Ann. Hum. Genet., Lo&. (1979), 42, 445
445
Printed in Great 3rit4&
Anencephaly in Japan: paternal age, maternal age and birth order BY YOKO IMAIZUMI Institute of Population Probtems, Ministry of Health and Wetfare, Kusumigaseki, Tokyo, Japan
INTRODUCTION
The recurrence risk after the birth of the first anencephalic child in a sibship was about 4 yo, but after two affected sibs the risk rose to 13 yo (Masterson, 1962). On the other hand, Rogers (1976) estimated that the concordance rates for anencephaly or spina bifida were 17.8 and 1.6 yo for monozygous and dizygous twins, respectively. In Japan, the concordance rate of anencephalic twins was 8.3 yo(Imaizumi, 1978).Imaizumi (1976,1977) studied parental consanguineous marriages of anencephalics and concluded that the inheritance of anencephaly is not related to a specific number of rccessive genes. Carter & Evans (1 973) suggested a multifactorial aetiology of the neural tube malformations, depending upon both genetic predisposition and environmental triggers. Many epidemiological studies were performed in many countries, especially in the United Kingdom. However, clear evidence about the aetiology of anencephaly was still not obtained. The present author examines the association between parental ages, birth order and the risk of delivering a child with anencephaly, using birth and foetal death records for the whole of of Japan for 1975-6 inclusive. MATERIAL AND METHOD
Data on 1815 foetal deaths with anencephaly and data on general population reported during 1975-6 incIusive have been obtained from the foetal death certificate records kept art the Ninistry of Health and Welfare. Weighted least squares estimation was used to estimate the parameters of the simple regression model where paternal age, maternal age, and birth order were the independent variables and the incidence of anencephaly was the dependent variable. For example, the parameters of the simple regression model (i.e. p i j k = b,+ b, (PA)i+ b2(MA)j+ b,(BO),) were estimated by least squares using weights
where @ijk is the incidence of anencephaly within a specific parental age-birth order category and mijkis the number of births for the ith paternal age, j t h maternal age and kth birth order. The quadratic model (Novitski & Kimball, 1968) was as follows: pijk =
6,
+ b,(PA)i + b,(MA)j+ b,(BO), + b11(PA)i2+ b2s(MA)j2+ b,(BO)k2 +b,,(PA),(MA)j+4,(PA),(BO),+b,(MA)j(BO),.
This equation was fitted to the 100 observed incidences given in Table 5 by the weighted least squares. 0003-4800/79/0000-4217 $02.00 0 1979
UCL
4 391
0
0
23 I424
34 191 1I7 37 8
109 584 496 164 48
Rural
A
27 I815
0
56
68039 3088 785
6 13646 848947
82406 388 783 26 I 720 79485 22906
263 5 10 '3'5987 I 041 836 313351 86 056
143 775 613 20 I
Rural
h
109 1I7
I
I I
I
4
0
Unknown
No. of live births and foetal deaths i
Urban
\
Total
No. of anencephalic cases
Urban
f
81794 3 937 849
8
345916 I704774 I 303 557 392 837 108963
Total
\
0.338 0.46 I
0
0.558
0.523
0.414 0'444 0.476
h
1000total
0.293 0.461
0
0.413 0.491 0.447 0.466 0.349
Rural
Incidence per Urban
f
-19
Total
20-24 25-29 30-34 35Unknown
0
0
I424
56 I8
391
212
7 98
16 297 794 242 75 3088785
8
18
0
I815
3
84
445 285 I 20 229 32588
848947
117
4 I4 9 3
10663
31583 718 166 I 683 554 522 158 133306
23 395 I 006 298 93 240 I74
Rural
Urban
Total
Unknown
h
Rural
No. of live births and foetal deaths f
h 3
No. of anencephalic cases
Urban
r
3 937849
I10
42 250 958354 2 128848 642 390 165897
Total
>
>
0.46 I
0'330
0.470 0.5 I 2 0-5I4 o
0.455
0.413
Total
births
46 1
0
507 414 472 464 563
Urban
r
46 1
0
656 408 476 466 552
Rural
h
461
0
544 412 473 464 561
Total
>
Incidence per million total births
Table 2. 2l'umber of foetal deaths with. anencephaly, number of live births and foetal deaths in general population, and anencephalic incidence by maternal age and area, 1975-6
Ma.terna1 age (years)
Total
Illegitimate
- 24 25-29 30-34 35-39 40unknown
Paternal age (Years)
Table 1. Number of foetal deaths with anencephaly, number of live births and foetal deaths in general population, and anencephalic incidence by paternal age and area, 1975-6
5f
F 2 2
0
w
0
*
Anencephaly in Japan
447
Urban
----- Rural 0.0006
> m z al Q
0) C
m r
a
6
P-
0.0003
C
-24
--
25-29
30-34
35-39
40-
Paternal age
Fig. 1. Incidence of anencephaly and paternal age by urban and rural areas of Japan, 1975-6.
RESULTS
Parental ages The average ages of father and mother of offspring with anencephaly were 29.94 5 4.67 and 27-125 3-87 years old, respectively. Table I and Fig. 1 show paternal age and anencephalic incidence by urban and rural areas. Fathers were divided into five groups, aged under 25, 26-29, 30-34, 35-39, and over 40 years. The incidence seems to increase with paternal age. I n order to compute the regression coefficient of incidence of anencephaly on the paternal age, the midpoint for each interval age group was used as mean paternal age. Thus, the regression coefficients of incidence of anencephaly on and 0-52 x paternal age in urban, rural and total areas, were 0.74 x 10-5, - 0-30x respectively, among which values in urban and total areas were significant at the 1% level. Table 2 and Fig. 2 show the relationship between maternal age and anencephalic inc-idence by urban and rural areas. Mothers were divided into five groups, aged under 20, 20-24, 25-29, 30-36 and over 35 years. The incidence in mothers aged under 20 was higher in rural (656 per million) than in urban (507 per million) areas, but the difference between these values was not Significant. Table 3 shows the observed and expected number of cases with anencephaly according to maternal age. The departure from homogeneity was significant at the 5 % level (x2= 9.90;
YOKOIMAIZUMI
448
Urban
0.0006
----- Rural
\ \ \ \
\
-z
c m n U 0)
5
9-
00003 0
m
2 u
-
0
I -19
I
I
I
1
20-24
25-29 Maternal age
30-34
35-
Fig. 2. Incidenoe of anencephaly and maternal age by urban and rural areas of Japan, 1975-6.
4). As number of births in mothers aged under 20 was small, number of births in mothers aged under 20 and aged between 20 and 24 were combined to compute the incidence, which value was 0.0004177 (418/1,000, 604). The departure from homogeneity in four maternal age groups was also significant at the 5 % level (x2= 7.98; D.F. = 3).
D.F. =
Birth order Table 4 shows birth order and anencephalic incidence by urban and rural areas. Birth order is a numerical order in relation to all children liveborn or having died prenatally in the 21st week of gestation or later. Of 203 792 foetal deaths 48 753 cases died between 12 and 20 weeks of gestation, but these data were included for the present analysis. Incidence of anencephaly was linearly increased with birth order (Fig. 3). The observed and expected number of cases with anencephaly according t o birth order showed significant departure from homogeneity (x2 = 86.4; P < 0.001). Parental age and birth order Parental ages and birth order are closely interrelated. Let us now consider simultaneous effects of paternal age, maternal age and birth order on the incidence of anencephaly. Five paternal age groups (aged under 25, 25-29, 30-34, 35-39, and over 40 years), five maternal age groups (aged under 20, 20-24, 25-29, 30-34, and over 35 years) and four groups of birth order
x2 = 9'90;D.F.
35Total
3 .So
= 4;P < 0'05.
9'90
x2 = 7.98;D.F.
25-29 30-34
0'01
I815
981 296 77
461
Expected numbers
= 3; P < 0.05.
1006 298 93 1815
418
Observed numbers
x2
7.98
3'32
0'01
0.64
4.01
3 a4 Total
2
I
Birth order
144 148 65 34 39'
566 570 209 79 1424 18x5
113
I
I 375 087 1278055 355 104 80539 3088785
Urban
848947
34.4 289 340553 127355 36750
Rural
1 I7
I
1
72 43
unknown
h
Total 710 718 274
>
h
Rural
I
Urban
No. of live births and foetal deaths
No. of anencephalic cases
-3
1719448 1618651 482460 117290 3 937849
Total
510
461
925
589
981 461
418 435
Rural
412 446
Urban
46 1
413 444 568 963
Total
7 -
Incidence per million total births
Table 4. Number of foetal deaths uith anencephaly, number of live births and foetal deaths in general population, and anencephlic incidence by birth order and area, 1975-6
Total
298 93 1815
5 '00
981 296 76 1815
age -24
Maternal
0.64
442
395 I 006
x2 0.45
23
-19 20-24 25-29 3-34 35-
Expected numbers 20
Observed numbers
Maternal age (years)
Table 3. Observed and expected numbers of foetal deaths from a 4
3
2
I
3 > 4
2
I
-
0
3 2 4
39222 2843 167 18 o o
352
561
0 0
2
580 o
0
12070 230 5
-
I 0
I
-
-
2
0
5
0
I8
3 a 4
o
66
I
2
0
0
196
0 0
0 921 o
0
559 Iog5
0
0
o
536
' P
2
2
I9
1086 184
7158 913 65 7
18645 1460 65 7
ra
< 19
-
r
I
3 3 4
2
I
3 3 4
I 2
3 2 4
2
I
Birt,li order
712604 221157 22176 2417
15582 3779 I297 475
*
415 449 648 1628
2105
0
'93 265
-
-
-
Per millbn.
347 861039 570 1011432 857 226885 I241 29492
0 0
71
148 607
0
0
I
-
835
0 0
0
1198
2095
0
466 531 500 976 506 1124
25763 54635 26000 5121
453 419 551 1421
412 459 884 2489
519314 468026 73562 8036 242963 460194 121613 I4779
0
3952 4447
0
282
27108 I647
-
0
-
I 0
-
0
692 I49 40
0
0
1044
1222
151
754 266
5302 3758
818
450 411 576 I495
334 612 720 1626
0
299 541 863
P*
53465 20350 2318 246
9%
25-29
I89328 50117
282 197
I20 748
6446 2838 I430 812
0
0
0
0
54 '72 153508 93 825 18917 28803 80606 74 103 22734 6 869 11740 9558 5 526
32070 9985 2 003
22 054
I435 427 125
2 404
n
0
408 312 60 I
0
0
0
4'6
P*
408 417 818
522
0
0
465 352
-
-
146 170 837 I81
880
405
447
556
609 430 373 1057
30-34
--
A
Age of mother (pears)
354 627 1860
P*
71129 41327 5205 669
410273 130693 12496 1230
'97748 43039 3226 256
n
20-24
163 532
34482 52266 44 I75 34974
3 590 I 706 I I74 I 146
0
0
0
0
21462 19889 12732 11631 16583 15863 I7 850
10718
5 634 9682 5 980 2669
I
2 646
2 547
362 187 I 06 45
Ib
9%
0
783 306 657 600
0
557 586 256
-
-
-
933 233 503 707 688 422 630 616
836 375
I
0
3
I 06
0
0
I
I03
I
0
I
3
0
0
0 0
0
0
0
0
0
0
0
1065 207
0
0
I
0
0
0
0
0
0
393 378 860
0
0
0
0
P*
UK ?%
1768201 1569898 482731 117019
2 506
4 188
I0201
64 899
I
0
4 3
23 562 33480 27670 24251
70782 160499 120818 40738
374984 664895 226 642 37036
634349 97271 I I 808
9 6 1 346
679
272624 66471 6 142
Total
405 454 568 966
293 392 716 399
-
-
467 418 650 536
447
593
485 418 485 1161
380 484 833 1863
0
356 572 I303
P*
-
Table 5. The incidence of anencephaly, p , and total number of births, n, by age of mother, age of father and birth order, 1975-6
w
0
3
% 0
Anencepha,ly in Japan
45 1
---_
General population Illegitimate
0~0010
->m r CL 0 W
m
: 0.0005
. I -
0
al
TI .0
-
0
1
I
I
1
2
3
I 4
Birth order
Fig. 3. Iiicidence of anencephaly and birth order in the whole of Japan and illegitimates.
( 1 , 2, 3 , 3 4) were used as independent variables. Table 5 shows the incidences of anencephaly simultaneously by parental ages and birth order. Table 6 shows the results from the weighted least squares estimation of simple and quadratic regression models using the three independent variables. In the simple linear regression model, birth order was the only factor significantly inAuencing the incidence of anencephaly among three independent variables. On the other hand, significant regression coefficients on the quadratic term for birth order and interaction terms (b13and b23)in the quadratic model were obtained. Thus, the strongest association between incidence of anencephaly and birth order was obtained. The multiple correlation coefficients for the linear and quadratic model were 0-24-0.37 and 0.61, respectively. Therefore, the quadratic model was more fitted than the linear model.
DISCUSSION
Imaizurni (1974) previously mentioned that 7.5 yoof the anencephalic foetuses were liveborn, and all of them died within the first month after birth. However, there is no information on parental ages and birth order in the death certificate record. Thus, only data on foetal deaths with anencephaly were used in the present study. Therefore, the incidence of anencephaly was an underestimate. The effect of birth order on the incidence of anencephaly was investigated by Ingalls, Pugh & MacMahon (1954), Naggan & MacMahon (1967) and Record (1961). They described the associations between anencephaly and birth order as U-shaped, the incidences being high in first births, low in second births, and then increasing with higher birth ranks. On the other hand, 29
H G E 42
0.03
0.29
0.28
(PA, MA, BO)
(Pil, MA)
(PA,BO)
(MA, BO)
(PA, MA, B0)2
R2 0.24
Model includes
(0.020)
- 0.065
(0.026)
0.030
(0.023)
- 0.008
b*
**
yo level; ***
yo level. 0.1
(0.024)
Significant a t the
- 0.087** 0.041
bl, (0'029)
bP2
I7
'7
22
94
D.F.
0'00 I
significant a t the
10~)
(0.017) I
x
0.117
bl,
103 (s.E.
(0.082)
b3
(0.022)
-0.013
Regression coefficient x
(0.028)
- 0-114**
b23
Table 6. Multiple regression analysis of the effect of paternal age, maternal age and birth order on anencephalic incidence with linear model and quadratic model
88
D.F.
0'
Anencepha,ly in Japan
453
General population
----
illegitimate
/
->m
/ /
/ / /
c
?2 C C
," 00005
-
m C
0
C
a
I
1
-19
I
20-24
I
I
25-29
30-34
I 35-
Maternal age
Fig. 4. Incidence of anencephaly and maternal age in the whole of Japan and illegitimates.
according to Naggan (1971), the incidence had the strongest associations with birth order, from a low to higher birth orders. However, simultaneous effects of paternal age, maternal age and birth order on the incidence have not been analysed until now. Simultaneous effects of the three factors on the incidence of anencephaly revealed the most significant effect to be birth order in the present study. Mutation rate may be expected to depend on parental age (Cavalli-Sforza& Bodmer, 1971). Because, in the male, spermatogenesis continues from puberty to old age, linear accumulation of mutant genes with age may be expected. Paternal age effects on mutations have been Rhown for cases of achondroplasia and acrocephalosyndactyly (Vogel, 1963). These defects are autosoma1 dominant traits. On the other hand, Fraser & Calnan (1961), Woolf (1963), and Almsaka (1970) have found a slight paternal age effect in harelip ( 5- cleft palate). However, few studies OC paternal age effects on anencephalic incidence were reported. Granroth, Hakama & Saxen ( 1 977) and C'zQizel<6vbsz (1970) have failed to show the rising incidence of anencephaly with paternal age. In the present study, in spite of linear increase of anencephalic incidence with paternal age in urban areas, this trend was not obtained in rural areas. It is very difficiiltto decide whether or not this phenomenon resulted from different environmental factors between urban i d rural areas. It is well known that anencephaly is uncommon in illegitimate infants (Edwards, 1958; Record & McKeown, 1949). The incidencc of anencephaly in illegitimate infants was 0.0003301 in Japan (see Table 1). This value is also lower compared with that in legitimate infants. The proportion of illegitimates was 2 yo in the whole of Japan. From Table 5 , the proportion of the first birth order in illegitimates was 7 9 yo,whereas the corresponding figure in the legitimates 'was 44% ( P < 0.001). I n the legitimates there was 15.4 % birth order over 3 whereas the corresponding figure in the illegitimates was 8.2% (P < 0.001). On the other hand, the incidence of anencephaly was linearly increased with birth order. Therefore, one reason for the lower 29-2
454
YOKO IMAIZUMI
incidence of anencephaly in illegitimates may be the lower mean birth order in illegitimate than in legitimate infants. Figure 4 shows the relationship between incidence of anencephaly and maternal age in illegitimate infants and the general population. The incidences of anencephaly born to mothers aged between 20 and 35 were lower in illegitimate infants than in the general population. This is partly another reason for lower incidence of anencephaly in illegitimates. According to James (1973), couples who produce anencephalics may be subfertile. If this is true, couples who produce illegitimate infants may be potentially of high fecundity - hence the uncommonness of anencephalics in illegitimate infants.
SUMMARY
The statistical association between incidence of anencephaly and paternal age, maternal age and birth order was analysed in 1815 cases of foetal deaths with anencephaly reported during 1975-6. The birth order association was confirmed with an extremely high degree of statistical significance. This investigation was supported in part by a grant from the Ministry of Health and Welfare of Japan for the Handicapped Children, 1977-8. I am grateful to the staff and especially Mr M. Hosaka, Health and Welfare Statistics Division, Ministry of Health and Welfare. I am also indebted to Dr M. Murata who computed the multiple regression coefficients of anencephalic incidence and Dr K. Tanaka for his helpful comments on the f i s t draft.
REFERENCES
AKASAKA,Y. (1970). Statistical and cytogenetic study on the cleft lip, alveolus and/or palate. Jup. J . Hum. Genet: 15, 35-96. C. 0. & EVANS,K. (1973). Spina bifida and anencephalus in Greater London. J . of Med. Genet. 10, CARTER, 209-234. CAVALLI-SFORZA, L. L. & BODMER,W. F. (1971). The Genetics of Human Populations. San Francisco: Freeman and Company. CZEIZEL, A. & RBVI~SZ, C. (1970). Major malformations of the central nervous system in Hungary. Brit. J . prev. soc. Med. 24, 205-222. EDWARDS, J. H. (1958). Congenital malformations of the central nervous system in Scotland. Brit. J . prew. aoc. Med. 12, 115-130. FRASEE,0. R. & CALNAN,J. S. (1961). Cleft lip and palate: Seasonal incidence, birth weight, birth rank, sex, site, associated malformations and parental age. A statistical survey. Arch. Dis. ChiZd. 36, 420 -423. GRANROTH,G., HAKAMA, M. & S A X ~ N L., (1977).Defects of the central nervous system in Finland. I. Varintions in time and space, sex distribution, and parental age. Brit. J . prev. ~ O C Med. . 31, 164-170. IMAIZUMI, Y. (1974). Statistical analysis on anencephaly, spina bifida and congenital hydrocephaly in Japan. Jap. J . Hum. Genet. 9, 115-135. IMAIZUMI, Y . (1976). Distribution uf the incidence of anencephaly in Japan. Social Biology 23, 66-72. IMAIZUMI, Y. (1977). Some further observations on parental consanguineous marriages of mcnccphaIy in Japan. Jap. J . Hum. Genet. 22, 49-51. IMAIZUMI, Y. (1978). Concordance and discordance of anencephaly in 109 twin pairs in Japan. J a p . J . Hum. Genet. 23, 389-393. INGALLS, T. H., PUGH,T. F. & MACMAHON,B. (1954). Incidence of anencephalus, spina bifida and hydrocephalus related to birth rank and maternal age. Brit. J . preo. soc. Med. 8 , 17-23. JAMES, W. H. (1973). Anencephaly, ovulation stimulation, subfertility, and illegitimacy. Lancet ii, 916. MASTERSON, J. G. (1962). Empiric risk, genetic counseling and preventive measures in anencophaly. Acta Genet. (Basel) 12, 219-229. NAGGAN, L. (1971). Anencephaly and spina bifida in Israel. Pediatrics 47, 677-586. NAGGAN, L. & MACMAHON, B. (1967). Ethnic differences in the prevalence of anencephaly and spina bifida in Boston. New England J . of Med. 277, 1119-1123.
Anencephaly in Japan
455
NOVITSICI, E. & KIMBALL, A. W. (1958). Birth order, parental ages, and aex of offspring. Am. J . Hum. Genet. 10, 268 275. HECORD, R. G. (1961). Anenceplialus in Scotland. Brit. J . prev. SOC. M d . 15, 93-105. It. G. & MCKEOWN, T. (1949).Congenital malformations of the central nervous system. I. A survey RECORD, of 930 cases. Brit. J . prev. SOC.Med. 3, 183-219. ROGERS, 8. C. (1976). Anencephalus, spina bifida, twins, and teratoma. Brit. J. prev. SOC. Med. 30, 26-28. VOGEL, E’. (1963). Mutations in man. I n Genetics Today (ed. 8. J. Geerts), pp. 833-850. (Proceedings of the Eleventh International Congress of Genetics.) Oxford : Pergamon. WOOLF,C. M. (1963). Paternal age effect for cleft lip and palate. Amer. J . Hum. Genet. 15, 389-393.
445
Printed in Great 3rit4&
Anencephaly in Japan: paternal age, maternal age and birth order BY YOKO IMAIZUMI Institute of Population Probtems, Ministry of Health and Wetfare, Kusumigaseki, Tokyo, Japan
INTRODUCTION
The recurrence risk after the birth of the first anencephalic child in a sibship was about 4 yo, but after two affected sibs the risk rose to 13 yo (Masterson, 1962). On the other hand, Rogers (1976) estimated that the concordance rates for anencephaly or spina bifida were 17.8 and 1.6 yo for monozygous and dizygous twins, respectively. In Japan, the concordance rate of anencephalic twins was 8.3 yo(Imaizumi, 1978).Imaizumi (1976,1977) studied parental consanguineous marriages of anencephalics and concluded that the inheritance of anencephaly is not related to a specific number of rccessive genes. Carter & Evans (1 973) suggested a multifactorial aetiology of the neural tube malformations, depending upon both genetic predisposition and environmental triggers. Many epidemiological studies were performed in many countries, especially in the United Kingdom. However, clear evidence about the aetiology of anencephaly was still not obtained. The present author examines the association between parental ages, birth order and the risk of delivering a child with anencephaly, using birth and foetal death records for the whole of of Japan for 1975-6 inclusive. MATERIAL AND METHOD
Data on 1815 foetal deaths with anencephaly and data on general population reported during 1975-6 incIusive have been obtained from the foetal death certificate records kept art the Ninistry of Health and Welfare. Weighted least squares estimation was used to estimate the parameters of the simple regression model where paternal age, maternal age, and birth order were the independent variables and the incidence of anencephaly was the dependent variable. For example, the parameters of the simple regression model (i.e. p i j k = b,+ b, (PA)i+ b2(MA)j+ b,(BO),) were estimated by least squares using weights
where @ijk is the incidence of anencephaly within a specific parental age-birth order category and mijkis the number of births for the ith paternal age, j t h maternal age and kth birth order. The quadratic model (Novitski & Kimball, 1968) was as follows: pijk =
6,
+ b,(PA)i + b,(MA)j+ b,(BO), + b11(PA)i2+ b2s(MA)j2+ b,(BO)k2 +b,,(PA),(MA)j+4,(PA),(BO),+b,(MA)j(BO),.
This equation was fitted to the 100 observed incidences given in Table 5 by the weighted least squares. 0003-4800/79/0000-4217 $02.00 0 1979
UCL
4 391
0
0
23 I424
34 191 1I7 37 8
109 584 496 164 48
Rural
A
27 I815
0
56
68039 3088 785
6 13646 848947
82406 388 783 26 I 720 79485 22906
263 5 10 '3'5987 I 041 836 313351 86 056
143 775 613 20 I
Rural
h
109 1I7
I
I I
I
4
0
Unknown
No. of live births and foetal deaths i
Urban
\
Total
No. of anencephalic cases
Urban
f
81794 3 937 849
8
345916 I704774 I 303 557 392 837 108963
Total
\
0.338 0.46 I
0
0.558
0.523
0.414 0'444 0.476
h
1000total
0.293 0.461
0
0.413 0.491 0.447 0.466 0.349
Rural
Incidence per Urban
f
-19
Total
20-24 25-29 30-34 35Unknown
0
0
I424
56 I8
391
212
7 98
16 297 794 242 75 3088785
8
18
0
I815
3
84
445 285 I 20 229 32588
848947
117
4 I4 9 3
10663
31583 718 166 I 683 554 522 158 133306
23 395 I 006 298 93 240 I74
Rural
Urban
Total
Unknown
h
Rural
No. of live births and foetal deaths f
h 3
No. of anencephalic cases
Urban
r
3 937849
I10
42 250 958354 2 128848 642 390 165897
Total
>
>
0.46 I
0'330
0.470 0.5 I 2 0-5I4 o
0.455
0.413
Total
births
46 1
0
507 414 472 464 563
Urban
r
46 1
0
656 408 476 466 552
Rural
h
461
0
544 412 473 464 561
Total
>
Incidence per million total births
Table 2. 2l'umber of foetal deaths with. anencephaly, number of live births and foetal deaths in general population, and anencephalic incidence by maternal age and area, 1975-6
Ma.terna1 age (years)
Total
Illegitimate
- 24 25-29 30-34 35-39 40unknown
Paternal age (Years)
Table 1. Number of foetal deaths with anencephaly, number of live births and foetal deaths in general population, and anencephalic incidence by paternal age and area, 1975-6
5f
F 2 2
0
w
0
*
Anencephaly in Japan
447
Urban
----- Rural 0.0006
> m z al Q
0) C
m r
a
6
P-
0.0003
C
-24
--
25-29
30-34
35-39
40-
Paternal age
Fig. 1. Incidence of anencephaly and paternal age by urban and rural areas of Japan, 1975-6.
RESULTS
Parental ages The average ages of father and mother of offspring with anencephaly were 29.94 5 4.67 and 27-125 3-87 years old, respectively. Table I and Fig. 1 show paternal age and anencephalic incidence by urban and rural areas. Fathers were divided into five groups, aged under 25, 26-29, 30-34, 35-39, and over 40 years. The incidence seems to increase with paternal age. I n order to compute the regression coefficient of incidence of anencephaly on the paternal age, the midpoint for each interval age group was used as mean paternal age. Thus, the regression coefficients of incidence of anencephaly on and 0-52 x paternal age in urban, rural and total areas, were 0.74 x 10-5, - 0-30x respectively, among which values in urban and total areas were significant at the 1% level. Table 2 and Fig. 2 show the relationship between maternal age and anencephalic inc-idence by urban and rural areas. Mothers were divided into five groups, aged under 20, 20-24, 25-29, 30-36 and over 35 years. The incidence in mothers aged under 20 was higher in rural (656 per million) than in urban (507 per million) areas, but the difference between these values was not Significant. Table 3 shows the observed and expected number of cases with anencephaly according to maternal age. The departure from homogeneity was significant at the 5 % level (x2= 9.90;
YOKOIMAIZUMI
448
Urban
0.0006
----- Rural
\ \ \ \
\
-z
c m n U 0)
5
9-
00003 0
m
2 u
-
0
I -19
I
I
I
1
20-24
25-29 Maternal age
30-34
35-
Fig. 2. Incidenoe of anencephaly and maternal age by urban and rural areas of Japan, 1975-6.
4). As number of births in mothers aged under 20 was small, number of births in mothers aged under 20 and aged between 20 and 24 were combined to compute the incidence, which value was 0.0004177 (418/1,000, 604). The departure from homogeneity in four maternal age groups was also significant at the 5 % level (x2= 7.98; D.F. = 3).
D.F. =
Birth order Table 4 shows birth order and anencephalic incidence by urban and rural areas. Birth order is a numerical order in relation to all children liveborn or having died prenatally in the 21st week of gestation or later. Of 203 792 foetal deaths 48 753 cases died between 12 and 20 weeks of gestation, but these data were included for the present analysis. Incidence of anencephaly was linearly increased with birth order (Fig. 3). The observed and expected number of cases with anencephaly according t o birth order showed significant departure from homogeneity (x2 = 86.4; P < 0.001). Parental age and birth order Parental ages and birth order are closely interrelated. Let us now consider simultaneous effects of paternal age, maternal age and birth order on the incidence of anencephaly. Five paternal age groups (aged under 25, 25-29, 30-34, 35-39, and over 40 years), five maternal age groups (aged under 20, 20-24, 25-29, 30-34, and over 35 years) and four groups of birth order
x2 = 9'90;D.F.
35Total
3 .So
= 4;P < 0'05.
9'90
x2 = 7.98;D.F.
25-29 30-34
0'01
I815
981 296 77
461
Expected numbers
= 3; P < 0.05.
1006 298 93 1815
418
Observed numbers
x2
7.98
3'32
0'01
0.64
4.01
3 a4 Total
2
I
Birth order
144 148 65 34 39'
566 570 209 79 1424 18x5
113
I
I 375 087 1278055 355 104 80539 3088785
Urban
848947
34.4 289 340553 127355 36750
Rural
1 I7
I
1
72 43
unknown
h
Total 710 718 274
>
h
Rural
I
Urban
No. of live births and foetal deaths
No. of anencephalic cases
-3
1719448 1618651 482460 117290 3 937849
Total
510
461
925
589
981 461
418 435
Rural
412 446
Urban
46 1
413 444 568 963
Total
7 -
Incidence per million total births
Table 4. Number of foetal deaths uith anencephaly, number of live births and foetal deaths in general population, and anencephlic incidence by birth order and area, 1975-6
Total
298 93 1815
5 '00
981 296 76 1815
age -24
Maternal
0.64
442
395 I 006
x2 0.45
23
-19 20-24 25-29 3-34 35-
Expected numbers 20
Observed numbers
Maternal age (years)
Table 3. Observed and expected numbers of foetal deaths from a 4
3
2
I
3 > 4
2
I
-
0
3 2 4
39222 2843 167 18 o o
352
561
0 0
2
580 o
0
12070 230 5
-
I 0
I
-
-
2
0
5
0
I8
3 a 4
o
66
I
2
0
0
196
0 0
0 921 o
0
559 Iog5
0
0
o
536
' P
2
2
I9
1086 184
7158 913 65 7
18645 1460 65 7
ra
< 19
-
r
I
3 3 4
2
I
3 3 4
I 2
3 2 4
2
I
Birt,li order
712604 221157 22176 2417
15582 3779 I297 475
*
415 449 648 1628
2105
0
'93 265
-
-
-
Per millbn.
347 861039 570 1011432 857 226885 I241 29492
0 0
71
148 607
0
0
I
-
835
0 0
0
1198
2095
0
466 531 500 976 506 1124
25763 54635 26000 5121
453 419 551 1421
412 459 884 2489
519314 468026 73562 8036 242963 460194 121613 I4779
0
3952 4447
0
282
27108 I647
-
0
-
I 0
-
0
692 I49 40
0
0
1044
1222
151
754 266
5302 3758
818
450 411 576 I495
334 612 720 1626
0
299 541 863
P*
53465 20350 2318 246
9%
25-29
I89328 50117
282 197
I20 748
6446 2838 I430 812
0
0
0
0
54 '72 153508 93 825 18917 28803 80606 74 103 22734 6 869 11740 9558 5 526
32070 9985 2 003
22 054
I435 427 125
2 404
n
0
408 312 60 I
0
0
0
4'6
P*
408 417 818
522
0
0
465 352
-
-
146 170 837 I81
880
405
447
556
609 430 373 1057
30-34
--
A
Age of mother (pears)
354 627 1860
P*
71129 41327 5205 669
410273 130693 12496 1230
'97748 43039 3226 256
n
20-24
163 532
34482 52266 44 I75 34974
3 590 I 706 I I74 I 146
0
0
0
0
21462 19889 12732 11631 16583 15863 I7 850
10718
5 634 9682 5 980 2669
I
2 646
2 547
362 187 I 06 45
Ib
9%
0
783 306 657 600
0
557 586 256
-
-
-
933 233 503 707 688 422 630 616
836 375
I
0
3
I 06
0
0
I
I03
I
0
I
3
0
0
0 0
0
0
0
0
0
0
0
1065 207
0
0
I
0
0
0
0
0
0
393 378 860
0
0
0
0
P*
UK ?%
1768201 1569898 482731 117019
2 506
4 188
I0201
64 899
I
0
4 3
23 562 33480 27670 24251
70782 160499 120818 40738
374984 664895 226 642 37036
634349 97271 I I 808
9 6 1 346
679
272624 66471 6 142
Total
405 454 568 966
293 392 716 399
-
-
467 418 650 536
447
593
485 418 485 1161
380 484 833 1863
0
356 572 I303
P*
-
Table 5. The incidence of anencephaly, p , and total number of births, n, by age of mother, age of father and birth order, 1975-6
w
0
3
% 0
Anencepha,ly in Japan
45 1
---_
General population Illegitimate
0~0010
->m r CL 0 W
m
: 0.0005
. I -
0
al
TI .0
-
0
1
I
I
1
2
3
I 4
Birth order
Fig. 3. Iiicidence of anencephaly and birth order in the whole of Japan and illegitimates.
( 1 , 2, 3 , 3 4) were used as independent variables. Table 5 shows the incidences of anencephaly simultaneously by parental ages and birth order. Table 6 shows the results from the weighted least squares estimation of simple and quadratic regression models using the three independent variables. In the simple linear regression model, birth order was the only factor significantly inAuencing the incidence of anencephaly among three independent variables. On the other hand, significant regression coefficients on the quadratic term for birth order and interaction terms (b13and b23)in the quadratic model were obtained. Thus, the strongest association between incidence of anencephaly and birth order was obtained. The multiple correlation coefficients for the linear and quadratic model were 0-24-0.37 and 0.61, respectively. Therefore, the quadratic model was more fitted than the linear model.
DISCUSSION
Imaizurni (1974) previously mentioned that 7.5 yoof the anencephalic foetuses were liveborn, and all of them died within the first month after birth. However, there is no information on parental ages and birth order in the death certificate record. Thus, only data on foetal deaths with anencephaly were used in the present study. Therefore, the incidence of anencephaly was an underestimate. The effect of birth order on the incidence of anencephaly was investigated by Ingalls, Pugh & MacMahon (1954), Naggan & MacMahon (1967) and Record (1961). They described the associations between anencephaly and birth order as U-shaped, the incidences being high in first births, low in second births, and then increasing with higher birth ranks. On the other hand, 29
H G E 42
0.03
0.29
0.28
(PA, MA, BO)
(Pil, MA)
(PA,BO)
(MA, BO)
(PA, MA, B0)2
R2 0.24
Model includes
(0.020)
- 0.065
(0.026)
0.030
(0.023)
- 0.008
b*
**
yo level; ***
yo level. 0.1
(0.024)
Significant a t the
- 0.087** 0.041
bl, (0'029)
bP2
I7
'7
22
94
D.F.
0'00 I
significant a t the
10~)
(0.017) I
x
0.117
bl,
103 (s.E.
(0.082)
b3
(0.022)
-0.013
Regression coefficient x
(0.028)
- 0-114**
b23
Table 6. Multiple regression analysis of the effect of paternal age, maternal age and birth order on anencephalic incidence with linear model and quadratic model
88
D.F.
0'
Anencepha,ly in Japan
453
General population
----
illegitimate
/
->m
/ /
/ / /
c
?2 C C
," 00005
-
m C
0
C
a
I
1
-19
I
20-24
I
I
25-29
30-34
I 35-
Maternal age
Fig. 4. Incidence of anencephaly and maternal age in the whole of Japan and illegitimates.
according to Naggan (1971), the incidence had the strongest associations with birth order, from a low to higher birth orders. However, simultaneous effects of paternal age, maternal age and birth order on the incidence have not been analysed until now. Simultaneous effects of the three factors on the incidence of anencephaly revealed the most significant effect to be birth order in the present study. Mutation rate may be expected to depend on parental age (Cavalli-Sforza& Bodmer, 1971). Because, in the male, spermatogenesis continues from puberty to old age, linear accumulation of mutant genes with age may be expected. Paternal age effects on mutations have been Rhown for cases of achondroplasia and acrocephalosyndactyly (Vogel, 1963). These defects are autosoma1 dominant traits. On the other hand, Fraser & Calnan (1961), Woolf (1963), and Almsaka (1970) have found a slight paternal age effect in harelip ( 5- cleft palate). However, few studies OC paternal age effects on anencephalic incidence were reported. Granroth, Hakama & Saxen ( 1 977) and C'zQizel<6vbsz (1970) have failed to show the rising incidence of anencephaly with paternal age. In the present study, in spite of linear increase of anencephalic incidence with paternal age in urban areas, this trend was not obtained in rural areas. It is very difficiiltto decide whether or not this phenomenon resulted from different environmental factors between urban i d rural areas. It is well known that anencephaly is uncommon in illegitimate infants (Edwards, 1958; Record & McKeown, 1949). The incidencc of anencephaly in illegitimate infants was 0.0003301 in Japan (see Table 1). This value is also lower compared with that in legitimate infants. The proportion of illegitimates was 2 yo in the whole of Japan. From Table 5 , the proportion of the first birth order in illegitimates was 7 9 yo,whereas the corresponding figure in the legitimates 'was 44% ( P < 0.001). I n the legitimates there was 15.4 % birth order over 3 whereas the corresponding figure in the illegitimates was 8.2% (P < 0.001). On the other hand, the incidence of anencephaly was linearly increased with birth order. Therefore, one reason for the lower 29-2
454
YOKO IMAIZUMI
incidence of anencephaly in illegitimates may be the lower mean birth order in illegitimate than in legitimate infants. Figure 4 shows the relationship between incidence of anencephaly and maternal age in illegitimate infants and the general population. The incidences of anencephaly born to mothers aged between 20 and 35 were lower in illegitimate infants than in the general population. This is partly another reason for lower incidence of anencephaly in illegitimates. According to James (1973), couples who produce anencephalics may be subfertile. If this is true, couples who produce illegitimate infants may be potentially of high fecundity - hence the uncommonness of anencephalics in illegitimate infants.
SUMMARY
The statistical association between incidence of anencephaly and paternal age, maternal age and birth order was analysed in 1815 cases of foetal deaths with anencephaly reported during 1975-6. The birth order association was confirmed with an extremely high degree of statistical significance. This investigation was supported in part by a grant from the Ministry of Health and Welfare of Japan for the Handicapped Children, 1977-8. I am grateful to the staff and especially Mr M. Hosaka, Health and Welfare Statistics Division, Ministry of Health and Welfare. I am also indebted to Dr M. Murata who computed the multiple regression coefficients of anencephalic incidence and Dr K. Tanaka for his helpful comments on the f i s t draft.
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