Emerging Topics and Controversies in Neonatology 9783030288280, 9783030288297

Table of contents :
Contents
Part I: The Fetus
Chapter 1: Pregnancy–Related Complications and Preterm Delivery
Introduction
Prematurity
Risk Factors for Prematurity
Cervical Length Screening
Cervical Cerclage
Vaginal Progesterone
Preterm Birth: Intrapartum Care
Magnesium Sulfate
Threshold of Viability
Non-cephalic Presentation
Group B Streptococcus
Stillbirth Prevention and Fetal Growth Surveillance
International: ‘Ending Preventable Stillbirth’
UK: Saving Babies’ Lives
Each Baby Counts
Fetal Growth Restriction
Customised Growth Charts
Fetal Dopplers
Early Onset, Small for Gestational Age
Late Onset SGA
Dawes Redman CTG
Impact on Neonates
Conclusion
References
Chapter 2: Maternal Chronic Conditions and the Fetus
Pre-conception Care
Epilepsy
Preconception Advice
Maternal and Fetal Implications
Delivery and Postnatal
Cardiovascular Disease
Preconception Advice
Maternal and Fetal Implications
Delivery and Postnatal
Hypertension
Preconception Advice
Maternal and Fetal Implications
Delivery and Postnatal
Respiratory Disease
Asthma
Maternal and Fetal Implications
Tuberculosis
Maternal and Fetal Implications
Postnatal
Cystic Fibrosis
Preconception Advice
Maternal and Fetal Implications
Gastro-Intestinal Disorders
Inflammatory Bowel Disease
Maternal and Fetal Implications
Delivery and Postnatal
Obstetric Cholestasis
Maternal and Fetal Implications
Delivery and Postnatal
Chronic Renal Disease
Maternal and Fetal Implications
Delivery and Postnatal
Connective Tissue Disorders
Systemic Lupus Erythematosus
Preconception Advice
Maternal and Fetal Implications
Delivery and Postnatal
Rheumatoid Arthritis
Maternal and Fetal Implications
Antiphospholipid Syndrome
Maternal and Fetal Implications
Metabolic and Endocrine Disorders
Diabetes
Preconception Advice
Maternal and Fetal Implications
Delivery and Postnatal
Endocrinology
Hyperthyroidism
Maternal and Fetal Implications
Hypothroidism
Maternal and Fetal Implications
Pituitary Disease
Maternal and Fetal Implications
Postnatal Care
Adrenal Disease
Maternal and Fetal Implications
Haematological Disorders
Thrombocytopenia
Maternal and Fetal Implications
Delivery and Postnatal
Anaemia
Maternal and Fetal Implications
Postnatal
Sickle Cell Disease
Preconception Advice
Maternal and Fetal Implications
Maternal Mental Health
Maternal and Fetal Implications
Dermatological Disorders
Maternal and Fetal Implications
Maternal Life Saving Therapies
Extra-Corporeal Membrane Oxygenation (ECMO)
Peri-Mortem Caesarean Section (Resuscitative Hysterotomy)
Summary
References
Chapter 3: Artificial Gestation
Introduction
Definition
Animal Models of Ectogestation
Current State of Science
Potential Applications of Ectogestation
Ethical Questions
Ectogestation: Research Ethics
Who Should Be Enrolled in Trials?
When Would Trials Be Ethical?
Ectogestation: Clinical Ethics
The Concept of Viability
Viability and Neonatal Care
Viability and Obstetric Care
Conclusion
References
Part II: The Term Infant: Evidence-Based Approach to Management
Chapter 4: Management of the Depressed Newborn; to Cool or Not to Cool
A Case Study
Hypoxic-Ischaemic Encephalopathy
Which Babies Will Most Benefit from Therapeutic Hypothermia?
Secondary Energy Failure
Why May Cooling Not Be Beneficial for All Babies Who Are Depressed After Birth?
Why May Some Babies with HIE Not Benefit from Cooling?
Severity of Encephalopathy
Pattern of Brain Injury
What Objective Early Bedside Biomarkers of Brain Injury Are Available That May Allow Us to Select Babies for Cooling?
When Should Cooling Be Commenced? Switching Off the Overhead Heater
Cooling Outside of Protocol, Cooling Longer, Deeper and Smaller
Cooling After Sudden Unexpected Postnatal Collapse
Therapeutic Hypothermia for Mild HIE
Novel Biomarkers for Selecting Babies for Cooling?
Back to the Case Study
Conclusions
References
Chapter 5: Neonatal Hypotonia
Features in the History
The Anatomical Perspective: Central and Peripheral Hypotonia
Clinical Examination
Neurological Examination
Investigations
Genetic Investigations
Cranial Imaging
Nerve Conduction Studies/Electromyography
Creatinine Kinase and Other Blood Investigations
Muscle and Nerve Biopsy
Lumbar Puncture
Specific Conditions
Spinal Muscular Atrophy
Classification of SMA
Genetics of Spinal Muscular Atrophy
Specific Treatment for SMA
Non-5q SMA
Congenital Myotonic Dystrophy
Myotonic Dystrophy: Clinical Features in the Mother
Outcome of Congenital Myotonic Dystrophy
Genetics of Congenital Myotonic Dystrophy
Prader-Willi Syndrome
Genetics of Prader-Willi Syndrome
Neuromuscular Disorders by Anatomical Site
Peripheral Nerve: Neuropathies
The Neuromuscular Junction
Muscle Disorders: Muscular dystrophies and Myopathies
Congenital Muscular Dystrophies
Congenital Myopathies
Metabolic and Mitochondrial Disorders Presenting with Neonatal Hypotonia
References
Chapter 6: Critical Congenital Heart Disease
Introduction
Genetics
Teratogens
Chromosomal Microarray and DNA Analysis
Genome Sequencing
Modification of Short Term Outcome
Prenatal Diagnosis
Targets for Antenatal and Fetal Intervention
Decreasing the Likelihood of Premature and Early Term Delivery
Fetal Aortic Valvuloplasty
In-Utero Stabilisation
Maternal Hyperoxygenation Therapy
Decision Making Around Surgical Approach
Gestational Age and Birth Weight
Surgical Strategy
Hypoplastic Left Heart Syndrome and Variants: Staged Palliation for a Single Ventricle Circulation
Outcome Data
Mortality
Survival
Conclusions
References
Chapter 7: Evidence Based Approach to the Management of Persistent Pulmonary Hypertension of the Newborn (PPHN)
Introduction
What Is on the Horizon in this Area?
Etiology and Risk Factors
Pathophysiology
Approach to a Diagnosis
Delivery Room Resuscitation
Supportive Measures
Mechanical Ventilation
Specific Management
Inhaled Nitric Oxide
Alternative and Newer Therapies
Sildenafil
Milrinone
Prostacyclin
Bosentan
Magnesium Sulphate
Vasopressin
Extracorporeal Membrane Oxygenation
Long Term Outcome
Novel Therapies Under Investigation
Conclusions
References
Chapter 8: Neonatal Surgical Conditions: Congenital Diaphragmatic Hernia and Short Bowel Syndrome
Congenital Diaphragmatic Hernia
Antenatal Imaging and Prognosis
Genetic Testing
Antenatal Intervention
Neonatal Interventions
Ventilatory Strategy
Management of Pulmonary Hypertension
Role of Extracorporeal Membrane Oxygenation
Minimally Invasive Surgery (MIS)
Short Bowel Syndrome
Definition of Short Bowel Syndrome and Intestinal Failure
Management of Short Bowel Syndrome
Malabsorption and Dysmotility
Intestinal Failure Associated Liver Dysfunction (IFALD)
Central Venous Catheter Care
Surgical Management
Improve Absorptive Surface Area
Overcome Dysmotility and Stasis
Slow Down Intestinal Transit
Long Term Outcome
Survival
Intestinal Transplant
Adaptation and Enteral Autonomy (Growth, Development)
Conclusion
References
Chapter 9: Managing the Difficult Airway in a Neonate
Introduction
Definition of a ‘Difficult Airway’
Anticipation of a Difficult Airway
Equipment to Manage a Difficult Airway
Bougies
Indirect Laryngoscopy
Video Laryngoscopes for Neonatal Use
Airtraq®
Supra Glottic Airways
iGel© Supraglottic Airway Device
Digital Intubation
Nasal Intubation
Additional Airway Adjuncts
Difficult Airway Kit
Human Factors
Organisational Factors
Individual Factors
Team Working
Suggested Approach to the Patient with a Difficult Airway
Conclusions
References
Chapter 10: Sudden Unexpected Postnatal Collapse
The Challenges of Definition
The Relationship Between SUPC and SUDI
Extrinsic Risk Factors for SUPC
Controversies in SUPC
Skin to Skin Care (SSC) in the Post-partum Period
Therapeutic Hypothermia After SUPC
Medico-Legal Aspects of SUPC
Improving Safety in the Early Postpartum Period
Conclusion
References
Part III: The Very Preterm Infant: Controversies in Postnatal Management
Chapter 11: Mechanical Ventilation of the Preterm Infant
Introduction
Indications for Mechanical Ventilation
Ventilation Modes
Volume-Targeted Ventilation
High Frequency Oscillatory Ventilation
Positive End Expiratory Pressure and ‘Open Lung’ Ventilation
Neurally Adjusted Ventilatory Assist
Surfactant
Medications for Neonatal Intubation
Videolaryngoscopy for Teaching Neonatal Intubation
Extubating Preterm Infants
Conclusions
References
Chapter 12: Non-invasive Respiratory Support
Non-invasive Respiratory Support for Neonates
Perinatal Transition: From Breathing Liquid to Air
Pulmonary Aeration: The Significance of Establishing the Functional Residual Capacity and Tidal Volume at Birth
Respiratory Distress Syndrome in the Very Preterm Infant
Mechanical Ventilation As a Risk Factor for Bronchopulmonary Dysplasia
Developing the Concept of Nasal Continuous Positive Airway Pressure in Preterm Infants
Different Modes of Non-invasive Respiratory Support
Continuous Positive Airway Pressure
Water-Lock, or “Bubble-CPAP”
CPAP Devices with Variable Gas Flow
Comparison of Constant Flow CPAP and Variable Flow CPAP
Early Nasal CPAP from Birth
Nasal High-Flow Nasal Cannula Therapy
Rationale for Alternative Modes of Non-invasive Respiratory Support
Definition of Non-invasive Positive Pressure Ventilation
Clinical Applications of Non-invasive Positive Pressure Ventilation
Non-synchronised and Synchronised NIPPV
Nasal High-Frequency Oscillation Ventilation
Chronological and Disease Specific Considerations
What Could Be Next? A Glimpse at the Future
References
Chapter 13: Oxygen Management in Neonatal Care
History
Evidence from More Recent Trials
Oxygen Therapy in the Later Weeks of the Clinical Course
Oxygen Therapy in the Early Weeks of the Clinical Course
Implications for Patients
Achieved SpO2 Patterns
International Guidelines
Conclusions
References
Chapter 14: Patent Ductus Arteriosus: The Conundrum and Management Options
Introduction
Natural History of Closure of the PDA
PDA Diagnosis
Echocardiography Assessment
Conventional Echocardiography
Tissue Doppler Imaging and Speckled Tracking
The Utility of Electrical Velocimetry: Non-invasive Cardiac Output Monitoring. (ICON(™) Monitor/NICOM) [16]
Near Infra-Red Spectroscopy
Utility of Perfusion Index
Feasibility of Biomarkers at the Point of Care
The Conundrum of PDA Management [32]
Is Conservative Approach Always Safe?
Restrictive Versus Liberal Fluids?
Does Furosemide Cause Any Benefits or Harm?
Does Choice of Respiratory Support Have Any Effect on the PDA?
Does Use of Caffeine Affect PDA?
Does Phototherapy Affect PDA?
Prophylactic Approach: Should We Still Consider This?
Early Targeted Approach for PDA Closure
Symptomatic Approach
Which Drug to Choose Amongst the Pharmacological Options?
Indometacin Therapy
Treatment Regimens
Ibuprofen Therapy
Paracetamol Therapy
How Safe Are NSAIDS?
Surgical Ligation: Is This Still an Option?
Do Newer Surgical Techniques Offer Any Promise?
The Influence of Genetics on Ductal Patency and Management
Conclusions
References
Chapter 15: Glucocorticoid Treatment for Bronchopulmonary Dysplasia
Introduction
Corticosteroids: Mechanism of Action
Corticosteroids and Inflammation
Corticosteroids and the Lung
Natural and Synthetic Corticosteroids
Natural Corticosteroids
Synthetic Corticosteroids
Application of Glucocorticoids in Neonates
Systemic Glucocorticoids
Early Systemic Dexamethasone
Early Systemic Hydrocortisone
Late Systemic Glucocorticoids
Inhaled Glucocorticoids
Intratracheal Glucocorticoids
Issues that May Be Important when Considering Glucocorticoids in Newborn Care
Conclusions
References
Chapter 16: Feeding and Nutrition
Introduction: The Nutritional Vulnerability of Preterm Infants
Starting and Increasing Milk Feeds: What’s New?
Parenteral Nutrition
Milk Feeding and Necrotising Enterocolitis
Donor Human Milk and NEC
Probiotics and Risk of NEC or Sepsis
Conclusions
References
Chapter 17: Blood Pressure Management in the Very Preterm Infant: More than Just Millimetres
Introduction
Etiology of Low Blood Pressure and/or Circulatory Failure
During Transition
Etiology of Circulatory Failure Beyond the Transitional Period
Suggested Assessment Strategies
Blood Pressure Intervention Standards
Clinical Bedside Assessment
Ancillary Investigations
Echocardiography
NIRS for the Assessment of Organ Oxygenation and Perfusion
Non-invasive Cardiac Output Monitoring
Perfusion Index for the Assessment of Peripheral Arterial Perfusion
Treatment Options
Volume Expansion
Inotropes, Vasopressors and Inodilators
Corticosteroids
Proposed Intervention Strategies
Future Perspectives
References
Chapter 18: Retinopathy of Prematurity
Introduction
ROP Imaging Modalities
Fluorescein Angiography
Ultra-Wide Field Imaging (UWFI)
Optical Coherence Tomography (OCT) in Prematurity
ROP Risk Algorithms and Tools
Ocular Treatment Using Anti Vascular Endothelial Growth Factor
Summary
References
Part IV: Long Term Effects Following Extreme Prematurity
Chapter 19: Neurodevelopmental Problems
Introduction
How Do Survival Rates Impact on Disability Rates?
How Has Survival Changed over Time and What Impact Has This Had on Neurodevelopment?
How Does Survival Change with Increasing Gestational Age and What Impact Does This Have on Neurodevelopment?
What About Infants Born at 22/23 Weeks of Gestation and Infants Less Than 500 g Birthweight?
Predicting Neurodevelopmental Problems: What Impact Do Factors Other Than Prematurity Have on Developmental Prognosis?
Antenatal Factors
Post-natal Factors
Cerebral Palsy
Cognitive Outcomes
Challenges in Measuring Cognitive Outcomes in Preterm Birth
What Are the Rates of Cognitive Impairment?
What Is the Relationship Between Risk of Cognitive Deficit and Decreasing Gestational Age?
What Is the Effect of Sex on Cognitive Outcomes?
What Happens to the Cognitive Deficit as the Extreme Preterm Infant Gets Older?
Improvement over Time?
How Should We Screen for These Problems to Optimise the Chance of Early Recognition and Intervention?
Adult Outcomes
Collection and Use of Neurodevelopmental Outcome Data
Individuals and Families
Healthcare Systems
Commissioning
Conclusion
References
Chapter 20: Long Term Effects Following Extreme Prematurity: Respiratory Problems
Definitions
Lung Development
Lung Pathology and Imaging
Respiratory Infection and Morbidity
Lung Function
Unanswered Questions, Future Research Directions
Phenotypes and Mechanisms of Disease
Treatment: Infection
Treatment: Inhaled Therapies
Conclusion
References
Chapter 21: Behavioural and Educational Outcomes Following Extremely Preterm Birth: Current Controversies and Future Directions
Introduction
Attention, Social and Emotional Problems
Mental Disorders
Behavioural Outcomes: Current Controversies and Research Directions
Academic Attainment and Special Educational Needs
Developmental Delay or Developmental Deficit?
Supporting the Learning of Children Born Preterm
Delayed School Entry
The Need for Theory Driven Research
Summary
References
Part V: The Infant Born Near Term
Chapter 22: Early Outcomes in Babies Born Close to Term
Introduction
Definitions
Neonatal Morbidity
Breast Feeding
Neonatal Respiratory Disease
Obstetric Antecedents of Late Preterm and Early Term Birth
Antenatal Corticosteroids in Late Preterm and Early Term Labour
The Impact of Late Preterm and Early Term Birth on Families
Burden on Health Care Services
Implications for Clinical Practice
Conclusions
References
Chapter 23: Long Term Outcomes in Moderate and Late Preterm Infants
Introduction
Neurodevelopment
Infancy
Pre-school and School Age
Cognitive Functioning and School Performance
Behaviour and Psychiatric Outcomes
Adulthood
Respiratory Outcomes
Vulnerability of the MLP Lung
Infancy and Childhood Outcomes
Adolescence and Adulthood
Lung Function Studies
Hospitalisation and Health Services Use
Functional and Other Outcomes
Research Gaps
Conclusion
References
Part VI: General Principles in Neonatal Care
Chapter 24: Delivery Room Stabilisation
Introduction
Management of the Umbilical Cord After Birth
Re-introducing ‘Normal’ Cord Care
Alternatives to Immediate Cord Clamping
Updating the Guidelines
Practicalities
Temperature Optimisation
Uncompromised Babies
Instituting Therapeutic Hypothermia at the Right Time
Monitoring of Resuscitation
Heart Rate
Respiratory Function Monitoring
Airway Management
Continuous Positive Airway Pressure With or Without Surfactant
Sustained Lung Inflation
Laryngeal Mask Airways
Oxygen: How Much and When?
Term and Near-Term Infants
Preterm Babies (Below 37 Weeks of Gestation)
Very Preterm Babies (Below 28 Weeks of Gestation)
The Most Recent ILCOR Evidence Evaluation for Initial Oxygen Concentration in Babies Requiring Respiratory Support
When Should We Stop Resuscitation?
Resuscitation and Stabilisation of Infants Born at the Margins of Viability
A Cautionary Note
(…What you read today was accurate when written, but may not be accurate when you read it, and what is used today may become obsolete in future)
References
Chapter 25: Principles of Family-Oriented and Family-Integrated Care
Introduction
Parental Presence On Ward Rounds
Negatives
Why Should Parents Have 24/7 Access to Their Baby?
Concerns Over 24 H Access
Siblings on the Neonatal Unit
Accountability and Delegation
Conclusion
References
Chapter 26: Quality and Patient Safety in Neonatal Care
Quality and Safety: Terminology and Frameworks
Clinical Microsystems
Assessing and Monitoring the Quality of Neonatal Care
Quality Indicators for Comparative Performance Measures
Quality Indicators for Improvement
Improving the Quality of Care
The Improvement Team
Collaboration
Aim: What Are We Trying to Accomplish?
Measurement: How Will We Know That a Change Is an Improvement?
What Changes Can We Make That Will Result in an Improvement?
Plan-Do-Study-Act Cycles
Ensuring Success and Sustainability of QI Projects
Leadership and Unit Culture
Why Is Quality Improvement Important in Neonatal Care?
Examples of Quality and Safety Improvement in Neonatal Care
QI Projects in Individual Units
Collaborative QI Projects
Conclusions
References
Chapter 27: Transport of the Sick Infant
Introduction
Physiological Effects of Transport on the Newborn
Thermoregulation in Neonatal Transport
Exposure to Vibration and Acceleration Forces
Exposure to Sound
Effect of Altitude
Working in the Transport Environment
Limitations of Transport Equipment to Deliver Mobile Intensive Care
Respiratory Support During Neonatal Transport
Managing the Baby with Difficult Oxygenation/Ventilation During Transport
Transporting the Infant with Hypoxic Ischaemic Encephalopathy Requiring Therapeutic Hypothermia
Communication Between Referring Unit, Receiving Unit and Transport Teams
Decision Making Around Inutero and Exutero Transfers Is Complex
In Utero Transfers
Role of a “Flying-Squad” to Attend Births in Neonatal Transport
Transport Team Skill-Mix
The Challenges of Pre-transport Stabilisation by Referring Units
Importance of a Robust Clinical Governance Programme to Reduce Risk in Neonatal Transport
Summary
References
Chapter 28: Neonatal Pain
Introduction
Development of the Nociceptive Brain
Cortical and Behavioural Measures of Pain
Assessment of Neonatal Pain
Long-Term Consequences of Neonatal Pain
The Burden of Neonatal Pain
Analgesic Treatment
Nonpharmacological Interventions
Prevention
Sweet Solutions
Swaddling, “Facilitated Tucking”, Touch, and Positioning
Nonnutritive Sucking
Skin-to-Skin Contact (Kangaroo Care)
Breast Feeding Analgesia
Pharmacological Treatment
Opioids
Morphine
Fentanyl
Remifentanil
Paracetamol
Topical Anesthetics
Conclusions
References
Chapter 29: Neonatal Infection
Neonatal Infection: Post Millennium But Still Not a Thing of the Past
Diagnostic Techniques and Biomarkers: Improvements and Future Promise
Molecular Tests
Biomarkers
Preventing Maternal to Infant Transmissions
Vaccinations to Prevent Vertical Transmission
Managing the Infant ‘At Risk’ of Early Onset Bacterial Infection
Antibiotic Choice, Duration and Governance
Treatment Adjuncts
References
Chapter 30: Withholding and Withdrawing Life-Sustaining Treatment
Introduction
Terminology and Biases
‘Good’ Palliative Care: Multi-Dimensional and Integrative
Optimal Delivery Models: Personalisation, Proximity and Trust
Communication: Broadening Concepts
Listening to Parents: Redefining Goals
Summary: The Last Chapter
References
Chapter 31: Effective Training in Neonatal Medicine
Simulation Based Training
In-Situ Simulation
Improving Fidelity
Rapid Cycle Deliberate Practice
Debriefing Techniques
Plus Delta
Advocacy with Enquiry
Narrative Debrief
Video Debriefing
Gather, Analyse, Summarise (GAS)
Debriefing: Moving from the Simulation Session to the Real World
Maintaining Simulation Standards
Technology Enhanced Learning: What Does the Future Hold?
References
Chapter 32: Genomics for the Neonatologist
Introduction
Important Concepts
Genomic Testing
Diagnostics
Diagnostic Yield
Effect on Management
Time to Reporting
Costs
Microbiology
Challenges for WGS on the Neonatal Unit
Interpretation of Variants
Incidental Findings
Prognostic Uncertainty
Rationing of Healthcare
Consent
Newborn Screening
References
Chapter 33: Research in the Newborn Period
Introduction
Informed Consent
Parental Role and Responsibility for Providing Consent
Validity of Informed Consent
Voluntariness
Information and Understanding
Competence
Different Forms of Consent
Prospective Consent
Waiver of Consent
Antenatal Notification and Consent
Deferred, Retrospective or Continuing Consent
Zelen’s Method of Consent
Opt-out
Parental Views on Consent
Research Outcomes
Advantages of Using Primary Composite Outcome
Statistical Efficiency
Financial Benefit
Importance of Individual Outcomes to Clinicians and Patients
Disadvantages of Using Primary Composite Outcomes
Selection of Components of a Composite Outcome
Reporting of Composite Outcomes
Contribution of Each Individual Component of the Composite Outcome
Clinical Interpretation
General Challenges in Delivering Research in the Neonatal Population
Conclusion
References
Chapter 34: Parent Perspectives of Neonatal Intensive Care
Initial Birth
Early Days
Communication
Psychological Care
Visitors
Parents of Non-premature Babies
Breastfeeding and Expressing
Transfers
Discharge
Index

Citation preview

Emerging Topics and Controversies in Neonatology Elaine M. Boyle Jonathan Cusack  Editors

123

Emerging Topics and Controversies in Neonatology

Elaine M. Boyle  •  Jonathan Cusack Editors

Emerging Topics and Controversies in Neonatology

Editors Elaine M. Boyle Department of Health Sciences George Davies Centre for Medicine University of Leicester Leicester UK

Jonathan Cusack Department of Health Sciences George Davies Centre for Medicine University of Leicester Leicester UK

Department of Neonatology University Hospitals of Leicester NHS Trust Leicester UK

Department of Neonatology University Hospitals of Leicester NHS Trust Leicester UK

ISBN 978-3-030-28828-0    ISBN 978-3-030-28829-7 (eBook) https://doi.org/10.1007/978-3-030-28829-7 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

Part I The Fetus 1 Pregnancy–Related Complications and Preterm Delivery������������������    3 Suzanna Dunkerton and Penny C. McParland 2 Maternal Chronic Conditions and the Fetus ����������������������������������������   19 Kate Jones, Abigail Anness, and Farah Siddiqui 3 Artificial Gestation����������������������������������������������������������������������������������   43 Dominic Wilkinson and Lydia Di Stefano Part II The Term Infant: Evidence-Based Approach to Management 4 Management of the Depressed Newborn; to Cool or Not to Cool������������������������������������������������������������������������������   59 Divyen K. Shah 5 Neonatal Hypotonia ��������������������������������������������������������������������������������   71 Robin Miralles and Deepa Panjwani 6 Critical Congenital Heart Disease����������������������������������������������������������  103 Katie Linter and Thomas Mukasa 7 Evidence Based Approach to the Management of Persistent Pulmonary Hypertension of the Newborn (PPHN)������������  119 Venkatesh Kairamkonda and Sumit Mittal 8 Neonatal Surgical Conditions: Congenital Diaphragmatic Hernia and Short Bowel Syndrome ��������  141 Yew-Wei Tan, Andrew Currie, and Bala Eradi 9 Managing the Difficult Airway in a Neonate ����������������������������������������  157 James Blythe and Jonathan Cusack

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Contents

10 Sudden Unexpected Postnatal Collapse ������������������������������������������������  179 Vix Monnelly and Julie-Clare Becher Part III The Very Preterm Infant: Controversies in Postnatal Management 11 Mechanical Ventilation of the Preterm Infant��������������������������������������  195 Kate Hodgson, Peter Davis, and Louise Owen 12 Non-invasive Respiratory Support ��������������������������������������������������������  211 Charles Christoph Roehr 13 Oxygen Management in Neonatal Care ������������������������������������������������  227 Ben Stenson 14 Patent Ductus Arteriosus: The Conundrum and Management Options ����������������������������������������  239 Kiran More and Samir Gupta 15 Glucocorticoid Treatment for Bronchopulmonary Dysplasia�������������  259 Tanja Restin and Dirk Bassler 16 Feeding and Nutrition������������������������������������������������������������������������������  275 Nicholas D. Embleton 17 Blood Pressure Management in the Very Preterm Infant: More than Just Millimetres��������������������������������������������������������������������  289 Eugene M. Dempsey and Elisabeth M. W. Kooi 18 Retinopathy of Prematurity��������������������������������������������������������������������  307 Samira Anwar and Aarti Patel Part IV Long Term Effects Following Extreme Prematurity 19 Neurodevelopmental Problems ��������������������������������������������������������������  323 Joe Fawke and Rebecca Lancaster 20 Long Term Effects Following Extreme Prematurity: Respiratory Problems������������������������������������������������������������������������������  351 John Lowe, Sarah J. Kotecha, and Sailesh Kotecha 21 Behavioural and Educational Outcomes Following Extremely Preterm Birth: Current Controversies and Future Directions������������  367 Jayne Trickett, Samantha Johnson, and Dieter Wolke Part V The Infant Born Near Term 22 Early Outcomes in Babies Born Close to Term������������������������������������  389 Elaine M. Boyle 23 Long Term Outcomes in Moderate and Late Preterm Infants������������  403 Jeanie L. Y. Cheong and Lex W. Doyle

Contents

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Part VI General Principles in Neonatal Care 24 Delivery Room Stabilisation��������������������������������������������������������������������  417 Victoria J. Monnelly, Sean B. Ainsworth, and Jonathan P. Wyllie 25 Principles of Family-Oriented and Family-­Integrated Care ��������������  437 Liz McKechnie and Kathy Dewhurst 26 Quality and Patient Safety in Neonatal Care����������������������������������������  447 K. Suresh Gautham 27 Transport of the Sick Infant��������������������������������������������������������������������  465 Joanna Behrsin and Andrew Leslie 28 Neonatal Pain ������������������������������������������������������������������������������������������  485 Ricardo Carbajal 29 Neonatal Infection������������������������������������������������������������������������������������  503 Janet Elizabeth Berrington and Eleri Jayne Williams 30 Withholding and Withdrawing Life-­Sustaining Treatment ����������������  517 Marlyse F. Haward and Annie Janvier 31 Effective Training in Neonatal Medicine ����������������������������������������������  531 Adam Bonfield and Jonathan Cusack 32 Genomics for the Neonatologist��������������������������������������������������������������  545 Richard Hastings and Abhijit Dixit 33 Research in the Newborn Period������������������������������������������������������������  559 Kamini Yadav and Elaine M. Boyle 34 Parent Perspectives of Neonatal Intensive Care������������������������������������  573 Samantha Batt-Rawden Index�������������������������������������������������������������������������������������������������������������������� 579

Part I

The Fetus

Chapter 1

Pregnancy–Related Complications and Preterm Delivery Suzanna Dunkerton and Penny C. McParland

Topics for Discussion in This Chapter • Prematurity prevention including identifying those at high risk and interventions such as cerclage, progesterone and cervical pessaries. • Intrapartum interventions to improve the outcome for the preterm neonate. • Delivery at the limits of viability. • Mode of delivery of the preterm breech baby. • International strategy on stillbirth prevention and the increase in iatrogenic prematurity. • Identification of fetal growth restriction.

Introduction It is inevitable that complications of pregnancy and their obstetric management will impact on the wellbeing of the newborn infant and the care provided by neonatologists. Almost all aspects of obstetrics will be encompassed by this principle. However, in this chapter we have endeavoured to focus on the aspects of obstetrics that are undergoing the greatest change at present and also have the greatest potential to impact on the newborn baby and its wellbeing. Although many of these changes are occurring internationally, particularly in the developed world, there is inevitably a focus on changes to practice within the UK. We have therefore focussed on prematurity (both prevention and intrapartum care) and prevention of stillbirth. Although the latter would seem intuitively to be less relevant to neonatal outcomes, the consequences of the changes in practice that have occurred will impact on the care of neonates especially with a potential increase in iatrogenic prematurity. S. Dunkerton · P. C. McParland (*) University Hospitals of Leicester NHS Trust, Leicester Royal Infirmary, Leicester, UK e-mail: [email protected] © Springer Nature Switzerland AG 2020 E. M. Boyle, J. Cusack (eds.), Emerging Topics and Controversies in Neonatology, https://doi.org/10.1007/978-3-030-28829-7_1

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Prematurity Preterm birth is the leading cause of perinatal morbidity and mortality in developed countries [1, 2]. 7.8% of babies in the UK in 2016 were born at less than 37 weeks of gestation [3]. Approximately one third of preterm births are ‘iatrogenic’ (e.g. due to conditions such as pre-eclampsia or fetal growth restriction). The remaining preterm births are spontaneous and may occur because of preterm labour with intact membranes or following preterm prelabour rupture of the membranes (PPROM). The majority of preterm births will arise in the apparently low-risk obstetric population. Whilst there are lifestyle changes that will impact on preterm birth risk for the population (such as smoking cessation and pregnancy spacing) there are as yet no reliable screening methods or interventions to offer to women in this group. Interventions are therefore usually targeted at women who are recognised as being at high risk of preterm birth [4]. Many major hospitals will have a specialist preterm birth antenatal clinic; however there is significant heterogeneity in practice between them in terms of investigations undertaken and interventions provided [5].

Risk Factors for Prematurity Risk factors for preterm birth include previous preterm birth, multiple pregnancy, congenital uterine anomaly and maternal smoking. Previous cervical surgery for cervical intraepithelial neoplasia, such as large loop excision of the transition zone and cone biopsy, is also now established as a risk factor for preterm birth. Hopefully with the introduction of the human papillomavirus (HPV) vaccine this will reduce the number of HPV positive cervical smear changes and reduce the number of cervical loop excisions undertaken. These risk factors are routinely screened for at the antenatal booking visit to allow appropriate targeted antenatal care. More recently, previous second stage Caesarean section has been identified as a risk factor for early preterm birth and late miscarriage [6–9] and is associated with a threefold increase in risk in delivery at less than 30 weeks gestation [7]. It has been suggested that this is caused by the interruption of the sphincteric muscle fibres around the cervix either due to unintentional surgical laceration of the cervix at the time of uterine incision or by the passage of the surgeon’s hand into the pelvis to disimpact the fetal head [7, 10]. This risk factor may gain greater importance in antenatal care as the rate of second stage Caesarean sections increases and that of mid-cavity and rotational instrumental deliveries decreases [11]. Novel systems such as the fetal pillow (Fig. 1.1) have been developed to aid disimpaction at second stage Caesarean section. These have been shown to reduce trauma to the fetal head and to reduce complex uterine extensions that can include the cervix [12]. However, it has yet to be demonstrated whether this will impact on the subsequent risk of prematurity in the next pregnancy.

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Fig. 1.1  This shows the positioning of the Fetal Pillow beneath the head of the baby, elevating the head within the maternal pelvis. (Figure from Safe Obstetric Systems, reproduced with permission)

Cervical Length Screening Women at high risk of preterm birth are typically offered cervical length assessment by transvaginal ultrasound in the second trimester. The exact timing and frequency of these assessments is not standardised. There is an established link between a short cervical length and subsequent preterm birth, with cervical length of less than 25mm in the second trimester being associated with an increased risk of preterm birth before 35 weeks [13]. The temporal relationship between the shortened cervix and subsequent delivery is not, however, reliably predictable.

Cervical Cerclage The purpose of assessment of cervical length in women at high risk of preterm birth is clearly to identify those in whom intervention can be offered to reduce the risk of preterm birth. The concept of the ‘incompetent’ cervix has now been refined and replaced with a model of a preterm parturition ‘syndrome’; with interaction between cervical function, vaginal flora, and the maternal immune system and inflammatory response [14]. Hence, the previous commonly used intervention of cervical cerclage has been challenged. Cervical cerclage is an intervention that has been widely used with a limited evidence base. The only previous randomised trial of cerclage carried out over 30 years ago indicated that its use conferred a reduction in risk of preterm birth before 33 weeks from 18 to 13% [15]. Further studies since then support a reduction in preterm birth risk for cerclage insertion in high risk women [16]. Cerclage insertion is now commonly used either as an elective procedure in women with multiple previous early preterm births, as an ultrasound-indicated procedure due to shortened cervix on scan, or as a ‘rescue’ procedure in women with a dilated cervix.

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Vaginal Progesterone It is, however, now clear that alternative interventions may have similar efficacy to cerclage in the prevention of preterm birth in the high risk population, most notably progesterone treatment and the use of the Arabin pessary. Progesterone has been used to reduce the risk of preterm birth in high risk women since 2003 [17, 18], particularly women with a short cervix on scan [19]. However, its use is controversial and clinical trials have given conflicting results regarding the benefit conferred. The largest, most recent UK trial suggested that it is of no benefit [20], although meta-analysis that includes this trial still favours progesterone use [21]. Internationally, guidelines differ, with advice from the American College of Obstetrics and Gynecology that states ‘a woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16–24  weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth’ [22] and UK advice which recommends it only in selected women with a cervix length of less than 25 mm [23]. It is commonly used as an alternative to cervical cerclage in women with a short cervix. A number of studies are now trying to compare the efficacy of progesterone with cervical cerclage and the Arabin pessary in order to identify the best treatment option [24]. The Arabin pessary is more commonly used in Europe and has the advantage of being inserted and removed in the outpatient setting without the need for anaesthesia (see Fig. 1.2). Abnormal vaginal flora, as indicated by a diagnosis of bacterial vaginosis especially in the first half of pregnancy, is recognised to have an association with preterm birth [25]. The role of routine screening and treatment with antibiotics remains controversial [26] and there is wide variation in the assessment and treatment of abnormal vaginal flora in the setting of the prematurity antenatal clinic [27].

Fig. 1.2  The Arabin pessary is a flexible silicone ring that sits within the vagina and supports the cervix. (Figure supplied by Dr. Birgit Arabin, reproduced with permission)

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Preterm Birth: Intrapartum Care The intrapartum management of preterm labour is focused on optimising the condition of the preterm neonate. Whilst tocolysis is an attractive option, there is no evidence that it reduces the chance of preterm birth [28, 29]. Instead the aim is to delay the inevitable preterm birth by a few days to permit interventions that may benefit the baby. There is limited evidence that this strategy improves neonatal outcome; however that may be due to the age and limitations of the trials that have been carried out. All trials of tocolysis have limited power to demonstrate any benefit to the baby, as the majority of women presenting with threatened preterm labour will deliver at term irrespective of interventions undertaken. Tocolytics in current UK use include the oxytocin receptor antagonist atosiban, and nifedipine [23]. They should only be used where there is no evidence of fetal or maternal compromise, and where delay in delivery may be of benefit to the baby. Commonly this time delay would be used for administration of corticosteroids, magnesium sulfate, and for consideration of transfer to a tertiary unit if needed. Corticosteroid administration prior to preterm deliveries is now routine practice to reduce risk of respiratory distress and its consequences. However maximal benefit is conferred if delivery is within a week of administration. If there is a significant time delay before preterm birth, then the risks of repeated course of steroids needs to be weighed up against the potential benefit. Current guidance is not to routinely give a second course of steroids but to consider it on an individual patient basis if there has been a significant time interval since the original course [23]. This is a horizon for future research.

Magnesium Sulfate Intrapartum magnesium sulfate administration improves neurodevelopmental outcome in preterm infants [30] but the timing, as with steroids, can be difficult to optimise. Consensus is that administration should occur within 24 h of delivery and it should therefore be given to those women diagnosed as being in established preterm labour, or those in whom prelabour delivery is planned within 24 h. Although different regimes have been used in clinical trials, it appears that its administration confers approximately 30% reduction in risk of cerebral palsy in the surviving preterm baby [30, 31]. In the UK, administration is recommended prior to all births at less than 30 weeks of gestation, and consideration of administration up to 34 weeks [23].

Threshold of Viability The greatest challenges for both the obstetric and neonatal teams are in dealing with babies born at the threshold of viability (22–25  weeks). Active resuscitation is attempted for 84% of those born between 23 + 0 and 23 + 6 weeks of gestation [32].

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When in labour at the limits of viability fetal monitoring is challenging. Continuous cardiotocogram (CTG) may be technically impossible and cannot be interpreted using the same criteria used at term. A frank discussion, including the neonatal team, is required with women at high risk of delivering at the limits of viability. This discussion should include information on likely neonatal outcomes, and the limitation of monitoring and intervention. There is no evidence that delivery by Caesarean section at this gestation will improve the fetal/neonatal survival, but it may impact significantly on maternal morbidity in both the current and future pregnancies. It should then be questioned that if intervention is not to be carried out, there may be no value in monitoring of the fetal heartbeat continuously or even intermittently. However the potential consequence of an intrapartum fetal death should be explained and discussed explicitly. This decision making should be individualised and cannot be standardised by a guideline [33].

Non-cephalic Presentation In spontaneous preterm labour there is a higher incidence of breech presentation compared to at term, making decision making more difficult. A recent large systematic review has shown Caesarean section reduced severe intraventricular haemorrhage by 41% and death by 49% in the extreme preterm breech. The study was limited to those actively resuscitated and born at less than 28 weeks of gestation and the advantages were more apparent at earlier gestations [34]. The EPIPAGE-2 study looked at preterm breech births from 26 to 34 weeks of gestation and showed no improved outcomes, including survival without associated morbidity, by delivering by Caesarean section [35]. Unfortunately, at earlier gestations there is an increased risk of the need for upper segment Caesarean section which comes with higher maternal morbidity for this and subsequent pregnancies. This includes increased rates of post-partum haemorrhage, need for caesarean hysterectomy and greater risk of uterine scar dehiscence in future pregnancies [36].

Group B Streptococcus Management of any preterm labour should also include consideration of antibiotic administration. Infection is a major underlying aetiology of preterm labour, especially at extreme preterm gestations. The ORACLE trial suggested that routine administration of broad spectrum antibiotics in preterm labour with intact membranes did not improve neonatal outcomes [37]. In the UK there is now a recommendation to give antibiotics for prophylaxis against Group B Streptococcus (GBS) to all women in established preterm labour, as the sequelae of GBS infection are more severe in the preterm neonate [38].

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Stillbirth Prevention and Fetal Growth Surveillance There are many new obstetric initiatives aiming to reduce rates of stillbirth. This has been highlighted as a major international priority. Reducing stillbirths will ultimately involve increasing iatrogenic preterm delivery and must be supported by the neonatal facilities to deal with this consequence.

International: ‘Ending Preventable Stillbirth’ The Lancet ‘Ending Preventable Stillbirth’ series in 2016, highlighted the annual estimated stillbirth incidence of 2.6 million and noted that half of these occur during labour and birth [39]. Ninety percent of stillbirths occur in countries with lower incomes; they can often be associated with maternal infection, notably syphilis and malaria, and poor access to care. With appropriate resources and recognition many of these stillbirths can be prevented. The availability of worldwide stillbirth data has increased significantly. Sixty-eight countries had no available data in 2009 and this has dropped to 38 countries in 2015. It is noted that global leadership and responsibility is key to improving outcomes. The United Nations inter-agency group for Child Mortality Estimation has now taken overall responsibility for reporting rates and it is hoped this will improve data available for assessment. The Every Newborn Action Plan aims to reduce stillbirth in all countries, to less than 12 per 1000 births by 2030 [39]. Considering the international impact of stillbirth, it is proportionally underfunded. The Lancet review recommends cohesive care, starting prenatally with health optimisation and access to contraception. Access to antenatal care, with adequate infection recognition and treatment and fetal surveillance, is required. Intrapartum care should include fetal monitoring and access to obstetric intervention if needed. It also recommends the de-stigmatisation of stillbirth with worldwide education and postnatal support for those affected. The burden is both psychological and financial, with many families struggling to return to work after such a traumatising event. Clearly the above ideology is sound, but implementing internationally in countries with poor resources and conflict or natural disaster will be complex. It is important to recognise the shift may see stillbirth rates drop but an increase in neonatal deaths if neonatal support in a country is inadequate to deal with neonates with complications.

UK: Saving Babies’ Lives The above recommendations are already being implemented in most developed countries.

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In the UK the ‘Saving Babies Lives’ care bundle, launched in 2016, and updated in 2019, aims to halve stillbirths by 2025. The care bundle includes improving smoking cessation, risk assessment and surveillance for fetal growth restriction, raising awareness of reduced fetal movements and effective fetal monitoring during labour [40]. In high income countries the stillbirth is often antenatal rather than intrapartum and may be associated with modifiable lifestyle factors such as obesity and smoking [41]. Smoking cessation can be improved with routine carbon monoxide (CO) testing at booking and cessation education given. Initial evaluation of the Saving Babies Lives care bundle has demonstrated good uptake of the themes outlined. CO testing was almost universally undertaken, and an increased proportion of small-for-gestational-age babies was identified antenatally (up from 33.8% to 53.7%). The stillbirth rates in the earlier adopter trusts fell by 20% [42].

Each Baby Counts Running in parallel with ‘Saving Babies Lives’, ‘Each Baby Counts’ is a 5-year programme launched by the Royal College of Obstetricians and Gynaecologists in 2015 to reduce the rate of term intrapartum related stillbirths, neonatal deaths and brain injuries. It collects data and implements local reviews on all term intrapartum stillbirths, hypoxic ischaemic encephalopathy grade 3 and neonatal deaths, reviewing whether the event was avoidable and assesses the quality of the local review undertaken. Obstetrics needs to strive to achieve safety levels that other industries such as aviation accomplish. Human factors training, popular in the aeronautical industry, is being implemented in many hospitals to improve situational awareness and reduce serious incidents [43, 44].

Fetal Growth Restriction ‘Saving babies lives’ highlights the need to monitor fetal growth as fetal growth restriction (FGR) is a major risk factor for stillbirth [44, 45]. Careful assessment of risk factors for FGR should be undertaken at booking for antenatal care (Fig. 1.3). Women who are assessed to have no risk factors can then have growth surveillance with midwifery symphysis-fundal height assessments from 26 to 28 weeks of pregnancy, with growth scans only carried out if triggered by abnormal measurements or growth velocity. If major risk factors for FGR are identified at booking, then serial ultrasound growth assessments from either 28 weeks (if abnormal uterine artery Doppler) or 32 weeks are recommended [54]. If multiple minor risk factors are identified then the Royal College of Obestetricians and Gynaecologists currently recommend uterine artery Dopplers at the 20 week anomaly scan, with serial growth scans if these are abnormal. Clearly,

Women unsuitable for monitoring of growth by SFH measurement (e.g. BMI ≥35kg/m2) Fibroids

Previous FGR Hypertensive disease in a previous pregnancy Previous SGA stillbirth Current pregnancy PAPPA  proximal Normal Prominent limb weakness Decreased Proximal > distal Decreased

Proximal > distal

Also seen in myotonic dystrophy

clinical findings [10, 12]. For instance, on our unit we have observed neuropathies with antigravity movements even though a neuropathy is a peripheral cause of hypotonia. Cervical spine injury will initially appear as hypotonia with weakness even though it is central cause anatomically [5]. A recommendation that Prader-­ Willi syndrome with central hypotonia should be excluded before undertaking a muscle biopsy has been put forward because of the overlap in clinical presentations. In addition, there can be disorders that have both central and peripheral features, such as congenital myotonic dystrophy, metabolic conditions, peroxisomal disorders, and mitochondrial myopathies.

Investigations Genetic Investigations The introduction of chromosome microarrays (array-based comparative genomic hybridisation: aCGH) in the place of traditional G-banded chromosome karyotype analysis has allowed the identification of more anomalies because of the superior resolution of detection (10–50 kb compared to 5 Mb for karyotype analysis) [13, 14]. However, because the microarray method assesses copy number variants it cannot detect balanced chromosome rearrangements. A karyotype with fluorescent in situ hybridisation is still the recommended investigation for whole chromosome aneuploidy (e.g. trisomies 21, 18, 13). Further tools available include targeted mutation testing, single gene sequencing and multigene panel testing based on next-­ generation sequencing [13]. Whole exome sequencing can be performed in cases where the genetic cause is elusive and other tests have been negative [14]. This is discussed further in Chap. 33. Methylation studies are needed for the diagnosis of

Fig. 5.2  Scheme for the assessment (history/examination) and investigation of neonatal hypotonia

76 R. Miralles and D. Panjwani

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Prader-Willi syndrome where imprinting may be the issue without a deletion being present. With the increasing number of techniques available, guidance from the clinical genetics team is essential beyond first-line testing.

Cranial Imaging A cranial MRI may be performed to look for structural abnormalities (e.g. cortical dysplasias/neuronal migration defects) particularly if a central cause of hypotonia is suspected. For most babies with a peripheral neuromuscular condition the MRI will be normal. However, brain abnormalities can be associated with specific conditions, such as the group of muscular dystrophies with CNS abnormalities (the dystroglycanopathies) [15, 16]. Cranial ultrasonography may also be able to demonstrate various structural abnormalities and identify acute pathology such as intraventricular haemorrhage. The availability of cranial ultrasound on neonatal units means that preliminary information will often be obtained before an MRI scan is performed.

Nerve Conduction Studies/Electromyography Nerve conduction studies (NCS) and electromyography (EMG) can prove useful in  localising a cause of hypotonia, particularly in peripheral hypotonia. NCS is thought to be reliable after 32 weeks gestation [17, 18]. In disorders with central hypotonia, the results are likely to be normal. With the loss of anterior horn cells in spinal muscular atrophy, muscle fasciculations (group of fibres) and fibrillation potentials (single fibres) may be seen at rest. A reduced nerve conduction velocity will be observed in some neuropathies. A myopathic pattern can also be identified in muscle disorders, although it is also recognised that EMG can be normal. When congenital myotonic dystrophy is suspected, the study will be more usefully performed in the mother as maternal inheritance is the general rule and myotonia is not present in the newborn. An abnormal response to repetitive nerve stimulation would point towards an issue at the neuromuscular junction (Fig. 5.2 and Table 5.4).

Creatinine Kinase and Other Blood Investigations A very raised level of creatinine kinase (5–10 times normal) is suggestive of a muscular dystrophy, while in other conditions, such as myopathies and SMA, creatinine kinase (CK) can be mildly elevated (Table 5.4) [18, 19]. CK can be raised in the first week after vaginal delivery which can make interpretation of an early measurement more difficult [20]. Levels can also be elevated after performing an EMG. In addition to CK (also referred to as creatinine phosphokinase), we check routine biochemistry:

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Table 5.4  Overview of creatinine kinase (CK), EMG and muscle biopsy results by location of deficit Site Central Anterior horn cell Peripheral nerve

CK Normal Normal or mild rise Normal

Neuromuscular junction

Normal

Muscle—muscular dystrophies Muscle—congenital myopathies

Raised or very raised Normal

EMG Normal Fasciculation/fibrillations at rest Fibrillation at rest/no fasciculations Decremental (incremental in botulism) Myopathica Myopathic or can be normal

Muscle biopsy Normal Denervation pattern Denervation pattern Normal Dystrophic changes Characteristic types

Slowed nerve conduction velocity in merosin-deficient (LAMA-2 related) CMD

a

serum electrolytes, liver function tests, calcium and magnesium. We test for congenital hypothyroidism and would screen for metabolic conditions in many cases, particularly if there is multi-system involvement or a suggestive biochemical derangement.

Muscle and Nerve Biopsy A muscle biopsy may be performed if the clinical picture or EMG points to a muscle disorder. Muscle biopsy with immunohistochemistry is used to distinguish between causes of muscular weakness and forms part of the investigation of myopathies, with characteristic histological appearances, and muscular dystrophies. Results can point to which genetic tests would be most appropriate. Muscle tissue may also be required for respiratory chain testing. Nerve biopsy may be needed if NCS indicates a neuropathy.

Lumbar Puncture A lumbar puncture may be performed to look for CNS infection. Protein may be raised in the absence of a white cell response in inflammatory demyelinating neuropathy.

Specific Conditions Spinal Muscular Atrophy Spinal muscular atrophy (SMA) is a condition characterised by hypotonia and weakness due to degeneration of the anterior horn cells in the spinal cord and motor nuclei of the lower brainstem. SMA is also the leading single gene cause of

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death in infancy [21]. It is now well-established that this degeneration is usually due to a lack of the survival motor neuron (SMN) protein caused by mutations in the SMN-1 gene. The SMN protein is known to have an important role in mRNA splicing [21, 22] and other cellular pathways [23]. As a condition affecting motor neurons, there is no impact on cognitive ability. It is unusual to find disturbance of eye movements or weakness of the facial muscles in SMA, so facial expression and feeding can be normal at diagnosis. Therefore, infants with SMA present as an alert infant with significant limb weakness and respiratory difficulties. Muscle fasciculation, and in particular tongue fasciculation (spontaneous contraction of a group of muscle fibres—a denervation phenomenon), strongly suggest the diagnosis of SMA. Further findings are in keeping with peripheral hypotonia with a lack of antigravity movements and reduced or no deep tendon reflexes [21, 24]. EMG is consistent with denervation, but with fasciculations and fibrillations at rest. Classification of SMA Earlier onset of SMA correlates with severity of the disease [24, 25] (Table 5.5). Type 1 SMA (Werdnig-Hoffman disease) presents in the first 6 months. Such infants do not acquire the ability to sit and respiratory deterioration is the main (primary) cause of death. This is a life-limiting illness with death by the age of 3 years. Where the onset of symptoms has started before delivery, with antenatal features such as reduced fetal movements, polyhydramnios and contractures, this can be termed type 0 SMA with a life expectancy of less than 6 months [25]. Genetics of Spinal Muscular Atrophy The vast majority of SMA occurs due to deletions of the survival motor gene, SMN-1 with autosomal recessive inheritance. The SMN-1 gene is located on the long arm of chromosome 5 (5q13) and contains nine exons. Ninety-five percent of Table 5.5  Classification of SMA by age of onset and severity, including SMN-2 copy numbers SMA type 0 1 2 3 4

Very severe SMA Werdnig-Hoffman disease Intermediate Krugelberg-­ Welander disease Late onset, adult

Not clearly defined

a

Age of onset Prenatal 18 months 2nd/3rd decadea

Life Motor milestones expectancy Reduced fetal