Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Familial risks of anencephaly and spina bifida in British Columbia McBride, Mary Louise 1977

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1977_A6_7 M32.pdf [ 3.35MB ]
Metadata
JSON: 831-1.0094037.json
JSON-LD: 831-1.0094037-ld.json
RDF/XML (Pretty): 831-1.0094037-rdf.xml
RDF/JSON: 831-1.0094037-rdf.json
Turtle: 831-1.0094037-turtle.txt
N-Triples: 831-1.0094037-rdf-ntriples.txt
Original Record: 831-1.0094037-source.json
Full Text
831-1.0094037-fulltext.txt
Citation
831-1.0094037.ris

Full Text

FAMILIAL RISKS OF ANENCEPHALY AND SPINA BIFIDA IN BRITISH COLUMBIA by MARY LOUISE McBRIDE B . A . , The U n i v e r s i t y of B r i t i s h Columbia, 1971 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES (Department of Medical Genet ics ) We accept t h i s t h e s i s as conforming to the requ i red standard THE UNIVERSITY OF BRITISH COLUMBIA September, 1977 © Mary Lou ise McBr ide , 1977 In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o r an advanced d e g r e e at t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by the Head o f my Depar tment o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t ten pe rm i ss ion . Depar tment o f M e d i c a l Genetics The U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date October 5 , 1977 - i i -ABSTRACT The purpose of th i s study has been to assess the r i sk of central nervous system trial formations to sibs of ind iv iduals born in B r i t i s h Columbia with e i ther anencephaly or spina b i f i d a c y s t i c a , two related central nervous system defects. Risks of anencephaly, spina b i f i d a c y s t i c a , and other central nervous system anomalies were der ived, both for a l l s ibs and for subsequent sibs of the index case. The sex, type of malformation, p a r i t y , and type of b i r th ( l i v e b i r t h or s t i l l b i r t h ) of the index case were a l l considered in the estimation of s i b l i n g r i s k . In add i t ion , various hypotheses regarding the aetiology of these malformations were discussed. An attempt was made to f i t a model for polygenic inheritance to the data and to estimate the degree of genetic determination in the causation of these defects in the province. Index cases of anencephaly and spina b i f i d a cys t i ca were ascertained from rout ine l y - co l lec ted records on morbidity and mor ta l i t y , obtained from the Div is ion of V i ta l S t a t i s t i c s of the B r i t i s h Columbia Department of Health. A l l affected cases born in the province from 1952 to 1970 were considered probands. The family information was acquired using l inked groupings of B r i t i s h Columbia marriage, b i r th and s t i l l b i r t h records for the period from 1946 to 1970. The use of these records was intended to avoid biases in ascertainment of indes cases and to provide complete family information. - i i i -The empiric r i s k of anencephaly or spina b i f i d a cys t i ca to a l l s ibs of ind iv iduals born in B r i t i s h Columbia with e i ther of these defects was 2.4%, about f i f t e e n times the population incidence. The r i sk to subse-quent-sibs of the f i r s t affected indiv idual in a family (2.1%) was not s i g -n i f i c a n t l y d i f fe rent from the r i s k to a l l s i b s . There was no di f ference in r i sk when the sex, type of malformation, p a r i t y , or type of b i r th of the proband were taken into account. Brothers and s i s te rs of index cases had the same r i s k of e i ther anencephaly or spina b i f i d a c y s t i c a , and there were equal proportions of each defect among s i b s . The r i sk of recurrence of e i ther of these anomalies a f te r two previously affected sibs was 4.8%, or approximately double the r i sk a f te r one affected s i b . No increased r i sk of any other central nervous system defect was observed in the fami l ies of the index cases. The s i b l i n g r i s k of anencephaly and spina b i f i d a cys t ica in B r i t i s h Columbia i s much lower than that reported elsewhere. Comparison of the resul ts of th is study with other family studies of anencephaly and spina b i f i d a cys t ica suggest that-geographical di f ferences in r i s k can be at t r ibuted largely to environmental factors in causation. The r i sk i s , however, large enough to j u s t i f y the continuation of amniocentesis service to mothers of chi ldren with anencephaly or spina b i f i d a c y s t i c a . The l inked family records avai lab le in B r i t i s h Columbia can be u t i l i z e d further in order to study the s i b l i n g r i sks of recurrence of other congenital malforma-t ions in the province, in par t i cu la r those with a higher frequency or those that present greater medical problems in the community. - i v-TABLE OF CONTENTS Page ABSTRACT i i LIST OF TABLES vi LIST OF FIGURES v i i ACKNOWLEDGMENTS v i i i Chapter 1 INTRODUCTION. 1 2 BACKGROUND 3 2.1 The'Mai formations 3 2.2 Embryology. 4 2.3 Epidemiology 5 2.3.1 Var iat ion in Populations 7 2.3.2 Var iat ion within Families 11 2.4 S ib l ing Risks of Anencephaly and Spina B i f i d a 14 2.5 Aetiology 19 2.5.1 Genetic Hypotheses 19 2.5 .2 Other Hypotheses 23 3 MATERIALS AND METHODS 2 5 3.1 Data 25 - V -Chapter Page 3.1.1 Ascertainment of Cases 25 3.1.2 Ascertainment of Families 26 3 .1 .3 Information 27 3.2 Procedures 29 3.2.1 Retr ieval 29 3 .2 .2 Analyses 32 4 RESULTS 33 4.1 Frequency of Malformations 33 4.2 Risks to Sibs 35 4.3 Recurrence Risks 38 4.4 Other Considerations 46 5 DISCUSSION 48 5.1 Ascertainment 48 5.2 Empiric S i b l i n g Risks 51 5.3 Theoretical S i b l i n g Risks 55 6 CONCLUSIONS 59 LITERATURE CITED 61 - v i -LIST OF TABLES Table Page I Var iat ion in Incidence of Anencephaly and Spina B i f i d a Cyst ica 6 II Studies of S i b l i n g Risks of Anencephaly and Spina B i f i d a Cystica 15 III Incidence of Anencephaly and Spina B i f i d a Cyst ica in B r i t i s h Columbia 34 IV Risks to Sibs of Anencephaly and Spina B i f i d a Cystica 36 V Risks to Sibs of Anencephaly and Spina B i f i d a C y s t i c a , by Type of B i r th of Proband 39 VI Recurrence Risks of Anencephaly and Spina B i f i d a Cyst ica 40 VII Recurrence Risks of Anencephaly and Spina B i f i d a C y s t i c a , by Type of B i r th of Proband 43 VIII Recurrence Risks of Anencephaly and Spina B i f i d a Cys t i ca , by Par i ty of Proband 44 IX Recurrence Risks of Anencephaly and Spina B i f i d a Cyst ica a f te r Two Affected Sibs 45 X Twin-born Index Cases of Anencephaly and Spina B i f i d a Cyst ica 47 XI Proportion of Sibs affected with Anencephaly and Spina B i f i d a Cyst ica in B r i t i s h Columbia and.London. 53 - v i i -LIST OF FIGURES Figure Page 1 D is t r ibut ion of l i a b i l i t y for polygenical ly inher i ted conditions 21 - v i i i -ACKNOWLEDGMENTS The helpful support of the members of my thesis committee during the course of t h i s project i s greatly appreciated: Dr. J .R . M i l l e r , Department of Medical Genetics (Chairman); Dr. B.K. Trimble, Department of Medical Genetics (Supervisor) ; Dr. J .M . Elwood, Department of Health Care and Epidemiology; Dr. C.W. Roberts, Department of Poultry Science; and Dr. P.A. Ba i rd , Department of Medical Genetics. In p a r t i c u l a r , I wish to express my sincere thanks to my thesis supervisor, Dr. B.K. Trimble, who has been most generous with his time and support, and Dr. J .R . M i l l e r , who has provided much valuable advice. Without the guidance and encouragement of these and other members of the Department of Medical Genetics, th is work would not have been nearly as st imulat ing and enjoyable as i t has been. - 1 -Chapter 1 INTRODUCTION Anencephaly and spina b i f i d a cys t ica (ASB) are two related severe congenital nervous system (CNS) defects. Several factors influence the population incidence^ of these malformations, including place of b i r t h , sex, and ethnic group (see section 2 . 3 . 1 ) . The aetiology of these anomalies i s not c l e a r , but family studies have indicated an increased r i sk of both conditions in subsequent s ib l ings of affected ind iv iduals (Warkany, 1971). The best avai lab le estimates of f a m i l i a l r i sks of anencephaly and spina b i f i d a cys t i ca come from empiric data co l lected in a number of centres in the United Kingdom (see section 2 .4) . However, there i s some question that these estimates are v a l i d for populations in other parts of the world. Furthermore, biases in the ascertainment of probands and in data c o l l e c t i o n lessen the r e l i a b i l i t y of the resul ts of these studies (see section 2 .4) . The purpose of the present study has been to assess the s i b l i n g r i sks of congenital central nervous system anomalies, among fami l ies who have had a c h i l d with anencephaly or spina b i f i d a cyst ica born in B r i t i s h B r i t i s h Columbia during the years 1952 to 1970. These r i sks were determined Throughout t h i s paper , the term inc idence has been used s p e c i f i -c a l l y to mean inc idence at b i r th . . . - 2 -using rou t ine l y - co l lec ted records on morbidity and mor ta l i t y , obtained from the D iv is ion of V i t a l S t a t i s t i c s of the B r i t i s h Columbia Department of Health, re la t ing to the B r i t i s h Columbia b i r th population of those years. Risks of anencephaly, spina b i f i d a c y s t i c a , and other congenital central nervous system defects were derived, taking into account the sex, type of malformation, and type of b i r th ( l i v e b i r t h or s t i l l b i r t h ) of the index case. A lso , an attempt was made to f i t a model for polygenic inheritance to the data and to estimate the degree of genetic determination .in the causa-t ion of anencephaly and spina b i f i d a cys t ica in the province. The use of l inked groupings of routinely-produced v i t a l and health records as a database for the present study was intended to avoid the ascertainment biases found in previous studies on f a m i l i a l r i s k s in anen-cephaly and spina b i f i d a c y s t i c a . Record linkage i s a procedure that brings together independently-derived records re la t ing to the same indiv idual or fami ly ; th i s can be done for the whole of a defined population. S p e c i f i c a l l y , i t can be used to assemble, on a large sca le , the health h i s to r ies of family members in order to provide data on morbidity and morta l i ty in family groups. Other family studies of neural-tube closure defects have not been able to obtain such comprehensive family h i s t o r i e s . It was f e l t that the data afford v i r t u a l l y complete ascertainment of cases born in B r i t i s h Columbia in the years 1952 to 1970. Furthermore, the l inked family groupings,..which include B r i t i s h Columbia marriage, b i r t h , death, hospital and reg is t ry records, also provide complete family information r e l a t i n g to a l l b i r t h s , both normal and abnormal, that have occurred in the province during the same period. - 3 -Chapter 2 BACKGROUND 2.1 The Malformations Anencephaly i s a lethal condit ion characterized by p a r t i a l or complete absence of the bra in , as d i s t i n c t from encephalocoele, another central nervous system anomaly in which the brain t issue i s exposed through a defect in the s k u l l . The term spina b i f i d a refers to several midl ine defects of the osseous spine, some with neural involvement, and some without. Those vertebral defects that inyolve the meninges or neural t i s s u e , of which there are several types, are c o l l e c t i v e l y ca l led spina b i f i d a c y s t i c a . A defect that consists of a protruding sac f i l l e d with meninges and spinal f l u i d i s ca l led a meningocoele. If spinal nerves or cord are included in the protrus ion, the defect i s known as a meningomyelocoele. Less common forms of spina b i f i d a cyst ica include myeloschis is , in which the neural plate has f a i l e d to form a tube, and a rare form ca l led myelocystocoele. Spina b i f i d a cyst ica i s found most commonly in the lumbosacral area of the spine. While anencephaly i s invar iab ly le thal at b i r t h , only about 25% of spina b i f i d a cys t ica cases are s t i l l b o r n (Laurence, 1966). Without treatment, a further 14% of the tota l would be expected to die in the f i r s t week of l i f e , and only 16% of to ta l cases would survive to the age of one year. However, with surgical in tervent ion , about 70% of l iveborn cases are - 4 -saved, although most become handicapped (Rickham and Mawdsley, 1966). Individuals with spina b i f i d a cyst ica frequently suffer from "meningi t is , hydrocephaly, para lys is and deformity of the lower l imbs, and urinary bladder para lys is and i t s consequences" (Sharrard et at., 1963); there are more females with these complications than males. Anencephaly and spina b i f i d a cys t ica const i tute a s i g n i f i c a n t proportion of the to ta l in fant morta l i t y and morbidity in western countr ies ; indeed, in Canada, anencephaly i s "the most common congenital abnormality causing per inatal death" (Elwood, J . M . , 1974). The j o i n t occurrence of anencephaly and spina b i f i d a cys t ica ranges from 9% (Record and McKeown, 1949) to 17% ((Frezal et al., 1964), a s i g n i f i -cant ly higher proportion than would be expected i f these two defects were unrelated. In add i t ion , hydrocephaly i s associated with about 80% of cases of meningomyelocoele (Lorber, 1961), as a resu l t of secondary defects related to the Arnold -Chiar i malformation (Buta, 1975). I ts incidence i s highest when the spinal defect i s in the lumbar region (Lorber, 1961). Most studies (Elwood, J . M . , 1976b) have not been able to demonstrate an associat ion of ASB with any other congenital defect . 2.2 Embryology The central nervous system in humans s tar ts to d i f f e r e n t i a t e mor-phological ly with the formation of the neural plate on the dorsal surface of the three-week old embryo. This plate info lds to form the neural groove; the folds then fuse to/form a tube, s ta r t ing in the mid-dorsal region and extending both c r a n i a l l y and caudally to the anter ior and poster ior neuropores. This process i s completed by the fourth week of development (Nakano, 1973; - 5 -C o r l i s s , 1976). At th i s stage the neural structure consists of a long tube (which develops into the spinal cord) with a broader cephal ic end (the future bra in ) . In the meantime, mesoderm has completely surrounded the.neural tube and separated the neuroectoderm from the ectoderm. Both anencephaly and spina b i f i d a cyst ica probably resu l t from a f a i l u r e of fusion of the neural fo lds during embryogenesis (Laurence, 1964; Nakano, 1973), and consequently these defects are present as early as the fourth week of development. I t i s in terest ing to note that , while anence-phaly i s caused by a f a i l u r e to fuse at the anter ior end of the embryo, and most spina b i f i d a cys t ica lesions are found near the poster ior end of the spinal cord, r e l a t i v e l y few defects are discovered in the mid-dorsal region. This observation suggests that there may be a very s p e c i f i c time during which the defects can occur. A l t e r n a t i v e l y , more severe manifestations of the defect may be los t early in pregnancy, and consequently not even recognized. Both abnormalities are obvious at b i r t h . 2.3 Epidemiology Epidemiological studies of anencephaly and spina b i f i d a cyst ica have revealed many pos i t ive assoc iat ions , some with a possible genetic basis (sex, ethnic group, family) and others that are suggestive of environmental factors (place of b i r t h , secular and seasonal t rends) . Demographic var ia t ion in the incidence of these conditions can be divided into two types: var ia t ion in populations and var iat ion within f a m i l i e s . The epidemiological aspects of the incidence of ASB are summarized in Table I; these s i g n i f i c a n t assoc ia -t ions are described more f u l l y below. Table I Var iat ion in Incidence of Anencephaly and Spina B i f i d a Cystica High Frequency Low Frequency Population Character is t ics Ireland (Leek and Rogers, 1967; Elwood, J .H . and Nevin, 1973) Scotland (Elwood, J . H . and MacKenzie, 1971) North and western B r i t a i n (Carter et al., 1968; Smithel ls et al.3 1968; Richards and Lowe, 1971) Northeast North America (A l te r , 1963; Horowitz and McDonald, 1969; MacMahon and Yen, 1971) A lexandr ia , Egypt (Stevenson et al.3 1966) Sikhs (Searle, 1959) Winter (Elwood, J . M . , 1976a,b) Lower social c lass (Edwards, 1958; Will iamson, 1965; Naggan and MacMahon, 1967; Horowitz and McDonald, 1969) South America (Stevenson et al.s 1966) Asia (Searle, 1959; Stevenson et al., 1966) A f r i ca (Simpkiss and Lowe, 1961; Nakano, 1973) Blacks (Leek, 1974) Ashkenazi Jews (Leek, 1974) South U.S. (A l ter , 1963) B r i t i s h Columbia (Elwood, J . M . , 1974; Trimble and Bai rd , 1977a) Family Character is t ics Young mothers (Edwards, 1958) Older mothers (McKeown, 1961) F i r s t b i r th and high p a r i t y 2 ( Ingal ls et al.3 1954; Naggan and MacMahon, 1967; Horowitz and McDonald, 1969; Elwood, J . M . , 1976a) Females (Leek, 1974) Second births ( Ingal ls et al.3 1954; Naggan and MacMahon, 1967; Horowitz and McDonald, 1969; Elwood, J . M . , 1976b) Par i t y : the number of v iable b i r ths carr ied by a par t i cu la r woman. - 7 -2.3.1 Var iat ion in Populations Place: The overa l l incidence of ASB i s approximately two per thousand tota l b i r ths (Warkany, 1971), but the geographical var ia t ion i s considerable. For anencephaly the highest rates (>1 per 1000 b i r ths ) are found in the B r i t i s h I s l e s , northeast North America, and the Middle East as far as India (Leek, 1974), with, except ional ly high f igures (>3 per 1000 b i r ths) being recorded in I re land, Scotland, the north and west of B r i t a i n , Alexandria, Egypt, and among the Sikhs of India (Leek, 1974). The incidence i s generally low (<0.6 per 1Q00 b i r ths ) in A s i a , A f r i c a , and South America, while most of the United States and Canada, Europe and Israel have i n t e r -mediate rates (Nakano, 1973). There i s a s i x t y - f o l d di f ference between the lowest reported incidence of anencephaly, in Bogota (0.11 per 1000 b i r ths ) (Stevenson et al., 1966) and the highest, among the Sikhs (6.5 per 1000 b i r ths) (Searle, 1959). The incidence of spina b i f i d a cyst ica i s s i m i l a r to that of anencephaly except in Oriental countr ies , where the rate of spina b i f i d a cyst ica i s very much lower than that of anencephaly (Leek, 1974). There are indicat ions of both a north-south and an east-west gradient in the incidence of neural - tube„closure defects in North America. The rates in the eastern part of the continent are one and one-half to three times those in the west (Elwood, J . M . , 1976a), while the f igures in the north show a two and o n e - h a l f - f o l d increase over those in the south (A l te r , 1963). Among Canadian provinces, the incidence of ASB declines s teadi l y from New Brunswick on the east coast , where the rate i s 4.0 per thousand t o t a l b i r t h s , to B r i t i s h Columbia in the west, where the incidence i s only 1.5 per thousand to ta l b i r ths (Elwood, J . M . , 1974). In f a c t , the population of B r i t i s h Columbia has one of the lowest rates of ASB among Caucasian populations (Elwood, J.In., 1974). - 8 -Ethnic Group: Racial background is another demographic var iable that shows a strong re lat ionsh ip to the occurrence of neural-tube closure defects . The incidence of anencephaly and spina b i f i d a cys t ica i s high among Sikhs, and r e l a t i v e l y low among blacks and Ashkenazi Jews, wherever members of these groups reside (Leek, 1974). This implies that there may be some genetic differences in predisposi t ion among these groups. However, the incidence among Caucasians shows marked geographical var ia t ion (Leek, 1972), impl icat ing environmental factors that vary with place of residence. For instance, the English in Quebec have a lower rate of neural-tube closure defects than those in B r i t a i n , while the incidence among the French in Quebec i s higher than that in France (Horowitz and McDonald, 1969). A l ternat ive explanations have been proposed for both these phenomena; the constant rates among people of Mongoloid, Negroid, or Lat in American o r ig in could be due to maternal factors rather than a genetic s u s c e p t i b i l i t y to the disease i t s e l f ; and se lect i ve migration could lead to genetic differences among Caucasians l i v i n g in d i f fe rent areas of the world (Leek, 1974). Secular Variation: Complicating the pattern of geographical var iat ion in incidence of neural-tube closure defects are changes in incidence that have occurred through time, in many parts of the world. However, not a l l areas have shown th is type of v a r i a t i o n ; and furthermore, the trends observed have not been consistent from place to place or through time. For instance, a gradual r i s e in the frequency of each defect , followed by a decl ine in incidence to the o r ig ina l l e v e l , occurred in Ber l in from 1945 to 1950, in Birmingham from 1950 to 1965, and in England and Wales as a whole in the period from 1920 to the 1940 ls (Rogers and Morr is , 1971). Scotland (Leek - 9 -and Rogers, 1967) and Ireland (Elwood, J . H . , 1970) showed s i m i l a r , though not ident ica l trends, to those in England. The incidence of ASB in New England rose dramatical ly between 1920 and 1935, culminating in a rate for the years 1929 to 1932 more than three times that preceding or fo l lowing the epidemic period (MacMahon and Yen, 1971; Janer ich, 1973). Canadian data show a gradual decl ine in incidence of ASB since 1950, except for an increase in spina b i f i d a cyst ica rates between 1960 and 1962 (Elwood, J . M . , 1974). The rate of anencephaly morta l i ty in Ontario declined most dramatical ly of a l l the provinces, whereas the rate for Quebec peaked around 1954 and then decreased. Mor ta l i t y rates for anencephaly in the P r a i r i e s and the Maritimes declined more slowly, with increases in 1958 in the P r a i r i e s , and 1956 in the Marit imes. There was a large decrease in anencephaly morta l i ty rates in the Maritimes in 1967. The rate in B r i t i s h Columbia has remained constant since 1950, except for a small peak in 1952. Such trends are ind icat i ve of environmental inf luences, and the consistent ly low rate in B r i t i s h Columbia would suggest that , i f environmental factors are a f fec t ing the incidence of ASB in the province, the i r e f fect has been constant through time (Elwood, J . M . , 1974). Seasonal Variation: The e f fect of season on the incidence of :. neural-tube closure defects varies considerably with year and l o c a l i t y . S ign i f i cant seasonal var iat ions have been found in the B r i t i s h Is les (Leek, 1974), and in Canada (Elwood, J . M . , 1976a), although not in the United States (Elwood, J . M . , 1974) or in Europe (Leek, 1974). However, the seasonal differences have not been consistent for e i ther anencephaly and spina b i f i d a c y s t i c a , varying with time and between populations (Leek, 1974). - 1 0 -A re la t ionsh ip between season and incidence of neural-tube closure defects has been establ ished for the four Canadian provinces of B r i t i s h Columbia, A lber ta , Manitoba, and New Brunswick from 1966 to 1969 (Elwood, J . M . , 1976a). The combined incidence of anencephaly and spina b i f i d a cyst ica in these provinces varied from 2.19 per thousand tota l b i r ths in the three-month period from March to May, to 1.77 per thousand tota l b i r ths from June to August and from December to February. This type of var ia t ion also suggests some environmental agent a f fec t ing the incidence of neural-tube closure : defects . Sooio-Economio Status: Socio-economic factors have a pronounced ef fect on the incidence of ASB, in most areas of the world. A higher incidence of neural-tube closure defects has been reported for those in the lower socio-economic groups, while rates among those of more prosperous soc io -economic status are r e l a t i v e l y low, although the extent of the dif ferences among groups i s var iable (Nakano, 1973; Leek, 1974). This associat ion has also been observed in Canada (Horowitz and McDonald, 1969; Elwood, J . M . , 1976a). It has not been found, however, in Hungary, I s r a e l , or among blacks (Nakano, 1973; Leek, 1974). Environment: In an e f f o r t to ident i f y some of the environmental influences on the development of central nervous system anomalies, several attempts have been made to corre late the incidence of these defects with various factors known to influence other condi t ions . Infections and other i l l n e s s e s , chemicals in diseased potatoes, minerals in dr inking water, and drugs that cause fo la te depletion are jus t a few of the many substances that have been examined recently in terms of the i r re lat ionsh ip to anencephaly - l i -ana1 spina b i f i d a cyst ica (Leek, 1974). The cor re la t ion with potato b l ight seems to have been spurious (Leek, 1974), and no re lat ionsh ip to s p e c i f i c i l l n e s s e s has been found (Nakano, 1973). Research into environmental agents i s cont inuing. 2..3.2 Var iat ion within Families Maternal Age and Parity: The combined ef fects of maternal age and par i ty resu l t in marked dif ferences in the incidence of both anencephaly and spina b i f i d a c y s t i c a , although the e f fect of age i s less than that of p a r i t y , and the extent of the var ia t ion d i f f e r s considerably among countries (Nakano, 1973). A low incidence among second bi r ths has been observed in a l l studies of ASB, and most places report an increase in incidence with par i ty greater than two. The frequency among f i r s t b i r ths i s low in I s r a e l , but high in most other areas, including North America (Leek, 1974). Several s tudies , including one Canadian study, describe a U-shaped d i s t r i b u t i o n of incidence with par i ty ( Ingal ls et al.3 1954; Record, 1961; Naggan and MacMahon 1967; Elwood, J . M . , 1976a). In B r i t a i n , incidence varies with the combined influence of age and par i t y , being highest in f i r s tborns to both young mothers and mothers over 35. A trend towards increased rates with increasing maternal age has been observed in most s tudies , although in Israel and B r i t a i n th is only occurs among primaparae. However, in cohort studies in New York ((Janerich, 1971; Janer ich, 1972) and in Canada (Elwood, J . M . , 1976a), the incidence of ASB was shown to decrease with increasing age. This implies that the U-shaped associat ions with par i ty may be merely a resu l t of a cohort e f f e c t , since the par i ty groups have d i f fe rent proportions of women of each age. - 1 2 -Sex Distribution: There are s t r i k i n g dif ferences in the incidence of ASB between the sexes. The incidence of neural-tube closure defects in females i s much higher than that in males, in western countr ies ; in Oriental populations, a sex di f ference i s not apparent (Leek, 1974). For anencephaly, the ra t io of males to females var ies considerably with l o c a l i t y , from 0.45:1 in the B r i t i s h Is les to near unity in Oriental countr ies ; while that for spina b i f i d a cys t ica i s f a i r l y constant at approximately 0.75:1 (Leek, 1974). The proportion of females is greater among s t i l l b i r t h s than among l iveborn in fants . It has been noted that the incidence of ASB among males is generally more stable over time than that among females (Leek, 1974). In Canada, the r a t i o of males to females with anencephaly from 1943 to 1970 i s 0.46:1 ( (Elwood, J . M . , 1974), with a barely s i g n i f i c a n t increase in the proportion of males within that time period (Elwood, J . M . , 1976a). Twin Studies: If the production of neural-tube closure anomalies was influenced by factors in the in t ra -u te r ine environment, one would expect a higher incidence of ASB among twins than among non-twin s ib l ings of affected cases. Furthermore, a genetic influence on the development of ASB would resu l t in a greater proportion of monozygotic than d izygot ic twins concordant for a neural-tube closure defect . In f a c t , concordance for ASB among twins seems to be uncommon; the proportion of affected among twins (2.8%) is lower than that reported among sibs (3% to 6%) (Elwood, J . M . , 1976b). However, the observed concordance rate among twins i s not incompatible with a postulated r i s k as high as 6% (Elwood, J . M . , 1976b). The number of twins among i n d i -viduals affected with ASB i s only s l i g h t l y lower than expected in the general - 1 3 -population (.Elwood, J . M . , 1976b), suggesting that concordance does not resu l t in great ly increased foetal l o s s . Unfortunately, the zygosity of observed concordant twin pairs has not been reported. However, a normal ra t io of l ike -sexed to unl ike-sexed concordant twin pairs i s found, implying that zygosity does not a f fec t concordance. This also suggests that the lower recurrence r i s k in twins may be related to the twinning process i t s e l f , perhaps due to an increased r i sk of ear ly abortion in concordant twin p a i r s . Sibling Risks:-.: Increased r i sks to s ib l ings of ind iv iduals affected with ASB are of three kinds; f i r s t , the r i s k of abortion and s t i l l b i r t h ; second, the chance of developing spina b i f i d a occu l ta , a spinal defect in? volving the vertebrae only; and t h i r d , the r i s k of another neural-tube ; closure defect (Leek, 1974). Apart from the increased incidence of hydro-cephaly associated with spina b i f i d a c y s t i c a , there seems to be no increased r i s k of any other types of congenital malformations among s i b s . Higher rates of abortion and s t i l l b i r t h s in mothers with affected chi ldren have been reported (McDonald, 1971; Richards, 1973); however, such data are open to bias because of d i f f i c u l t i e s in ascertainment of pregnancy loss and therefore are hard to assess. Studies that show an increase in the proportion of affected foetuses (Nishimura, 1970; Alberman et al.3 1973) from los t pregnancies have led to suggestions that such d i f f e r e n t i a l loss may contribute to the geographical di f ferences in incidence and to the increased rate among f i r s t b o r n s , although not to the seasonal and socio -economic d i f ferences , nor to the var ia t ion with higher maternal par i ty and age (Leek, 1974). - 1 4 -The information on an increased l i a b i l i t y to spina b i f i d a occulta i s also d i f f i c u l t to quant i fy , due to the d i f f i c u l t y in assessing i t s preva-lence in the general population. One of the more important r i sks to sibs of affected chi ldren i s that of an increased s u s c e p t i b i l i t y to ASB. A more detai led account of the extent and s ign i f i cance of s i b l i n g r i s k s of neural-tube closure defects i s given in section 2 .4 . Other Family Studies: There have been several studies that have examined the r i s k s of neural-tube closure defects among family members other than s i b s . The r i s k to h a l f - s i b s of affected ind iv iduals i s s i g n i f i c a n t l y increased (Leek, 1974); moreover, i t seems to be greater for maternal than paternal h a l f - s i b s . In studies of cousins, only those on the maternal side showed an increased incidence (Carter and Evans, 1973). This maternal inf luence, however, may only be due to ascertainment b ias , since information from the maternal side of the family i s l i k e l y to be more complete. 2.4 S ib l ing Risks of Anencephaly and Spina B i f i d a Cyst ica The ca lcu la t ion of the r i sks of other neural-tube closure defects in sibs of ch i ldren with anencephaly or spina b i f i d a cyst ica i s an important aspects of the study of these condi t ions , both from the point of view of family counsel l ing and in studies of aet io logy . Estimates of the r i s k to s ibs of e i ther anencephaly or spina b i f i d a cyst ica have varied from 1.4% (Naggan, 1971) in Israel from 1958 to 1968, to 6.1% (Lorber, 1965) to sibs of spina b i f i d a cyst ica cases from a hospital ser ies in S h e f f i e l d . The var ia t ion in r i sks to sibs among nine studies car r ied out since I960 (see T a b l e II S t u d i e s 1 o f S i b l i n g R i s k s o f A n e n c e p h a l y and S p i n a B i f i d a C y s t i c a L o c a l i t y N o . P r o p o s i t i N o . S i b s * A f f e c t e d P o p u l a t i o n I n c i d e n c e per 1000 b i r t h s S o u r c e o f P r o p o s i t i R e f e r e n c e I s r a e l 776 _ _ 2 1 . 3 4 1 . 4 6 d e a t h and h o s p i t a l r e c o r d s N a g g a n , 1971 New Y o r k 139 308 3 . 2 4 2 . 0 0 b i r t h , s t i l l b i r t h , h o s p i t a l r e c o r d s M i l ham, 1962 London 870 1484 4 . 5 2 . 9 5 m o r t a l i t y d a t a , h o s p i t a l r e c o r d s , r e g i s t r y C a r t e r and E v a n s , 1973 Rhode I s l a n d 1095 , 1 2 6 3 4 . 6 4 . 4 6 h o s p i t a l r e c o r d s Yen and HacMahon, 1968 Southampton 101 • 1 9 1 5 . 6 5 . 1 7 b i r t h and h o s p i t a l r e c o r d s W i l l i a m s o n , 1965 G lasgow 318 904 5 . 6 5 . 6 v i t a l r e c o r d s R i c h a r d s et at., 1972 L i v e r p o o l 1338 1790 3 . 9 6 . 5 m o r t a l i t y d a t a , r e g i s t r y S m i t h e l l s et al., 1968 S o u t h Wales 829 1562 5 . 2 7 . 6 7 m o r t a l i t y d a t a C a r t e r et al., 1968 S h e f f i e l d 3 722 1256 6 . 1 — h o s p i t a l r e c o r d s L o r b e r , 1965 s i n c e 1960 number n o t g i v e n i n p a p e r ' s p i n a b i f i d a c y s t i c a p r o p o s i t i o n l y - 1 6 -Table II) can be at t r ibuted sometimes to incomplete ascertainment and followup of f a m i l i e s , and sometimes to genuine dif ferences in the populations studied. Three studies (Lorber, 1965; Carter and Roberts, 1967; Smithel ls et al. 3 1968) examined the r i sk af ter two affected c h i l d r e n , and reported rates much greater than 6%. The differences in incidence among sibs are not nearly as great as the var ia t ion in the population incidence of these defects . There i s a tendency for the r i s k to be higher proportional to the population incidence in areas of low prevalence than in areas of high prevalence. Thus, in London (Carter and Evans, 1973), where three thousand tota l b i r ths are affected with anencephaly or spina b i f i d a c y s t i c a , the r i s k among sibs i s f i f t e e n times that in the general population, or 4.5%; and in South Wales (Carter et al.3 1968), which has 7.7 per thousand b i r ths a f fec ted , the incidence among sibs i s 5.2%, or seven times the population r i s k . In general , the lower the incidence of anencephaly and spina b i f i d a cyst ica in the study population, the lower the r i s k of occurrence of the defects among s i b s . Excluding the I s r a e l i study (Naggan, 1971), which almost ce r ta in l y gives an underestimate of the true r i s k since i t excludes some affected s i b s , the lowest reported r i s k , of 3.2%, occurs in New York (Milham, 1962). The highest r i s k s to sibs (5.2% to 5.6%) are found in Southampton (Will iamson, 1965), Glasgow (Richards et al. 3 1972) and South Wales (Carter et al. 3 1968), with a r e l a t i v e l y high incidence of ASB (over f i v e per thousand b i r t h s ) . The more moderate r i sk among sibs in Liverpool (Smithells et al. 3 1968) of 3.9% is an exception to th i s pattern since the incidence of neural tube closure defects there (6.5 per 1,000 b i r ths ) i s quite high. A l l four of these ser ies were based on v i t a l and hospital records, family information was obtained in every case through home v i s i t s , and the study periods were overlapping, so the di f ference between the Liverpool study and the others can he regarded as r e a l . The only other recent American study was in Rhode Island (Yen and MacMahon, 1968), where both the population incidence (4.5 per thousand b i r ths ) and the proportion affected among sibs (4.6%) were somewhat higher than in New York. In Glasgow (Richards et al. 3 1972) and in London (Carter and Evans, 1973) the r i s k of a neural-tube closure defect in sibs of anencephalic cases was elevated over that for patients with spina b i f i d a c y s t i c a , although not s i g n i f i c a n t l y so in the London study. In two other se r ies , in Liverpool (Smithells et al. 3 1968) and Rhode Island (Yen and MacMahon, 1968), no d i f -ference was seen and in Southampton (Will iamson, 1965) and South Wales ••, (Carter et al., 1968) the r i sk was actua l l y s l i g h t l y higher among sibs of spina b i f i d a cys t ica index pat ients . In most studies the neural-tube closure defects seen in the s ibs were more often the same as those in the p r o p o s i t i ; one study (Yen and MacMahon, 1968), that considered subsequent sibs only, did not observe t h i s pattern. The sex di f ference in incidence that i s observed in population studies of anencephaly and spina b i f i d a cys t ica i s also found among sibs of these pat ients . Studies in South Wales (Carter et al. 3 1968), Glasgow (Richards et al. 3 1972), and London (Carter and Evans, 1973) a l l had a higher proportion of females than males among the i r index pat ients , t h i s di f ference being greater in a l l cases among the anencephalic probands than among the spina b i f i d a cys t ica index cases. A l l except the Glasgow ser ies also reported an increased r i s k to female sibs of the i r index pat ients . The London study reported a p a r t i c u l a r l y high r i s k among female sibs of female anencephalic probands, while the survey in South Wales found an increased r i s k in a l l female sibs except those of female spina b i f i d a cyst ica p r o p o s i t i . An increased r i s k to female sibs was also observed in Southampton, but the ser ies was too small to be analyzed by sex or malformation of the propositus. The Glasgow survey was unusual in that the r i s k to male and female sibs of male index cases was the same, and the r i s k to jnale sibs of female probands was s l i g h t l y above that of s i s t e r s of female index cases. When the data were broken down by malformation, however, i t was observed that there was an increased r i sk to female sibs of female spina b i f i d a cys t ica cases, but that the r i s k to sibs of anencephaly probands was elevated for those of the same sex as the proband. The r i s k of malformations other than anencephaly and spina b i f i d a cys t ica to sibs of affected ind iv iduals did not seem to be increased over the general population l e v e l s , although, an increase in foeta l loss was observed in Southampton (Will iamson, 1965) and one hospital ser ies in Shef f ie ld (Lorber, 1965) reported an increase in hydrocephaly among sibs of spina b i f i d a cyst ica pat ients . In discussion of the s i b l i n g r i sks of anencephaly and spina b i f i d a c y s t i c a , a d i s t i n c t i o n must be made between the incidence among a l l sibs of affected c h i l d r e n , which i s the r i s k that has been quoted above, and the r i s k to subsequent s i b s , which i s the r i s k used for most counsel l ing purposes. Studies in Southampton (Will iamson, 1965), South Wales (Carter et al.3 1968), Glasgow (Richards et al.3 1972), and London (Carter and Evans, 1973) examined the ltisk to sibs both before and af ter the index pat ient , and found no di f ference in incidence among sibs between the two groups. However, an increase in r i s k to subsequent s ibs of affected index cases was reported in Liverpool (Smithells et al.3 1968), and in the family study, of spina b i f i d a cyst ica at Shef f ie ld (Lorber, 1965). The recurrence r i s k was also found to be greater in younger sibs of f i r s t - b o r n cases of ASB, in Glasgow (Richards et al. 3 1972). The r i s k of recurrence of neural-tube closure defects a f ter two affected sibs i s also important in genetic counsel l ing . Studies in Liverpool (Smithells et al.3 1968) and in Shef f ie ld (Lorber, 1965) reported very high incidence rates among sibs fo l lowing two cases of ASB (over 50%); however, i t i s d i f f i c u l t to put confidence in these estimates since both samples were small and biased in favour of h igh - r i sk f a m i l i e s . A more r e l i a b l e estimate i s given by a B r i t i s h study (Carter and Roberts, 1967) that followed up 113 fami l ies with at least two affected cases. Out of 69 subsequent sibs in 47 f a m i l i e s , eight ch i ld ren , or 12%, also had anencephaly or spina b i f i d a c y s t i c a . The r i s k of e i ther malformation was the same. The study concluded that r i s k of a recurrent neural-tube closure defect a f te r two affected cases was about double the r i s k af ter one affected c h i l d had been born. Since s i b l i n g r i sks vary among areas with d i f fe rent incidence rates , i t may be that the recurrence r i s k af ter the b i r th of two sibs with ASB varies s i g n i f i -cant ly a l so . 2.5 Aetiology 2.5.1 Genetic Hypotheses The influence of genetic factors in the causation of neural-tube closure defects i s suggested by the observation of an increased frequency of the condit ions among the re la t i ves of affected ind i v idua ls . However, family studies have also shown that the disease i s not inher i ted in a simple Mendelian manner. - 2 0 -The most widely accepted genetic model of the aetiology of ASB i s that of polygenic inheritance with a threshold e f f e c t . In the case of anencephaly and spina b i f i d a c y s t i c a , th i s model assumes that a number of genes are acting add i t i ye l y in the development of the neural tube. This pro-duces a normal d i s t r i b u t i o n of l i a b i l i t y to malformation in the population, with a threshold above which a defect i s produced (Figure 1). In re la t i ves of affected i n d i v i d u a l s , the mean l i a b i l i t y i s sh i f ted upwards (Figure 1) ; therefore a higher percentage of re la t i ves w i l l have genotypes that are above the threshold. The polygenic threshold model can be used to estimate the degree of genetic determination, in these malformations, that i s , the yar ia t ion between ind iv iduals that can be at t r ibuted to genetic dif ferences (Falconer, 1965). The degree of addi t ive genetic variance, as a proportion of the to ta l phenotypic variance (genetic and non-genetic) , can be ca lcu la ted . This pro-por t ion , known as the h e r i t a b i l i t y , has been used as a minimum estimate of the degree of genetic determination. There are several consequences of the polygenic threshold model (Carter, 1969). F i r s t , the r i sk of recurrence of the defects would be greater in re la t i ves than in the general :populat ion, and higher in f i r s t -degree r e l a t i v e s than in more remote r e l a t i o n s . Second, in areas of high incidence, the r i s k to sibs would be higher in absolute terms than the r i s k in areas of low incidence, but lower in proportion to the population incidence. Th i rd , the recurrence r i s k should increase the greater the number of affected ind iv idua ls in the fami ly . A l l of these predict ions are corroborated in family s tudies . - 2 1 -L i a b i l i t y in Population MEAN L i a b i l i t y among Relat ives ! ME.AN THRESHOLD Figure 1: D is t r ibut ion of l i a b i l i t y for polygenical ly inher i ted condit ions. - 2 2 -One consequence of the polygenic model seems to be contradicted by empirical evidence. Since the incidence of ASB i s greater among females than among males, the polygenic model implies that affected females have a lower threshold of s u s c e p t i b i l i t y , and therefore the r i s k for the i r s ibs should be lower than that for brothers and s i s t e r s of affected males. In f a c t , family studies show that the highest r i s k i s often among s i s t e r s of affected females. It may be that males ac tua l l y do have an increased sus-c e p t i b i l i t y to neural-tube closure defects , and also are more severely :. affected than females, being los t ear ly in pregnancy. This suggestion i s compatible with the obseryed sex dif ferences in s i b l i n g r i sks as well as the female preponderance in the general population. Edwards (1960) has shown that the overal l r i s k to sibs in conditions inher i ted in th i s manner is approximately /p when p, the population incidence, i s between 0.1% and 1%. Other researchers (Smith, 1971; Curnow, 1972) have extended t h i s analysis to determine the theoret ica l r i s k s to sibs in a wide range of s p e c i f i c family s i t u a t i o n s . The recurrence r i sks for anencephaly and spina b i f i d a cyst ica in various types of fami l ies has been estimated (Bonai t i -Pe l 1 ie - and Smith, 1974), using data on the population incidence and overal l r i sks to sibs of these two defects in London (Carter and Evans, 1973). However, the confidence in terva ls for these estimates are very large (Smith, 1971) and the i r usefulness i s consequently reduced considerably. An a l te rnat i ve genetic hypothesis i s the suggestion that anen-cephaly and spina b i f i d a cyst ica may be inher i ted through maternal cytoplasm (Nance, 1969). A higher reported r i s k of ASB among maternal h a l f - s i b s of affected ind iv iduals than among paternal h a l f - s i b s , and an increased pro-portion of affected ind iv iduals among mat r i l inea l r e l a t i v e s , have been c i ted - 2 3 -as evidence for cy top lasmic inher i tance. This could explain the low concor-dance rate among twins, but pooled data from three studies (Carter et.ial.3 1968; Yen and MacMahon, 1968; Carter and Evans, 1973) show that the di f ference in r i s k between maternal and paternal h a l f - s i b s i s not s i g n i f i c a n t . Further-more, cytoplasmic inheritance has not been demonstrated so far in man. Another a l te rnat i ve to the polygenic model i s the concept of foetus-foetus interact ion (Knox, 1970), which suggests that every singleton b i r th of anencephaly i s the resu l t of an ear ly (implantation stage) immuno-log ica l react ion between dizygous twins, in which one twin i s k i l l e d and the other l e f t with a neural-tube closure defect . This idea i s supported by the fact of a cor re la t ion between dizygot ic twinning rates and incidence of anencephaly around the world (Stevenson et al. s 1966), and the r e l a t i v e l y low concordance rate among twins, who according to t h i s hypothesis are ;i actua l l y the resu l t of t r i p l e t conceptions. Unfortunately, th is hypothesis does not explain how an immunological in teract ion in very ear ly embryogenesis would cause a systemic defect such as ASB that apparently occurs in the th i rd week of embryological development. A lso , th i s hypothesis cannot account for the higher female preponderance of affected cases in areas of higher -incidence, or the increase in incidence with b i r th rank greater than two. 2.5.2 Other Hypotheses The associat ions of neural-tube closure defects with time, place, socio-economic s tatus , and maternal par i ty and age a l l suggest environmental factors inf luencing the development of these abnormalit ies. Despite a great deal of descr ipt ive inves t iga t ion , however, no s p e c i f i c factors have been conclusively i d e n t i f i e d , and c e r t a i n l y none of the common environmental agents - 2 4 -(drugs, v i ruses , chemicals) has been shown to be involyed in the causation of these anomalies. Possibly the ef fects of environmental factors are also small and cumulative ( leek, 1974). Descript ive and family studies of anencephaly and spina b i f i d a cys t ica over the l a s t twenty-f ive years haye reyealed a great deal of i n f o r -mation about how the incidence of these conditions ya r ies , but unfortunately have provided few ins ights .as to why t h i s var ia t ion occurs. Anencephaly and spina b i f i d a cyst ica must have s imi la r a e t i o l o g i e s , since they show s imi la r patterns of var ia t ion in incidence, and also show increased r i s k s of e i ther anomaly in s ib l ings of affected ind i v idua ls . Furthermore, there i s evidence for both environmental and genetic factors inf luencing the development of these defects . The increased incidence of neural-tube closure defects in the fami l ies of affected i n d i v i d u a l s , and the var ia t ion in incidence among d i f -ferent ethnic groups both suggest genetic involvement; and yet the low con-cordance rate among monozygotic twins and the associat ions with t ime, place, and maternal factors imply the operation of environmental factors as w e l l . What i s not known i s the extent of these two influences in determin-ing neural-tube closure defects. Both genetic and environmental factors must be complex, since there i s no s i tuat ion in which more than a small proportion of ch i ldren i s a f fec ted , even that of monozygotic twins who share both the same genetic const i tut ion and the same in t ra -u te r ine environment (Leek, 1974). That th i s s i tuat ion should ex is t seems e n t i r e l y reasonable, given the complexity of the developmental processes of the central nervous system. At present neither environmental norvgenetic hypotheses can provide accurate estimates of f a m i l i a l r i s k s of anencephaly and spina b i f i d a c y s t i c a . The best estimates of these r i s k s , therefore, come from empiric data. - 2 5 -Chapter 3 MATERIALS AND METHODS 3.1 Data 3.1.1 Ascertainment of Cases Index cases of anencephaly and spina b i f i d a cys t ica were ascer-tained from v i t a l records of s t i l l b i r t h from the Div is ion of V i ta l S t a t i s t i c s of the Department of Health in B r i t i s h Columbia, and from records of l i v e -born chi ldren with congenital malformations retr ieved from the reg is ter for handicapped chi ldren and adults of the B r i t i s h Columbia Health Sur-ve i l lance Registry . The reg is ter i t s e l f acquires i t s cases through voluntary reg is t ra t ion of affected ind iv iduals and through routine surve i l lance of B r i t i s h Columbia v i t a l and hospital records (Lowry et at., 1.975). The study covered b i r ths from 1952 to 1970, since i t was for those years that both computerized v i t a l and reg is ter records were ava i lab le . During the study period there were 678,401 l i v e b i r t h s recorded in the province. The d e f i n i t i o n of s t i l l b i r t h changed in 1963 so that from 1952 to 1962, a tota l of 4,326 s t i l l b i r t h s . . f r o m twenty-eight weeks gesta-t ion were recorded, and from 1963 to 1970, there were 3,599 s t i l l b i r t h s of twenty weeks gestation or more. Because of the sever i ty of the condi t ions , i t i s reasonable to assume that ascertainment from the above sources was v i r t u a l l y complete - 2 6 -(Trimble and Ba i rd , 1977a). Individuals with botn anencephaly and spina b i f i d a cys t i ca were categorized as anencephaly; those with spina b i f i d a cys t ica and hydrocephaly were classed as spina b i f i d a c y s t i c a . 3 .1.2 Ascertainment of Families The fami l ies of index cases were ascertained through computer l inkage of records of the probands with f i l e s of v i t a l records of marriage and b i r th that had been compiled into family groups ( i f the marriage record was avai lable) or s ib groups ( i f no marriage record was a v a i l a b l e ) . The records of marriage, l i v e - and s t i l l b i r t h in these family f i l e s came also from the Div is ion of V i ta l S t a t i s t i c s of the B r i t i s h Columbia Department of Health. The marriage records pertained to a l l B r i t i s h Columbia marriages and bi r ths from 1946 to 1970. Only b i r ths that occurred from 1952 to 1970 were considered in t h i s study. There were over a m i l l i o n records in the l inked marr iage - to -b i r th and b i r t h - t o - b i r t h f i l e s , a l l in alpha-bet ica l order by coded surname - about 52,000 records per l e t t e r of the alphabet. These records had already been grouped into fami l ies or s ibships by Trimble and Uh (1977) using record l inkage techniques developed largely by Newcombe (Newcombe, 1967). This technique matched several items of ident i f y ing information found on both marriage and b i r th records, the most important of which was a double "soundex" code for the surname and maiden surname of the parents of the index case. A l l the records with a pa r t i cu la r double soundex code consti tuted a "pocket." In the marr iage - to -b i r th f i l e , the marriage records preceded the b i r th records within each pocket. The b i r th records were ordered by birthyear and b i r th reg is t ra t ion number. - 2 7 -Family or s ibship groups were i d e n t i f i e d through " f l a g s " at the end of each record. The strength of the l inkage to the family or s ib groups was indicated by a spec i f i c value, the l inkage weight, that was assigned to each b i r th record. It has been estimated that , with a l inkage weight of e ight , none of the records represent fa lse linkages and that a maximum of 1.8% of true l inks are missed. The only fami l ies l e f t out of these f i l e s are those with the surname combinations Singh-Kaur or Kaur-Kaur; the programme was not able to r e l i a b l y discr iminate separate fami l ies among a l l the marriage and b i r th records with these surname combinations. 3 .1 .3 Information The study base consisted of reg is ter records and v i t a l records of l i v e b i r t h , s t i l l b i r t h , and marriage. Two types of information avai lab le on these records were used in t h i s study: f i r s t , i dent i f y ing information, required for l inkage of the records of the index cases to those in the family f i l e s ; and second, descr ipt ive data that were u t i l i z e d in the analyses. Information on the index cases of anencephaly and spina b i f i d a cyst ica was recorded in revised i l l - h e a l t h summary (abbreviated "summary") format. The v i t a l records of the family f a i l e s were in marriage index and b i r th index formats respect ive ly . A double soundex code for the surname and maiden surname of the parents of the index cases was present on a l l three records. The marriage and b i r th index records had been coded for.double soundex by The Univers i ty of B r i t i s h Columbia by Trimble (Trimble and Uh, 2 1977); the i l l - h e a l t h summaries had been soundexed by Newcombe. H.B. Newcombe, Head, P o p u l a t i o n Research -Branch , Chalk R ive r Nuc lear L a b o r a t o r i e s , Chalk R i v e r , O n t a r i o KOJ 1 J 0 . ' - 2 8 -Spec i f i c de ta i l s of b i r th were also avai lab le on both i l l - h e a l t h summaries and b i r th index records and were used in the l inkage procedure. These included the type of birth, ( l i y e b i r t h or s t i l l b i r t h ) , the b'irthyear, and the b i r th reg is t ra t ion number. The l inkage weight, recorded on each b i r th record, was used as a check on the strength of the l inkage of that record to the family or s ib group. The data used in the analys is of cases was retr ieved mainly from the summary records, and included information on the type of malformation, the type of b i r t h , the b i r th date, and the sex of the c h i l d . The congenital malformation was o r i g i n a l l y documented on the v i t a l records using the codes l i s t e d in the coeval International C l a s s i f i c a t i o n of Diseases ( L C D . ) or International C l a s s i f i c a t i o n of Diseases, Adapted ( I . C D . A . ) . These codes were revised on the reg is ter records as fo l lows: A l l those cases wi th anencephaly w i t h or w i thout any o ther c o n g e n i t a l d e f e c t (except sp ina b i f i d a c y s t i c a ) were g iven one code. A l l cases w i th anencephaly and sp ina b i f i d a c y s t i c a together were given one code. Spina b i f i d a c y s t i c a wi thout hydrocephaly was g iven a s p e c i f i c code, and sp ina b i f i d a c y s t i c a w i th hydrocephaly was g iven another code. Other congen i ta l d e f e c t s of the c e n t r a l nervous system and m u l t i p l e CNS d e f e c t s e x c l u d i n g anence-phaly and sp ina b i f i d a c y s t i c a were separate codes. Because the s t i l l b o r n index cases were ascertained from v i t a l records and not reg is ter records, i t was necessary to re-code the data on the type of malformation when reformating the s t i l l b i r t h records. The l inkage procedure i t s e l f made avai lable a further piece of information - the par i ty of the mother. Since the dates of a l l b i r ths were - 2 9 -documented in the f i l e s , information on the number of v iable sibs before and a f te r the index case was immediately a v a i l a b l e . This study is part of the Record Linkage Project being carr ied out at The Univers i ty of B r i t i s h Columbia. Access to a l l records was subject to appropriate r e s t r i c t i o n s to ensure c o n f i d e n t i a l i t y of data. 3.2 Procedures 3.2.1 Retr ieval The or ig ina l records for the study came from two sources. The l iveborn index cases were ascertained from the records of the prov inc ia l reg is ter for handicapped chi ldren and adu l ts , in i l l - h e a l t h summary format. Data on each case was contained in a header record, and there were a var iable number of records pertaining to v i t a l documents of death, documents of r e g i s t r a t i o n , and hospital admissions. S t i l l b i r t h cases were ascertained from computerized revised v i t a l records of s t i l l b i r t h . The prov inc ia l reg is ter has rout inely surveyed v i t a l records of l i v e b i r t h since i t s inception in 1952, but s t i l l b i r t h records were not included in i t s survei l lance system unt i l 1964. Therefore the records of affected s t i l l b i r t h s were duplicated in the f i l e s of v i t a l documents and in the reg is ter from 1964 to 1970. It was decided that the re t r ieva l of a l l s t i l l b i r t h cases, from 1952 to 1970, from the v i t a l records would resu l t in the greatest accuracy. The f i r s t step was to ret r ieve the records of a l l chi ldren with cen-t ra* nervous system defects born in B r i t i s h Columbia from 1952 to 1970. From the f i l e of a l l reg is ter cases born in the years 1946 to 1970, ordered by - 3 0 -date of b i r t h , those cases with, central nervous system anomalies born from 1952 to 1970 were selected. A f i l e of s t i l l b o r n cases with central nervous system defects born from 1952 to 1970 was already ava i lab le in order of date of b i r t h . The malformation code on these s t i l l b i r t h records was a l t e r e d , and the surnames were soundexed. The resu l t ing f i l e s contained a l l the index cases of anencephaly and spina b i f i d a c y s t i c a , and cases of other central nervous system anomalies, some of which were sibs of anencephalic or spina b i f i d a cys t ica c h i l d r e n . The i l l - h e a l t h , summary format was then revised to include only the information to be used in the study, and the s t i l l b i r t h records were reformatted to correspond with those for l i v e b i r t h s . The t h i r d step consisted of merging the two f i l e s containing the l i v e b i r t h and s t i l l b i r t h records. The merging process was accomplished in two steps. F i r s t , the two f i l e s were sorted, by double soundex code, control code (for type of b i r t h ) , b i r thyear , and b i r th reg is t ra t ion number. They were then merged into one f i l e , preserving the i r sorted order. The order of the new f i l e corresponded to that of the family f i l e s . This would make the subsequent re t r ieva l process easier and f a s t e r . The records of the index cases, coded for anencephaly and/or spina b i f i d a c y s t i c a , were then separated from those that coded for other CNS defects . The re t r ieva l of index cases from the family f i l e s could then proceed. The re t r ieva l procedure consisted of searching the family f i l e s for the b i r th record of each index case. A l l of the records pertaining to the family of the index case were then i d e n t i f i e d and extracted from the f i l e . - 3 1 -Except for records with the surname combination Singh-Kaur or Kaur-Kaur, every index case should have l inked to a b i r th record in e i ther the marr iage - to -b i r th f i l e or the b i r t h - t o - b i r t h f i l e . Each summary record was f i r s t tested against the b i r th records in the marr iage - to -b i r th f i l e ; then, i f a l i n k was not found, i t was tested against the b i r th records in the b i r t h - t o - b i r t h f i l e . The resu l t ing output grouped the records into fami l ies or s ibsh ips , with the summary records fol lowing the marriage and b i r th records, and with a family number assigned to each group. I t was decided to keep fa l se linkages to a mi.mimum. When the family f i l e s had o r i g i n a l l y been l i n k e d , a l l of the fa l se l i n k s had been found in records with l inkage weights of seven or l e s s . Therefore the threshold for a true l i n k in t h i s study was set at e ight . With th i s threshold, there should have been no fa l se l i n k s . Af ter the l inkage of summary records and family f i l e s was accomp-l i s h e d , the resu l t ing f i l e was searched for b i r t h records that corresponded to a summary record of a b i r t h with a CNS malformation other than anen-cephaly or spina b i f i d a c y s t i c a . When a match was found, that summary record was labe l led with the family number and added to the f i l e as the las t record in the family group. The f i n a l f i l e consisted of a l l B r i t i s h Columbia marriage and b i r th records of fami l ies with B r i t i s h Columbia-born anencephaly and spina b i f i d a cys t i ca cases, and summary records specify ing a l l the central nervous system malformations among recorded b i r t h s . - 3 2 -3 .2 .2 Analyses Because th.e se lect ion of affected ind iv iduals was through v i t a l and reg is ter records, each index case was ascertained independently. Ascertainment was considered to be v i r t u a l l y complete, since the nature of the two conditions studied makes i t un l ike ly that any cases would be missed or misdiagnosed. Therefore, when ca lcu la t ing the r i sk for a l l s ibs of an affected i n d i v i d u a l , every case of anencephaly and/or spina b i f i d a cyst ica was considered to be a proband, and each family was counted as many times as there were probands in the fami ly . To assess the recurrence r i s k af ter one affected s i b , only the f i r s t case in each family was i d e n t i f i e d ..as a proband, and a l l sibs born af ter the f i r s t affected case were counted. And, to assess the r i sk a f te r two affected s i b s , a l l b i r ths subsequent to the proband, designated the second affected b i r th in a fami ly , were counted. The analyses were designed to answer the fo l lowing questions. What are the e m p i r i c s i b l i n g r i s k s f o r anencephaly and sp ina b i f i d a c y s t i c a in B r i t i s h Columbia? How accura te are these e m p i r i c r i s k s ? How do they vary w i th the type of de fec t i n v o l v e d , the type of b i r t h ( l i v e b i r t h or s t i l l b i r t h ) , and important demographic v a r i a b l e s such as sex and p a r i t y ? Are the r i s k s f o r these d e f e c t s d i f f e r e n t from the r i s k s in o ther par ts of the world? Are these e m p i r i c r i s k f i g u r e s d i f f e r e n t from t h e o r e -t i c a l r i s k s fo r these two c o n d i t i o n s ? - 3 3 -Chapter 4 RESULTS 4.1 Frequency of Malformations Overall Birth Frequency: The incidence of anencephaly and spina b i f i d a cys t ica obtained in th i s study i s shown in Table I I I . A tota l of 1063 index cases were ascertained, 466 (43.4%) with anencephaly, and 597 (56.6%) with spina b i f i d a c y s t i c a . There were sixteen twin-born cases, and one concordant twin pa i r . The ra t io of males to females was 0.48:1 for anencephaly cases, and 0.87:1 for spina b i f i d a cys t i ca cases, resu l t ing in an overal l ra t io of males to females of 0 . 6 8 : 1 . S t i l l b i r t h s accounted for 75% of the anencephaly cases and 11% of the spina b i f i d a cys t ica cases. According to th i s study, 1.55 per thousand tota l b i r ths in the province from 1952 to 1970 resulted in e i ther an anencephalic or a spina b i f i d a cyst ica c h i l d . This i s s imi la r to incidence f igures for B r i t i s h Columbia reported elsewhere (Trimble and Ba i rd , 1977a). The incidence of anencephaly and spina b i f i d a cys t ica in the province has not changed during the period under study. Families: One thousand and f i f t y - o n e index cases in 1028 fami l ies l inked to the family f i l e s . Two hundred and s i x t y - s i x of the fami l ies had only the s ingle affected b i r th in the study per iod, and 762 fami l ies had two Table III Incidence of Anencephaly and Spina B i f ida Cystica in B r i t i s h Columbia Anencephaly Spina B i f i d a Total Abnormal Total B i r ths Number Per Thousand Number Per Thousand Number Per Thousand 686,326 466 0.68 597 0.87 1063 1.55 From 1952 to 1970; includes l i v e b i r t h s and s t i l l b i r t h s . - 3 5 -or more c h i l d r e n . The average family s ize throughout the study group, count-ing a l l b i r ths to 1970, was 2.9 bi r ths per fami ly . In comparison, the average family s ize among fami l ies with a v iable c h i l d born in B r i t i s h Columbia in 1952 was 2.5;those fami l ies with a v iable c h i l d born in the province in 1970 were of an average s ize of 2.2 b i r ths per fami ly . Twelve cases (1.1%) did not l i n k to the family f i l e s , and there-fore were not included in the estimates of r i sk - three with spina b i f i d a cys t ica and nine with, anencephaly. Of these twelve cases, ten had surname combinations of Singh-Kaur or Kaur-Kaur, and thus could not be l i nked . Nine of the ten were female anencephalics; the other was a female with spina b i f i d a c y s t i c a . Therefore the b i r th records of only two cases (0.2%) were not i d e n t i f i e d by the l inkage procedure. One of these was a female with spina b i f i d a cys t i ca without a second surname recorded on the summary record; the other was a male spina b i f i d a cys t ica case with d i f fe rent double soundex codes on the summary record and the b i r th index record, due to s l i g h t d i f -ferences in the o r ig ina l soundexing procedures for the summary records and the marriage and b i r th index records. 4.2 Risks to Sibs Anencephaly: The r i sks to sibs of anencephaly index cases are summarized in Table IV. There were 332 anencephaly probands with s i b s . Of 396 brothers of anencephalics, one had anencephaly and f i v e had spina b i f i d a c y s t i c a . Of 401 s i s t e r s , anencephaly was present in n ine, and spina b i f i d a cyst ica was present in seven. Thus 1.5% of brothers and 4.0% of s i s te rs were also affected with a neural-tube closure malformation. The overal l r i sk of both defects was 2.8%, with 1.3% of sibs affected with Table IV Risks to Sibs of Anencephaly and Spina B i f ida Cystica Index Cases Total Brothers % affected Total S isters % affected Total A l l Sibs % affected Male Anencephaly 147 124 1 .6 (0A.2S) 122 1.6 OA, IS) 246 •1 ; 6 • (1A.3S) Female Anencephaly 310 272 1.5 (1A,3S) 279 5.0 (8A,6S) 551 3.3 (9A,9S) Anencephaly TOTAL 457 396 1.5 (1A,5S) 401 4.0 (9A.7S) 797 2.8 . (±1.1) ' (10A.12S) Male Spina b i f i d a 277 262 3.1 (2A,6S) 238 2.1 (3A,2S) 500 2.6 (5A.8S) Female Spina b i f i d a 317 319 0.9 (1A,2S) 290 2.8 (6A,2S) 609 1.8 (7A.4S) Spina b i f i d a TOTAL 594 581 1.9 (3A.8S) 528 2.5 (9A,4S) 1109 2.2 (±0.9) (12A.12S) GRAND TOTAL 1051 977 1.7 (±0.8) (4A.13S) 929 3.1 (±1.1) (18A,11S) 1906 2.4 (±0.7) (22A,24S) A = anencephaly; S = spina b i f i d a cys t i ca The 95% confidence l i m i t s were calculated according to the formula p ±_1.96/pq/n where p = proportion affected q = 1 - p n = number of cases - 3 7 -anencephaly, and 1.5% affected with, spina b i f i d a c y s t i c a . The r i sks for 3 ei ther defect were not s i g n i f i c a n t l y d i f f e r e n t . There was no s i g n i f i c a n t di f ference in the proportions of affected sibs of male and female probands (1.6% as compared to 3.3%), nor was there any dif ference in r i s k between brothers and s i s t e r s of a l l anencephaly p r o p o s i t i . The s i s te rs of female anencephaly probands did have a s i g n i f i c a n t l y higher r i s k (5.0%) than a l l other sibs taken together (1.5%). Spina Bifida Cystica: Four hundred and f i f t y - t w o spina b i f i d a cys t ica probands had s i b s . The r i sks to those sibs are also shown in Table IV. Among the 581 male sibs there were eleven a f fec ted , or 1.9%; three with anencephaly and eight with spina b i f i d a c y s t i c a . Nine of 528 s i s t e r s had anencephaly, and four had spina b i f i d a c y s t i c a , resu l t ing in an overal l r i sk to female sibs of 2.5%. The combined r i sk to brothers and s i s t e r s of spina b i f i d a cys t ica proposit i was 1.1% for anencephaly and 1.1% for spina b i f i d a c y s t i c a , or 2.2% for e i ther defect . The r i sks to sibs of male and female probands were not s i g n i f i c a n t l y d i f fe rent (2.6% as compared to « 1.8%). A higher r i s k was seen in sibs of the same sex of the proband, although these increases were also not s i g n i f i c a n t . For example, the r i s k to brothers of male probands was 3.1%, as compared to a r i sk of 2.1% to s i s te rs of male probands. S i m i l a r l y , the r i sk to s i s t e r s of female probands, 2.8%, was greater than the 0.9% observed among the brothers of affected females. 3 2 The X s t a t i s t i c was used throughout t h i s s e c t i o n to i n v e s t i g a t e agreement between sample p r o p o r t i o n s , us ing 2xk cont ingency t a b l e s w i t h k-1 degrees of freedom. Tests were compared to a c r i t i c a l X 2 at p = 0 . 0 5 . - 3 8 -The overal l r i s k - o f a neural - tube.closure malformation to sibs of both anencephaly and spina b i f i d a cys t ica probands was 2.4%. No di f ference was seen in the r i sks to sibs of anencephaly; proposi t i and the sibs of spina b i f i d a cyst ica p r o p o s i t i . L ikewise, there was no di f ference in r i sk to sibs of male probands (2.3%) and female probands (2.5%). Although the r i s k to s i s t e r s was greater than that to brothers of proposit i (3.1% as compared to 1.7%), again, th is increase was not s i g n i f i c a n t . However, there was a s i g n i f i c a n t increasej in the proportion of affected female sibs with anen-cephaly (1.9%) compared to the proportion of affected male sibs with anen-cephaly (.0.4%). The proportion of affected sibs of s t i l l b o r n probands (2.9%) (Table V) was not appreciably greater than that to sibs of l iveborn probands (2.1%). Therefore, the only s i g n i f i c a n t dif ferences in the r i sks to sibs of neural-tube closure defects were found when considering the e f fec t of sex on the r i s k of anencephaly. There was a tendency for female s i b s , p a r t i c u l a r l y the s i s t e r s of anencephalic probands, to have a higher r i sk of anencephaly than male s i b s . This may be par t l y due to d i f f e r e n t i a l loss of male sibs ear ly in pregnancy. I t may also be par t ly a consequence of the higher proportion of affected females than males in the study popula-t ion (par t i cu la r l y among the anencephalics) , and the fact that the ca lcu la t ion of s i b l i n g r i sks involves the counting of mul t ip l y -a f fec ted fami l ies more than once. 4.3 Recurrence Risks There were 1073 sibs born af ter 560 index cases that were the f i r s t affected in a fami ly , as shown in Table VI. - 3 9 -Table V Risks to Sibs of Anencephaly and Spina B i f i d a Cys t i ca , by Type of B i r th of Proband Index Cases Sibs Total % affected L ivebi r ths 644 1226 2.1 (13A,13S) S t i l l b i r t h s 407 680 2.9 (9A,11S) TOTAL 1051 1906 2.4 (22A,24S) (±0.7)1 95% confidence l i m i t s . Table VI Recurrence Risks of Anencephaly and Spina B i f ida Cystica Index Cases Total Brothers % affected Total S is ters % affected Total A l l Sibs % affected Male Anencephaly 147 ••"78 2.6 (0A.2S) 67 0.0 (OA,OS) 145 1.4 (0A,2S) Female Anencephaly 310 154 2.6 (1A,3S) 149 2.7 (3A,1S) 303 2.6 (4A,4S) Anencephaly TOTAL 457 232 2.6 (1A.5S) 216 •1.9 (3A,1S) 448 2.2 (±1 .4) ' (4A.6S) Male Spina b i f i d a 277 135 2.2 (0A,3S) 122 0.0 (OA,OS) 257 1.2 (UA.3S) Female Spina "bif ida 317 198 1.5 (1A.2S) 170 3.5 (5A.1S) 368 2.4 (6A.3S) Spina b i f i d a TOTAL 594 333 1.8 (1A,5S) 292 2.1 (5A,1S) 625 1.9 (±1.1) (6A,6S) GRAND TOTAL 1051 565 2.1 (±1.2) (2A.10S) 508 2.0 (±1.2) (8A,2S) 1073 2.1 (±0.9) ' (10A,12S) A = anencephaly; S = spina b i f i d a ^95% confidence l i m i t s . - 4 1 -Anencephaly: Among 232 younger brothers of anencephaly probands, there were f i v e with spina b i f i d a cyst ica and one with anencephaly. Out of a tota l of 216 younger s i s t e r s , three had anencephaly and one had spina b i f i d a c y s t i c a . Thus the recurrence r i s k a f te r one affected was 2.6% for males and 1.9% for females, or 2.2% o v e r a l l , with no di f ference in the r i sk of e i ther neural-tube closure defect (0.9% for anencephaly and 1.3% for spina b i f i d a c y s t i c a ) . The r i sk to subsequent s ibs of male anencephalic probands (1.4%) was not s i g n i f i c a n t l y changed from that to subsequent sibs of female proposit i (2.6%). The higher r i s k to s i s t e r s of female anencephaly probands was not evident when considering subsequent female sibs only . Spina Bifida Cystica: The proportion affected of 333 younger brothers of spina b i f i d a cyst ica was 1.8%; of which one was an anencephalic and f i ve had spina b i f i d a c y s t i c a . Of 292 younger s i s t e r s , 2.1% were af fected , f i ve with anencephaly and one with spina b i f i d a c y s t i c a . Thus there was an equal number of younger sibs affected with anencephaly and with spina b i f i d a c y s t i c a , the overal l r i sk being 1.9%. There was no s i g n i f i c a n t di f ference in r i sk with respect to the sex of the proband (1.2% for males as compared to 2.4% for females). S is ters of female spina b i f i d a cyst ica proposi t i had the highest r i s k (3.5%), while s i s t e r s of male spina b i f i d a cys t ica proposi t i had the lowest r i s k (0.0%); however, these differences were also not s i g n i f i c a n t . The overal l recurrence r i s k a f te r one neural-tube closure malfor -mation was 2.1%, or 22 out of 1073 subsequent s i b s . This r i s k was the same regardless of the sex or the type of malformation of the proband. There was - 4 2 -no tendency for subsequent sibs to have the same type of malformation the proband, although there was a liigher proportion of anencephaly cases among affected younger s i s te rs of probands than among younger brothers with neural-tube closure malformations (1.6% as compared to 0.4%); and a higher proportion of spina b i f i d a cys t i ca cases among younger brothers than among younger s i s t e r s of probands (1.9% as compared to 0.4%). Again, d i f f e r -ent ia l ear ly loss of affected ind iv iduals of one sex may account for these d i f ferences . The r i s k to subsequent sibs of s t i l l b o r n cases (Table VII) was the same as the recurrence r i s k af ter a l iveborn case (2.1% as compared to 2.0%). Parity: The r i sk of recurrence of neural-tube closure defects was examined by par i ty of the f i r s t index case in Table VI I I . Among 255 sibs of f i r s tbo rn male probands, three, or 1.2%, were also affected with a neural-tube closure defect . Only one of 94 subsequent sibs of secondborn male probands, or 1.1%, had a neural-tube closure malformation. Among 428 sibs of primapara female p r o p o s i t i , 2.6%, or fourteen, were also affected with anencephaly or spina b i f i d a c y s t i c a , while 3.1%, or f i v e , of 160 younger sibs of secondborn female proposit i had anencephaly or spina b i f i d a c y s t i c a . The r i sk to younger sibs of a l l f i r s tborn probands was 2.0%. The r i sk to subsequent sibs of secondborn proposi t i was 2.4%. There was no dif ference in recurrence r i sk by par i ty or sex of the f i r s t affected case. Risk after Two Affected: There were 21 fami l ies with at least two s ibs with neural-tube closure defects , of which seven had chi ldren born af ter the second affected case (Table IX). Of twelve subsequent female - 4 3 -Table VII Recurrence!Risks of Anencephaly and Spina B i f i d a Cys t i ca , Type of B i r th of Proband Sibs Index Cases Total % affected L ivebi r ths 644 688 2.o (7A,7S) S t i l l b i r t h s 407 385 2 1 (3A,5S) TOTAL 1051 1073 2.1 (10A,12S) (±0.9) ' 95% confidence l i m i t s . Table VIII Recurrence Risks of Anencephaly and Spina B i f ida Cyst ica , by Par i ty of Proband Recurrence Risk a f te r One Affected (%) Sibship Number of Cases Total Subsequent Sibs % Affected 1 male affected J para 1 132 255 1 .2 1 male a f fec ted , para 2 52 94 1.1 1 female af fected , para 1 201 428 2.6 1 female af fected , para 2 89 160 3.1 1 affected (ei ther sex) , para 1 333 683 2.0 1 affected (ei ther sex) , para 2 141 254 2.4 OVERALL RISK 1051 1073 2.1 (±0.9r affected with e i ther anencephaly or spina b i f i d a c y s t i c a . 95% confidence l i m i t s . Table IX Recurrence Risks of Anencephaly and Spina B i f ida Cystica af ter Two Affected Sibs j , r Affected No. of Index Case older Sib Families Number of subsequent s ib l ings % Affected Total Number ; Affected M F M F anencephaly spina b i f i d a 3 spina b i f i d a anencephaly ; 1 spina b i f i d a spina b i f i d a 3 5 6 0 2 4 4 0 1 0 0 0 0 9.1 0.0 0.0 TOTAL 7 9 12 0 1 4.8 n (±9.1) 95% confidence l i m i t s . - 4 6 -ch i id ren , one was affected with anencephaly. None of the nine younger brothers had a neural-tube closure malformation. The proportion of subse-quent chi ldren af fected , then, was 4.8%. None of the chi ldren born af ter the second affected case had any other central nervous system malformation. 4.4 Other Considerations Twins: Information on the sixteen twin-born index cases i s summarized in Table X. The proportion of twins among the index cases (1.5%) i s lower, though not s i g n i f i c a n t l y so, than the proportion expected in the general population^ (Parkes, 1969). One pai r of male twins was concordant for anencephaly. In add i t ion , two female twins of anencephaly index cases were reported to have hydrocephaly. Other CNS Malformations: Among the 1871 sibs of index cases nine had other central nervous system malformations. These included one with microcephaly, one with congenital absence of the nucleus of a f a c i a l nerve, and seven with congenital hydrocephaly without spina b i f i d a c y s t i c a . The proportion of cases of hydrocephaly does not d i f f e r s i g n i f i c a n t l y from the B r i t i s h Columbia population frequency (1.04 per 1000 b i r t h s ) . The p r o p o r t i o n of twin b i r t h s in most Western c o u n t r i e s i s from one in 80 to one in 100 b i r t h s , imply ing t h a t , in the general p o p u l a t i o n , one person in k$ i s a t w i n . Table X Twin-born Index Cases of Anencephaly and Spins B i f i d a Cystica Malformation Total Pairs Sex of Twin Pairs^ Concordant Twins MF FM MM FF Anencephaly 8 Spina B i f i d a 7 1 0 3 4 2 1 2 2 2 1 - MM 0 Sex of affected twin l i s t e d f i r s t . Two FF twin pairs had a second twin with hydrocephaly. - 4 8 -Chapter 5 DISCUSSION 5.1 Ascertainment Both anencephaly and spina b i f i d a cys t ica are e a s i l y recognizable at b i r t h . Anencephaly i s a lethal condit ion and about 90% of cases are documented on morta l i ty records (Elwood, J . M . , 1976a). A smaller proport ion, at most about 70%, of cases of spina b i f i d a cyst ica are also found on morta l i ty records (Elwood, J . M . , 1976a). Hospital records are not a r e l i a b l e source of ascertainment of spina b i f i d a cyst ica patients since the diagnosis of malformation i s not always c lear (Lorber, 1961). Therefore, in order to ascertain most of the cases of these neural-tube closure defects occurring in a populat ion, a comprehensive search must be made of several types of records of morta l i ty and morbidity . Previous family studies of neural-tube closure malformations have u t i l i z e d various combinations of ava i lab le records to ascertain cases. The best ascertainment has been achieved in London and in L iverpoo l , where death and s t i l l b i r t h records, reg is t ry records, and (in London) hospital records were searched. The London ser ies reported approximately 95% ascer-tainment; other recent studies reported proportions"lower than t h i s . - 4 9 -The B r i t i s h Columbia study u t i l i z e s several types of records of morta l i ty and morbidity in i d e n t i f i c a t i o n of index cases, including v i t a l records of death, s t i l l b i r t h , and l i v e b i r t h , and reg is ter records. The process of ascertainment by means of computerized pooled records is an excel lent one for conditions such as anencephaly or spina b i f i d a cyst ica that are e a s i l y recognized and diagnosed, and that are rout inely documented on population-based records. The scanning of these types of documents for the whole of the B r i t i s h Columbia b i r th population from 1952 to 1970 has resulted in truncate select ion of cases; consequently biases due to the nonrepresentativeness of the sample or small sample s ize are avoided. Because ascertainment i s on an indiv idual bas is , the probab i l i t y of i d e n t i f y -ing an index case is independent of the s ize of the family or the number of affected s i b s . The use of population-based records ensures also that there are no missing ind iv iduals in a pedigree. Therefore ascertainment biases do not a r i s e . The computerization of these records makes possible the analysis of the large amounts of data that are generated in a survey of th i s s i z e . Because of the nature of the records searched, and the pro-cedures used in the i d e n t i f i c a t i o n process, ascertainment of B r i t i s h Columbia-born cases of anencephaly and spina b i f i d a cys t ica between 1952 and 1970 i s considered to be greater than 95% complete. Errors in th is method of ascertainment ar ise when instances of neural-tube closure defects are not recorded on the appropriate documents, or when malformations are incor rect l y coded. Furthermore, only information noted on the o r ig ina l records i s ava i lab le to the researcher; because of the conf ident ia l nature of these documents, i t i s d i f f i c u l t i f not impossible to go back to the index case or the family of the index case in order to confirm a diagnosis or to ret r ieve addit ional information. In th i s study, there - 5 0 -may be cases included in which encephalocoele has been misdiagnosed as anencephaly. In add i t ion , there may be instances where the aetiology of the neural-tube closure defect i s known to be other than m u l t i f a c t o r i a l (Holmes, 1976). For example, meningomyelocoele i s known to be associated with chromosomal anomalies and with cer ta in teratogens. However, the re la t i ve r a r i t y of these errors and the low f a m i l i a l r i sk associated with these a l te rnat i ve aet io log ies means that these errors should not appreciably a f fec t the resu l ts of the study. This method i s less useful for conditions that are not e a s i l y recognized or that const i tute a problem in diagnosis . Other conditions for which ascertainment by means of pooled records i s less e f fec t i ve include those that are not rout inely recorded on v i t a l records or other population-based health documents. A large source of error among previous family studies of anencephaly and spina b i f i d a cys t i ca has been the loss of family information. From 18% (Carter and Evans, 1973) to 47% (Smithells et at.3 1968) of fami l ies of index cases have been los t to fol low-up because of d i f f i c u l t i e s in t racing f a m i l i e s , non-co-operation, or i l l e g i t i m a c y . Unfortunately, i t i s very d i f f i c u l t to assess the degree of bias introduced in th i s manner. In con-t r a s t , a search of the family groupings of B r i t i s h Columbia b i r th and marriage records retr ieved a l l but 1.1% of the fami l ies of the index cases. These family groupings are p a r t i c u l a r l y useful for genetic studies . They are current ly being extended, through the B r i t i s h Columbia Record Linkage Pro ject , to include second-degree r e l a t i v e s , so that more extensive family analyses can be carr ied out in the future. - 5 1 -The family f i l e s used in the study did not include records of b i r ths that occurred outside the province of B r i t i s h Columbia, nor did they include records of b i r ths before 1952 or a f te r 1970. However, neither of these omissions should bias the resul ts of the study since there i s no reason to suppose that the s i b l i n g r i s k for those missed bi r ths i s any d i f fe rent from that among the observed b i r t h s . Therefore the resu l ts obtained from th is study can be considered representative of the r i s k s in the population of B r i t i s h Columbia during the years 1952 to 1970. 5.2 Empiric S i b l i n g Risks The r i sk of neural-tube closure malformations among sibs of chi ldren affected with e i ther anencephaly or spina b i f i d a cyst ica in B r i t i s h Columbia i s lower than that reported in any other l o c a l i t y . Furthermore, th i s r i sk does not change according to the type of malformation, the type of b i r t h , or the sex of the proband, or by the sex of the s i b s . Other studies of f a m i l i a l r i sks of anencephaly and spina b i f i d a cys t ica have been conducted among largely Caucasian populations. Most of these studies have taken place in the B r i t i s h I s l e s . The r i s k among sibs of neural-tube closure defects in Great B r i t a i n varies from 3.9% (Smithells et al., 1968) to 5.6% (Will iamson, 1965; Richards et al., 1972). About 60% of the population of B r i t i s h Columbia came o r i g i n a l l y from the B r i t i s h I s l e s , and 25% from Western Europe; yet the r i s k in B r i t i s h Columbia fami l ies is only 2.4%, or approximately one=half of the r i sk in Great B r i t a i n . The r i sk to s ibs in B r i t i s h Columbia is also lower than the two North American studies reported: 3.2% in New York (Milham, 1962) and 4.6% in Rhode Island (Yen and MacMahon, 1968). These large di f ferences in r i sk between populations of - 5 2 -e s s e n t i a l l y the same genetic background suggest that environmental factors may be largely responsible f o r the low r i sks in North America as compared to Great B r i t a i n , and in pa r t i cu la r the extremely low r i s k in B r i t i s h Columbia. In f a c t , these di f ferences may be even greater than the above-mentioned studies ind icate . The ca lcu la t ion of the proportion of sibs affected in surveys previous to the B r i t i s h Columbia study has been car r ied out on the basis of s ingle ascertainment; that i s , on the assumption of just one proband per fami ly . Since ascertainment was not considered to be complete in any of these studies , th i s procedure underestimated the true s i b l i n g r i s k . Therefore other areas may have an even higher r i sk among sibs than has been reported. No consistent changes were observed when examining the dif ferences in r i s k to sibs of neural-tube closure defects by various factors that •.' influence the population incidence of ASB. However, cer ta in trends observed in the data were consistent with those in other s tud ies , p a r t i c u l a r l y the family study in London (Carter and Evans, 1973). The London study i s of pa r t i cu la r in terest since i t was conducted in a r e l a t i v e l y low-incidence area of the B r i t i s h I s l e s , and i t examined several of the same variables that were considered in the B r i t i s h Columbia study. A comparison of the population incidence and the proportion of sibs affected in the two areas i s shown in Table XI. Both studies observed fewer affected brothers of probands than s i s t e r s . The sibs of anencephaly index cases were more often a f fec ted , in both London and B r i t i s h Columbia, than the sibs of spina b i f i d a cys t ica p r o p o s i t i . In London, there were fewer affected sibs of male anencephaly cases than female anencephaly cases; no dif ference was seen among spina b i f i d a cys t i ca probands. The r i s k to sibs of male anencephalics was also higher than the s i b l i n g r i sk of female Table XI Proportion of Sibs Affected with Anencephaly and Spina B i f ida Cystica in B r i t i s h Columbia and London .Area Malformation Incidence in Population (per thousand b i r ths) Incidence among Sibs (%) Recurrence Risk (%) Relat ive Proportion Sibs/Population B.C. anencephaly 0.68 2.76' 2 2.23' 40.6' • 2.41 ± 0.69 2.05± - - 15.5 spina b i f i d a 0.87 2.16 0.85 24.8 1 .92 London anencephaly 1.54 5.44' 4.17" 35.3' • 4.45 ± 1.05 4.61 ± - 15..1 spina b i f i d a 1.41 3.42 '1.67 24.3 5.17 Carter and Evans 1973 95% confidence l i m i t s . - 5 4 -anencephaly cases in B r i t i s h Columbia; however, the reverse trend was evident among spina b i f i d a cyst ica index cases. In both London and B r i t i s h Columbia, the highest r i sk was for female sibs of female anencephaly index cases. However, none of these dif ferences were s i g n i f i c a n t in e i ther study, except for the l a s t mentioned, and, in both studies , there i s no real ind icat ion that there i s a dif ference in the proportion of sibs affected according to the malformation of the index case. In London, the r i sk for subsequent sibs of anencephaly probands was lower than for a l l sibs (4.17% of younger s i b s ; 5.44% of a l l s i b s ) ; the r i sk for later -born sibs of spina b i f i d a cys t ica index cases was higher than the r i sk to a l l s ibs (5.17% of younger s i b s ; 3.42% of a l l s i b s ) . For the London study, the r i s k to a l l s ibs was calculated counting each family only once, considering the f i r s t ascertained case in each family as the index case. The recurrence r i sk among younger sibs of both type of probands in the B r i t i s h Columbia study was lower than the corresponding r i sk to a l l s i b s , since the ca lcu la t ion of the r i sk to a l l s ibs involved accounting for mul t ip l y -a f fec ted fami l ies more than once. Therefore, the differences between the r i sk to a l l s ibs and the recurrence r i s k in the two studies are probably due to differences in the methods of ca lcu la t ing r i s k . The r i s k to sibs and r i sk of recurrence a f te r one affected s ib were not appreciably d i f fe rent from one another in e i ther study. Several other studies (Will iamson, 1965; Carter et al., 1968; Smithel ls et al. , 1968; Richards et al., 1972; Carter and Evans, 1973) have reported a tendency for sibs of an affected indiv idual to have the same type of malformation as the index case; th is tendency was not observed in the B r i t i s h Columbia study. - 5 5 -The resu l ts of th i s study and other family studies of neural-tube closure defects indicate that the r i s k of a neural-tube closure malforma-t ion among sibs of affected ind iv iduals i s not markedly influenced by factors such as the sex, type of malformation, type of b i r t h , or par i ty of the proband, at least for the population studied. Certain consistent trends in the data from both London and B r i t i s h Columbia do suggest, however, that these factors may influence the r i sk to sibs of neural-tube closure defects , but that studies so far have been too small to detect th i s in f luence. The r i s k of recurrence a f te r two affected in a s ibship has been estimated as 12% in one English study (Carter and Roberts, 1967), or about twice the r i s k a f te r one affected c h i l d . Although the amount of data for B r i t i s h Columbia i s smal l , the calculated r i sk of 4.8% suggests that the recurrence r i sk af ter two affected i s also lower in B r i t i s h Columbia than in England. If one assumes that the r i s k a f te r two chi ldren with ASB i s double the r i sk a f te r one affected case, the recurrence r i sk a f te r two affected would be 4.2% in B r i t i s h Columbia - appreciably lower than the r i sk in the south of England. 5.3 Theoretical S i b l i n g Risks The f indings of the present study, l i k e those of previous studies on ASB, are suggestive of a m u l t i f a c t o r i a l aetiology for neural-tube closure defects , depending on both a genetic predisposi t ion to these condi t ions , and environmental inf luences. As mentioned previously , the increased frequency of these conditions among re la t i ves of affected i n d i v i d u a l s , and the var ia t ion in incidence among d i f fe rent ethnic groups ( in par t i cu la r the extremely low incidence - 5 6 -among blacks in a l l parts of the world) are strong indicat ions of a genetic influence in the causation of these defects . Another test of the degree of genetic influence in the aetiology of these malformations i s the estimate 5 of h e r i t a b i l i t y . The h e r i t a b i l i t y estimates, using Falconer's method, are 61%, 58%, 66%, and 68%, for the B r i t i s h Columbia, South Wales, Glasgow, and London s e r i e s , respect ive ly . These proportions have been used as minimum estimates of the degree of genetic determination. However, since the h e r i t -a b i l i t y i s derived from the cor re la t ion between r e l a t i v e s , i t inev i tab ly includes the influence of common family environment asiwel l as genetic causes of resemblance between r e l a t i v e s . Therefore, although these f igures are suggestive of genetic fac to rs , the degree of genetic determination c cannot be accurately assessed using th is method. The s i m i l a r i t y among ; these estimates does imply, however, that the combined influence of genetic factors and common family environment does not vary a great deal in these d i f fe rent areas. Therefore the var ia t ion in population incidence and s i b l i n g r i sks must be due to other fac to rs . The data in th i s study demonstrate a r i sk of neural-tube closure defects to sibs of affected ind iv iduals greater than that for the general population; a further increase in r i sk a f te r two affected ind iv iduals in a fami ly ; and a lower s i b l i n g r i sk compared to the s ib r i sk in an area of higher population incidence. A l l these resu l ts are compatible with a polygenic mode of inheritance of neural-tube closure defects . A s t r i c t l y ''The formula fo r c a l c u l a t i n g the h e r i t a b i l i t y i s : x - x n 2 = 2(—2 r,V. where x = d e v i a t i o n of t h r e s h o l d from mean in general p o p u l a t i o n x = d e v i a t i o n of t h r e s h o l d from mean in r e l a t i v e s r a = mean d e v i a t i o n of a f f e c t e d i n d i v i d u a l s from the popu la t ion mean (Fa lconer , 1 9 6 5 ) -- 5 7 -environmental model would also account for a l l these f indings ,but seems less p lausib le when considering the above-mentioned evidence of genetic influence in the development of these anomalies. The information on twins in th is . study is also not incompatible with a polygenic hypothesis. One area of disagreement between the polygenic model and the B r i t i s h Columbia data i s in estimation of s i b l i n g r i s k . The theoret ical overal l r i sk to sibs of chi ldren with anencephaly and spina b i f i d a cys t ica is approximately the square root of the population incidence in B r i t i s h Columbia, or 3.9%. This f igure i s higher than the empiric r i s k ; therefore the actual r i s k is less than would be expected from genetic considerations alone. However, there i s a s i g n i f i c a n t error factor in th i s theoret ica l r i s k . The model also predicts that the lower the population incidence, the higher the relative r i sk to s i b s . As indicated in Table XI , th is does hold true in a comparison between London and B r i t i s h Columbia ra tes , although comparisons with areas of extremely high (Will iamson, 1965; Richards et al. 3 1972) or extremely low (Smithells et al., 1968) incidences do show a greater d i f ference . Certa in ly the hypothesis of polygenic inheritance cannot account for a l l the var ia t ion observed in l i a b i l i t y to these condi t ions , and i t does not lead to an accurate estimate of the r i sk to s i b s , although i t does furnish an adequate explanation of the genetic factors involved. Therefore environ-mental factors must continue to be taken into account when studying the causation of these defects . Furthermore, in order to determine the extent of genetic influence in the aetiology of these defects , more information on twins, h a l f - s i b l i n g s , and second-degree re la t i ves i s needed. - 5 8 -Since the r i sk of neural-tube closure defects to sibs of affected ind iv iduals cannot be predicted by e i ther genetic or environmental factors alone, the best possible estimates of r i sk come from empiric information. Therefore, the data from th is study give the best possible estimates of s i b l i n g r i sk in B r i t i s h Columbia at t h i s time. S t r i c t l y speaking, the v f igures derived in t h i s study are appl icable only to the population from which they were derived, that i s , the population of B r i t i s h Columbia b i r ths from 1952 to 1970. However, the fact that the population incidence in the province has not changed during the period under study i s a f a i r l y good ind icat ion that the factors that influence the causation of neural-tube defects in t h i s province are r e l a t i v e l y constant over time, and that the r i s k s calculated from t h i s data are relevant also to the present population. There i s a p o s s i b i l i t y that the population incidence and s i b l i n g r i sk are higher in some ethnic groups (e.g. I r i s h , Sikhs) res id ing in B r i t i s h Columbia, and lower in others (e .g . Or ienta ls ) . Although the present study was not able to determine th is due to i n s u f f i c i e n t data, i t perhaps should be considered in genetic counsel l ing s i t u a t i o n s . Further studies are needed to estab l ish the r i sks for these groups. The resul ts of the present survey have pa r t i cu la r impl icat ions for the B r i t i s h Columbia amniocentesis programme. At present about 3.8% of cases of anencephaly and spina b i f i d a cys t ica born in th i s province are f a m i l i a l . The proportion of recurrent cases is about half that estimated from other data, yet i t i s s t i l l much higher than the r i sk of a Down Syndrome c h i l d , for example, to a woman aged 38 (0.31%) (Trimble and Ba i rd , 1977b), for whom amniocentesis i s rout inely of fered . Therefore a continuation of the screening of pregnancies subsequent to the b i r th of a c h i l d with a neural-tube closure defect seems worthwhile. - 5 9 -Chapter 6 CONCLUSIONS Empiric r i sks of anencephaly, spina b i f i d a c y s t i c a , and other central nervous system malformations were determined for the sibs of chi ldren affected with anencephaly or spina b i f i d a cys t ica born in B r i t i s h Columbia. The r i s k to sibs of e i ther anencephaly or spina b i f i d a cys t ica was found to be 2.4%, about f i f t e e n times the population incidence in B r i t i s h Columbia. The r i s k to subsequent sibs of the f i r s t affected indiv idual in a family was not s i g n i f i c a n t l y d i f fe rent from the r i sk to a l l s i b s . Subdividing the data by sex, type of malformation, p a r i t y , or type of b i r th of the proband showed no appreciable differences in r i s k . Brothers and s i s t e r s of proposit i had the same r i sk of a neural-tube closure defect ; and there were equal proportions of cases of anencephaly and spina b i f i d a cyst ica among s i b s . The r i sk of recurrence of anencephaly or spina b i f i d a cys t ica a f te r two previously affected sibs was 4.8%, or approximately double the r i sk a f te r one affected s i b . No increased r i s k of any other central nervous system defect was observed in the fami l ies of the index cases. The s i b l i n g r i sks of anencephaly and spina b i f i d a cys t ica in B r i t i s h Columbia are much lower than that reported elsewhere. They are approximately one-half the s i b l i n g r i sks in Great B r i t a i n . They are also - 6 0 -the lowest reported in North America. Comparison of the resul ts of th is : study with other family studies of ASB indicate that geographical di f ferences in r i s k can be at t r ibuted largely to environmental factors in causation. A tendency towards a higher r i sk among sibs of anencephaly cases, and among s i s t e r s of a l l index cases, was observed in B r i t i s h Columbia and in London, suggesting that these factors may influence the s i b l i n g r i sks of anencephaly and spina b i f i d a cys t ica to some degree. The observed s i b l i n g r i sks of these condit ions were less than that predicted by one model of polygenic inheritance with a threshold e f f e c t . The degree of genetic determination of these defects in B r i t i s h Columbia was estimated to be about 60%. The technique used in th i s study, of u t i l i z i n g the l inked family records ava i lab le in B r i t i s h Columbia to assess s i b l i n g r i sks ,has proved useful in j u s t i f y i n g the continuation of amniocentesis service to mothers of chi ldren with anencephaly or spina b i f i d a c y s t i c a . This technique can be extended to study the s i b l i n g r i sks of other congenital malformations in the province, in par t i cu la r those with a higher frequency or those that present greater medical problems to the community. - 6 1 -LITERATURE CITED Alberman, E. , Creasy, M., and P o l a n i , P.E. [1973). "Spontaneous abortion and neural tube defects" ( l e t t e r ) , Br. Med. J., 14:230. A l t e r , M. (1963). "Anencephalic b i r ths in a northern and a southern community," Am. J. Bis. Child., 106:536. Bona i t i -Pe l l i e " , C , and Smith, C. (1974). "Risk tables for genetic couse l -l i n g in some common congenital malformations," J. Med. Genet., 11:374. Buta, J . L . (1975). "Spina b i f i d a occulta and spina b i f i d a cys t ica and related malformations," Mich. Med., 74 (24):451. Carter , C O . (1969). "Genetics of common d isorders , " Br. Med. Bull., 25:52. Carter , C O . (1974). "Clues to the aetiology of neural-tube malformations," Dev. Med. Child. Neurol., 16 ( supp l . ) :3 . Carter , C O . , David, P .A . , and Laurence, K.M. (1968). "A family study of major central nervous system malformations in South Wales," J. Med. Genet., 5 :81. Carter , C O . , and Evans, K. , (1973). "Spina b i f i d a and anencephaly in Greater London," J. Med. Genet., 10:209. Carter , C O . , and Roberts, J . A . F . (1967). " T r i e r i s k of recurrence af ter two chi ldren with central nervous malformations," Lancet, 1:306. C o r l i s s , C E . (1976). Patten's Human Embryology, New York, McGraw-Hi l l . Curnow, R.N. (1972). "The m u l t i f a c t o r i a l model for the inheritance of l i a b i l i t y to disease and i t s impl icat ions for re la t i ves at r i s k , " Biometrics, 28:931. - 6 2 -Edwards,;!J.H. (1958). "Congenital malformations of the central nervous system in Scotland," Br. J. Prev. Soc. Med., 12:115. Edwards, J . H . (1960). "Fami l ia l predisposi t ion in man," Br. Med. Bull., 25:58. Elwood, J . H . (1970). "Anencephalus .in Be l fas t . Incidence and secular and seasonal va r ia t ions , 1950-66," Br. J. Prev. Soa. Med.3 24:78. Elwood, J . H . (1976). "Anencephaly and spina b i f i d a in the B r i t i s h I s l e s , " in Birth Defeats: Risks and Consequences, Ke l ley , S . , Hook, E .B . , Janer ich, D.T., and Porter , I.H. (eds . ) , New York, Academic Press, Inc . , p. 21. Elwood, J . H . , and MacKenzie, G. (1971). "Comparisons of secular and seasonal var iat ions in the incidence of anencephalus in Bel fast and four Scott ish c i t i e s , 1956-66," Br. J. Prev. Soa. Med., 24:78. Elwood, J . H . , and Nevin, N.C. (1973). "Factors associated with anencephalus and spina b i f i d a in B e l f a s t , " Br. J. Prev. Soc. Med.3 27:73. Elwood, J .M . (1974). "AnenceDhalus in Canada, 1943-1970," Am. J. Epid.3 100:288. Elwood, J .M. (1976a). "Anencephalus and spina b i f i d a in North America," in Birth Defects: Risks and Consequences, Ke l ley , S . , Hook, E .B . , Janer ich , D.T., and Porter , I.H. (eds . ) , New York, Academic Press, Inc . , p. 3. El/wood, J .M. (1976b). "An epidemiological study of anencephalus in Canada," Doctor of Medicine'Thesis, Queen's Univers i ty , B e l f a s t , Norther I reland. Falconer, D.S. (1965). "The inheritance of l i a b i l i t y to cer ta in diseases, estimated from the incidence among r e l a t i v e s , " Ann. Hum. Genet., 29:51. Fre*zal, J . , Ke l ley , J . , Gui l lemot, H.L . , and Lamy, M. (1964). "Anencephaly in France," Am. J. Hum. Genet., 16:336. Holmes, L . B . , D r i s c o l l , S . G . , and A tk ins , L. (1976). "E t io log ic heterogeneity of neural-tube defects , " N. Engl. J. Med., 294:365. Horowitz, I., and McDonald, A.D. (1969). "Anencephaly and spina b i f i d a in the province of Quebec," Can. Med. Ass. J., 100:748. - 6 3 -Inga l l s , T . H . , Pugh, T . F . , and MacMahon, B. 0 9 5 4 ) . "Incidence of anencephalus, spina b i f i d a , and hydrocephalus re lated to b i r th rank and maternal age," Br. J. Prev. Soc. Med.3 8 :17. Janer ich, D.T. (1971). "Anencephaly and maternal age," Amer. J. Epid., 95:319. Janer ich, D.T. (1972). "Maternal age and spina b i f i d a : Longitudinal vs. c ross -sect ional a n a l y s i s , " Amer. J. Epid., 96:.389. Janer ich, D.T. (1973). "Epidemic waves in the prevalence of anencephaly and spina b i f i d a in New York S ta te , " Teratology, 8:253. Knox, E.G. (1970). "Fetus-fetus interact ion - a model aetiology for anen-cephal us ," Dev. Med. Child. Neurol., 12:167. Laurence, K.M. (1964). "The natural h istory of spina b i f i d a c y s t i c a , " Arch. Dis. Child., 39:41. Laurence, K.M. (1966). "The survival of untreated spina b i f i d a c y s t i c a , " Dev. Med. Child,Neurol, suppl., 11:31. Leek, I. (1972). "The et iology of human malformations: Insights from epidemiology," Teratology, 5:303. Leek, I. (1974). "Causation of neural tube defects: Clues from epidemiology," Br. Med. Bull., 30(2):158. Leek, I., and Rogers, S.C. (.1967). "Changes in the incidence of anencephalus," Br. J. Prev. Soo. Med., 21:177. Lorber, J . (1961). "Systematic ventr icu lography studies in infants born with meningomyelocele and encephalocele. The incidence and development of hydrocephalus," Arch. Dis. Child., 36:381. Lorber, J . (1965). "The family h istory of spina b i f i d a c y s t i c a , " Pediatrics, 35:589. Lowry, R .B . , M i l l e r , J . R . , Scott , A .E . and Renwick, D.H.G. (1975). "The B r i t i s h Columbia Registry for Handicapped Children and Adults : Evolutionary changes over twenty years , " Can. J. Public Health, 66:322. McDonald, A.D. (1971;). "Abortion in neural tube defect f r a t e r n i t i e s , " Br. J. Prev. Soc. Med., 25:220. - 6 4 -McKeown, T. (1961). "Sources of var ia t ion in the incidence of malformations," in Abstracts, 1st Intl. Conf. on Congenital Malformations, Fishbein , M. C e d . ) , Ph i lade lph ia , J . B . L ippincott Co . , p. 45. MacMahon, B. , and Yen, S. (1971). "Unrecognized epidemic of anencephaly and spina b i f i d a , " Lancet, 1:31. Milham, S. (1962). "Increased incidence of anencephalus and spina b i f i d a in s ib l ings of affected cases," Science, 138:593. Naggan, L. (1971). "Anencephaly and spina b i f i d a in I s r a e l , " Pediatrics, 47:577. Naggan, L . , and MacMahon, B. (1967). "Ethnic differences in the prevalence of anencephaly and spina b i f i d a in Boston," N. Engl. J. Med., 277:1119. Nakano, K.K. (1973). "Anencephaly: A review," Dev. Med. Child Neurol., 15:383. Nance, W.E. (1969). "Anencephaly and spina b i f i d a : a possible example of cytoplasmic"inheritance in man," Nature, 224:373. Newcombe, H.B. (1967). "Record l i n k i n g . The design of e f f i c i e n t systems for l i n k i n g records into indiv idual and family h i s t o r i e s , " •Am. J. Hum. Genet., 19:335. Nishimura, H. (1970). "Incidence of malformations in abort ions ," in Congenital Malformations: Proc. 3rd Intl. Conf., Amsterdam, Excerpta Medic'a., p. 275. Parkes, A .S . (1969). "Mult ip le b i r ths in man," J. Reprod. Fert. suppl., 6:105. Record, R.G. (1961). "Anencephalus in Scot land," Brit. J. Prev. Soc. Med., 15:93. Record, R.G. , and McKeown, T. (1949). "Congenital malformations of the central nervous system. I. A survey of 930 cases," Br. J. Soc. Med., 3:183. Richards, I.D.G. (1973). "Fetal and infant morta l i ty associated with con-genital malformations," Br. J. Prev. Soc. Med., 27:85. - 6 5 -Richards, I .D.G. , and Lowe, C.R. (1971). "Incidence of congenital defects in South Wales, 1964=66," Br. J. Prev. Soc. Med., 25:59. Richards, I .D.G. , Mcintosh., H.T., and Sweenie, S. (1972). "A genetic study of anencephaly and spina b i f i d a in Glasgow," Dev. Med. Child Neurol., 14:626. Rickham, P . P . , and Mawdsley, T. (1966). "The ef fect of ear ly operation on the survival of spina b i f i d a c y s t i c a , " Dev. Med. child Neurol, suppl., 11 :1 . Rogers, S . C . , and Morr is , M. (.1971). "Infant morta l i ty from spina b i f i d a , congenital hydrocephalus, monstrosity, and congenital diseases of the cardiovascular system in England and Wales," Ann. Hum. Genet., 34:295. Sear le , A.G. (1959). "Anencephaly in a polytypic populat ion," Ann. Hum. Genet., 23:279. Sharrard, W.J.W., Zachary, R .B . , Lorber, J . , and Bruce, A.M. (1963). "A contro l led t r i a l of intermediate and delayed closure of spina b i f i d a c y s t i c a , " Arch. Dis. Child., 38:18. Simpkiss, M., and Lowe, A. (1961). "Congenital abnormalit ies in the Afr ican newborn," Arch. Dis. Child'., 36:404. Smith, C.(1971). "Recurrence r i sks for m u l t i f a c t o r i a l inher i tance , " Am. J. Hum. Genet., 23:578. Smithe l l s , R.W., D'Arcy, E .E . , and M c A l l i s t e r , E.F. (1968). "The outcome of pregnancies before and af ter the b i r th of infants with nervous system malformations," Dev. Med. Child Neurol., suppl., 15:6. Stevenson, A . C . , Johnston, H.A., Stewart, M . I . P . , and Golding, D.R. (1966). malformation. A report of a study of ser ies of consecutive b i r ths in 24 centres ," Bull. World Health Organ., 34 (suppl . ) . Trimble, B.K. , and Ba i rd , P.A. (1977a). "Congenital anomalies of the central nervous system: Incidence in B r i t i s h Columbia 1952-72" (submitted to Teratology). Trimble, B .K. , and Ba i rd , P.A. (1977b). "Maternal age and Down syndrome: Age -spec i f ic incidence rates by s ingle year in te rva ls " (submitted to Amer. J. Med. Genet.). - 6 6 -Trimble, B.K. , and Uh, S.H. (.1977). "Automatic l inkage of marriage and b i r t h records into family groups" ( in preparation) . Warkany,,J.W. (1971). Congenital Malformations: Notes and Comments, Chicago, Year Book Med. Pub ! . , Inc. Wil l iamson, E.M. (1965). "Incidence and family aggregation of major con-genital malformations of central nervous system," J. Med. Genet., 2:161. Yen, S . , and MacMahon, B. (1968). "Genetics of anencephaly and spina b i f ida? ' Lancet, 2:623. 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0094037/manifest

Comment

Related Items