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Intrauterine growth retardation as an endpoint in mutation epidemiology: an evaluation based on paternal age
Genetic Toxicology
ELSEVIER
Mutation Research 344 (1995) 89-94
Intrauterine growth retardation as an endpoint in mutation epidemiology: an evaluation based on paternal age A n d r e w F. O l s h a n a,b,., C a n d e V. A n a n t h a, David A. Savitz a
a
Department of Epidemiology University of North Carolina CB#7400 Chapel Hill, NC 27599, USA b Birth Defects Center University of North Carolina, Chapel Hill, NC 27599, USA
Received 14 December 1995; revised 30 March 1995;accepted 7 June 1995
Abstract
Czeizel recently suggested that intrauterine growth retardation might be of value as a phenotypic endpoint in mutation epidemiology. We hypothesized that if some fraction of small-for-gestational age (SGA) births are due to new germinal mutations, then an association with advanced paternal age should be present. We evaluated the relation between paternal age and SGA, low birthweight, and preterm births using a large sample of births (n = 254,892) from North Carolina. The analyses were restricted to births of mothers aged 20-34 years and adjusted for maternal age, race, education, marital status, gravidity, and smoking. No material increase in the risk of SGA, low birthweight, and preterm delivery was found for fathers in any age category. For example, odds ratios for SGA ranged from 0.87 (fathers aged 50 years or greater) to 1.13 (fathers aged 45-49 years). The results indicate no discernable relationship between SGA and related endpoints and the increase in increase of mutations that accompany advanced paternal age. Keywords: Father; Mutation; Low birth weight; Epidemiology
1. Introduction
Czeizel (1993) recently proposed that intrauterine growth retardation ( I U G R , operationally defined as small for gestational age, SGA) might be of value in mutation epidemiology as a phenotypic endpoint. He cited mouse data that showed an excess of 'dwarfism' or 'runted fetuses' after male or female germ cell exposure to
* Corresponding author. Tel.: (919)966-7424; Fax: (919)9662089.
chemicals and ionizing radiation. The results from epidemiologic studies of parental preconceptual exposure to toxic agents and SGA and low birthweight are sparse and inconsistent (Savitz et al., 1989; Sanjose et al., 1991). Compared to other endpoints such as specific birth defects, S G A has the advantage of being relatively common and routinely available in vital statistics. Advanced paternal age, independent of maternal age, has been shown to be associated with several rare dominant conditions in offspring (e.g., achondroplasia), and possibly with a subset of common birth defects such as cardiac and neural
0165-1218/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0165-1218(95)00035-6
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t u b e d e f e c t s ( R i s c h , 1987; O l s h a n , S c h n i t z e r a n d B a i r d , 1994; M c I n t o s h , O l s h a n , a n d B a i r d , 1995). It is p r e s u m e d t h a t t h e s e a b n o r m a l i t i e s w e r e d u e to a new dominant mutation arising in the germ cells of the father. The basis for an increased risk with increasing paternal age has been attributed t o t h e ' c o p y e r r o r ' m e c h a n i s m . T h i s m o d e l assumes that the probability of spontaneous mutation increases with increasing age due to the potential for a higher rate of replication error w i t h c o n t i n u o u s m a l e g e r m cell d i v i s i o n ( P e n r o s e , 1955). A n a n a l y s i s b y R i s c h e t al. ( 1 9 8 7 ) f o u n d
t h a t t h e r e is s o m e h e t e r o g e n e i t y a m o n g d o m i n a n t syndromes for the rate of increase with age implying that the simple copy-error model may not h o l d f o r all c o n d i t i o n s . We have hypothesized, by extension from the b i r t h d e f e c t s d a t a , t h a t if s o m e f r a c t i o n o f S G A could be due to new germinal mutations, then an association with advanced paternal age should be p r e s e n t . T h e p u r p o s e o f t h i s p a p e r is t o e v a l u a t e the relation between paternal age and SGA, low birthweight, and preterm births using a large sample of births from North Carolina.
Table 1 Selected maternal characteristics of small-for-gestational age, low birth weight and preterm births: North Carolina 1988-1991 Small-for-gestational age a
Low birthweight d
%
Preterm delivery c
OR b
95% CI c
%
OR
95% CI
%
OR
95% CI
1.21-1.35 1.11-1.24 1.03-1.16
6.3 5.9 5.4 5.1 5.0 5.0 5.3
1.23 1.16 1.06 1.00 0.99 0.98 1.04
1.16-1.31 1.09-1.23 1.00-1.12
10.2 9.5 8.8 8.5 8.4 8.6 9.2
1.20 1.12 1.05 1.00 1.00 1.02 1.08
1.15-1.26 1.07-1.17 1.00-1.09
Maternal age 20-21 22-23 24-25 26-27 f 28-29 30-31 32-34
7.1 6.5 6.1 5.6 5.2 5.2 4.7
1.27 1.17 1.09 1.00 0.94 0.93 0.85
Maternal race Black White f
5.5 5.8
0.94 1.00
0.90-0.98
9.4 4.4
2.12 1.00
2.05-2.19
14.9 7.6
1.96 1.00
1.91-2.01
Gravidity Primigravid Multigravid f
6.5 5.4
1.20 1.00
1.16-1.24
5.6 5.3
1.06 1.00
1.02-1.10
8.4 9.3
0.90 1.00
0.87-0.92
Education (yrs) < 12 12 f 13 +
9.9 6.1 4.3
1.62 1.00 0.70
1.55-1.70
8.1 5.8 4.3
1.41 1.00 0.75
1.34-1.47
11.5 9.5 7.8
1.21 1.00 0.82
1.16-1.25
Marital s t a t u s Unmarried Married f
8.1 5.5
1.50 1.00
1.43-1.58
9.4 5.0
1.98 1.00
1.89-2.08
14.1 8.4
1.79 1.00
1.72-1.85
11.9 4.3
2.79 1.00
2.70-2.88
9.3 4.5
2.07 1.00
2.00-2.15
11.1 8.5
1.31 1.00
1.27-1.35
Smoking Yes No f
a Total number of births = b OR, odds ratio. c 95% CI, 95% confidence d Total number of births = Total number of births = f Referent category.
235 237. interval. 237 934. 254 639.
0.88-1.00 0.87-0.99 0.79-0.91
0.67-0.74
0.93-1.05 0.92-1.05 0.98-1.11
0.72-0.78
0.95-1.05 0.97-1.07 1.03-1.14
0.80-0.84
91
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2. Materials and methods D a t a for this study w e r e d e r i v e d f r o m the birth files of the state of N o r t h C a r o l i n a , for t h e y e a r s 1988 t h r o u g h 1991. S t a r t i n g with 413372 p r e g n a n c i e s t h a t r e s u l t e d in live b i r t h s d u r i n g t h a t p e r i o d , t h e following s e q u e n t i a l exclusions w e r e m a d e : r e s i d e n c e o u t s i d e N o r t h C a r o l i n a (n = 6973), m u l t i p l e b i r t h s (n = 9574), m a t e r n a l r a c e o t h e r t h a n b l a c k o r white (n = 7577), a n d missing d a t a on p a t e r n a l age (n = 42 445). In a d d i t i o n , in o r d e r to isolate p a t e r n a l from m a t e r n a l age effects, we r e s t r i c t e d o u r analyses to m o t h e r s age 2 0 - 3 4 years, excluding 91911 births to y o u n g e r a n d o l d e r m o t h e r s . A total of 254892 singleton live births r e m a i n e d available for analysis. P a t e r n a l age was c a t e g o r i z e d into 8 age intervals: < 19 years, 2 0 - 2 4 , 2 5 - 2 9 , 3 0 - 3 4 , 3 5 - 3 9 , 4 0 - 4 4 , 4 5 - 4 9 , a n d 50 y e a r s a n d older. T h e reference c a t e g o r y for the analysis o f p a t e r n a l age was the 2 5 - 2 9 y e a r o l d group. T h e y w e r e c h o s e n b e c a u s e t h e y a r e a large e n o u g h g r o u p to yield stable relative risk e s t i m a t e s a n d a r e e x p e c t e d to have no i n c r e a s e in risk (i.e., relative risk = 1.0). A d v e r s e b i r t h o u t c o m e s i n c l u d e d low b i r t h weight (birth weight ( B W T ) < 2499 grams), p r e t e r m delivery ( g e s t a t i o n a l age ( G A ) < 37 weeks), a n d small-for-gestational-age-SGA (BWT below the 10th p e r c e n t i l e for a given g e s t a t i o n a l age, race, a n d fetal gender). S t a n d a r d s to d e f i n e S G A births w e r e d e r i v e d from t h o s e of B r e n n e r et al. (1976),
a c c o u n t i n g for b l a c k - w h i t e a n d m a l e - f e m a l e differences. P o t e n t i a l m a t e r n a l c o n f o u n d e r s i n c l u d e d line a r a n d q u a d r a t i c t e r m s for m a t e r n a l age ( c e n t e r e d at 26.3 years), r a c e ( b l a c k / w h i t e ) , gravidity ( p r i m i g r a v i d vs. mutligravid), smoking d u r ing p r e g n a n c y ( y e s / n o ) , m a r i t a l status, a n d e d u c a t i o n ( c e n t e r e d at 13 c o m p l e t e d y e a r s of schooling). In a d d i t i o n , g e n d e r o f t h e infant was t r e a t e d as a c o n f o u n d e r . A q u a d r a t i c t e r m for m o t h e r ' s age has b e e n u s e d to a c c o u n t for a ' U ' s h a p e d age-risk function. N o n e of t h e s e c o v a r i a t e s w e r e significant m o d i f i e r s of t h e effect of p a t e r n a l age on t h e risk of e a c h o f t h e o u t c o m e s . A s s o c i a t i o n s b e t w e e n p a t e r n a l age a n d b i r t h o u t c o m e s w e r e assessed t h r o u g h t h e c o m p u t a t i o n o f o d d s ratio e s t i m a t e s with 95% c o n f i d e n c e intervals. T h e o d d s r a t i o r e p r e s e n t s t h e r a t i o o f the o d d s of the o c c u r r e n c e of t h e b i r t h o u t c o m e s a m o n g t h e exp o s e d ( o l d e r fathers) a n d u n e x p o s e d (fathers a g e d 2 5 - 2 9 y e a r s ) p r e g n a n c i e s a n d is an a p p r o x i m a tion o f the relative risk. O d d s ratios a d j u s t e d for c o n f o u n d e r s w e r e directly d e r i v e d from t h e regression coefficient c o r r e s p o n d i n g to the p a t e r n a l age t e r m in a logistic r e g r e s s i o n m o d e l (Breslow a n d Day, 1980).
3. Results T h e d i s t r i b u t i o n o f m a t e r n a l factors including age, race, gravidity, e d u c a t i o n , m a r i t a l status, a n d
Table 2 Relationship between paternal age and small-for-gestational age: North Carolina, 1988-1991 Paternal age (years)
No. of births a
% Small-forgestational age
Crude odds ratio b
95% CI
Adjusted odds ratio c
95% CI
< 19 20-24 25-29 d 30-34 35-39 40-44 45 -49 50 +
2729 48630 86245 66535 22898 5964 1545 691
7.5 6.4 5.8 5.3 5.1 6.3 7.4 6.1
1.31 1.12 1.00 0.90 0.87 1.10 1.30 1.05
1.13-1.51 1.07-1.17
1.03 0.98 1.00 1.01 0.95 1.05 1.13 0.87
0.88-1.20 0.93-1.04
0.86-0.94 0.82-0.93 0.98-1.22 1.08-1.58 0.77-1.43
0.96-1.06 0.89- 1.03 0.93-1.18 0.92-1.38 0.63-1.19
a Total number of births = 235 237. b 95% Confidence interval. c Adjusted for maternal age (linear and quadratic terms), maternal race, gravidity, maternal smoking, marital status, maternal education, and infant gender. d Referent category.
A.F. Olshan et al. / Mutation Research 344 (1995) 89-94
92
Table 3 Relationship between paternal age and low birthweight: North Carolina, 1988-1991 Paternal age (years)
No. of births a
% Low birthweight
Crude odds ratio b
95% CI
Adjusted odds ratio c
95% CI
~<19 20-24 25-294 30-34 35-39 40-44 45-49 50 +
2768 49351 87259 67159 23104 6036 1559 698
7.4 6.1 5.3 4.9 5.3 6.5 6.7 6.0
1.44 1.16 1.00 0.92 0.99 1.25 1.28 1.14
1.24-1.66 1.10-1.21
1.13 1.04 1.00 0.96 0.96 1.09 1.00 0.81
0.97-1.32 0.98-1.09
0.88-0.96 0.93-1.06 1.12-1.39 1.05-1.56 0.84-1.57
0.91-1.01 0.89-1.03 0.97-1.21 0.81-1.23 0.59-1.12
a Total number of births = 237 934. b 95% Confidence interval. c Adjusted for maternal age (linear and quadratic terms), maternal race, gravidity, maternal smoking, marital status, maternal education, and infant gender d Referent category.
smok i n g a m o n g S G A a n d n o n - S G A (small-for-gestational age), low birthweight, a n d p r e t e r m births is given in T a b l e 1. T h e overall p e r c e n t a g e o f S G A , low birthweight, and p r e t e r m births w e r e 5.8, 5.4, 8.9, respectively. T h e c r u d e o d d s ratios p r e s e n t e d suggest an i n c r e a s e d risk for S G A , low birthweight, and p r e t e r m delivery a m o n g infants of m o t h e r s u n d e r age 2 0 - 2 1 , t h o s e w h o h a d less t h a n 12 years o f e d u c a t i o n , those w h o w e r e unm a r r i e d , and t h o s e w h o s m o k e d cigarettes. Black m o t h e r s had e l e v a t e d odds ratios for low birth weight and infant and p r e t e r m delivery, but not SGA.
A l t h o u g h t h e c r u d e odds ratios s h o w e d s o m e i n c r e a s e d risks a m o n g y o u n g e r and o l d e r fathers, the a d j u s t e d odds ratios show no indication of an e l e v a t i o n in risk for any p a t e r n a l age group; the e s t i m a t e s w e r e n e a r the null v al u e o f 1.0 ( T a b l e 2). T h e largest odds ratio was 1.13 for m e n a g e d 4 5 - 4 9 years (relative to m e n age 2 5 - 2 9 years). A similar lack o f association was also f o u n d for low b i r t h w e i g h t an d p r e t e r m birth (Tables 3 an d 4). O n c e again, y o u n g f at h er s had e l e v a t e d c r u d e o d d s ratios that d i m i n i s h e d after a d j u s t m e n t for race, g e n d e r , gravidity, m ar i t al status, and m a t e r nal e d u c a t i o n . O l d e r f at h er s h ad no odds ratios
Table 4 Relationship between paternal age and preterm delivery: North Carolina, 1988-1991 Paternal age (years)
No. of births a
% Preterm delivery
Crude
95% CI odds ratio b
Adjusted
95% CI odds ratio c
~<19 20-24 25-29 d 30-34 35-39 40-44 45-49 50 +
2971 52842 93333 71852 24729 6486 1687 739
12.2 10.1 8.6 8.4 9.2 9.7 10.6 11.2
1.47 1.18 1.00 0.97 1.07 1.14 1.26 1.34
1.31-1.64 1.14-1.23
1.23 1.09 1.00 0.98 1.03 1.05 1.09 1.08
1.10-1.39 1.05-1.14
0.94-1.00 1.02-1.12 1.04-1.24 1.07-1.47 1.06-1.68
0.95-1.02 0.97-1.08 0.96-1.14 0.93-1.28 0.85-1.36
a Preterm delivery (< 37 weeks LMP); total number of births = 254 639. b 95% Confidence interval. c Adjusted for maternal age (linear and quadratic terms), maternal race, gravidity, maternal smoking, marital status, maternal education, and infant gender. d Referent category.
A.F. Olshan et al. / Mutation Research 344 (1995) 89-94
as large as 1.10 for low birthweight or preterm birth. The largest odds ratio found was 1.25 for preterm birth among men less than 20 years old. There was also no increase in risk for very-lowbirthweight ( < 1500 g) infants among any paternal age group (data not shown).
4. Discussion
The results of this study clearly indicate that advanced paternal age is not associated with an increased risk of intrauterine growth retardation, low birthweight or preterm delivery after adjustment for potential confounders. This lack of association is consistent with the results of a recent analysis of paternal characteristics and low birth weight among nearly 9 million births in the United States (Parker and Schoendorf, 1992). A strength of our study is the large number of births, reflected in the narrow confidence intervals. The study sample had greater than 80% power to detect as statistically significant odds ratios as small as 1.5 for all age categories and outcomes. Because of the interrelationship of paternal and maternal age, we employed two different methods to isolate any paternal age effect from maternal age. First, we restricted the analysis to births of mothers aged 20 to 34 years, a range in which effects of maternal age are thought to be modest. Second, we used statistical methods, including polynomial models, to adjust for any residual confounding due to mother's age. The quality of the data recorded on the North Carolina birth certificate is known to generally be of acceptable quality for the factors under study (Buescher et al., 1993), specifically maternal and paternal age and birthweight. However, gestational age based on the date that the last normal menses began (LMP) is known to be subject to inaccuracy for p r e t e r m delivery and S G A (David, 1980). Tobacco use ( y e s / n o ) as reported on the North Carolina birth certificate has been shown to be of fair quality with an 84% exact agreement with medical records for use during pregnancy (Buescher et al., 1993). Some residual confounding due to the potential misclassification of maternal tobacco use is probable.
93
Our findings suggest that S G A is not a sensitive indicator of new dominant mutations, assuming that advanced paternal age is related to an increased risk of de n o v o dominant mutations. Such an association for paternal age has been clearly demonstrated for a number of relatively rare conditions and possibly for some more common birth defects. As Czeizel (1993) notes, the etiology of S G A is complex and heterogenous, potentially reducing its value as a specific indicator in mutation epidemiology studies. Even if a small fraction of reduced fetal growth were caused by paternal mutations, it might well be undectable among all the other factors influencing SGA. In addition to other exogenous determinants (e.g., tobacco, diet), a sizable fraction of S G A babies are probably normal, small infants (Wilcox, 1993). We have provided only one specific evaluation of S G A as a valid endpoint in mutation epidemiology, with no support for the types of mutations related to paternal age. Further study is needed to evaluate mutations due to other specific parental mutagenic exposures such as occupational chemicals or ionizing radiation.
References Brenner, W.E., D.A. Edelman and C.H. Hendricks (1976) A standard of fetal growth for the USA, Am. J. Obstet. Gynecol., 126, 555-564. Breslow, N.E. and N.E. Day (1980) Statistical Methods in Cancer Research. Vol 1: The Analysis of Case-control Studies. IARC Scientific Publication 32, IARC, Lyon, France. Buescher, P.A., K.P. Taylor, M.H. Davis and J.M. Bowling (1993) The quality of the new birth certificate data: a validation study in North Carolina, Am. J. Public Health, 83, 1163-1165. Czeizel, A.E. (1993) Intrauterine growth retardation as a potential endpoint in mutation epidemiology, Mutation Res., 296, 211-219. David, R.J. (1980) The quality and completeness of birth weight and gestational age in computerized birth files, Am. J. Public Health, 70, 964-973. Mclntosh, G.C., A.F. Olshan and P.A. Baird (1995) Paternal age and the risk of birth defects in offspring, Epidemiology, in press. Olshan, A.F., P.G. Schnitzer and P.A. Baird (1994) Paternal age and the risk of congenital heart defects, Teratology 50, 80-84.
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Parker, J.D. and K.C. Schoendorf (1992) Influence of paternal characteristics on the risk of low birth weight, Am. J. Epidemiol, 136, 399-407. Penrose, L.R. (1955) Paternal age and mutation, Lancet, 2, 312. Risch, N., E.W. Reich, M.M. Wishnick and J.G. McCarthy (1987) Spontaneous mutation and parental age in humans, Am. J. Hum. Genet., 41,218-248. Sanjose, S., E. Roman and V. Beral (1991) Low birthweight
and preterm delivery, Scotland, 1981-84: effect of parents' occupation, Lancet, 2, 428-431. Savitz, D.A., E.A. Whelan and R.C. Kleckner (1989) Effect of parents' occupational exposures on risk of stillbirth, preterm delivery, and small-for-gestational-age infants, Am. J. Epidemiol., 129: 1201-1208. Wilcox, A.J. (1993) Birth weight and perinatal mortality: the effect of maternal smoking, Am. J. Epidemiol., 137, 10981104.
ELSEVIER
Mutation Research 344 (1995) 89-94
Intrauterine growth retardation as an endpoint in mutation epidemiology: an evaluation based on paternal age A n d r e w F. O l s h a n a,b,., C a n d e V. A n a n t h a, David A. Savitz a
a
Department of Epidemiology University of North Carolina CB#7400 Chapel Hill, NC 27599, USA b Birth Defects Center University of North Carolina, Chapel Hill, NC 27599, USA
Received 14 December 1995; revised 30 March 1995;accepted 7 June 1995
Abstract
Czeizel recently suggested that intrauterine growth retardation might be of value as a phenotypic endpoint in mutation epidemiology. We hypothesized that if some fraction of small-for-gestational age (SGA) births are due to new germinal mutations, then an association with advanced paternal age should be present. We evaluated the relation between paternal age and SGA, low birthweight, and preterm births using a large sample of births (n = 254,892) from North Carolina. The analyses were restricted to births of mothers aged 20-34 years and adjusted for maternal age, race, education, marital status, gravidity, and smoking. No material increase in the risk of SGA, low birthweight, and preterm delivery was found for fathers in any age category. For example, odds ratios for SGA ranged from 0.87 (fathers aged 50 years or greater) to 1.13 (fathers aged 45-49 years). The results indicate no discernable relationship between SGA and related endpoints and the increase in increase of mutations that accompany advanced paternal age. Keywords: Father; Mutation; Low birth weight; Epidemiology
1. Introduction
Czeizel (1993) recently proposed that intrauterine growth retardation ( I U G R , operationally defined as small for gestational age, SGA) might be of value in mutation epidemiology as a phenotypic endpoint. He cited mouse data that showed an excess of 'dwarfism' or 'runted fetuses' after male or female germ cell exposure to
* Corresponding author. Tel.: (919)966-7424; Fax: (919)9662089.
chemicals and ionizing radiation. The results from epidemiologic studies of parental preconceptual exposure to toxic agents and SGA and low birthweight are sparse and inconsistent (Savitz et al., 1989; Sanjose et al., 1991). Compared to other endpoints such as specific birth defects, S G A has the advantage of being relatively common and routinely available in vital statistics. Advanced paternal age, independent of maternal age, has been shown to be associated with several rare dominant conditions in offspring (e.g., achondroplasia), and possibly with a subset of common birth defects such as cardiac and neural
0165-1218/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0165-1218(95)00035-6
90
A.F. Olshan et aL / Mutation Research 344 (1995) 89-94
t u b e d e f e c t s ( R i s c h , 1987; O l s h a n , S c h n i t z e r a n d B a i r d , 1994; M c I n t o s h , O l s h a n , a n d B a i r d , 1995). It is p r e s u m e d t h a t t h e s e a b n o r m a l i t i e s w e r e d u e to a new dominant mutation arising in the germ cells of the father. The basis for an increased risk with increasing paternal age has been attributed t o t h e ' c o p y e r r o r ' m e c h a n i s m . T h i s m o d e l assumes that the probability of spontaneous mutation increases with increasing age due to the potential for a higher rate of replication error w i t h c o n t i n u o u s m a l e g e r m cell d i v i s i o n ( P e n r o s e , 1955). A n a n a l y s i s b y R i s c h e t al. ( 1 9 8 7 ) f o u n d
t h a t t h e r e is s o m e h e t e r o g e n e i t y a m o n g d o m i n a n t syndromes for the rate of increase with age implying that the simple copy-error model may not h o l d f o r all c o n d i t i o n s . We have hypothesized, by extension from the b i r t h d e f e c t s d a t a , t h a t if s o m e f r a c t i o n o f S G A could be due to new germinal mutations, then an association with advanced paternal age should be p r e s e n t . T h e p u r p o s e o f t h i s p a p e r is t o e v a l u a t e the relation between paternal age and SGA, low birthweight, and preterm births using a large sample of births from North Carolina.
Table 1 Selected maternal characteristics of small-for-gestational age, low birth weight and preterm births: North Carolina 1988-1991 Small-for-gestational age a
Low birthweight d
%
Preterm delivery c
OR b
95% CI c
%
OR
95% CI
%
OR
95% CI
1.21-1.35 1.11-1.24 1.03-1.16
6.3 5.9 5.4 5.1 5.0 5.0 5.3
1.23 1.16 1.06 1.00 0.99 0.98 1.04
1.16-1.31 1.09-1.23 1.00-1.12
10.2 9.5 8.8 8.5 8.4 8.6 9.2
1.20 1.12 1.05 1.00 1.00 1.02 1.08
1.15-1.26 1.07-1.17 1.00-1.09
Maternal age 20-21 22-23 24-25 26-27 f 28-29 30-31 32-34
7.1 6.5 6.1 5.6 5.2 5.2 4.7
1.27 1.17 1.09 1.00 0.94 0.93 0.85
Maternal race Black White f
5.5 5.8
0.94 1.00
0.90-0.98
9.4 4.4
2.12 1.00
2.05-2.19
14.9 7.6
1.96 1.00
1.91-2.01
Gravidity Primigravid Multigravid f
6.5 5.4
1.20 1.00
1.16-1.24
5.6 5.3
1.06 1.00
1.02-1.10
8.4 9.3
0.90 1.00
0.87-0.92
Education (yrs) < 12 12 f 13 +
9.9 6.1 4.3
1.62 1.00 0.70
1.55-1.70
8.1 5.8 4.3
1.41 1.00 0.75
1.34-1.47
11.5 9.5 7.8
1.21 1.00 0.82
1.16-1.25
Marital s t a t u s Unmarried Married f
8.1 5.5
1.50 1.00
1.43-1.58
9.4 5.0
1.98 1.00
1.89-2.08
14.1 8.4
1.79 1.00
1.72-1.85
11.9 4.3
2.79 1.00
2.70-2.88
9.3 4.5
2.07 1.00
2.00-2.15
11.1 8.5
1.31 1.00
1.27-1.35
Smoking Yes No f
a Total number of births = b OR, odds ratio. c 95% CI, 95% confidence d Total number of births = Total number of births = f Referent category.
235 237. interval. 237 934. 254 639.
0.88-1.00 0.87-0.99 0.79-0.91
0.67-0.74
0.93-1.05 0.92-1.05 0.98-1.11
0.72-0.78
0.95-1.05 0.97-1.07 1.03-1.14
0.80-0.84
91
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2. Materials and methods D a t a for this study w e r e d e r i v e d f r o m the birth files of the state of N o r t h C a r o l i n a , for t h e y e a r s 1988 t h r o u g h 1991. S t a r t i n g with 413372 p r e g n a n c i e s t h a t r e s u l t e d in live b i r t h s d u r i n g t h a t p e r i o d , t h e following s e q u e n t i a l exclusions w e r e m a d e : r e s i d e n c e o u t s i d e N o r t h C a r o l i n a (n = 6973), m u l t i p l e b i r t h s (n = 9574), m a t e r n a l r a c e o t h e r t h a n b l a c k o r white (n = 7577), a n d missing d a t a on p a t e r n a l age (n = 42 445). In a d d i t i o n , in o r d e r to isolate p a t e r n a l from m a t e r n a l age effects, we r e s t r i c t e d o u r analyses to m o t h e r s age 2 0 - 3 4 years, excluding 91911 births to y o u n g e r a n d o l d e r m o t h e r s . A total of 254892 singleton live births r e m a i n e d available for analysis. P a t e r n a l age was c a t e g o r i z e d into 8 age intervals: < 19 years, 2 0 - 2 4 , 2 5 - 2 9 , 3 0 - 3 4 , 3 5 - 3 9 , 4 0 - 4 4 , 4 5 - 4 9 , a n d 50 y e a r s a n d older. T h e reference c a t e g o r y for the analysis o f p a t e r n a l age was the 2 5 - 2 9 y e a r o l d group. T h e y w e r e c h o s e n b e c a u s e t h e y a r e a large e n o u g h g r o u p to yield stable relative risk e s t i m a t e s a n d a r e e x p e c t e d to have no i n c r e a s e in risk (i.e., relative risk = 1.0). A d v e r s e b i r t h o u t c o m e s i n c l u d e d low b i r t h weight (birth weight ( B W T ) < 2499 grams), p r e t e r m delivery ( g e s t a t i o n a l age ( G A ) < 37 weeks), a n d small-for-gestational-age-SGA (BWT below the 10th p e r c e n t i l e for a given g e s t a t i o n a l age, race, a n d fetal gender). S t a n d a r d s to d e f i n e S G A births w e r e d e r i v e d from t h o s e of B r e n n e r et al. (1976),
a c c o u n t i n g for b l a c k - w h i t e a n d m a l e - f e m a l e differences. P o t e n t i a l m a t e r n a l c o n f o u n d e r s i n c l u d e d line a r a n d q u a d r a t i c t e r m s for m a t e r n a l age ( c e n t e r e d at 26.3 years), r a c e ( b l a c k / w h i t e ) , gravidity ( p r i m i g r a v i d vs. mutligravid), smoking d u r ing p r e g n a n c y ( y e s / n o ) , m a r i t a l status, a n d e d u c a t i o n ( c e n t e r e d at 13 c o m p l e t e d y e a r s of schooling). In a d d i t i o n , g e n d e r o f t h e infant was t r e a t e d as a c o n f o u n d e r . A q u a d r a t i c t e r m for m o t h e r ' s age has b e e n u s e d to a c c o u n t for a ' U ' s h a p e d age-risk function. N o n e of t h e s e c o v a r i a t e s w e r e significant m o d i f i e r s of t h e effect of p a t e r n a l age on t h e risk of e a c h o f t h e o u t c o m e s . A s s o c i a t i o n s b e t w e e n p a t e r n a l age a n d b i r t h o u t c o m e s w e r e assessed t h r o u g h t h e c o m p u t a t i o n o f o d d s ratio e s t i m a t e s with 95% c o n f i d e n c e intervals. T h e o d d s r a t i o r e p r e s e n t s t h e r a t i o o f the o d d s of the o c c u r r e n c e of t h e b i r t h o u t c o m e s a m o n g t h e exp o s e d ( o l d e r fathers) a n d u n e x p o s e d (fathers a g e d 2 5 - 2 9 y e a r s ) p r e g n a n c i e s a n d is an a p p r o x i m a tion o f the relative risk. O d d s ratios a d j u s t e d for c o n f o u n d e r s w e r e directly d e r i v e d from t h e regression coefficient c o r r e s p o n d i n g to the p a t e r n a l age t e r m in a logistic r e g r e s s i o n m o d e l (Breslow a n d Day, 1980).
3. Results T h e d i s t r i b u t i o n o f m a t e r n a l factors including age, race, gravidity, e d u c a t i o n , m a r i t a l status, a n d
Table 2 Relationship between paternal age and small-for-gestational age: North Carolina, 1988-1991 Paternal age (years)
No. of births a
% Small-forgestational age
Crude odds ratio b
95% CI
Adjusted odds ratio c
95% CI
< 19 20-24 25-29 d 30-34 35-39 40-44 45 -49 50 +
2729 48630 86245 66535 22898 5964 1545 691
7.5 6.4 5.8 5.3 5.1 6.3 7.4 6.1
1.31 1.12 1.00 0.90 0.87 1.10 1.30 1.05
1.13-1.51 1.07-1.17
1.03 0.98 1.00 1.01 0.95 1.05 1.13 0.87
0.88-1.20 0.93-1.04
0.86-0.94 0.82-0.93 0.98-1.22 1.08-1.58 0.77-1.43
0.96-1.06 0.89- 1.03 0.93-1.18 0.92-1.38 0.63-1.19
a Total number of births = 235 237. b 95% Confidence interval. c Adjusted for maternal age (linear and quadratic terms), maternal race, gravidity, maternal smoking, marital status, maternal education, and infant gender. d Referent category.
A.F. Olshan et al. / Mutation Research 344 (1995) 89-94
92
Table 3 Relationship between paternal age and low birthweight: North Carolina, 1988-1991 Paternal age (years)
No. of births a
% Low birthweight
Crude odds ratio b
95% CI
Adjusted odds ratio c
95% CI
~<19 20-24 25-294 30-34 35-39 40-44 45-49 50 +
2768 49351 87259 67159 23104 6036 1559 698
7.4 6.1 5.3 4.9 5.3 6.5 6.7 6.0
1.44 1.16 1.00 0.92 0.99 1.25 1.28 1.14
1.24-1.66 1.10-1.21
1.13 1.04 1.00 0.96 0.96 1.09 1.00 0.81
0.97-1.32 0.98-1.09
0.88-0.96 0.93-1.06 1.12-1.39 1.05-1.56 0.84-1.57
0.91-1.01 0.89-1.03 0.97-1.21 0.81-1.23 0.59-1.12
a Total number of births = 237 934. b 95% Confidence interval. c Adjusted for maternal age (linear and quadratic terms), maternal race, gravidity, maternal smoking, marital status, maternal education, and infant gender d Referent category.
smok i n g a m o n g S G A a n d n o n - S G A (small-for-gestational age), low birthweight, a n d p r e t e r m births is given in T a b l e 1. T h e overall p e r c e n t a g e o f S G A , low birthweight, and p r e t e r m births w e r e 5.8, 5.4, 8.9, respectively. T h e c r u d e o d d s ratios p r e s e n t e d suggest an i n c r e a s e d risk for S G A , low birthweight, and p r e t e r m delivery a m o n g infants of m o t h e r s u n d e r age 2 0 - 2 1 , t h o s e w h o h a d less t h a n 12 years o f e d u c a t i o n , those w h o w e r e unm a r r i e d , and t h o s e w h o s m o k e d cigarettes. Black m o t h e r s had e l e v a t e d odds ratios for low birth weight and infant and p r e t e r m delivery, but not SGA.
A l t h o u g h t h e c r u d e odds ratios s h o w e d s o m e i n c r e a s e d risks a m o n g y o u n g e r and o l d e r fathers, the a d j u s t e d odds ratios show no indication of an e l e v a t i o n in risk for any p a t e r n a l age group; the e s t i m a t e s w e r e n e a r the null v al u e o f 1.0 ( T a b l e 2). T h e largest odds ratio was 1.13 for m e n a g e d 4 5 - 4 9 years (relative to m e n age 2 5 - 2 9 years). A similar lack o f association was also f o u n d for low b i r t h w e i g h t an d p r e t e r m birth (Tables 3 an d 4). O n c e again, y o u n g f at h er s had e l e v a t e d c r u d e o d d s ratios that d i m i n i s h e d after a d j u s t m e n t for race, g e n d e r , gravidity, m ar i t al status, and m a t e r nal e d u c a t i o n . O l d e r f at h er s h ad no odds ratios
Table 4 Relationship between paternal age and preterm delivery: North Carolina, 1988-1991 Paternal age (years)
No. of births a
% Preterm delivery
Crude
95% CI odds ratio b
Adjusted
95% CI odds ratio c
~<19 20-24 25-29 d 30-34 35-39 40-44 45-49 50 +
2971 52842 93333 71852 24729 6486 1687 739
12.2 10.1 8.6 8.4 9.2 9.7 10.6 11.2
1.47 1.18 1.00 0.97 1.07 1.14 1.26 1.34
1.31-1.64 1.14-1.23
1.23 1.09 1.00 0.98 1.03 1.05 1.09 1.08
1.10-1.39 1.05-1.14
0.94-1.00 1.02-1.12 1.04-1.24 1.07-1.47 1.06-1.68
0.95-1.02 0.97-1.08 0.96-1.14 0.93-1.28 0.85-1.36
a Preterm delivery (< 37 weeks LMP); total number of births = 254 639. b 95% Confidence interval. c Adjusted for maternal age (linear and quadratic terms), maternal race, gravidity, maternal smoking, marital status, maternal education, and infant gender. d Referent category.
A.F. Olshan et al. / Mutation Research 344 (1995) 89-94
as large as 1.10 for low birthweight or preterm birth. The largest odds ratio found was 1.25 for preterm birth among men less than 20 years old. There was also no increase in risk for very-lowbirthweight ( < 1500 g) infants among any paternal age group (data not shown).
4. Discussion
The results of this study clearly indicate that advanced paternal age is not associated with an increased risk of intrauterine growth retardation, low birthweight or preterm delivery after adjustment for potential confounders. This lack of association is consistent with the results of a recent analysis of paternal characteristics and low birth weight among nearly 9 million births in the United States (Parker and Schoendorf, 1992). A strength of our study is the large number of births, reflected in the narrow confidence intervals. The study sample had greater than 80% power to detect as statistically significant odds ratios as small as 1.5 for all age categories and outcomes. Because of the interrelationship of paternal and maternal age, we employed two different methods to isolate any paternal age effect from maternal age. First, we restricted the analysis to births of mothers aged 20 to 34 years, a range in which effects of maternal age are thought to be modest. Second, we used statistical methods, including polynomial models, to adjust for any residual confounding due to mother's age. The quality of the data recorded on the North Carolina birth certificate is known to generally be of acceptable quality for the factors under study (Buescher et al., 1993), specifically maternal and paternal age and birthweight. However, gestational age based on the date that the last normal menses began (LMP) is known to be subject to inaccuracy for p r e t e r m delivery and S G A (David, 1980). Tobacco use ( y e s / n o ) as reported on the North Carolina birth certificate has been shown to be of fair quality with an 84% exact agreement with medical records for use during pregnancy (Buescher et al., 1993). Some residual confounding due to the potential misclassification of maternal tobacco use is probable.
93
Our findings suggest that S G A is not a sensitive indicator of new dominant mutations, assuming that advanced paternal age is related to an increased risk of de n o v o dominant mutations. Such an association for paternal age has been clearly demonstrated for a number of relatively rare conditions and possibly for some more common birth defects. As Czeizel (1993) notes, the etiology of S G A is complex and heterogenous, potentially reducing its value as a specific indicator in mutation epidemiology studies. Even if a small fraction of reduced fetal growth were caused by paternal mutations, it might well be undectable among all the other factors influencing SGA. In addition to other exogenous determinants (e.g., tobacco, diet), a sizable fraction of S G A babies are probably normal, small infants (Wilcox, 1993). We have provided only one specific evaluation of S G A as a valid endpoint in mutation epidemiology, with no support for the types of mutations related to paternal age. Further study is needed to evaluate mutations due to other specific parental mutagenic exposures such as occupational chemicals or ionizing radiation.
References Brenner, W.E., D.A. Edelman and C.H. Hendricks (1976) A standard of fetal growth for the USA, Am. J. Obstet. Gynecol., 126, 555-564. Breslow, N.E. and N.E. Day (1980) Statistical Methods in Cancer Research. Vol 1: The Analysis of Case-control Studies. IARC Scientific Publication 32, IARC, Lyon, France. Buescher, P.A., K.P. Taylor, M.H. Davis and J.M. Bowling (1993) The quality of the new birth certificate data: a validation study in North Carolina, Am. J. Public Health, 83, 1163-1165. Czeizel, A.E. (1993) Intrauterine growth retardation as a potential endpoint in mutation epidemiology, Mutation Res., 296, 211-219. David, R.J. (1980) The quality and completeness of birth weight and gestational age in computerized birth files, Am. J. Public Health, 70, 964-973. Mclntosh, G.C., A.F. Olshan and P.A. Baird (1995) Paternal age and the risk of birth defects in offspring, Epidemiology, in press. Olshan, A.F., P.G. Schnitzer and P.A. Baird (1994) Paternal age and the risk of congenital heart defects, Teratology 50, 80-84.
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Parker, J.D. and K.C. Schoendorf (1992) Influence of paternal characteristics on the risk of low birth weight, Am. J. Epidemiol, 136, 399-407. Penrose, L.R. (1955) Paternal age and mutation, Lancet, 2, 312. Risch, N., E.W. Reich, M.M. Wishnick and J.G. McCarthy (1987) Spontaneous mutation and parental age in humans, Am. J. Hum. Genet., 41,218-248. Sanjose, S., E. Roman and V. Beral (1991) Low birthweight
and preterm delivery, Scotland, 1981-84: effect of parents' occupation, Lancet, 2, 428-431. Savitz, D.A., E.A. Whelan and R.C. Kleckner (1989) Effect of parents' occupational exposures on risk of stillbirth, preterm delivery, and small-for-gestational-age infants, Am. J. Epidemiol., 129: 1201-1208. Wilcox, A.J. (1993) Birth weight and perinatal mortality: the effect of maternal smoking, Am. J. Epidemiol., 137, 10981104.