Season of birth: a study of schizophrenia and other mental disorders 0720428270, 0444107959, 9780444107954, 9780720428278

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season ofbirth

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season ofbirth a study ofschizophrenia and other mental disorders

PerDalén SL Jöigen's Hospital University of Göteboig Sweden

1975 N O R T H - H O L L A N D PUBLISHING C O M P A N Y - A M S T E R D A M · O X F O R D A M E R I C A N ELSEVIER PUBLISHING C O M P A N Y , INC. - NEW Y O R K

© NORTH-HOLLAND PUBLISHING COMPANY - 1975 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photo­ copying, recording or otherwise, without the prior permission of the copyright owner.

Library of Congress Catalog Card Number 74-28993 ISBN North-HoUand 0 7204 2827 0 ISBN American Elsevier 0 444 10795 9

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INTRODUCTION According to a widely held view, there is no link whatsoever between the time of birth, and the subsequent fate of an individual human being. This view is sometimes dogmatically defended, as if it were a bulwark of rational science against rank superstition. Historically this attitude may be justified, but it clearly exaggerates the importance of a hypothesis which is not only far from being self-evidently true, but has in fact been repeatedly disproved by the findings of reliable empirical studies. One of the most puzzling, and also one of the best studied among these findings is the excess of persons born in the first three or four months of the year in samples of schizophrenic patients. There are analogous findings in samples of certain congenital malformations, but we tend to regard this as less puzzling. This is probably so because the apparent time span between cause and effect is much shorter in these cases, and pialformations are also obviously somatic phenomena. The null-hypothesis of no relationship between time of birth and later events is the natural starting-point of any study in this area - one should try to overthrow it, using appropriate statistical tests of significance and relevant control figures. Some of the early studies on season of birth failed to achieve this because of methodological shortcomings, and even now the situation is less than satisfactory because of a lack of suitable statistical methods, and difficulties with control figures. The season-of-birth effect in schizophrenia is by now a fairly well established fact, in spite of the above-mentioned difficulties. Yet so far we have no satisfactory explanation of it. One of the aims of the present study is to indicate how this phenomenon could be made to serve useful scientific puφOses in spite of our ignorance of its origin. The literature in this field has expanded considerably during the past few decades. Bailar and Curian (1964, 1965, and 1967) have published very valuable reviews, but since then no one has attempted to survey the whole field. The review part of this book will therefore go beyond the limits of psychiatric research in various directions. Huntington's (1938) well-known book adequately summarises the literature up to the 1930's, and anyone with an interest in the early history of this subject will have to go back to his work. The first seven chapters include reviews of studies that are more or less relevant to the problem of season of birth and mental disorders, which is the main subject of this book. Other fields are then surveyed in the four last chapters in order to cover most of the medical aspects of season of birth. Asterisks in the text refer to the appended notes. For technical reasons some recent material has been assembled in that section.

Chapter 1

V I T A L STATISTICS The study of season of birth in a sample selected for some peculiar attribute is meaningful only if we know the distribution of births by season in the population from which the sample is drawn. In practice this gives rise to considerable problems, because the relative birth frequencies per month vary with time and place, and the figures needed are not always available. In many countries official statistics do not include births by month of occurrence except for a few of the most recent decades. Migration between areas with different seasonal birth patterns is another problem, which may be very difficult to solve in a country like the USA. Detailed discussion of various problems of this kind will follow later as the need arises, in the literature review, and in the chapters describing the present study. There are many sources of error in this field of study, and not all of them can be eliminated. If elimination is impossible, one ought to estimate the size of the error to see if it could possibly affect the conclusions of the study. This is a commonplace, and of course every scientist knows where to draw the line between reasonable demands and nit-picking in his own field. Such knowledge belongs to the tradition of any established science, but here is a novel field where implicit knowledge of this kind is still lacking, and it can only be acquired by careful explicit discussion. General survey and geographical variations As is well known, birth rates vary with the seasons in a predictable manner. The general rule appears to be that more children are born in the first half of the year in the northern hemisphere, while the maximum in the southern hemisphere is in the second half of the year. The relation of the birth rate to the seasons is thus the same in both hemispheres, according to this rule, but there are important exceptions, notably in North America. Cowgill (1964, 1966 a -c) has surveyed extensive data from all parts of the world. The details of the differences between geographical areas need not concern us here, but the interesting findings in North America deserve some further comment. In the USA more children are born in the second half of the year, with a maximum in August and September. This is more or less a reversal of the pattern of births in the rest of the northern hemisphere. The amplitude of the annual variation in US births seems to have been increasing up to the 1950's (Rosenberg, 1966), but in the 1960's there is evidence of a decline in amplitude (Lyster, 1971). The peculiar US pattern was already evident in 19th century data from Massachusetts (Cowgill, 1966c) Canada in the 1920's, when figures first became available, still had the regular "northern" pattern, but since then the US pattern has gradually become superimposed. Mexico, on the other hand, has a typical "northern" pattern up to the present time (Cowgill, 1966c).

Puerto Rico had a "northern" pattern of births in the period 1 9 4 1 - 1 9 4 5 , but as Cowgill (1964) has shown, there was a rapid and complete transition to the US pattern during the following 16 years. It is highly likely that cultural factors are behind this peculiar pattern which originated in the USA, but nothing is actually known about the causes of this phenomenon. It also appears likely that the fairly regular birth pattern of the rest of the world, with a maximum of births in the late winter and early spring months, is conditioned by climate and biological factors in a broad sense. There have been numerous attempts to explain this pattern, but since there are obviously many determinants, and no real experimentation is possible, those explanations are all more or less untestable and ad hoc. The attempts of many authors in the 19th century to establish a "basic animal rhythm" of human conceptions - still very much to the fore in Huntington's (1938) book - may accordingly be doomed to failure, not because the idea as such is preposterous, but because the problem is too complex and the available data do not admit proper testing of hypotheses.* The same of course applies to social and cultural explanations, if they are intended to cover the pattern as a whole, but minor details of the pattern may have rather obvious explanations. The secondary September peak of births in most European countries will surely have to do with the festivities of Christmas and the New Year nine months earlier. The idea of a "basic animal rhythm" gets some support from the findings of Parkes (1968) of a close positive correlation between the English monthly conception rate in 1963, and the average sales per month of contraceptives from an English firm in the years 1963-66. Parkes' paper illustrates in an entertaining yet admirably critical manner several of the pitfalls and difficulties encountered in this area (cf. also Parkes, 1971). Huntington (1938) used the "basic animal rhythm" rather as a unifying concept into which he subsumed various kinds of explanations - meteorological, dietary, medical - of why the season of birth is important, and why certain seasons are "favourable" while others are not. There is a wealth of fascinating data and interesting explanations in his book, but it is often hard to escape the conclusion that too much is being explained in rather too sweeping terms. Socio-economic factors Socio-economic factors have been implicated in causal explanations of mental disorders, notably schizophrenia (Hollingshead and Redlich, 1958; Hare, 1967), and the deviations of season-of-birth patterns found in schizophrenic samples were attributed to socio-economic differences by Barry and Barry (1964). It is therefore very important in this context to find out whether there are any differences between socio-economic subgroups in the population in regard to seasonal birth patterns. There are only a handful of studies of this particular problem, two from the United Kingdom and six from the USA. UK: Record (1961) studied anencephalus, a malformation which is more common among winter births in several samples, and which is also more common in the lower social strata. He obtained control data on all births in Birmingliam during * See page 131

7

1951 and 1952 (36,649 births) by social class. The percentual distributions by trimester of birth (February-April, etc.) were very similar between his three social class levels. In February-April, which is a period of particular relevance to schizophrenia and season of birth, the highest social class had the highest percentage of births compared to the other two classes. This difference is small, but if social class differences were to explain the findings in schizophrenic samples, the lowest class should have the highest percentage of births in this trimester. James (1971a) examined 371,315 births in various samples from the UK in the 1950's and 1960's. He found a higher amplitude of the seasonal curve in the upper social classes as compared to the lower. This, again, means that relatively more children of the upper classes were born in first half of the year, where the peak of the seasonal curve is found. USA: Pintner and Forlano (1933) studied the influence ^of month of birth on intelligence quotients in 17,502 New York children subdivided into three social levels. The medium status subgroup showed the highest relative birth rates in the first quarter, and in the first half of the year, but the differences were small throughout. A study by Goodenough (1941) of 3,275 Minnesota children must be judged in relation to the rather small sample size. According to her own analysis, comparatively fewer births take place in the upper social classes during "winter" months, which here means December, January, and February. If the data are regrouped into the conventional quarters, this tendency is however reversed, so that again the upper classes contribute relatively more to the number of births in the first quarter. Lederberg (1963) studied a 10% sample of all births in California in 1959 31,285 births classified by father's occupation into two groups, A and B. Fathers in professional, managerial, or administrative occupations accounted for 6,699 births which formed group A. There was a marked difference between those two groups when distributed by month of birth. Group Β showed the typical US pattern, with a major peak in September and the adjacent months. Group A had no peak at this time of the year, and its curve was flatter than that of group B. If we consider the quarters, group A contributed relatively more to the births in the first three months of the year. Pasamanick, Dinitz, and Knobloch (1960) analysed 115,490 Baltimore births during 1952-1956, subdividing them firstly according to race, with 42,768 non-white births which were not further subdivided. White births were distributed into five socio-economic classes by census tract of residence of the mother. Their findings agree well with Lederberg's data. The annual curve for the higliest white socio-economic group was almost flat, and there was a gradient of increasing amplitudes with decreasing socio-economic class. The typical US pattern is evident in all but the two highest subgroups. The authors entertain the completely gratuitous idea that the "normal expec­ tancy" would be a wholly flat distribution of births througliout the year, and they regard the departures from this expectancy as indirect evidence of the effects of climatic adversity on the lower classes. This must be pointed out here, because the same idea recurs in the two following studies, which were also done in Baltimore. Zelnik (1969) replicated the foregoing study with a similar sample covering the years 1961-1965. He studied only two socio-economic classes, the higliest and

lowest fifths for both white and non-white births. His statistical procedures were aimed at testing the deviation of the monthly figures from a straight line, and he found that all four of his subgroups deviated from this distribution. He then went back to the data of Pasamanick, Dinitz, and Knobloch and found tliat even their highest fifth of white births deviated significantly from a rectilinear distribution by the Kolmogorov-Smirnov test. The present author has reanalysed Zelnik's data by quarter of the year, comparing his results to those of the foregoing study. There is little if any difference between the higliest white socio-economic fifths of both studies. Zelnik's lowest white fifth, which only includes 8,865 births, differs markedly from the lower socio-economic groups in the foregoing study by showing less of the typical US peak in the third quarter. This may be a random effect due to the relatively small sample size, but as Lyster (1971) has shown, the amplitude of the US curve decreased during the I 9 6 0 ' s (cf p. 6 above). Chaudhury's (1972) study is yet another replication of the original Baltimore study, now covering the years 1968-1969, and the procedure of Zelnik's work was closely followed. Chaudhury also subdivided his samples according to educational group of the mother. His samples were smaller, and he found no significant differences from rectilinearity in the highest white group, whether defined by residential or educalional classification. There were significant differences (accord­ ing to the Kolmogorov-Smirnov two-sample test) between the two white subgroups. Chaudhury's white births numbered 6,742 when classified according to census tract of residence, but only 1,420 when classification was made by educational group of the mother. The latter subsamplc is much too small to be of interest here. The present author reanalysed the former sample by quarter. The highest socio­ economic group was then seen to contribute relatively more to births in both the first, and the second quarter. Chaudhury's 2,465 births in the lowest white group were like Zelnik's corresponding group in showing less of the third quarter maximum typical of the USA. In spite of the scarcity of studies of season of birth by social class, it is clear that socio-economic differences could not explain the findings of an excess of births of future schizophrenic patients in the first quarter, which is the main topic of this book. There are, moreover, good reasons for doubting that the parents of schizophrenics differ from the general population in their social class distribution (Hare, 1967; Birtchnell, 1971; Hare, Price, and Slater, 1972b). Cowgill's (1966b) conclusion that low social status increases the amplitude of the seasonal birth curve was contradicted by the findings of James (1971a) in the UK. So far only samples from the northern hemisphere have been published, but it appears that births in the upper social classes have a greater tendency to follow the general rule of relatively higher birth frequencies in late winter and early spring. Illegitimacy Data on illegitimate births by month are available from the official statistics of several countries. Gini (1912) studied figures from various European regions, where the amplitude of the seasonal varation was much higher for illegitimate births. His data from Mexico did not show any marked difference between legitimate and illegitimate births in that country. Cowgill (1966 a and b) reviewed data from England and Wales, G e m a n y and Sweden. She still found a marked difference in

amplitude as in the older data of Gini. There was no such difference in her data from the Dominican Republic. James (1971a) confirmed these observations with respect to England and Wales, but he pointed out that since about 1957 the situation is reversed, with legitimate births showing the greater amplitude. Data from the USA (Rosenberg, 1966), which were probably not available to Cowgill, fail to reveal any notable difference between legitimate and illegitimate births in that country in 1963. Erhardt, Nelson, and Pakter (1971) studied season of conception in New York City, 1960-1967. The curves for non-white, Puerto Rican, and illegitimate white conceptions were all alike, and they differed from the curve for legitimate white conceptions in showing a higher relative frequency of conceptions in October through December. In New York City all conceptions should in principle be registered, even those ending in fetal death. The authors do not discuss this, but it is doubtful whether their findings can be cpmpared to those based on live births only. Considering the social circumstances surrounding illegitimate births, it is reasonable to assume that they are less often planned than are legitimate births, and, consequently, that mothers of illegitimate children are selected for high fecundability (James, 1973). This tallies well with the findings in Europe of a high illegitimacy rate during the season when the general birth rate is also at its highest. It is puzzling that this is so only in European data (cf. chapter 9).

Multiple births There are only a few scattered reports on the relative frequency of multiple births by season of the year. Seasonal variations in the frequency of (like-sexed) twinning in Swedish cattle have been reported (Korkman, 1948), and one would expect a certain variation to occur in human twinning as well. Weinberg (1902) briefly discussed seasonal variations in data from Denmark and Switzerland. In both countries the percentage of multiple births was somewhat higher in the first half of the year. Edwards (1938) thought the ratio of multiple to single births might show "the seasonal effect uninfluenced by artificial control". His study of births in Liverpool, 1935-1937, is thus an attempt to find evidence for a "basic animal rhythm". Unfortunately his figures were distorted by a smoothing procedure, and they are therefore not well suited for statistical examination. There were 11.9 multiple births per 1,000 single births in the first half of the year, as compared to 12.3 in the second half (present author's calculations), and there is thus no agreement with the foregoing study, but Edwards' sample appears to be relatively small. Timonen and Carpen (1968) studied Finnish data in an attempt to test their theory that human gonadotrophin levels, like those of many animals, are influenced by changes in exposure to light throughout the year. The rationale for this test is the well-known fact that administration of exogenous gonadotrophins often leads to multiple pregnancies (Gemzell, 1966). They studied over 300,000 deliveries and found in the distribution of multiple births an exaggeration of the European pattern, with a spring peak of higher amplitude than that for single births in Finland. In northern Finland this difference was even more marked, and the peak of multiple births was about a month earlier than in the rest of the country. Erhardt, Nelson, and Pakter (1971) found little or no seasonal variation in the 10

relative frequency of multiple births in their large New York City sample. Selvin and Janerich (1972) studied a large New York State sample (excluding New York City) from the same time period (1960-1967) and found no significant seasonal variation. A reexamination of their data by half-year of birth reveals a slightly higher proportion of multiple births in the second half Under the theories of Edwards, and of Timonen and Carpen, one would expect this proportion to be distinctly higher in the first half instead, provided that the US pattern of births is "artificial". As was also the case with illegitimacy, we have here a situation where Europ\;an findings are not confirmed by studies from other parts of the world. The reason for this discrepancy is not clear. Birth order The birth order distribution in samples of schizophrenic patients has attracted considerable attention, but the significance of these studies is questionable, see Price and Hare (1969), and Erlenmeyer-Kimling, van den Bosch and Denham (1969). Birth order is nevertheless a biologically interesting variable, and it is correlated with maternal age, among other things. Noack and Otto Ο Ο Ο Ο θ Ν θ Ν θ Ν θ θ Ν θ Ν θ Ν

OOOOO

o o o o o ON ON o

^0Ν0ΝΓ~-»-ΗΘΝ·Ο'-ΗΓ0^ΓΟ

v o < N O O N r - f o O r - ^ f o O f o ON ON O N O N

ON

o oooo

r-rOrO>

§

N.S. N.S. 5%

England. No control data. Northumberland and Durham

X2 x

(l) X2 x (l) X2 x (l) X2 x (l) X* X1 X

2

N.S.

U.K. and Eire

N.S. N.S.

Milan, Italy

N.S. 5% 5% 5%

Prague

5% N.S. N.S.

South Wales

U.S.A.: Phair (1947) Lutz and Moor (1955) Hewitt (1962)

1,134 150?

285

Wisconsin Los Angeles

■

X

2

N.S.

New York City

(Table 13.1 continued) Authors (U.S.A.): Woolf, Woolf and Broadbent (1963) Silberg, Watson and Martin (1968)

No. of cases

Excess

218 671

P Land LP

(ll) runs

N.S. N.S.

Utah

Dec.-Apr.

384

P

Jul.-Sep.

X X

2

10%

Missouri

476

LP

-

X X

2

289 Wehrung and Hay (1970)

6,797

-

LandLP

136

LP

Fujino, Tanaka and Sanui (1963)

454

P

1,100 1,230

A

L

OTHER COUNTRIES: Charlton(1966)

LP L

Statistical test

Place of origin, etc.

Type of cleft

(3) 2 X(3) X

10% N.S.

- Mar. -

(3) Edwards

5%

29 States (see text)

- Jun. -

Edwards

1%

2 X *(3) 2 X(3) X

N.S.

South Australia. Data for other types N.S. (see text) Kyushu,Japan

2

1%

Mar.-May Mar.-May

X X

(3)

10%

Legend: Type of cleft — L - lip; P = palate; LP = lip and palate; L/P = lip and/or palate. Excess - Month between dashes * month of maximum incidence; otherwise period of above average incidence, or dash for lack of data.

method of Hewitt et al., 1971) in a group of 84 cases called "Rest of alimentary". They were reported by month of last menstrual period, but the excess was in birth months March through August, assuming nine months gestation. Small samples were reported by Silberg, Watson and Martin (1968), and Klingberget al.(1971). T h e genito-uriiiary s y s t e m Hypospadias The series of 262 Danish boys with hypospadias pubUshed by S^rensen (1953) showed no consistent seasonal trend and X Q D was not significant. Slater, Watson and McDonald (1964) found no seasonal trend in a sample of 236 cases. Bailo, Beolchini and Ballestrin (1966) published 214 cases by month of concep­ tion in which there was no seasonal variation. Theander (1970) found that 79 of his 124 cases were born in April through September (quarters 2+3). In the very large U.S. sample of Wehrung and Hay (1970), including 5,145 cases of hypospadia, this anomaly is significantly more common among births in quarters 1+2, and this is especially marked in the climatic region called "Moderate Summer - Moderate Winter". Roberts, Lowe and Lloyd (1972) reported 102 cases from South Wales with a highly significant seasonal trend (by three different test methods). There was a maximum of conception dates in November. Roberts and Lloyd (1973) analysed a series of 93 simple hypospadias (apparent­ ly derived from the series in the foregoing paper) by month of conception. There was a winter peak and a summer trough as before. This paper was followed by four short reports on similar series. Campbell, Newcombe and Weatherall (1973) ob­ tained data from the official statistics of England and Wales, 1 9 6 7 - 7 1 . Only relative numbers by month of birth are given in the paper, and there is no obvious seasonal trend. Record and Armstrong (1973) reported a Birmingham series from the years 1 9 5 0 - 5 9 , and 1 9 6 3 - 7 2 (314 cases), in which no seasonal trend was found. Trichopoulos et al. (1973) failed to find any seasonal pattern in 145 consecutive cases from Athens. Harlap and Davis (1973) reported 178 cases from West Jerusalem with two yearly incidence maxima (spring and autumn). The variations were however small and of doubtful significance. Epispadias and extrophia vesicae The only large sample is that of 574 cases of epispadia reported by Silberg, Watson and Martin (1968), but there was no seasonal trend in their data. Small samples were published by Slater, Watson and McDonald (1964), and Bailo, Beolchini and Ballestrin (1966). Other or unspecified anomalies Hewitt (1962) reported quarter of birth of 336 children with "malformations of 112

genitourinary system". There was an excess in quarters 1+2, but this was not significant. Slater, Watson and McDonald (1964) reported several small samples, and 110 cases with "other malformations of genitalia", but none showed any significant seasonal variations. Of the 367 boys studied by Theander (1970), 221 had urethral valves or folds, and of these 136 had obstructing valves. There was no seasonal trend in those subgroups. Roberts, Lowe and Lloyd (1972) reported 115 cases with "other urogenital" malformations, but found no significant seasonal variation. Small samples of various anomalies were published by Bailo, Beolchini and Ballestrin (1966), SUberg, Watson and Martin (1968), and Klingberg et al. (1971). The musculo-skeletal s y s t e m Congenital dislocation of the hip There are no less than 23 studies to be reviewed in this section, see table 13.2. Comments: Nagura (1955), and Record and Edwards (1958) suggested that the seasonal trend in C.D.H. could be explained by the fact that infants born in the cold season wear heavier clothes, which prevent free movements of the legs. Flexion and abduction of the t h i ^ s would otherwise lead to a spontaneous correction of this defect. Andren and Palmen (1963) found the same preponderance of winter births in their series B, in which the diagnosis was made at birth. This shows that the above explanation cannot be correct, even if this mechanism might be expected to aggravate the anomaly in children born in the winter. Several other authors have confirmed that the seasonal variation is present already at birth. Andren and Pahnén (1963) plausibly discuss hormonal changes as an explanation of the seasonal trend. Of all anomalies present at birth which show seasonal variations, C.D.H. is the one with the most consistent pattern. Other or unspecified anomalies Polydactyly, syndactyly, hypodactyly, and positional foot defects are reviewed in table 13.3. Achondroplasia: Small samples were reported by Slater, Watson and McDonald (1964), Bailo, Beolchini and Ballestrin (1966), and Silberg, Watson and Martin (1968). Reduction Deformities: Slater, Watson and McDonald (1964) reported four groups of R.D., all of them small. Of the 61 cases with "partial absence of upper limb", only nine were born in the fourth quarter, and in the group with "partial absence of lower limb", which numbered 26, only four were born in the fourth quarter. Silberg, Watson and Martin (1968) reported 146 cases of "missing extremity", but here (Missouri) the rate was highest in the fourth quarter. Wehmng and Hay (1970) included 2,658 cases of R D . , but Edwards' test yielded no significant value, and the seasonal distribution of the series is not given in the paper. 113

Table 13.2. Summary of studies of congenital dislocation of the hip by month of birth. Excess

Statistical test

Place of origin - Comments

1,306

Nov.—Mar.

tffnp

Japan. There is an excess of 117% in January alone!

Pap (1956)

217

Dec.-Feb.

Record and Edwards (1958)

186

Oct.-Mar.

Authors Nagura(1955)

Uibe (1959)

No. of cases

4,345

(Winter)

Zacharias(1960)

553

(Winter)

Edwards (1961b) Bailow(1962)

186 139

- Jan. -

Schmidt-Peter (1962)

793

(Winter)

Andren and Palmen (1963) Slater, Watson and McDonald (1964) Medalieetal. (1966) Weissman and Salama (1966) Kevrev(1967)

X

(3) Edwards

1%

5%

-

A 1,313 B 816 271 342 45

Sep.-Nov.

1,782

Sep.-Dec.

Oct.-Mar. Oct.-Jan. (Winter)

Illyes(1968)

768

(Winter)

Robinson (1968)

339

- Dec. -

V

(1D

V

(D

Edwards

2.5% 0.5% 1%

5%

Hungary. 96 cases born in Dec.-Feb. No control figures. Birmingham, England. 61% born in quarters 1+4 (49% expected) Germany. 56% born in quarters 1+4. No control figures. Germany Same series as in Record and Edwards (1958)(?) Manchester, England. Only a graph, no control figures. Germany. 55% born in quarters 1+4. No control figures. Sweden. Group B diagnosed at birth. U.K. and Eire. Israel. Israel. 34 were born in the six "winter" months. Ortolani test at birth. Czechoslovakia. Another study by Poh'vka (1960) cited. Hungary. No controlfigures.Luxation more common in Sep.-Dec, dysplasia in Jan.-Feb. Upstate New York

(Table 13.2 continued) Authors

No. of cases

Silberg, Watson and Martin (1968)

61

Woolf, Koehn and Coleman (1968)

476

Excess

Statistical test v

Sep.-Jan.

(3)

XI1)

Place of origin - Comments

N.S.

Missouri

2.5%

Utah

Weissman and Salama (1969)

29

(Winter)

Israel. 17 where born in the six "winter" months. Ortolani test at birth.

Chen etal. (1970)

84

(Winter)

Israel. Rate 0.36% in Dec-Mar., 0.23% in the rest of the year.

589

Oct.-Mar.

Scotland. Winter/summer ratio 1.5 for neonatal C.D.H., 1.3 for late-diagnosis cases.

3,000

Oct.-Feb.

Wynne-Davies(1970) Czeizel, Vizkelety and Szentpeteri (1972)

74

Roberts, Lowe and Lloyd (1972) Charlton(1966)

A B

145 204

- Jun. - Jul. - '

0.1%

Budapest, 1962-1967.

Edwards

N.S.

South Wales

Edwards

5% 2%

Adelaide, South Australia Brisbane, Queensland

*(1D

Table 13.3. Summary of studies of polydactyly, syndactyly, hypodactyly, and positional foot deiecis oy month of birth. Authors

Type and No. of cases Excess

Hewitt (1962) Slater, Watson and McDonald (1964)

Bailo, Beolchini and Ballestrin (1966) Silberg, Watson and Martin (1968)

Wehrungand Hay (1970)

Roberts, Lowe and Lloyd (1972)

Statistical test 2 (3)

503 P

168

Jan.-June

S

154

Jul.-Dec.

F

795

PfS+H

97

F

339

P

820

S

451

F

1,488

P S

8,033 2,003

F

11,218

F

282

2 (1) 2 (1) 2 (1) 2 (1) 2 (1) 2 (3) 2 (3) 2 (3) Edwards Edwards

Aug.; Oct.-Nov. Conceptions

N.S.

New York City

N.S.

U.K. and Eire

4% N.S. 1%

Italy. The authors picked the "best" six-month period for statistical testing.

N.S. N.S.

Missouri

N.S. N.S. N.S. N.S.

Jan.-May

Edwards

Conceptions Oct.-Jan.

Hewitt &al. 5%

Legend: P = polydactyly; S = syndactyly; H = hypodactyly; F = positional foot defects.

Place of origin - Comments

0.1%

U.S.A. and climatic regions Significant at 5% in "Hot Summer - Moderate Winter" reg. Significant in all regions except "Mod. Summer - Cold Winter". South Wales

Unspecified: Slater, Watson and McDonald (1964) reported several more groups of musculo-skeletal malformations, including one called "Other abnormal forms of lower limbs". Of 126 cases only 17 were bom in the first quarter. Klingberg et al. (1971) put all their musculo-skeletal cases (74) under the same heading, dividing them between the "cold" season ( D e c - A p r . ) , and the "warm" season (May-Nov.). The incidence was 1.6% in the cold season, and only 0.7% in the warm season. Hewitt (1962) reported his samples by W.H.O. number. No. 758 (malformation of bone and joint) included 562 cases, but there was no seasonal trend. No. 749 (other deformities of musculo-skeletal system) included 65 cases, a significantly greater proportion of which were born in quarters 3+4. Roberts, Lowe and Lloyd (1972) reported 335 cases under "rest of limbs and skeleton", which showed a significant seasonal variation, both by Edwards' test and by the rank sum method of Hewitt et al. (1971). By month of last menstrual period, the maximum was in June, and the birth maximum would have been in March.

Other malformations Eye defects Slater, Watson and McDonald (1964) reported three groups of eye defects, among them 106 cases of cataract, which were significantly more often born in quarters l+4(X(2i);2%). Silberg, Watson and Martin (1968) reported 30 cases of anophthalmos and seven cases of microphthalmos. In both there is a significant seasonal trend with more cases than expected born in the second quarter, 15 of the first group, and five of the second. Skin and appendages Absent or malformed external ear occurred significantly more often in quarters 1+2 in the series of 58 cases of Slater, Watson and McDonald (1964).

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Chapter 14

Ν Ε 0 Ρ ί Α 8 Ή € DISEASES A debate on lung cancer and month of birth A paper by Dijkstra (1963) was quoted in a Lancet Editorial (1963), and this gave rise to a debate which lasted for a year. Dijkstra had found seasonal trends in a sample of 330 Dutch cases, with a winter excess of births. He also found suggestive differences in incidence between years of birth. Dijkstra proposed an explanation for this, involving a seasonal deficiency of vitamin A in milk during the late winter months, which might cause irreversible metaplasia of the growing bronchial epi­ thelium. Davies (1963) reported 2,042 English lung cancer cases, with no seasonal variation of birth dates. Another 741 English cases studied by Loxton (1963) showed a slight excess of births in July through October.* Baas and Strackee (1964) contributed 1,346 more Dutch cases, which did not support Dijkstra's conclusions. Another 95 English cases reported by Jones (1964) also provided no support, nor did the 150 Dutch cases of v. d.Wal et al. (1964). Loxton (1964) discussed the series published up to that time, finding significant deviations in several of them by a different statistical method. After a rejoinder by Dijkstra (1964), Allan (1964) pointed out that if the data of all three Dutch series were combined, and divided into three-month periods, there was a marked excess of births in February through April. MacSween and Miller (1964) reported 200 cases from Scotland with no significant seasonal trend, but the subgroup of 56 cases with oat-cell carcinoma were significantly more often born in May through July. Nolting (1964b) mentioned a series of 15,091 Dutch cases of cancer (one third of which had lung cancer) in which he had found an excess of births between November and April, but no details are given. Pabner (1964), and Cochrane and Palmer (1964) discussed the problem of differences in the month-of-birth distribution of a survivor population as compared to the corresponding population of live births. This is an important problem, see pp. 1 2 - 1 4 , 4 9 , and 73ff. Hyde and Stinson (1965) added another 200 cases from California, with a control group of equal size, but there were no significant differences between these small groups. The debate on lung cancer and month of birth ended in uncertainty, mainly because not enough data were available.

Other types of adult cancers Stur (1953) compared 2,829 unspecified cancer cases with 19,621 cases of other diseases; both samples were from autopsies at a Vienna hospital during 21 years. There were differences between the samples in season of birth, the most note­ worthy being a deficit of cancer cases in May through August ( X Q D = 32.38, 0.1% * L o x t o n also reported 3 8 9 cases of astrocytoma of the cerebrum, with evidence o f an excess from November to April.

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level). Subdivision by sex, by year of death in seven-year periods, and by anatomic localisation of the tumour did not yield any conclusive results, possibly because the subgroups were too small. There was no tendency for any anatomical subgroup to differ from the total sample. A study by Maurer and Wendt (1958) of 2,400 female cancer cases compared with an equal number of female non-tumour cases from the same hospital showed no significant differences, and there was no summer deficit like that in the foregoing study. More than half of the patients had uterine cancers, and there were 515 cases of breast cancer. Bailar and Curian (1964) analysed nearly 20,000 cancer deaths in Connecticut by sex, age, anatomical site, and month of birth. They used data on the month-ofbirth distribution of the current Connecticut population for comparison to avoid the error due to differential survival by month of birth. Only quarter of birth was available for the current population, so the monthly figures had to be estimated.^ The cancer data were given as absolute frequencies, and ratios of observed to expected frequenties. The authors concluded, apropos of the table of ratios: "we find no evidence from this table, or from a more detailed study of specific sites and age groups, that mortality from cancer is related to month of birth." The present author tried to check this by calculating the expected frequencies by means of the ratios given. values were then obtained for the total male group (X(ll) = 0·^^^^ ^®^^^)' ^^^^^ ^^^^^^ S^^^P ( ^ ( 1 1 ) = ^ ^ ' ^ ^ ' ^-^^^ ^^^^^)' and for both sexes combined ( X ( f i ) = 47.82, 0.05% level). There is a deficit of cases born in January through April, and a very large excess in October. The extremely high values would rather suggest that there is something wrong with the control data, which were after all estimated from quarterly data. However, analysis by quarter yields extreme values too ( X Q ) = 26.85 for the total sample), with deficits in quarters 1 and 3, and excesses in the others. Bemdt and Wildner (1966) analysed large samples from the Cerman Democratic Republic using two different control samples of hospital patients, " A " from geriatric hospitals (16,487 cases, including an unknown number of cancer patients), and " B " from all hospitals in East Berlin (38,092 patients 5 0 - 6 9 years old, cancer cases excluded). It is not clear whether some of the patients in sample A were also included in sample B. There was a total of 23,685 cancer cases, which were subdivided according to sex, and site of the tumour. A significant deviation (5% level) was found in the subgroup of 332 patients with adenocarcinoma of the lung, which showed an excess of births in December and January, and a deficit in May-June. The male subgroup of 4,665 patients with gastric cancer also deviated significantly from the control figures ( 1 % level), but the pattern was more irregular. There were no noteworthy seasonal trends in the other subgroups in this study.

^Certain details about their control data were given in another paper (Kesselman and Bailar, 1 9 6 4 ) . There are unfortunately n o raw data o n the population in these papers. It would have been interesting to study the differences between the current population and the related births, because such data are rarely available. It appears from the paper by Kessebnan and Bailar that a spurious excess in birth m o n t h s January through March occurs among the cancer cases when Üiey are compared with birth statistics. This may simply be due to immigration from countries in which the European birth pattern prevails, because nothing indicates that immigrants were excluded from the cancer sample. It is indeed unlikely that differential survival w o u l d create differences of the size found in these papers (cf. p. 73ff.).

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The authors emphasised the importance of using a contemporary control sample, and they compared their control data with German birth statistics from the years 1893-1906. Both control samples showed a deficit of cases born in April through June in this comparison, 7.3% below expectancy in sample A, and 3.5% in sample B. In September through February there were corresponding excesses. Berndt and Wildner attributed these differences mainly to variations of infant mortality.^ In two papers by Nolting (1966 and 1968), an Australian sample of 1,242 cases collected by E.V. Keogh was mentioned, which showed a reversal of the month-ofbirth pattem compared to the northem hemisphere. This is the only cancer sample from the southem hemisphere known to the present author, and it is unfortunate that the original data were not published."* Malignant diseases in childhood Bailar and Gurian (1964) reported over 2,000 cases of chilähood leukaemia, which were tested by the present author against birth data published elsewhere (Rosenberg, 1966; northeastern U.S. in 1956 - X ¿ i ) = 13.40) without a significant result. Ederer et al. (1965) analysed U.S. data on (Caucasian) children who died from malignant neoplasms before the first birthday (1950—1959), There were 961 leukaemia cases, and 1,552 cases with other neoplasms. They found a peak in the ratio of observed to expected births in May-June for the leukaemia cases, and October-November for the others. When tested against each other, the two series were significantly different (X ^^^^^ 24Al, 2% level).^ Glass and Fraumeni (1970) studied U.S. data on all children dying from primary bone cancer during 1960—1966 (1,532 cases), but found no evidence of any seasonal variation in births.

' T h e data o n mortality in the first m o n t h of life given by Gini ( 1 9 1 2 ) for Saxony, 1 8 8 0 - 1 8 8 4 , are o f course n o t wholly adequate for direct comparison, but they showed above average mortality in May through October, and the range was from 5.3% (February) to 9.6% (July). We may double these percentages as an estimate of mortality during the w h o l e of the first year. The rate of survival would then b e 86% for the w h o l e year, 8 9 . 4 % in February, and 80.8% in July. The ''deficit" in July is accordingly 6%, which is more or less the same as that found in the data of Berndt and Wildner for April-June (cf. p. 4 9 ) . *The results o f some calculations which are rather hard to follow showed an excess of Australian cancer patients in those birth months which the author regarded as "favourable" in the north, apparently June and July. There were also 3 2 1 cases in Australian residents born in the northem hemisphere (it is not clear whether they were included in the grand total o f 1,242), and they were said t o conform t o the n o r t h e m p a t t e m . In Nolting ( 1 9 6 8 ) there are references to three earlier papers (Nolting, 1 9 5 6 , 1 9 6 1 , and 1 9 6 3 ) which were n o t available for this review. Nolting ( 1 9 6 4 a ) referred t o the same 15,091 cancer cases as above (Nolting, 1 9 6 4 b ) , and birth months May through August were said t o be "favourable". * Month of birth had to be estimated in these series. The authors tested their data also by a procedure o f fitting sine curves (Bliss, 1 9 5 8 ) which yielded significant values for both series. Virus aetiology was discussed.

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Hodgkin's disease In an article by Fraumeni and Li (1969) on Hodgkin's disease in childhood a series of 354 deaths from this cause from all over the U.S.A. were analysed by various epidemiological variables, including month of birth. The authors found a very marked peak in July-August for the male cases. This was tested against expected figures based on U.S. birth statistics for 1960, but X ^ l ) was not significant in the whole series of 354 cases. It seems that the authors then took the contributions to in July and August, regarding them as two individual X tests significant at the 5% level. This procedure is open to several objections. The data for the 261 males were tested by the present author with bimonthly groupings of cases (January-February, etc.) and with U.S. birth statistics for 1950 (Rosenberg, 1966; X(5) = 15.40, 1% level). Since most of the children were over ten years old at ascertainment in 1960-1964, it does not seem adequate to use data from 1960. The July-August excess is very marked indeed (49% above expectancy). Vianna, Greenwald and Davies (1971) suggested that the unknown agent in Hodgkin's disease is a virus of low virulence and infectivity, which enters via the oral route. The habitat of the virus might be the female genital tract, where the fetus is exposed to it at the time of birth. Their hypothesis explains many relevant facts, including the possible season-of-birth trend, and the findings of Fraumeni and Li obviously had an important place in the framing of the hypothesis. Concluding remarks As discussed by Bailar and Curian (1964), induction of cancers in laboratory animals by several agents - radiation, chemicals, steroid hormones, and viruses occurs much more easily immediately after birth than later in life. If there are viruses which may induce malignant growths in human tissues, the time for their entry into the organism may be in intrauterine life, or immediately after birth, even if they are then latent for many years. Many viral infections show seasonal patterns of incidence. This is the rationale for studying season of birth in cancer and other malignant diseases. The results pubUshed so far are inconclusive, but not entirely discouraging.

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Chapter 15

OTHER PATHOLOGICAL CONDITIONS Dental malocclusion Janerich and Garios (1968) studied a random sample of the high school population in upstate New York in which a score of occlusal abnormality was determined from plaster casts of the dentition of each child. In 1,368 cases the month of birth was also known. The sample was dichotomised into "low" and "high" according to occlusal score, with 133 children in the latter group. The distribution by quarter of the year showed a marked excess of children with high scores in the second quarter (X(^3) = 10.83, 2% level). In order to check this finding, the authors searched a Central Registry File for cases with severe malocclusion, obtaining 5,278 cases which were distributed by quarter of birth and comparedr with total live births in the same area. There was again a marked excess during the second quarter (X('3) = 10,27, 2% level).*

Refractive errors Miller (1963) studied distant visual acuity in grammar school children in Hiroshima and Nagasaki. The percentage of children with Snellen scores of 20/70 or worse (not due to organic disease) was higher for those born in the first half of the year, but the difference was less evident in Nagasaki, which contributed 319 of the 462 children in the "pathological" group.

Goitre Lang (1929) obtained a large sample of (13,750) Bavarian military conscripts, partly from areas with a very high prevalence of endemic goitre. The percentage of individuals with goitre varied considerably with month of birth, especially in the endemic areas. This diagnosis occurred in 25.8% of all men born in the first quarter of the year, as against 21.6% of those born in the last quarter. Another sample included people of both sexes who had had a strumectomy, excluding hyperthyroid and malignant cases. There was a preponderance of women among those 4,249 patients. Their distribution by month of birth was compared with that of a control sample of 17,379 hospital admissions. Comparisons by quarter showed an excess of goitre patients born in the first quarter, which was more evident in the male subsample, and particularly so for males under age 20 years.

* There is a link between malocclusion and psychiatry in that thumb- and finger-sucking apparently contributes t o the development o f occlusal abnormalities, see Popovich and Thompson ( 1 9 7 3 ) .

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Diabetes mellitus A preliminary report by Tromp (1972) on month of birth of over 23,000 Dutch diabetics showed a highly significant first-quarter excess (+6.7%) in the female subgroup (13,498 cases, X(^3) = 30.70, test by the present author). The data used by Tromp for comparison were however from Dutch birth statistics for the years 1956—68. There are no data on the age distribution of the sample, but it appears likely that the majority of patients were born before that period. According to Tromp, there was a similar seasonal trend in the male subgroup, but this did not reach statistical significance. Rheumatoid arthritis Loxton and Gold (1961) compared 379 patients and 758 controls. The "relative incidence" of rheumatoid arthritis was higher in patients born from September to February than from March to August. There was also an effect of maternal age in the patient group, with a marked increase of the incidence at maternal ages above 35 years. Systemic lupus erythematosus There was no significant seasonal trend in a sample of 191 S.L.E. patients studied by Oleinick (1969), but on inspection of his data one finds a slight tendency towards an excess of births in September through February. Multiple sclerosis Tromp (1972) reported very briefly on diagnosis of multiple sclerosis. He found maximum number of births were found about the control data, but presumably March.

a Dutch sample of 2,023 patients with a no significant seasonal deviations, but the in February and March. Nothing is said there was a relative excess in February-

Fractures of the femur Alffram (1964) analysed the month-of-birth distribution of 1,271 Swedish patients with fractures of the proximal end of the femur associated with moderate or no trauma. Total live births in Sweden during an appropriate period (1881—1890) were used for comparison. An excess of patients were born in July through October ( ^ ( 1 1 ) ~ 19.71, 5% level). Alffram did not attempt to explain this surprising result, but he pointed out that measles in early childhood may give rise to sclerotic areas in the skeleton, which are known not to change appreciably throughout life. In a sample of patients born in the late 19th century, the bias due to infant mortality will be relatively great. In Alffram's sample there was a 14% excess of cases b o m in JulyOctober. The data on the present Swedish population with bhrth years 1 8 7 8 - 9 2 given in table 9.6 (p. 74) show a slight net excess of survivors born in the months July through October. The actual number of persons born in these months who were included in the population sample is 2,116. The corresponding expected number is 2,094, and there is accordingly an excess of survivors amounting to 1.0%. Alffram's findings cannot therefore be explained by a statistical artifact of this kind. 123

Chapter 16

N O R M A L SOMATIC C H A R A C T E R I S T I C S ABO blood type Gershowitz (1967) studied month of birth in 1,197 parents and 2,160 of their offspring, which he subdivided m different ways by ABO blood type. He did not control for month-of-birth pattern in the general population, nor did he correct his data for the different lengths of the months before testing them with the Edwards test. This may explain his finding of a deficit in the second generation of cases with blood type Ai in February and adjacent months. Shaw and Stone (1958) found a seasonal increase in titers of anti-A in persons with blood type 0 roughly from June to September. Assuming that ABO incompatibility has an effect on fetal death, Gershowitz predicted a relative deficit of children conceived in these months as a consequence, but this was not borne out. An analysis of the type Ai children by the present author, using data on U.S. births in 1955 for comparison (Rosenberg, 1966) yielded a X ^ ^ ) of 17.96. The greatest contributions to this came from an isolated deficit in February, and a September peak. Testing the predicted months of deficit (March-June) against the others gave a very low x]^) · Cohen (1968) critically reviewed Gershowitz's study and analysed two large New York City samples by month of birth and maternal ABO type: 10% of all live births in 1954-1956 (33,743 births), and all fetal deaths during the same period (15,340 cases). Analysis of live births by blood type was significant for heterogeneity in a 4 by 12 table with all months and blood types (X{33) = 55.42), but otherwise nothing remarkable emerged. The analysis of fetal deaths did not reveal any noteworthy trends.^ Weig^it and length A sample of 93 Moscow children aged 7 - 8 years reported by Blonsky (1929) showed a slightly higher mean weight in the group born in March-May compared to

* Cohen did not define "fetal death". In New York City registration of any product o f conception is required b y law (Hewitt, 1 9 6 2 ) , and about 1 2 0 fetal deaths per 1,000 live births were registered in the years covered by her sampling. One would accordingly expect about 4 0 , 0 0 0 fetal deaths to be included, but only 1 5 , 3 4 0 were reported. N e w c o m b e ( 1 9 6 3 ) used the same data source, and in his study the proportions of fetal deaths to live births are as expected. However, N e w c o m b e used only fetal deaths with less than ten weeks gestation for his further analyses, and since these were about 30% of the total number, Cohen may conceivably have used the same restriction. This would in any case make a study of fetal deaths by m o n t h of occurrence more meaningful. There is an oddity in Cohen's live birth data in that the usual U.S. pattern is not found, and December shows a 14% excess o f births compared to expected numbers (live births in northeastern U.S.A. in 1 9 5 5 , Rosenberg, 1 9 6 6 ) . Χλ^ is 7 3 . 3 0 when cases of all blood types are tested against expectancy, and this absurdly tiign value would indicate some error in the data rather than an anomaly in N.Y.C. birth patterns. (The December excess can be traced to the subgroup o f cases with blood type 0 ) . Cohen's (negative) conclusions may therefore n o t be well founded.

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those born in November-December, and this was so in spite of the fact that the children in the latter group were about seven months older than the others. Schiötz and Seland (1933) made a careful study of 1,952 Norwegian school­ children aged 7 - 1 6 years. They found no noteworthy differences in weight, or length by month of birth. Chenoweth and Canning (1941) found only slight differences in height and weight by month of birth in 10,005 male students at the University of Cincinnati, both measurements being somewhat higher in students born in the first half of the year. Fitt (1941) reviewed some early studies not mentioned here, and reported a sample of his own with 1,506 ten-year old New Zealand school children. In this study children conceived in autumn were the tallest, and spring children were the shortest, but the difference is only .41 inches. Mills (1941) published data on over 45,000 college freshmen from four state universities in the U.S.A. There were certain small differences between seasons, but since the age of the freshmen varied between 16 and 19 years and no allowance seems to have been made for this, it is doubtful whether Mills' results can be interpreted at all. Over 21,000 men from the New Zealand army draft of Worid War II were studied by Fitt (1955). Mean height showed a maximum in (birth month) February and a minimum in June, the difference being only .31 inches. Mean weight was highest in December and lowest in June, with a difference of 1.32 lb. HiUman, Slater and Nelson (1970) studied a sample of about 2,700 nurses and female students from New York. Women born in summer were slightly taller than those born in winter months, but the opposite was true of body weight. Hillman and Conway (1972) looked for seasonal trends in month of birth of 9,103 patients attending a public health nutrition clinic, but there was no com­ parison with any data on month of birth in the general population. Concluding Remarks: There is little or no variation in body weight, and length by season of birth when mean values are studied. It might be more rewarding to look for the frequency of extreme values in different seasons, but no such study has been found. Age at menarche If the incidence of menarche is subject to a seasonal trend, age at menarche will vary with season of birth, and this would have nothing to do with any influence in the fetal or early postnatal period.^ School entry is a highly seasonal phenomenon, and by the same mechanism age at school entry will vary with month of birth, but in this case we know more about the background. If age at menarche is in fact (partly) determined by a factor operating at about the time of birth which varies seasonally, the incidence of menarche would of course also show a seasonal trend, so we really have a difficulty here, not knowing at which end we should look for the causal factor. * There is in fact a very marked seasonal variation o f the incidence o f menarche, for review see Bojlén and Bentzon ( 1 9 7 4 ) . A frequent observation in European samples is that of a sharp incidence peak in January.

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Mills (1941) reported mean age at menarche for 24,715 female students. The highest mean (13.7 years) was found in birth months May and June, and the lowest (13.5) in December. Hillman, Slater and Nelson (1970) also found a maximum in May(-June), and a minimum in December, the difference being 3.7 months. Their sample numbered 2,937 women. A study of age at menarche of over 47,000 South African Bantu schoolgirls living in the Transkei reserve (Burrell, Healy and Tanner, 1961) showed a curiously abrupt rise of mean age between birth months December and January (difference 3^ months). The highest age at menarche was found in January through March (warm months in South Africa). Bantu births are not registered in this country, and therefore the distribution of the girls by month of birth cannot be compared with official statistics, but in the other ethnic groups of South Africa there is a birth maximum roughly from August to November (Cowgill, 1966b). The girls of the Bantu sample show a maximum in March through June, and this discrepancy is hard to explain except by a systematic error in the data.

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ACKNOWLEDGEMENTS The first Swedish sample of the present study was analysed in Uppsala during 1965-1966. My chief at that time was Assistant Professor Mats Gruvstad, and I am most grateful to him for his open-minded support, which made it possible for me to get over the initial difficulties of a study of this kind. The rest of the work was done at St. Jörgen's Hospital in Göteborg, and I wish to thank Professor Hans Forssman, Director of the Psychiatric Research Centre, for kindly allowing me the time and research facilifies needed for carrying this study to a conclusion. I am much indebted to Professor Lennart Wetterberg for both moral and practical support throughout this work. Professor Jörgen Lehmann provided me with a most interesting explanatory hypothesis out of his rich store of ideas. I am also indebted to Ernest Hard for many helpful discussions, and to Anders Oden for statistical advice. Conny Ivarsson greatly facilitated my work by his skilful assistance with the data processing. I was aided by a grant from the Medical Society of Göteborg.

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APPENDIX Tests of significance Notation: The symbol is used for chi square, and the number of degress of freedom is usually given within parentheses - X ( i i ) . If the degrees of freedom are t w o and above, and nothing else is stated, the ordinary test for goodness of fit was used, with expected frequencies derived from birth statistics (or other appropriate data on the population at risk). The X^i) values in table 11.1 are also of this kind. The X(i) values in tables 1 0 . 2 , 10.7, 1 0 . 9 , 1 0 . 1 1 , and 10.13 are from a test suggested by fil.lic. Anders Oden, Department of Mathematics, University of Göteborg. The hypothesis of equality between schizophrenic patients and the normal population was tested by a modified version of Edwards' (1961a) test. In order t o take into account the seasonal fluctuations of birth rates in the population, the following test variable was used, ^ ^ "i T => — ^ Di i = i Pi

. 2ni sm - 12 . '

where n^ denotes the number of future schizophrenic patients born in month /, and pj denotes the probability (derived from birth statistics) of being born in the same m o n t h . The test has a great power against such alternatives that mean that the schizophrenic groups deviate from the normal population by having a higher birth rate in March, and a lower rate in September.

The Poisson problem in chapter 8 The expected number of births o f future patients per day is denoted by N. The probability of observing no such birth in a given day is PQ, the probability o f one birth is P j , etc. Ν = P j + 2P2 + 3P3 + . . . iPj. The computer will retain a record of only one patient for each day in which one or more patients were b o m . The expected number of patients retained per day is accordingly = Ρχ + P2 + P3 + . . . Pj = 1 - PQ. In the Poisson distribution PQ = 6 " ^ , The expected number of patients lo^t per day is therefore = Ν - (1 - e - N ) = Ν - 1 + e - N , and the proportion of patients lost: , _ N - 1-»· e - N Ν

Other statistical methods The statistical methods used in the present study were described above, and they are quite simple. It is of course possible to make a Fourier analysis of seasonal phenomena, and one advantage of this is that the phase o f the variation can be more accurately defined (see Bliss, 1 9 5 8 ; Bliss and Blevins, 1 9 5 9 ; Edwards, 1961a; and Stutvoet, 195 l a ) . For other types of tests for seasonality, see David and Newell ( 1 9 5 6 ) , and Hewitt et al. ( 1 9 7 1 ) . Roberts, Lowe and Lloyd ( 1 9 7 2 ) made a practical comparison of different tests. Tests for space-time interaction in epidemics of low intensity have been described by Knox ( 1 9 6 3 ) , and David and Barton ( 1 9 6 6 ) . See also Stark and Mantel ( 1 9 6 7 ) .

Season of conception In some of the papers reviewed above season of conception was studied instead of season of birth (see also Erhardt, Nelson and Pakter, 1 9 6 6 ) . This is natural when the object o f .study is early fetal loss or some other event during pregnancy. Anencephalus is perhaps best studied by sea­ son of conception, because of the tendency o f anencephalus births to be premature. But there is always the problem that no adequate control data are available by month of conception. In

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