp and threw a party in the State Banqueting Hall, where Ylppo¨ conversed with his guests in six languages. Arvo Ylppo¨ died in 1992 at the age of 104 years. The legacy of this “little big man” for the pediatric community could be summarized by a quote from his study on the physiology of preterm infants in 1919: “My pathological-anatomical studies have shown that these infants by no means die of their too early birth nor their small size alone, not even of their ‘incapability of living’ (an empty phrase!), but primarily following traumatic damages that they experience during birth or early extrauterine life. These are, however, quite unpredictable and vary considerably even between two infants of similar size. Thus, every attempt to draw conclusions about the vitality of an individual merely on the basis of any physical measurement must be considered misguided. This applies to the smallest of babies as well as to adults. Are we not, as a rule, unable to judge the physical or mental capabilities of an adult by any measure of bodily size.”

Suggested Reading Dunn PM. Arvo Ylppo¨ (1887–1992): pioneer of Finnish paediatrics. Arch Dis Child Fetal Neonatal Ed. 2007;92: F230 –F232 ¨ ber den Einfluss der Rona P, Ylppo¨ A. U Wasserstoffionenkonzentration auf die Sauerstoffdissoziationskurve des Ha¨moglobins. Biochem Zeitschr. 1916;76: 187–217 Ylppo¨ A. Das Wachstum der Fru¨hge-

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borenen von der Geburt bis zum Schulalter. Zeitschr Kinderheilk. 1919;24: 111–178 Ylppo¨ A. Icterus neonatorum (inclus. I.n. gravis) und Gallenfarbstoffsekretion beim Foetus und Neugeborenen Quantitative (spektrophotometrische) Studien u¨ber das Verhalten des Gallenfarbstoffes im fo¨etalen und im Neugeborenenorganismus Zeitschr Kinderheilk. 1913;9:208 –318 Ylppo¨ A. Neugeborenen-, Hunger-, und

Intoxikationsacidosis in ihren Beziehungen zueinander Studien u¨ber Acidosis bei Sa¨uglingen, insbesondere im Lichte des Wasserstoffionen-“Stoffwechsels”. Zeitschr Kinderheilk. 1916;14:1–184 Ylppo¨ A. New classification and nomenclature for newborn infants including prematures and abortions. Acta Paediatr. 1948;35(suppl 1):160 –163 Ylppo¨ A. Pathologisch-anatomische Studien bei Fru¨hgeborenen. Makroskopische un

mikroskopische Untersuchungen mit Hinweisen auf die Klinik und mit besonderer Beru¨cksichtigung der Ha¨morrhagien. Zeitschr Kinderheilk. 1919;20: 212– 431 Ylppo¨ A. Premature children—should they fast or be fed in the first days of life? Ann Paediatr Fenn. 1954;1:99 –104 Ylppo¨ A. Zur Physiologie, Klinik, und zum Schicksal der Fru¨hgeborenen. Zeitschr Kinderheilk. 1919;24:1–110

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Perinatal Profile: Klaus Riegel: A Swabian “Someone” Hans T. Versmold, MD*

Introduction

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Versmold has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

Klaus Riegel, when asked about his distinguished career, claims that there is nothing worth mentioning, other than the fact that he has always been lucky. He was born May 14, 1926, and attended school in the Swabian town of Schorndorf in Southern Germany. Near the end of World War II, he was recruited, at the age of 17, for military service in both the German air force (Luftwaffe) and as a naval cadet on the Baltic Sea. He had the good luck to return home intact, in November 1945, after captivity as a prisoner of war. Riegel wanted to be a physician, but he did not want to follow his father into a career as a general practitioner. Rather, he became a pediatrician because he had the good luck to encounter a charismatic teacher at the University of Tu¨bingen, Professor Alfred Nitschke, Chairman of the Department of Pediatrics. Because of Nitschke “I went into pediatrics for 14 months, but stayed for 40 years,” says Riegel. “But, really, all my ‘luck’ started when I met Elsbeth,” who became his wife.

The Many Faces of Klaus Riegel Gentleman

The young doctor Riegel had had excellent pediatric training and already had become a respected member of the rather formal pediatric community at the venerable University of Tu¨bingen when a new chair*Professor Emeritus of Pediatrics, Charite´ Campus Benjamin Franklin, Universita¨tmedizin Berlin, Berlin, Germany. 64     NeoReviews

man arrived. Professor Klaus Betke came to Tu¨bingen from Freiburg, along with his Fellow, Enno Kleihauer. At his first clinical rounds, Betke watched his new faculty bending over their patients with neckties swinging back and forth. “For hygienic reasons,” all neckties were immediately forbidden throughout the Department. The medical staff complained, but obeyed. Not so Klaus Riegel; he has worn a bow tie ever since (Fig. 1).

Physiologist

In 1959, Riegel followed his interest in applied physiology to work as a research fellow with the developmental physiologist, Heinz Bartels, a rising star at the University of Tu¨bingen. Betke and Kleihauer pursued their penetrating research on the structural properties of hemoglobins, resulting in an important clinical byproduct: the BetkeKleihauer test, which stains single fetal red blood cells, identifiable within a sea of adult maternal blood cells. Riegel extended this view by focusing on the functional properties of blood and its developmental changes, the delicate balance of the oxygen loading and unloading of hemoglobin, and red cells under the conditions of intrauterine and extrauterine existence. Together, Bartels and Riegel studied various mammalian species, including gorillas, camels, and elephants. Their goal was to understand the functions of fetal and adult hemoglobin; the very different influences of pH, carbon dioxide, and oxygen tensions; and the different gradients of hydrogen ion concentration from outside to inside the red NeoReviews Vol.11 No.5 May 2010 e219

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Leaf on the Clement Smith Family Tree

Figure 1. “Klaus Riegel thanks” for his

80th birthday party by Klaus P. Riegel, 2006, watercolor and felt pen.

cell. All of these considerations presented an exciting focus for study and an insight into a global functional context. This excitement was the common link for an entire group of physiologic “addicts”: Klaus Riegel, Klaus Betke, Enno Kleihauer, Heinz Bartels, and others. However, Riegel did not focus solely on hemoglobin. He also studied pulmonary and systemic blood flow as well as gas exchange, using the meticulous and cumbersome methods of those days, and these studies finally extended to include the circulatory system. The famous article by Bartels, Hilpert, and Riegel on gas exchange and cardiac output in goats, and sheep, and lambs during the first weeks of life was published 1963. (1) Years later, George Lister called this paper a highlight for all those interested in perinatal respiration and oxygen transport. In 1963, Riegel also received his “Habilitation” (European certification) as an academic teacher and faculty member at the University of Tu¨bingen. e220 NeoReviews Vol.11 No.5 May 2010

In 1964, Klaus Riegel entered the orbit around Clement A. Smith at the Boston Lying-in Hospital (Harvard) as a National Institutes of Health research associate. This period is best witnessed by Professor Nicholas M. Nelson, his close friend and another member of the “Smith Gang,” as Riegel called this unique group of researchers in perinatal physiology. In the famous “Clement Smith Family Tree of Neonatal Research” (illuminated by Nick Nelson’s mother and presented in his review of his mentor, Clement Smith, in this journal), (2) Klaus Riegel is at the upper right between Samuel Prod’hom, Leonard Strang, and Alexandre Minkowski, on the branch below that of ¨ sterlund. Petter Karlberg and Kalle O Riegel apparently was perceived as an “established European scientist,” in contrast to the “yet unpolished eager Americans” described in Nick Nelson’s review. Nick Nelson provides the following “fond recollections” (minimally edited by this author) of Klaus Riegel: Klaus Riegel, exceptional in all ways, is: • Above all, a gentleman • German, yes, but proudly Swabian (like Hoelderlin, Daimler, and Schiller, who once said: “If Swabians go abroad, they become someone”) • A devout, but unostentatious Christian • A man who delights in making marvelous Christmas tree ornaments from “found” materials (like IV sets) • A man who hand-produces his own Christmas cards with wonderful little watercolor designs on gently religious themes

• A gently extroverted and extremely warm personality • A gourmet who introduced me to “Ba¨rlauch,” a delectable leek soup available only in white asparagus time in the spring • One so in thrall to chamber music that he carried his cello throughout his service (in several military entities) during World War II • One so in thrall to his beloved string group that, some years ago, I had a memorable 2-day Munich visit with (his wife) Elsbeth and (daughter) Angela plus her husband, but Klaus could only separate himself from his cello (and his string group) to share a brief (and wonderful) Bavarian luncheon. Klaus’ work in the United States was largely, if not exclusively, with me, and we spent many hours attempting to measure pulmonary diffusing capacity in infants, using the (mildly) hypoxic (15% oxygen) breathing techniques (rather than carbon monoxide) of Robert Forster. My recall is that these measurements were successful in showing that infant diffusing capacity was rather normal. The data were submitted for publication in JCI, but publication was denied on a reviewer’s (underinformed) opinion that our effort represented “paper-splitting.” I was so disheartened by this charge that I never resubmitted this paper, but Klaus did publish a “precis” of the material, (3) thus earning a modicum of credit for his year of hard work that my immature pouting had denied him. We also published a schematic approach to acid-base therapy in the newborn, (4) a brief analysis of what happens “acid-base-wise” to an infant with respiratory failure (this preceded effective artificial infant ventilation by 4 to 5 years) if one were to attempt acid-base restitution by infusing bicarbonate to combat hypercapnia. This NeoReviews  65

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posture, of course, horrified any normal adult pulmonary physiologist with long experience in successful artificial respiration. I think it was with Klaus that we also began to attempt measuring arterial PO2 with a variation of the Scholander technique and when polarography began to arrive, we tried making PO2 measurements with an electrode we developed on the model of John Pappenheimer. None of this early stuff was published. Klaus arrived in Clem Smith’s Lab at the Boston Lying-in Hospital (now the Brigham and Women’s Hospital) on a Monday morning, speaking perfectly accented and brisk English. Going to lunch required squeezing through a smallish slot to pass from the laboratory area to the main hospital, where the dining hall was located. Klaus and I arrived at this slot simultaneously, bumped shoulders, tried (and bumped) again. Finally, I simply bulldozed my way through the slot; Klaus followed and we enjoyed lunch. However, I noticed during the afternoon that this formerly voluble German had little to say and I began to worry that I had somehow offended him at the slot. Klaus said, “Not at all, but I have been thinking since that had that bump event occurred at a German university, I would have had to think ‘What is his rank?’ before I could manage a proper response.” Klaus and I once attended ward rounds at the Children’s Hospital (across Longwood Avenue), being conducted by (I think) Dr Charles Janeway. Klaus expressed fascinated shock at the (apparently) disrespectful attitude of American house officers who were plainly challenging the chief, if not actually attempting to trip him up. After recovery from his European shock at such ungentlemanly behavior, Klaus began to see the pedagogical worth of such exchanges and (he told me much later) at66     NeoReviews

tempted (without success) to encourage such a questioning style at his own rounds in Tu¨bingen and Munich. (Riegel, in his modesty, may not have perceived that his rounds, open to any question and criticism, were, in fact, highly appreciated by his students and fellows.) It was Clem Smith’s tradition to celebrate the departure of each Fellow with a bit of whimsical doggerel. Klaus had spent much of the year doing oxygen content assays in the Natelson microgasometer, which procedure involved a lot of loud slamming of the machine against a metal stop. Clem memorialized Klaus’ year with a little verse entitled “Eine Kleine ‘Knock’ Music.” For me, the Boston period of Klaus Riegel’s academic life remained omnipresent. Whenever I entered his office in Munich, he was sitting in his splendid Harvard Chair, beclouded by the scent of his tobacco pipe. Even today, in his private music and working office, there is his Harvard Chair and some tobacco scent in the air. Since he had allegedly “stopped smoking” long since, I do not ask questions. Following his great experience in the United States, Riegel became not a “paper-splitter” but a “someone” (in Schiller’s sense of Swabians abroad). He returned to Tu¨bingen and later followed his Chairman, Klaus Betke, to the University of Munich, where he was promoted to Professor of Pediatrics and Head of the Division of Neonatology. He now had full responsibility for his patients, his research, and the organization of perinatal care.

Research on Oxygen Transport

A critical observation of Benesch and Benesch (5) in New York had thrown new light on one of the great questions in the work of Riegel and Betke: Why were fetal and adult hemoglo-

bin so different in their oxygen loading and unloading properties? What accounted for this essential difference in maternal and fetal oxygen transport? The Benesch team (husband and wife) showed that 2,3diphosphoglycerate (2,3-DPG), an organic phosphate abundant within red cells, was bound to deoxygenated adult hemoglobin, thus reducing the affinity of hemoglobin for oxygen and favoring oxygen unloading. Bartels, Riegel, and Bartels’ brilliant young associate, Christian Bauer, immediately suspected that 2,3-DPG was the key to the different oxygen behaviors of fetal and adult hemoglobin. Christian Bauer visited the Benesch laboratory at Columbia University and participated in experiments demonstrating that the differing oxygen affinities of fetal and adult hemoglobin were due to the reduced binding of 2,3-DPG by fetal hemoglobin. This favors the binding of oxygen to fetal hemoglobin, thus facilitating the fetal uptake of oxygen from maternal blood in the placenta, where oxygen is bound more loosely to maternal (adult) hemoglobin, being “displaced” by 2,3-DPG. In confirmation of this concept, exchange transfusions with adult blood (in newborns who had erythroblastosis fetalis) resulted in infants whose blood displayed adult-type lower oxygen affinity. These observations were published almost simultaneously by Oski and DelivoriaPapadopoulos and by Riegel and myself. (6) These findings were often (too) directly translated into concluding that low blood oxygen affinity means more oxygen for tissues. Riegel, being aware of the complex interactions of oxygen saturation, intra- and extracellular pH gradients, and the resulting changes of the Bohr effect, always was opposed to such banal overinterpretation. In any case, “2,3NeoReviews Vol.11 No.5 May 2010 e221

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DPG” became a synonym for “Direct Pathway to Grants.” During this entire fascinating decade, the effects of 2,3-DPG on the adaptive changes of blood oxygen affinity in infancy and childhood in anemia, cyanotic heart disease, or methemoglobinemia were a major and fruitful area for our research. However, other aspects of oxygen transport and oxygen consumption also came into Riegel’s focus, primarily through the Fellows whose interests he had seduced into pursuing these aspects.

Klaus Riegel’s Fellows

As a sensitive teacher, Riegel attracted people through his modest, gently convincing personality and deep knowledge, paired with his art of constructive criticism (Fig. 2). He especially attracted those who first needed to understand: the “physiologists” rather than the “machinists,” as he liked to label his colleagues. With the writing of an excellent booklet on perinatal physiology, (7) which spread the ideas of Clement Smith‘s Physiology of the Newborn to a larger German public, he established his standards of care for newborns.

Here he encountered the dilemma of being absolutely opposed to “cookbooks of intensive care.” Nonetheless, he knew that clinical standards were needed to define the quality of care as well as its comparative evaluation. It became my task to adapt these standards, which were “evidence-based” well before that term became popular. They formed the basis for Riegel’s large-scale outcome studies. We could not prevent these standards from being widely used as (Riegel-opposed) “cookbooks” for improving care that, unfortunately, lacked the necessary critical flexibility. When I started my work in neonatology, I had to learn the lesson of Riegel’s applied ethics: Don’t provide excessive intensive care. One morning, after I had tried, without success, to keep an unfortunate preterm infant alive throughout the night with an oxygen mask, Klaus gently asked me, “Do you feel you did him any good?” In addition to adopting his clinical standards for neonatal care, Riegel’s Fellows were motivated by his scientific curiosity. Riegel considered curiosity to be the most important quality in his coworkers, supported by their knowledge, discipline, and devotion. Four of us—Christian Bauer, Hans Versmold, Otwin Linderkamp, and Karl Bauer— enjoyed successful academic careers. We all had had similar academic experiences with Riegel, relished our intense education with him, and were encouraged by him to go abroad and return as autonomous researchers.

Christian Bauer

Figure 2. Klaus P. Riegel watching a

flower. (Photograph Hans T. Versmold)

e222 NeoReviews Vol.11 No.5 May 2010

I previously cited Bauer’s observation that the high oxygen affinity of fetal hemoglobin depends on its reduced binding of 2,3-DPG. He was not a Fellow of Klaus Riegel, in the

strict sense of that word. He was a younger associate of the physiologist, Heinz Bartels, with whom Riegel had studied mammalian hemoglobin function. Being in Tu¨bingen at the same time, Riegel became Bauer’s fatherly mentor and friend. Bauer later became the Chairman of Physiology in Zu¨rich.

Hans Versmold

In 1967, Klaus Betke recruited me to pediatrics from biochemistry, where I had worked on tissue oxygenation and cytochrome redox states. I became involved with the work of Riegel and Betke on hemoglobin function, primarily because I was able to measure 2,3-DPG. Through Riegel’s relationships, I became a friend of Christian Bauer, Marcello Orzalesi in Rome, and Gabriel Duc in Zu¨rich. I also shared Riegel’s interest in transcutaneous PO2 (tc PO2) monitoring. We obtained one of the first transcutaneous electrodes and found that tc PO2 really does represent arterial PO2, but it also reflects the circulatory state of sick infants. (8) Our experience in tc PO2 monitoring attracted Alexandre Minkowski (also profiled in this journal (9)), who visited us in 1976 from Paris (you can locate him next to Klaus Riegel on the Clement Smith Family Tree). In turn, I traveled to Paris to study their many infants who weighed less than 1,000 g at birth (and have a sip of the famous 100year-old cognac found by Paul Toubas when he restored the floor of his cellar). On the recommendation of Klaus Riegel to his friend William H. Tooley, I had the privilege of becoming a member of the Cardiovascular Research Institute at the University of California, San Francisco, from 1977 through 1978. There I worked with George Lister on oxygen delivery and consumption; John Severinghaus on transcuNeoReviews  67

historical perspectives

taneous carbon dioxide monitoring; and Joe Kitterman, Bill Tooley, Rod Phibbs, and George Gregory on arterial blood pressure of infants whose birthweights were less than 1,000 g. (10) Following my return to Munich, I later was elected Chairman of the Department of Pediatrics and Neonatology at the Freie Universita¨t of Berlin, an achievement reinforced by Riegel, my highly regarded mentor.

Otwin Linderkamp

Linderkamp worked with Riegel on his MD thesis on the blood volume of newborns. He performed excellent studies of fetal-placental and neonatal blood volume, on the relation of blood volume to hematocrit, and on the venous-capillary hematocrit difference. His great review on placental transfusion in the Clinics of Perinatology in 1982 (11) is widely known. In line with Riegel’s interest in blood oxygen transport, Linderkamp became an expert on the viscosity of blood, plasma, and red cells in newborns. (12) He worked with H. J. Meiselman on rheology in Los Angeles, then returned to Munich and eventually was elected Chairman of the Department of Neonatology at the University of Heidelberg.

Karl Bauer

Klaus Riegel was Bauer’s advisor for his MD thesis on blood volume and blood pressure. Bauer then extended his studies on the body water compartments of very low-birthweight infants and their energy expenditure, demonstrating that their early postnatal weight loss was due to the loss of extracellular water, rather than tissue starvation under adequate nutrition. (13) As suggested by Riegel, Bauer went to William Oh in Providence, where he worked on the energy metabolism of growthrestricted preterm infants, (14) with admirable precision in his methods. 68     NeoReviews

Karl Bauer later followed me to Berlin. A remarkable result was the evidence that the oxygen consumption of extremely low-birthweight infants was not disturbed during skin-toskin (“kangaroo”) care outside an incubator. (15) Karl Bauer became President of the German Society of Perinatal Medicine and was elected Head of the renowned Division of Neonatology at the University of Frankfurt. Unfortunately, he died very early of lymphoma in 2007 at the age of 48 years.

Perinatal Quality Control

In concert with his research in neonatal and perinatal physiology, Riegel pursued his second major line of improving perinatal outcomes by introducing standards and quality control into perinatal care, while avoiding an algorithmic “cookbook” approach. Improving infant mortality and morbidity required knowledge of underlying perinatal conditions. This could be obtained only by an interdisciplinary approach, a difficult task in Germany during the 1970s because in that era, a newborn death was blamed by obstetricians on pediatricians and, of course, vice versa. Klaus Riegel was the pediatrician to break this ice and to win over the obstetricians. With his modest and amiable personality, he inspired mutual confidence (in both camps) in a common goal: improving perinatal outcomes. It soon became clear to all that Riegel’s ambition was the survival of babies, rather than a parochial agenda and an enhanced personal reputation. With such sensitive statesmanship, Riegel was able to create one of the earliest interdisciplinary regional networks (1970). He initiated several large-scale population-based perinatal background and outcome studies, including a systematic com-

parison of Bavaria with Finland, the European country with the lowest perinatal mortality. These were the “Mu¨nchener Perinatalstudie” (1975 to 1977), the “Bayerische Perinatalerhebung” (from 1979) and the “Su¨dbayerisch-Finnische Perinatalstudie”—the “Arvo-Ylppo¨-Studies” (1979 to 1982), (16) with Dieter Wolke and Barbara Ohrt as collaborators in this huge task. This fruitful ¨ sterlund of cooperation with Kalle O Helsinki also had roots in the “Bos¨ sterlund’s ton connection”; Kalle O name is on the upper right branch of the Clement Smith Family Tree. Riegel also became a trusted friend of Arvo Ylppo¨, also profiled in this journal, (17) and had the honor of joining the sauna on Arvo’s island in the Finnish archipelago. These perinatal surveys became a model for all of Germany and beyond. As a major part of his total lifework, these careful, prospective studies of perinatal background and outcome comprise Riegel’s greatest impact on society.

Klaus Riegel’s Awards, Honors

Riegel became Vice President, then President of the German Society for Perinatal Medicine and, in fact, was one of the first pediatricians in this obstetrically oriented society. He was awarded the prestigious international Maternite´ Prize. He served as President of the European Society for Pediatric Research and was honored with the Arvo-Ylppo¨ Medal. When Riegel received the Federal Cross of Merit of Germany, Betke’s citation for his nomination is impressive: “. . . several thousand Bavarian infants have escaped death as neonates . . . .” This statement preceded the availability of data from all of Germany. Although the Federal Cross of Merit was honorable, Riegel was really proud of the honor of being elected a member of the venerable NeoReviews Vol.11 No.5 May 2010 e223

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German Academy of Natural Scientists Leopoldina. As President of the European Society of Pediatric Research, he officially closed the meeting in Munich in 1985 with some of his delicate, witty, critical, and self-critical verses in the rhythm of classical limericks. This meeting was a great success, perfectly organized, of excellent scientific quality, and of a memorable warm-hearted ambiance especially engendered by his wife Elsbeth and his engaged organization crew. Alistair Philip still has “a lasting memory of the ESPR meeting in Munich (which includes Peter Hope “doing his thing”).” Peter Hope from London, a giant not only in neonatal brain research, but also physically, with his wild beard like a lumberjack, had tried to dance a Bavarian “Schuh-Plattler” on the table that ended unforgettably. Klaus Riegel created a great community of friends who liked to return. He was happy when a visitor came, like Jack Sinclair from McMaster, Hamilton, Ontario, with whom he could disappear for days with their cellos inside Riegel’s home.

Personal Qualities

Betke said of Klaus Riegel on the occasion of his 60th birthday: “Musician (conductor), artist (observation), poet of cheerful verses, scientific curiosity—put it all together and you have a pediatrician. There you have it all, artistic quality combined with a deft hand and sharp observation.” He was (indeed still is) a devoted painter and made lovely miniature watercolors (Fig. 3). If we were lucky, we Fellows received one or another of these treasures, wishing us a Merry Christmas, a Happy Birthday, or maybe a little portrait, perfectly capturing one’s own personality. Riegel’s drawing art once was e224 NeoReviews Vol.11 No.5 May 2010

tant following his retirement from neonatal medicine. He regularly and seriously attended painting classes and joyfully uses his delicate oeuvres to link his friends together.

Final Words

Figure 3. Birthday card by Klaus P. Rie-

gel, 2009, watercolor and felt pen. “Dear Hans, a little late all the best to your birthday.”

tested in July 1952, as told enthusiastically by Enno Kleihauer. They happened to be in Baghdad, Iraq, as part of a prestigious AmericanCanadian-German research group, consisting of John Metcalfe, Jim Parer, Enno Kleihauer, Heinz Bartels, and Klaus Riegel. They studied the hematologic adaptation and hemoglobin function of camels before and after a desert tour. One day, a fierce firefight started in the streets: the Kassem Revolution. They pulled their beds up to the wall under the windows, so as to be protected from bullets and were thus confined to their rooms for days. The excitement slowly turned into boredom, and Riegel, the artist, saved the situation by devising a complete card deck. Eventually, they were flown out to Beirut and Uganda to study elephant hematology. (18) When I asked Kleihauer whether this was not even more thrilling than the Kassem Revolution, he nodded, replying, “You bet. We had just chased a baby elephant and drawn blood samples. I can still see Klaus with his Dewar flasks in both hands as these giants charged us. We really had to hurry!” Painting remains, along with his cello, Riegel’s alternative dedication, besides medicine and family that have become even more so impor-

The final words on Klaus Riegel I leave to Klaus Betke, his former chairman, now 95 years old: “A universal genius: a brilliant artist; an excellent cellist; an exact scientist; and a sympathetic, caring, admirable physician; all this embedded within a broad general education. At the same time, he has a good share of critical humor. We got along very well, and this was equally true for our wives. Our work together became a cordial friendship.”

References

1. Bartels H, Hilpert P, Riegel K. Gas

exchange and cardiac output in nonanaesthetized goat kids and ewe lambs during the first weeks of life [German]. Arch Ges Physiol. 1963;277:61–75 2. Nelson NM. Historical perspectives: perinatal profiles: Clem Smith: a gentle gardener. NeoReviews. 2008;9:e137– e141 3. Nelson NM, Smith CA, Cherry RB, Riegel K. The diffusion factor and the effective capillary blood volume of the lungs in idiopathic respiratory distress syndrome of newborn infants [German]. Monatsschr Kinderheilk. 1967;115:224 –225 4. Nelson NM, Riegel KP. A schematic approach to acid-base therapy in the newborn. Pediatrics. 1969;43:821– 826 5. Benesch R, Benesch RE. The effect of organic phosphates from the human erythrocyte on the allosteric properties of hemoglobin. Biochem Biophys Res Commun. 1967; 26:162–167 6. Versmold H, Wenner J, Riegel K. Changes of blood oxygen affinity and capacity and red cell 2,3-diphosphoglycerate evoked by exchange transfusion with ACD preserved blood in newborn infants: influences on oxygen supply of tissues and erythropoiesis. Z Kinderheilk. 1972;113:1–18 7. Bartels H, Riegel K, Wenner J, Wulf H. Perinatale Atmung. Berlin, Germany: Springer; 1972 8. Versmold HT, Linderkamp O, HolzNeoReviews  69

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mann M, Strohhacker I, Riegel KP. Limits of tcPo2 monitoring in sick neonates: relation to blood volume, peripheral blood flow, and acid base status. Acta Anaesth Scand Suppl. 1978;68:87–90 9. Philip AGS. Historical perspectives: perinatal profile: Alexandre Minkowski: founder of “biology of the neonate.” NeoReviews. 2008;9:e5– e7 10. Versmold HT, Kitterman JA, Phibbs RH, Gregory GA, Tooley WH. Aortic blood pressure during the first 12 hours of life in infants with birth weight 610 to 4220 grams. Pediatrics. 1981;67:607– 613 11. Linderkamp O. Placental transfusion: determinants and effects. Clin Perinatol. 1982;9:559 –592 12. Linderkamp O, Versmold HT, Riegel

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KP, Betke K. The contribution of red cells and plasma to blood viscosity in preterm and full-term infants and adults. Pediatrics. 1984; 74:45–51 13. Bauer K, Bovermann G, Roithmaier A, Gotz M, Proiss A, Versmold HT. Body composition, nutrition, and fluid balance during the first two weeks of life in preterm neonates weighing less than 1500 grams. J Pediatr. 1991;118:615– 620 14. Bauer K, Cowett RM, Howard GM, vanEpp J, Oh W. Effect of intrauterine growth retardation on postnatal weight change in preterm infants. J Pediatr. 1993; 123:301–306 15. Bauer K, Pyper A, Sperling P, Uhrig C, Versmold H. Effects of gestational and postnatal age on body temperature, oxygen con-

sumption, and activity during early skin-toskin contact between preterm infants of 25–30-week gestation and their mothers. Pediatr Res. 1998;44:247–251 ¨ sterlund 16. Riegel K, Ohrt B, Wolke D, O K. The development to the fifth year of life of infants born at risk. The Arvo-Ylppo¨Newborn-Follow-up-Study in Southern Bavaria and Southern Finland [German]. Stuttgart, Germany: Enke; 1995 17. Raivio K. Historical perspectives: perinatal profiles: Arvo Ylppo¨: little big man. NeoReviews. 2010;11:e169 – e173 18. Riegel K, Bartels H, Buss IO, et al. Comparative studies of the respiratory functions of mammalian blood. IV. Fetal and adult African elephant blood. Resp Physiol. 1967;2:182

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Perinatal Profiles: Bengt Robertson: A Pioneer of Surfactant Research Henry L. Halliday,* Christian P. Speer†

Introduction

The Underpinnings of Neonatal/Perinatal Medicine Dr Halliday has disclosed that he is a consultant for Chiesi Farmaceutici. Dr Speer has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

Bengt Robertson, a Swedish pediatric pathologist, teamed up with his countryman Go¨ran Enhorning, an obstetrician, in the 1960s and 1970s to conduct seminal basic research on surfactant replacement in animal models of respiratory distress syndrome (RDS). This research formed the foundation for the very successful randomized clinical trials of natural surfactant replacement for RDS in the 1980s and 1990s.

The Early Years

Bengt Robertson was born in Stockholm in 1935, just 6 years after another Swede, Kurt van Neergaard, first demonstrated the importance of pulmonary surfactant for normal lung function. (1) Robertson was educated at So¨dra Latins Gymnasium in Stockholm and graduated from high school in 1953 before studying medicine at the Karolinska Institutet. He graduated as MD in 1960, and in 1968, he successfully defended his PhD thesis entitled “The intrapulmonary arterial pattern in normal infancy and in transposition of the great arteries” at the Karolinska Institutet in Stockholm. In 1970, he was appointed as a Consultant in Pediatric Pathology at St. Go¨ran’s Hospital in Stockholm, and from 1974, he was Director of the *Honorary Professor of Child Health, Queen’s University Belfast; retired Consultant Neonatologist, Regional Neonatal Unit at Royal Maternity Hospital, Belfast, Northern Ireland. † Chairman of Pediatrics, University Hospital of Wurzburg, Wurzburg, Germany.

Division for Experimental Perinatal Pathology in the Department of Women and Child Health at the Karolinska Institutet.

Early Surfactant Studies

At least two unsuccessful trials of surfactant replacement for RDS in preterm neonates were completed in the 1960s. (2)(3) The surfactant used in these trials was dipalmitoylphosphatidylcholine, and it was administered by aerosolization. Robertson and Enhorning reasoned that natural surfactant administered by direct instillation into the lungs would be more effective, and they designed some animal studies to prove this. First, they showed that natural surfactant instilled into the tracheas of immature rabbits was an effective treatment for RDS. (4)(5) Second, they believed that successful use of surfactant necessitated instillation before the first breath, (5) but in subsequent experiments, they showed that pharyngeal deposition of natural surfactant prevented or ameliorated RDS in preterm rabbits. (6)(7) In 1978, with colleagues in Toronto, Robertson and Enhorning showed that preterm primates (rhesus monkeys) also responded well to natural surfactant treatment, with improvement in lung morphology and ventilatory status, (8)(9) paving the way for subsequent clinical trials of surfactant in preterm neonates.

The First Clinical Trials

In preparation for the first clinical trials of surfactant replacement, Robertson needed to find a clinical chemist to help him develop a surfactant NeoReviews   71 NeoReviews Vol.11 No.9 September 2010 e471

preparation suitable for treating human babies. About 1980, he met Tore Curstedt from the Department of Clinical Chemistry at the Karolinska Institutet and together they developed surfactants prepared from bovine and porcine lungs. Incidentally, it was also in 1980 that Tetsuro Fujiwara reported the first successful administration of a modified bovine surfactant in human newborns in Japan. (10) After some preliminary studies, Curstedt and Robertson opted for the porcine preparation, which they called Curosurf, a name derived from the first two letters of their surnames. (11) Robertson assembled a multinational team of neonatologists to participate in a number of clinical trials using Curosurf (later to be known as poractant alfa). The first of these trials, conducted from 1985 to 1987, demonstrated that Curosurf reduced pulmonary air leaks and neonatal mortality in preterm infants who had severe RDS. (12) Subsequent trials defined dosing regimens, (13)(14) the optimal timing of treatment, (15)(16)(17) and the role of the combination of continuous positive airway pressure and surfactant. (18)(19) Robertson was the coordinator and driving force behind these international clinical trials, which helped to define the optimal treatment regimens for surfactant in the management of preterm infants who had RDS. (20) Without doubt, the contribution of Bengt Robertson to the development of pulmonary surfactant was immense and led to the saving of many hundreds of thousands of lives of preterm babies worldwide. In 1996, he was awarded the King Faisal International Prize for Medicine, jointly with Tetsuro Fujiwara, for their research on surfactant that led to improved survival of the preterm infant. 72      NeoReviews e472 NeoReviews Vol.11 No.9 September 2010

Later Studies and Awards

While enduring a number of health problems, Robertson continued his studies with surfactant until his untimely death in 2008 at the age of 73 years. (21) His research output was huge, with five textbooks and more than 700 publications, including about 270 original articles and about 150 review papers in addition to numerous abstracts and letters. In later years, his research was directed toward the development of a synthetic surfactant containing proteins, which would avoid the need for biologic materials, (22)(23)(24) the last of these papers being published posthumously. These rabbit studies suggested that both surfactant proteins B and C are needed for optimal function of a synthetic surfactant. (23)(24) This work continues in the capable hands of Robertson’s close colleagues, Tore Curstedt and Jan Johansson, and clinical trials are expected in the near future. Apart from the King Faisal Prize, Robertson received many other awards and honors for his major contribution to surfactant research. These included: Fellowship of the Royal College of Physicians of Edinburgh in 1996, the Hilda and Alfred Eriksson’s Prize awarded by the Royal Swedish Academy of Sciences in 1998 (jointly with Tore Curstedt), the Maternite Prize of the European Association of Perinatal Medicine in 2002, and the Lars Werko Prize awarded by the Heart Lung Foundation in 2004 (jointly with Tore Curstedt).

Other Interests and Talents

In addition to his 700 publications, Bengt Robertson published three books of short stories and poetry early in his career: Nachspiel in ¨ ga in 1970, and 1967, Nefertites O

Naturens Gong in 1975. Later in life, he learned to write Haiku poetry after a visit to Japan to undertake collaborative research with his long-time friend Tsutomu Kobayashi. On returning to Stockholm, he became a very active member of the Swedish Haiku Association and won competitions for his poems. In addition to his creative writing and poetic talents, Robertson spoke many languages fluently and was a gifted musician, playing piano, flute, trumpet, and tuba in the Jubilee Jazz band. The band, which specialized in Dixieland music, played at Robertson’s funeral in Stockholm in February 2009. Ian Laing from Edinburgh composed and played a reel on his fiddle as a tribute at the funeral. Also at this great but sad occasion were colleagues and friends from Brazil, China, France, Germany, Italy, Japan, Norway, United Kingdom, and, of course, Sweden, indicating the great esteem with which Robertson was held worldwide.

Final Word

On hearing of Robertson’s death, Colin Morley from Melbourne commented, “He was one of my research heroes since I was a fellow in the 1970s when I read his seminal papers about surfactant in rabbit pups. The extraordinary thing about Bengt was that he continued to do very relevant and high-quality research on surfactant all his life. He was the primary leader in surfactant research all his working life, continuing to produce innovative and significant findings right up to the end.” (21) He will be remembered by all those who knew him and who were profoundly influenced by both his teaching and his warm and welcoming personality.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specification • Know the management of RDS, including surfactant replacement.

References

1. Von Neergaard K. Neue Auffassungen

u¨ber einen Grundbegriff der Atemmechanik. Die Retraktionskraft der Lunge, abha¨ngig von der Oberfla¨chenspannung in den Alveolen. Z Gesamte Exp Med. 1929;66: 373–394 2. Robillard E, Alarie Y, Dagenais-Perusse P, Baril E, Guilbeault A. Microaerosol administration of synthetic beta-gammadipalmitoyl-L-alpha-lecithin in the respiratory distress syndrome: a preliminary report. Can Med Assoc J. 1964;90:55–57 3. Chu J, Clements JA, Cotton EK, Klaus MH, Sweet AY, Tooley WH. Neonatal pulmonary ischemia. I. Clinical and physiological studies. Pediatrics. 1967;40:709 –782 4. Enhorning G, Robertson B. Lung expansion in the premature rabbit fetus after tracheal deposition of surfactant. Pediatrics. 1972;50:58 – 66 5. Enhorning G, Grossman G, Robertson B. Tracheal deposition of surfactant before the first breath. Am Rev Respir Dis. 1973; 107:921–927 6. Robertson B, Enhorning G. The alveolar lining of the premature newborn rabbit after pharyngeal deposition of surfactant. Lab Invest. 1974;31:54 –59 7. Enhorning G, Robertson B, Milne E, Wagner R. Radiologic evaluation of the premature newborn rabbit after pharyngeal deposition of surfactant. Am J Obstet Gynecol. 1975;121:475– 480

8. Cutz E, Enhorning G, Robertson B,

Sherwood WG, Hill DE. Hyaline membrane disease. Effect of surfactant prophylaxis on lung morphology in premature primates. Am J Pathol. 1978;92:581–594 9. Enhorning G, Hill D, Sherwood G, Cutz E, Robertson B, Bryan C. Improved ventilation of prematurely delivered primates following tracheal deposition of surfactant. Am J Obstet Gynecol. 1978;132: 529 –536 10. Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T. Artificial surfactant therapy in hyaline-membrane disease. Lancet. 1980;i:55–59 11. Halliday HL, Speer CP. Bengt Robertson: a surfactant pioneer. Biol Neonate. 2002;82:272–273 12. Collaborative European Multicenter Study Group. Surfactant replacement therapy for severe neonatal respiratory distress syndrome: an international randomised clinical trial. Pediatrics. 1988;82:683– 691 13. Speer CP, Robertson B, Curstedt T, et al. Randomized European multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: single versus multiple doses of Curosurf. Pediatrics. 1992;89:13–20 14. Halliday HL, Tarnow-Mordi WO, Corcoran JD, Patterson CC. Multicentre randomised trial comparing high and low dose surfactant regimens for the treatment of respiratory distress syndrome (the Curosurf 4 trial). Arch Dis Child. 1993;69: 276 –280 15. Egberts J, de Winter JP, Sedin G, et al. Comparison of prophylaxis and rescue treatment with Curosurf in neonates less than 30 weeks’ gestation: a randomized trial. Pediatrics. 1993;92:768 –774 16. Walti H, Paris-Llado J, Breart G, Couchard M. Porcine surfactant replacement therapy in newborns of 25–31 weeks’ gestation: a randomized, multicentre trial of prophylaxis versus rescue with multiple low doses. The French Collaborative Multicen-

tre Study Group. Acta Paediatr. 1995;84: 913–921 17. Bevilacqua G, Parmigiani S, Robertson B. Prophylaxis of respiratory distress syndrome by treatment with modified porcine surfactant at birth: a multicentre prospective randomized trial. J Perinat Med. 1996;24: 609 – 620 18. Verder H, Robertson B, Greisen G, et al. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. DanishSwedish Multicenter Study Group. N Engl J Med. 1994;331:1051–1055 19. Verder H, Albertsen P, Ebbessen F, et al. Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 weeks’ gestation. Pediatrics. 1999; 103:e24 20. Robertson B, Halliday HL. Principles of surfactant replacement. Biochim Biophys Acta. 1998;1408:346 –361 21. Halliday HL, Speer CP. Bengt Robertson (1935–2008): a pioneer and leader in surfactant research. Neonatology. 2009;95: VI–VIII 22. Almlen A, Stichtenoth G, Robertson B, Johansson J, Curstedt T. Concentration dependence of a poly-leucine surfactant protein C analogue on in vitro and in vivo surfactant activity. Neonatology. 2007;92: 194 –200 23. Almlen A, Stichtenoth G, Linderholm B, et al. Surfactant proteins B and C are both necessary for alveolar stability at end expiration in premature rabbits with respiratory distress syndrome. J Appl Physiol. 2008;104: 1101–1108 24. Almlen A, Walther FJ, Waring AJ, Robertson B, Johansson J, Curstedt T. Synthetic surfactant based on analogues of SP-B and SP-C is superior to single-peptide surfactants in ventilated premature rabbits. Neonatology. 2010;98:91–99

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Perinatal Profiles: Bent Friis-Hansen: A Danish Pioneer of Neonatology Gorm Greisen, MD*

Introduction

The Underpinnings of Neonatal/Perinatal Medicine Author Disclosure Dr Greisen has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

Bent Julius Friis-Hansen was the prime mover in developing neonatology as a pediatric field in Denmark starting in 1964. He had been a cofounder of the European Club of Pediatric Research in 1959, which evolved into the European Society for Pediatric Research. He and his American colleagues Leo Stern and later William Oh led the International Perinatal Collegium, an informal group of pioneers from both sides of the Atlantic, through a series of biannual meetings from 1971 until he retired in 1990. (1)

An Immature and Rebellious Boy

Friis-Hansen was born in 1920 in Svendborg, a small town in Southern Funen. The primary income of the town came from shipping, and all families had fathers and brothers on the high seas. When the young Bent and his older brother were in kindergarten, the woman who taught them to write decided that they should be in primary school, in grades 2 and 3, respectively. At that time, Bent was only 5 years old. He later wrote that he probably was too immature for his class, which was the reason why he had frequent conflicts with teachers. His dyslexia and problems with reading also may have contributed. He often shirked school, preferring the free life of a young boy to schoolwork. When he started high school, staying quiet in class still was a problem for him. His father died when he was 16, and his mother and elder *Department of Neonatology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. 74     NeoReviews

brother moved to Copenhagen. He remained in Svendborg, living with friends of the family for the last year of his high school. He wrote that the conflicts with teachers persisted. Although the head master often threatened to expel him from school, he got his certificate, joined his mother in Copenhagen, and started the study of medicine. To make it to his last examination in January 1945, he missed a meeting of the resistance group of which he was a member. Leaving the examination room, he received a message that the Gestapo of the German occupation forces had been informed about the group and had taken them to prison. Four of them were later executed. Friis-Hansen lived under cover until the liberation of Denmark in May 1945.

Rapidly Into Research

The first year of clinical practice was spent in Kolding, Western Denmark, doing internal medicine and surgery. Friis-Hansen already was engaged in research, publishing first on glucose tolerance of partially hepatectomized rabbits, then on glucose tolerance in artificial diphtheria toxemia. One evening, a newborn was brought in who had been found on the railway track, presumably having been delivered on the toilet of the train and fallen directly onto the tracks. The mother was found and reunited with her child. Friis-Hansen cited this event as one of the sources for his life’s work in neonatology. Back in Copenhagen and working in the medical department of Frederiksberg Hospital, he published on gastric acid production after histaNeoReviews Vol.11 No.11 November 2010 e613

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mine stimulation in 12 febrile adult patients in the ward. Perhaps because of his talent and energy and perhaps because of his service in the resistance during the war, the professor of surgery at Rigshospitalet, Erik Husfeldt, who himself had played a central role in the resistance movement, mediated a contact with a blood bank in Boston. While Friis-Hansen prepared himself by reading everything he could find on blood transfusions, he was informed that they had found an American who, as Friis-Hansen writes in his autobiography, hopefully was a better qualified physician. As an alternative he was invited to join the team of the newly appointed professor in surgery at the Peter Bent Brigham Hospital in Boston, the 32-year-old Francis D. Moore. FriisHansen borrowed money and left Denmark. On his arrival in Boston, he obtained a fellowship from the American-Scandinavian Foundation and worked from 1948 to 1950 as a research fellow in surgery at Harvard in Dr Moore’s laboratory.

within 1 hour. Moore also was a good host to a young and somewhat miserable stranger from postwar Denmark. It became a happy time.

Heavy Water

Friis-Hansen joined a team of young colleagues who refined the falling drop method to measure the relative abundance of heavy water. In principle, a small drop of water obtained by distillation of a sample of blood was allowed to fall through a carefully temperature-controlled column of o-fluoro-toluene (Fig. 1). The group refined the method to an astonishing precision of 0.0012 vol% deuterium/ normal water in a blood sample of 150 to 200 mL. (2) Bent FriisHansen’s wife once told me, however, that this was not easy; one late

night, the instrument was thrown through the window into the street. Friis-Hansen studied inpatients in the Children’s Hospital in Boston, (3) and after his return to Copenhagen, he studied inpatients first at Rigshospitalet during his years as a research fellow of the professor of pediatrics at Rigshospitalet, Preben Plum, and later in Queen Louise’s Children’s Hospital as “reservelæge” with professor Oluf Andersen. The measurements of deuterium in Copenhagen were carried out at the department of biologic isotope research at the Institute of Zoophysiology headed by Professor Hans Ussing. The money for the very expensive deuterium came from many sources. This work led to six publications and a Doctor of Medical Sciences thesis

Happy Postwar Days in Boston

Moore was a pioneer, using the new advances of the physical sciences that had produced radioactive isotopes of hydrogen, sodium, and potassium. These achievements had made it possible to study the fluid spaces of the human body in health and disease. Moore was particularly interested in burns, but his laboratory hosted young researchers from many countries who used this new methodology in other applications. Moore was an extraordinary leader. He had reported measurement of total body water using the indicator dilution principle and intravenous administration of the nonradioactive isotope of deuterium in the form of heavy water in Science in 1946. Moore had shown that equilibrium takes place e614 NeoReviews Vol.11 No.11 November 2010

Figure 1. The instrument used for determining the deuterium concentration in body

fluids. By turning the handle from S1 to S2, a well-defined volume is pressed through the glass tubing and a small drop is formed at the end H. The rate of falling of the drop in the cylinder with o-fluoro-toluene is proportional to gravity, and gravidity is proportional to the concentration of heavy water. Reprinted with permission from Keston et al. J Bio Chem. 1938. NeoReviews  75

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in 1956. Before, the only data available had come from desiccation of dead human fetuses and a few dead newborns. Friis-Hansen showed that the total body water decreases from 79% on the first day after birth to 58% at puberty. These numbers fit in perfectly with desiccation data from the fetus and in vivo studies in adults (Fig. 2). He also showed that the decrease in total body water is exclusively due to a decrease in extracellular water, whereas intracellular water is nearly constant from birth to puberty. These conclusions are still valid. Friis-Hansen was a tall man, and his friend and coauthor, Jørgen Vesterdal, later told me that often during those early years, Friis-Hansen’s head disappeared in clouds of heavy water.

Africa and Nutrition

In 1957, Friis-Hansen again contacted Husfeldt. Husfeldt was born in Indonesia, and after the war, he had considerable international activity based at the school of anesthesia and intensive care in Copenhagen that had been developed during the polio epidemic during which hundreds of paralyzed patients were manually ventilated until recovery. Husfeldt had become a World Health Organization (WHO) advisor. Friis-Hansen wanted to go the Far East, but Husfeldt advised him to go to Africa as an expert in nutrition. Friis-Hansen said that he was not interested in Africa and that he was not an expert in nutrition. Husfeldt told him that nutrition was easy to learn and that Africa was unknown and, therefore, twice as interesting. Friis-Hansen spent 1 year in the Northern province of Northern Rhodesia (now Zambia) with a Scottish parasitologist, Fergus McCullough. He found widespread symptoms of vitamin A deficiency in children (4) and devised plans for interventions. He wrote that the plans were lost 76     NeoReviews

Figure 2. Total body water and intracellular and extracellular water during childhood. Each point represents the data from clinical investigation of a child admitted to the hospital in Boston or Copenhagen. The fetal values were taken from the literature and represent averages obtained by desiccation of dead fetuses. Reprinted with permission from Friis-Hansen B. Changes in body water compartments during growth [thesis]. Acta Paediatr Suppl. 1957;46(suppl 110):1– 68.

during the process of independence in the following years, but he remained active for WHO in childhood nutrition, and Africa stayed in his mind.

The Neonatal Intensive Care Unit at Rigshospitalet

Professor Trolle at the department of obstetrics and professor Plum at the department of pediatrics at Rigshospitalet in Copenhagen had agreed that a dedicated person was needed to develop the new field of neonatology. Thus, a department with a separate medical and nursing staff and a separate budget was established in 1964, with Friis-Hansen as the head. Rigshospitalet at the time was

state-owned and had a particular responsibility for research and developing highly specialized care for the small Danish nation (population: 5 million). At the time, it had been only 54 years since Rigshospitalet had introduced the first pediatric hospital department in the country, and it was only during the preceding 10 years that the country’s regional hospitals had developed pediatric departments of their own. Developing neonatology required practical sense. Dr R. Cooke from South Africa helped to start intensive care of newborns and, in particular, mechanical ventilation. In 1967, the group first published the results of assisted ventilation in 14 babies of 28 to 37 weeks gestational age in NeoReviews Vol.11 No.11 November 2010 e615

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which 5 babies survived. (5) FriisHansen wrote: “No definite criteria were used in the selection of infants for artificial ventilation. Initially, only those infants that were clinically moribund and in gross respiratory and circulatory collapse, were subjected to this treatment.” The inspiratory pressures used ranged from 15 to 40 cm H2O, and often negative pressure was used during expiration “to overcome the resistance in the narrow naso-tracheal tube.” In an addendum, he wrote, “Since the completion of this study a further 18 infants have been treated on the respirator with 9 survivals. The lowest weight of an infant that survived the treatment being 1120 g.” The survival rate for such babies only improved slightly (Table 1), until George Gregory presented his results using continuous positive airway pressure (CPAP) delivered by endotracheal tube at the International Perinatal Collegium in August 1971. This principle was rapidly adopted at Rigshospitalet, and results improved (Table 2). Soon, a high degree of centralization of preterm deliveries to Rigshospitalet from all of Eastern Denmark was achieved. Jens Kamper worked with Friis-Hansen in this early period, (6) published several papers, and wrote his thesis on treat-

Mechanical Ventilation of Newborns*

Table 1.

Birthweight (g)

Survivors/ Total Infants