RESEARCH ARTICLE

Sex Ratios Among Infants with Birth Defects, National Birth Defects Prevention Study, 1997–2009 Adrian M. Michalski,1* Sandra D. Richardson,1 Marilyn L. Browne,1 Suzan L. Carmichael,2 Mark A. Canfield,3 Alissa R. VanZutphen,1 Marlene T. Anderka,4 Elizabeth G. Marshall,5 and Charlotte M. Druschel1 1

New York State Department of Health, Congenital Malformations Registry, Albany, New York

2

Department of Pediatrics, Stanford University, Stanford, California

3

Texas Department of State Health Services, Austin, Texas Massachusetts Department of Public Health, Boston, Massachusetts

4 5

Department of Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey

Manuscript Received: 20 June 2014; Manuscript Accepted: 11 October 2014

A small number of population-based studies have examined sex differences among infants with birth defects. This study presents estimates of sex ratio for both isolated cases and those with multiple congenital anomalies, as well as by race/ethnicity. Male–female sex ratios and their 95% confidence intervals were calculated for 25,952 clinically reviewed case infants included in the National Birth Defects Prevention Study (1997– 2009), a large population-based case-control study of birth defects. The highest elevations in sex ratios (i.e., male preponderance) among isolated non-cardiac defects were for craniosynostosis (2.12), cleft lip with cleft palate (2.01), and cleft lip without cleft palate (1.78); the lowest sex ratios (female preponderance) were for choanal atresia (0.45), cloacal exstrophy (0.46), and holoprosencephaly (0.64). Among isolated cardiac defects, the highest sex ratios were for aortic stenosis (2.88), coarctation of the aorta (2.51), and d-transposition of the great arteries (2.34); the lowest were multiple ventricular septal defects (0.52), truncus arteriosus (0.63), and heterotaxia with congenital heart defect (0.64). Differences were observed by race/ethnicity for some but not for most types of birth defects. The sex differences we observed for specific defects, between those with isolated versus multiple defects, as well as by race/ethnicity, demonstrate patterns that may suggest etiology and improve classification. Ó 2015 Wiley Periodicals, Inc.

Key words: sex ratio; birth defects; race/ethnicity

INTRODUCTION Sex differences in the prevalence of congenital malformations may provide insight into their etiologic mechanisms or etiologic heterogeneity [Kallen, 1988; Lubinsky, 1997; Rittler et al., 2004]. Only a limited number of published studies have examined sex ratio for a variety of anomaly subtypes [Lary and Paulozzi, 2001; Shaw et al.,

Ó 2015 Wiley Periodicals, Inc.

How to Cite this Article: Michalski AM, Richardson SD, Browne ML, Carmichael SL, Canfield MA, VanZutphen AR, Anderka MT, Marshall EG, Druschel CM. 2015. Sex ratios among infants with birth defects, National Birth Defects Prevention Study, 1997–2009. Am J Med Genet Part A 167A:1071–1081.

2003; Rittler et al., 2004; Lisi et al., 2005; Tennant et al., 2011; Sokal et al., 2014]. Differences in the sex ratio of certain birth defects by racial/ethnic group may provide additional insight into genetic susceptibility or environmental exposures. The large sample size and detailed case classification of the National Birth Defects Prevention Study (NBDPS) enabled us to examine sex differences for a large number of birth defect subtypes, by isolated and multiple birth defect status, and by race/ethnicity.

MATERIALS AND METHODS The NBDPS is a multi-site population-based case-control study that began in 1997 [Yoon et al., 2001]. Infants with one or more of over 30 different categories of major structural defects (cases), Conflict of interest: none. Grant sponsor: Centers for Disease Control and Prevention; Grant number: U01/DD00048702.
Correspondence to: Adrian Michalski, Congenital Malformations Registry, Empire State Plaza-Corning Tower, Rm 1203, Albany, NY 12237. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 25 February 2015 DOI 10.1002/ajmg.a.36865

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1072 excluding those attributed to a known chromosomal abnormality or single-gene condition, were ascertained through birth defects surveillance systems in 10 states (AR, CA, GA, IA, MA, NC, NJ, NY, UT, and TX). Control infants were liveborn infants without birth defects randomly selected from hospital records (AR, CA, NY, TX), birth certificates (IA, MA, NC, NJ, UT), or both (GA: hospital record, 1997–2000; birth certificate, 2001–2007) in the same time period and geographic areas as the cases. Each study site obtained institutional review board approval for the NBDPS; informed consent was provided by all families who participated in the study. The authors had full access to all the data in the study. Populationbased data were collected from either the entire state or selected regions of the state. In the present study, we included singleton livebirths, stillbirths, and terminations of pregnancy with an estimated date of delivery (EDD) from October 1997 through December 2009. Eligible case infants were those for which the diagnosis and subsequent maternal interview occurred before 24 months after EDD. Additional NBDPS case inclusion criteria have been described by Yoon et al. [2001]. Relatively homogeneous birth defect categories were analyzed, which we will refer to as “specific” birth defects (as opposed to larger categories that include specific birth defects for example orofacial clefts vs. cleft palate). Clinical geneticists reviewed and classified each case infant as having isolated or multiple birth defects (two or more major unrelated defects) [Rasmussen et al., 2003]. To reduce etiologic heterogeneity within case groups, we excluded infants classified as having a complex sequence (a group of defects that are believed to be pathogenetically related, but for which the primary defect is not apparent such as Pentallogy of Cantrell). However, we make the exception to include case groups consisting primarily of complex defects such as amniotic band sequence and heterotaxia with congenital heart defect. Only ileal, jejunal, and multiple intestinal atresias or stenoses were counted as small intestinal atresias; duodenal atresias were counted separately. Infants with esophageal or small intestinal atresia that occurred as a component of VATER or VACTERL association of defects were included in the study and were classified as having multiple defects. Cases of hypospadias were ascertained for males only and were excluded from the analysis. Multiple ventricular septal defects refers to cases that have more than one type of ventricular septal defect (e.g., two muscular or one muscular and one perimembranous). We excluded cases among non-interviewed mothers, since these cases did not undergo the rigorous clinical review and classification described above. Only structural heart defects confirmed by echocardiography, cardiac catheterization or autopsy were included in the NBDPS. Congenital heart defect (CHD) cases were further categorized as simple associations or complex [Botto et al., 2007]. Most of the heart phenotypes included in this study were simple CHDs (defined as a single CHD or CHD “entity”) or common CHD associations (e.g., coarctation of the aorta þ ventricular septal defect). Cases recorded as “atrial septal defect (ASD) not otherwise specified” were viewed as probably ASD secundum type but are shown separately in the analysis. Certain study sites did not ascertain cases during the entire study period for oral clefts and pulmonary valve stenosis, and muscular ventricular septal defects were included for only the first year of data collection for sites participating in 1997–

AMERICAN JOURNAL OF MEDICAL GENETICS PART A 1998. When we analyzed those birth defects, cases were excluded for the study sites and years for which case ascertainment was incomplete, i.e., analyses of muscular ventricular septal defects were restricted to the first year of data collection for sites participating in 1997–1998. Our analysis comprised birth defect case groups with 20 or more cases. We presented birth defect–specific sex ratios calculated as odds ratios compared to NBDPS control infants {(#male cases/ #male controls)/(#female cases/#female controls)}. In this paper we refer to this odds ratio as “sex ratio.” As an internal comparison we calculated risk ratios (male prevalence/female prevalence) using population denominators for isolated cases, all races and ethnicities combined, and determined that there was little difference between the risk ratio and the odds ratio. A table comparing estimates calculated using each of these methods is available as supplementary material at [wileyonlinelibrary.com/journal/ajmg]. Sex ratios greater than one indicate a male preponderance, while those less than one indicate female preponderance. We calculated 95% confidence limits and sex-specific frequencies overall and stratified by clinical pattern (isolated vs. multiple birth defects) and race/ ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian/Pacific Islander). To address a potential for participation/ response bias in our estimates, we compared the distribution of infant sex among interviewed cases to all eligible cases and interviewed controls to all eligible controls. A total of 15,498 noninterviewed cases were ascertained; 58.1% were male (N ¼ 9,007) and 41.9% were female (N ¼ 6,491), and a total of 5,942 noninterviewed controls were ascertained; 51.1% were male (N ¼ 3,037) and 48.9% were female (N ¼ 2,905). This compares to 58.5% male (N ¼ 20,536) and 41.5% female (N ¼ 14,578), and 51.2% male (N ¼ 6,958) and 48.8% female (N ¼ 6,618) among interviewed cases and controls, respectively. Analyses were conducted using SAS software version 9.3, copyright 2002–2010 (SAS Institute Inc., Cary, NC).

RESULTS A total of 23,990 interviewed cases from the NBDPS were analyzed after excluding male cases of hypospadias. There were 13,211 male infants and 10,779 female infants with congenital anomalies, and controls included 5,034 males and 4,859 females. The overall sex ratio among NBDPS interviewed cases compared to controls was 1.18 (95% CI ¼ 1.13, 1.24). The male:female sex ratio among all birth defect categories ranged from 0.30 to 2.86. For non-cardiac birth defects the sex ratios ranged from 0.30 to 2.05 and among CHDs, the overall sex ratios ranged from 0.44 to 2.86 (Table I). When stratifying by isolated or multiple birth defect status, the sex ratios ranged from 0.45 to 2.88 for all isolated birth defects and from 0.13 to 4.99 for all multiple birth defects. For most defects, the sex ratio for the isolated defect was similar to the sex ratio for multiple defect cases. However, some birth defect groups had considerable differences in sex ratio at birth for isolated cases as compared to those with multiple defects. The sex ratio for multiple defect cases differed from isolated cases by 50%, 63%, 71%, 90%, 127%, and over 200% for amniotic band sequence, anomalous pulmonary venous return, cloacal exstrophy, encephalocele, heterotaxia with CHD, and bilateral renal agenesis

Birth Defect Non-cardiac birth defects Amniotic band sequence Neural tube defects Anencephaly Spina bifida Encephalocele Hydrocephaly Dandy–Walker malformation Cerebellar hypoplasia Holoprosencephaly Cataracts Anophthalmos/microphthalmos Glaucoma/anterior chamber defects Anotia/microtia Choanal atresia Oral clefts Cleft palate only Cleft lip w/wo cleft palate Cleft lip with cleft palate Cleft lip without cleft palate Esophageal atresia Small intestinal atresia/stenosis Duodenal atresia/stenosis Colonic atresia/stenosis Anorectal atresia/stenosis Cloacal exstrophy Biliary atresia Bladder exstrophy Bilateral renal agenesis or hypoplasia Limb deficiency Longitudinal limb deficiency Transverse limb deficiency Intercalary limb deficiency Craniosynostosis Diaphragmatic hernia Omphalocele Gastroschisis Sacral agenesis Congenital heart defects Heterotaxia with CHD Conotruncal defects 0.81 (0.64, 1.02) 1.58 (1.42, 1.75)

133/159 1108/678

(0.91, 1.48) (0.88, 1.08) (0.77, 1.12) (0.89, 1.15) (0.65, 1.16) (1.04, 1.55) (0.81, 1.55) (1.04, 3.59) (0.44, 0.87) (0.67, 1.08) (0.73, 1.31) (0.71, 1.36) (1.12, 1.57) (0.39, 0.80) (1.26, 1.46) (0.68, 0.85) (1.71, 2.04) (1.70, 2.12) (1.57, 2.08) (0.81, 1.12) (0.79, 1.18) (0.72, 1.29) (0.40, 1.33) (1.44, 1.92) (0.17, 0.54) (0.73, 1.35) (1.00, 2.81) (1.38, 2.76) (1.13, 1.47) (1.11, 1.68) (1.04, 1.45) (0.70, 2.15) (1.81, 2.32) (1.19, 1.64) (1.04, 1.61) (0.87, 1.11) (0.63, 1.55)

1.16 0.97 0.93 1.01 0.87 1.27 1.12 1.93 0.62 0.85 0.98 0.98 1.32 0.56 1.35 0.76 1.87 1.90 1.81 0.95 0.97 0.97 0.73 1.67 0.30 0.99 1.68 1.95 1.29 1.37 1.23 1.23 2.05 1.40 1.29 0.99 0.99

Sex Ratio (95% CI)

144/120 863/856 223/232 550/524 90/100 236/179 79/68 30/15 53/83 128/142 90/89 75/72 333/243 46/80 2315/1647 604/764 1711/883 1109/562 602/321 291/295 199/199 93/93 19/25 540/313 15/48 83/81 40/23 97/48 584/437 224/158 339/266 28/22 853/402 403/278 190/142 594/581 39/38

M/F

Total

14/21 933/582

130/99 736/761 198/210 477/471 61/80 167/126 51/40 16/9 40/60 110/130 56/50 64/61 236/167 22/47 2003/1404 466/633 1537/771 978/469 559/302 131/117 167/171 56/59 17/24 244/135 12/25 67/70 30/19 66/42 425/321 128/81 277/233 19/15 780/355 333/207 122/90 540/525 7/6

M/F (0.97, 1.65) (0.84, 1.04) (0.75, 1.11) (0.86, 1.12) (0.53, 1.03) (1.01, 1.62) (0.81, 1.87) (0.76, 3.89) (0.43, 0.96) (0.62, 1.03) (0.74, 1.59) (0.69, 1.41) (1.11, 1.67) (0.27, 0.75) (1.27, 1.49) (0.63, 0.80) (1.75, 2.11) (1.79, 2.26) (1.54, 2.06) (0.84, 1.39) (0.76, 1.17) (0.63, 1.32) (0.37, 1.27) (1.41, 2.16) (0.23, 0.92) (0.66, 1.29) (0.86, 2.71) (1.03, 2.24) (1.10, 1.49) (1.15, 2.02) (0.96, 1.37) (0.62, 2.41) (1.86, 2.42) (1.30, 1.86) (0.99, 1.72) (0.87, 1.13) – 0.64 (0.33, 1.27) 1.55 (1.38, 1.73)

1.27 0.93 0.91 0.98 0.74 1.28 1.23 1.72 0.64 0.80 1.08 0.99 1.36 0.45 1.37 0.71 1.92 2.01 1.78 1.08 0.94 0.92 0.68 1.74 0.46 0.92 1.52 1.52 1.28 1.53 1.15 1.22 2.12 1.55 1.31 0.99

Sex Ratio (95% CI)

Isolated

36/24 175/96

14/21 127/95 25/22 73/53 29/20 69/53 28/28 14/6 13/23 18/12 34/38 11/11 97/76 24/33 312/243 138/131 174/112 131/93 43/19 160/178 32/28 37/34 2/1 296/178 3/23 16/11 10/4 31/6 159/116 96/77 62/33 9/7 73/47 70/71 68/52 54/56 32/32

M/F

1.45 (0.86, 2.43) 1.76 (1.37, 2.26) (Continued)

(0.33, 1.27) (0.99, 1.69) (0.62, 1.95) (0.93, 1.90) (0.79, 2.48) (0.88, 1.80) (0.57, 1.63) (0.86, 5.87) (0.28, 1.08) (0.68, 2.94) (0.54, 1.37) (0.41, 2.18) (0.91, 1.67) (0.41, 1.19) (1.04, 1.47) (0.80, 1.29) (1.18, 1.90) (1.04, 1.77) (1.27, 3.75) (0.70, 1.08) (0.66, 1.83) (0.66, 1.68) – 1.61 (1.33, 1.94) 0.13 (0.04, 0.42) 1.40 (0.65, 3.03) – 4.99 (2.08, 11.96) 1.32 (1.04, 1.69) 1.20 (0.89, 1.63) 1.81 (1.19, 2.77) – 1.50 (1.04, 2.17) 0.95 (0.68, 1.33) 1.26 (0.88, 1.81) 0.93 (0.64, 1.36) 0.97 (0.59, 1.58)

0.64 1.29 1.10 1.33 1.40 1.26 0.97 2.25 0.55 1.41 0.86 0.94 1.23 0.70 1.24 1.01 1.50 1.36 2.18 0.87 1.10 1.05

Sex Ratio (95% CI)

Multipleb

TABLE I. Sex Ratio and Counts by Infant Sex for Isolated Birth Defects, Multiple Birth Defects, and Overall, Among Singleton Births, National Birth Defects Prevention Study, 1997–2009*

MICHALSKI ET AL. 1073

0.77 (0.65, 0.90) 1.68 (1.21, 2.35)

(0.33, 0.60) (0.46, 0.93) (0.60, 1.36) (0.81, 0.96) (0.84, 1.10) (0.49, 0.98) (0.55, 3.09) (0.34, 1.01) (0.77, 0.96) (0.72, 0.92) (0.83, 1.27)

0.44 0.66 0.91 0.88 0.96 0.69 1.30 0.59 0.86 0.82 1.03

63/137 53/78 46/49 1301/1429 478/485 63/96 12/9 21/35 733/822 547/647 186/175 291/367 96/55

56/28 114/90 32/26 452/556 84/51 345/472 23/33

(1.33, 3.18) (0.93, 1.55) (0.74, 1.84) (0.71, 0.91) (1.15, 2.28) (0.62, 0.82) (0.51, 1.35)

2.06 1.20 1.16 0.80 1.62 0.71 0.83

64/30 138/111 41/34 489/588 89/53 370/499 30/35

227/292 87/42

51/121 41/67 41/45 1073/1214 416/437 58/84 11/7 16/30 576/680 423/538 153/142

M/F 30/46 9/9 471/321 352/145 25/19 19/10 23/27 62/86 159/92 137/78 22/14 854/363 319/163 322/124 209/70

Sex Ratio (95% CI) 0.79 (0.52, 1.20) 1.13 (0.52, 2.44) 1.45 (1.27, 1.66) 2.35 (1.94, 2.84) 1.45 (0.82, 2.55) 1.86 (0.98, 3.55) 0.88 (0.53, 1.47) 0.69 (0.51, 0.93) 1.73 (1.35, 2.23) 1.75 (1.34, 2.30) 1.63 (0.88, 3.03) 2.20 (1.94, 2.49) 1.86 (1.54, 2.23) 2.37 (1.95, 2.89) 2.86 (2.19, 3.73)

M/F 41/50 14/12 586/390 377/155 30/20 27/14 28/31 75/105 176/98 149/82 27/16 925/406 346/180 354/144 219/74

TABLE I. (Continued )

(0.29, 0.57) (0.40, 0.87) (0.57, 1.35) (0.78, 0.93) (0.80, 1.07) (0.51, 1.05) – (0.28, 0.96) (0.73, 0.92) (0.66, 0.87) (0.82, 1.31)

(1.22, 3.04) (0.92, 1.62) (0.71, 2.00) (0.69, 0.89) (1.12, 2.26) (0.61, 0.81) (0.39, 1.15)

0.75 (0.63, 0.90) 2.00 (1.38, 2.90)

0.52 0.82 0.76 1.04

0.41 0.59 0.88 0.85 0.93 0.73

1.93 1.22 1.19 0.78 1.59 0.70 0.67

Sex Ratio (95% CI) 0.63 (0.40, 1.00) – 1.42 (1.22, 1.64) 2.34 (1.92, 2.85) 1.27 (0.70, 2.31) 1.83 (0.85, 3.95) 0.83 (0.48, 1.45) 0.70 (0.50, 0.97) 1.67 (1.29, 2.16) 1.70 (1.28, 2.24) 1.52 (0.78, 2.97) 2.27 (2.00, 2.58) 1.89 (1.56, 2.29) 2.51 (2.03, 3.09) 2.88 (2.19, 3.79)

Isolated

64/75 8/13

12/16 12/11 5/4 228/215 62/48 5/12 1/2 5/5 157/142 124/109 33/33

8/2 24/21 9/8 37/32 5/2 25/27 7/2

M/F 11/4 5/3 115/69 25/10 5/1 8/4 5/4 13/19 17/6 12/4 5/2 71/43 27/17 32/20 10/4

0.82 (0.59, 1.15) 0.59 (0.25, 1.43)

0.72 (0.34, 1.53) 1.05 (0.46, 2.39) – 1.02 (0.85, 1.24) 1.26 (0.86, 1.84) – – – 1.07 (0.85, 1.34) 1.10 (0.85, 1.42) 0.97 (0.59, 1.57)

– 1.10 (0.61, 1.98) – 1.12 (0.69, 1.79) – 0.89 (0.52, 1.54) –

Sex Ratio (95% CI) – – 1.61 (1.19, 2.17) 2.41 (1.16, 5.03) – – – 0.66 (0.33, 1.34) 2.73 (1.08, 6.94) – – 1.59 (1.09, 2.33) 1.53 (0.83, 2.82) 1.54 (0.88, 2.70) –

Multipleb

ABS–LBWC, amniotic band syndrome–limb body wall complex; AS, aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; CHD, congenital heart defect; CI, confidence interval; COA, coarctation of the aorta; DORV, double outlet right ventricle; LVOTO, left ventricular outflow tract obstruction; NOS, not otherwise specified; OS, other specified; PAPVR, partial anomalous pulmonary venous return; PVS, pulmonary valve stenosis; RVOTO, right ventricular outflow tract obstruction; TAPVR, total anomalous pulmonary venous return; TGA, transposition of the great arteries; VSD, ventricular septal defect. ’–’, not calculated (less than 20 cases total). * *Sex ratios were calculated as odds ratios using NBDPS controls (M ¼ 5034, F ¼ 4859; Control counts differed for the following defects: cleft palate M ¼ 4972, F ¼ 4789; VSD conoventricular, VSD OS, Multiple VSDs M ¼ 3348 F ¼ 3265; VSD muscular M ¼ 343 F ¼ 362; PVS M ¼ 4807 F ¼ 4619) includes only birth defect groups with a minimum of 20 cases. a aEbsteins anomaly is not included in the RVOTO category. b bCases with multiple congenital anomalies may be counted in multiple defect categories. Statistically significant results are printed in bold.

Birth Defect Truncus arteriosus IAA type B Tetralogy of Fallot d-Transposition of the great arteries DORV-TGA DORV-Other VSD conoventricular AVSD APVR TAPVR PAPVR LVOTO defects Hypoplastic left heart syndrome Coarctation of the aorta Aortic stenosis Common LVOTO associations COA þ AS COA þ VSD COA þ ASD þ VSD RVOTO defectsa Pulmonary atresia Pulmonary valve stenosis Tricuspid atresia Common RVOTO associations PVS þ ASD PVS þ VSD Ebstein anomaly Septal defects VSD, perimembranous VSD, muscular VSD, OS Multiple VSDs ASD secundum or ASD NOS ASD secundum ASD NOS Common septal defect associations VSD þ ASD Single ventricle

Total

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FIG. 1. a: Isolated non-cardiac birth defects with highest and lowest sex ratio. Not all ratios presented are statistically significant. b: Isolated cardiac birth defects with highest and lowest sex ratio. AVSD, atrioventricular septal defect; CHD, congenital heart defect; VSD, ventricular septal defect. Not all ratios presented are statistically significant.

or hypoplasia, respectively. For the birth defect types with significant sex ratios within isolated and multiple defects strata, the sex ratio deviated in the same direction. Of the 13 specific isolated non-cardiac birth defects with sex ratios significantly different than 1.0, nine showed a male preponderance and four showed a female preponderance. The five isolated non-cardiac birth defects with the highest sex ratios were craniosynostosis, cleft lip with cleft palate, cleft lip without cleft palate, anorectal atresia/stenosis, and cerebellar hypoplasia and the five defects with the lowest sex ratios were choanal atresia, cloacal exstrophy, holoprosencephaly, colonic atresia/stenosis, and cleft palate only (Fig. 1a). Specific non-cardiac multiple birth defects with significantly elevated sex ratios included cleft lip without cleft palate, cleft lip with or without cleft palate, anorectal atresia/ stenosis, bilateral renal agenesis, and transverse limb deficiency (Table I). The only non-cardiac multiple birth defect with a significantly reduced sex ratio was cloacal exstrophy with a sex ratio of 0.13. The range of sex ratios for isolated CHDs was 0.41–2.88. The five specific isolated cardiac defects with the highest sex ratios include aortic stenosis, coarctation of the aorta, d-transposition of the great arteries, single ventricle, and hypoplastic left heart syndrome (Fig. 1b). Specific isolated cardiac birth defects with the highest female preponderance were atrio-ventricular septal defect (AVSD), tricuspid atresia, heterotaxia with CHD, truncus arteriosus, and multiple ventricular septal defects. Of the 13 isolated cardiac birth defects with significant sex ratios, 7 showed a male preponderance and 6 showed a female preponderance. Stratified estimates of the sex ratios of isolated birth defects by race/ethnicity are presented in Table II. Similar sex ratios were found for orofacial clefts among Hispanics and non-Hispanic Whites. A significant male preponderance was seen for Dandy– Walker malformation and hydrocephaly, with sex ratios of 2.38 and 2.65, respectively, among non-Hispanic Blacks but not among other race categories. The greatest sex ratio among Hispanics for non-cardiac defects was observed for longitudinal limb deficiency with a sex ratio of 2.56. Compared to other racial/ethnic groups, this

represented the highest sex ratio among isolated cases of longitudinal limb deficiency. Among CHD case groups, high sex ratios were seen in non-Hispanic Whites and Hispanics for the left ventricular outflow tract defects hypoplastic left heart syndrome, coarctation of the aorta and aortic stenosis. For all defect groups with significant sex ratios across more than one race/ethnicity group, the sex ratios varied in the same direction as the overall sex ratio in Table I.

DISCUSSION The male:female sex ratio was elevated for many birth defects indicating an overall male preponderance. For a small number of defects, the sex ratio was less than one and showed a strong female preponderance. This pattern also held true for most defect categories when stratified by isolated and multiple defect status; most anomaly subtypes had sex ratios greater than one. The defects with the strongest elevations of the sex ratio included craniosynostosis, bilateral renal agenesis or hypoplasia, aortic stenosis, and d-transposition of the great arteries. Due to the large population-based nature of the NBDPS, we were able to present sex ratios by race/ethnicity. Overall, sex ratios for non-Hispanic White cases were similar to those for Hispanic cases whereas sex ratios for non-Hispanic Whites and non-Hispanic Blacks differed more often. Notable differences included significant shifts toward male preponderance among non-Hispanic Black cases of isolated Dandy–Walker malformation and hydrocephaly, but a sex ratio closer to one for non-Hispanic Whites and Hispanics. For cleft lip with or without cleft palate the reverse was observed, a male preponderance in non-Hispanic Whites and Hispanics but not in non-Hispanic Blacks. Also, for longitudinal limb deficiency the sex ratio was highest among Hispanics. Due to small numbers, the results for Asian/Pacific-Islanders are extremely limited. Sufficient numbers and significant results were only found for two categories: neural tube defects and cleft lip with or without cleft palate. Differences in the sex ratios of certain birth defects by racial/ethnic group may reflect genetic susceptibility and/or environmental

Birth defect Non-cardiac birth defects Amniotic band sequence Neural tube defects Anencephaly and craniorachischisis Spina bifida Encephalocele Hydrocephaly Dandy–Walker malformation Holoprosencephaly Cataracts Anophthalmos/microphthalmos Glaucoma/anterior chamber defects Anotia/microtia Choanal atresia Oral clefts Cleft palate only Cleft lip w/wo cleft palate Cleft lip with cleft palate Cleft lip without cleft palate Esophageal atresia Small intestinal atresia/stenosis Duodenal atresia/stenosis Anorectal atresia/stenosis Cloacal exstrophy Biliary atresia Bladder exstrophy Bilateral renal agenesis or hypoplasia Limb deficiency Longitudinal limb deficiency Transverse limb deficiency Intercalary limb deficiency Craniosynostosis Diaphragmatic hernia Omphalocele Gastroschisis Congenital heart defects Conotruncal defects Truncus arteriosus Tetralogy of Fallot d-Transposition of the great arteries VSD conoventricular

Sex ratio (95% CI) (0.92, 2.02) (0.76, 1.03) (0.67, 1.20) (0.76, 1.09) (0.41, 1.11) (0.83, 1.50) (0.39, 1.53) (0.49, 1.64) (0.57, 1.11) (0.62, 1.83) (0.63, 1.68) (1.21, 2.53) (0.30, 0.91) (1.34, 1.64) (0.69, 0.95) (1.82, 2.32) (1.84, 2.50) (1.61, 2.31) (0.73, 1.33) (0.78, 1.50) (0.45, 1.26) (1.25, 2.23) (0.26, 1.35) (0.86, 2.21) (0.87, 3.27) (0.95, 2.82) (1.02, 1.51) (0.96, 1.96) (0.87, 1.39) (0.72, 4.11) (1.97, 2.70) (1.42, 2.27) (1.03, 2.14) (0.88, 1.26) (1.30, 1.73) (0.35, 1.11) (1.05, 1.55) (1.92, 3.11) (0.26, 1.27)

1.36 0.89 0.89 0.91 0.67 1.11 0.78 0.89 0.79 1.06 1.02 1.75 0.52 1.48 0.81 2.05 2.14 1.93 0.98 1.08 0.75 1.67 0.59 1.38 1.69 1.64 1.24 1.37 1.10 1.72 2.30 1.79 1.49 1.06 1.50 0.62 1.28 2.44 0.58

M/F 61/44 364/404 88/97 250/269 26/38 95/84 15/19 20/22 66/80 27/25 33/31 80/45 19/36 1285/849 322/389 963/460 579/265 384/195 87/87 77/70 26/34 129/76 9/15 42/30 24/14 35/21 244/193 74/53 155/139 14/8 588/251 206/113 74/49 278/259 547/359 19/30 251/193 241/97 10/17

Non-Hispanic White

97/61 1/5 66/38 20/5 2/5

21/23 60/65 11/16 41/36 8/13 29/11 19/8 4/11 17/17 10/8 13/13 3/7 6/0 94/103 29/47 65/56 46/32 19/24 8/5 21/35 10/7 23/12 1/4 8/15 1/2 5/3 38/31 13/14 22/16 3/3 24/14 24/15 20/10 46/36

M/F (0.50, 1.68) (0.64, 1.34) (0.32, 1.50) (0.72, 1.82) (0.25, 1.50) (1.31, 5.35) (1.03, 5.49) – (0.47, 1.86) – (0.43, 2.05) – – (0.67, 1.24) (0.38, 1.00) (0.80, 1.69) (0.90, 2.30) (0.43, 1.46) – (0.35, 1.05) – (0.95, 3.90) – (0.23, 1.27) – – (0.75, 2.01) (0.43, 2.00) (0.72, 2.66) – (0.88, 3.36) (0.83, 3.09) (0.93, 4.33) (0.82, 2.02) 1.60 (1.13, 2.25) – 1.74 (1.15, 2.64) 4.01 (1.50, 10.77) –

1.72 1.61 2.01 1.28

1.23 0.93 1.38

0.54

1.92

0.60

0.91 0.62 1.16 1.44 0.79

0.94

0.94

0.92 0.93 0.69 1.14 0.62 2.65 2.38

Sex ratio (95% CI)

Non-Hispanic Black

219/121 9/9 118/69 67/30 7/5

37/23 252/254 78/86 156/143 18/25 34/24 13/11 13/22 18/25 14/12 13/14 133/100 2/4 476/335 84/138 392/197 282/136 110/61 24/17 60/53 16/14 73/31 2/3 7/18 3/2 21/16 118/75 30/11 87/61 1/2 129/70 76/57 20/20 171/175

M/F (0.89, 2.55) (0.77, 1.13) (0.62, 1.17) (0.80, 1.30) (0.37, 1.24) (0.78, 2.25) (0.49, 2.48) (0.28, 1.11) (0.36, 1.23) (0.50, 2.38) (0.40, 1.84) (0.95, 1.64) – (1.13, 1.57) (0.43, 0.76) (1.55, 2.26) (1.56, 2.42) (1.22, 2.34) (0.71, 2.48) (0.73, 1.55) (0.52, 2.21) (1.44, 3.39) – (0.15, 0.88) – (0.64, 2.37) (1.09, 1.99) (1.28, 5.13) (0.95, 1.87) – (1.28, 2.34) (0.88, 1.78) (0.50, 1.75) (0.73, 1.15) 1.70 (1.34, 2.15) – 1.60 (1.18, 2.18) 2.09 (1.35, 3.25) –

1.73 1.25 0.94 0.92

1.23 1.48 2.56 1.34

0.36

1.33 0.57 1.87 1.95 1.69 1.32 1.06 1.07 2.21

1.51 0.93 0.85 1.02 0.68 1.33 1.11 0.55 0.67 1.09 0.86 1.25

Sex ratio (95% CI)

Hispanic

34/22 1/0 17/13 13/5 2/0

7/4 25/8 12/4 8/4 5/0 3/2 1/0 1/1 3/3 1/3 1/2 7/8 0/0 53/56 13/29 40/27 24/17 16/10 3/3 4/3 2/2 4/5 3/0 3/3 0/0 2/2 7/9 4/0 2/8 1/0 10/10 11/9 1/4 19/12

M/F

1.64 (0.92, 2.94) – 1.39 (0.65, 2.97) – –

– 3.32 (1.45, 7.61) – – – – – – – – – – – 0.99 (0.64, 1.54) 0.47 (0.24, 0.94) 1.55 (0.91, 2.67) 1.48 (0.76, 2.87) 1.68 (0.74, 3.82) – – – – – – – – – – – – 1.06 (0.43, 2.63) 1.30 (0.52, 3.23) – 1.68 (0.79, 3.59)

Sex ratio (95% CI)

Asian/Pacific Islander

TABLE II. Sex Ratio and Counts by Infant Sex for Isolated Birth Defects Stratified by Race/Ethnicity Among Singleton Births, National Birth Defects Prevention Study, 1997–2009*

1076 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

M/F 13/9 15/5 9/2 45/38 27/22 17/13 1/3 3/3 11/8 2/2 64/86 11/5 49/76 4/5 8/24 6/10 3/2 153/158 75/67 2/5 2/1 72/83 52/68 20/15 21/24 11/4

Sex ratio (95% CI) 0.64 (0.43, 0.94) 1.41 (0.99, 1.98) 1.46 (1.01, 2.13) 2.46 (2.10, 2.87) 2.10 (1.64, 2.67) 2.58 (1.99, 3.33) 3.11 (2.29, 4.23) (1.33, 4.43) (0.81, 1.63) (0.71, 2.58) (0.69, 0.97) (0.97, 2.40) (0.62, 0.89) (0.37, 1.68) (0.23, 0.57) (0.32, 0.91) (0.45, 1.30) (0.72, 0.93) (0.71, 1.03) (0.46, 1.06) (0.16, 0.92) (0.67, 0.93) (0.63, 0.90) (0.66, 1.37)

2.43 1.15 1.35 0.82 1.52 0.74 0.79 0.36 0.54 0.77 0.82 0.85 0.70 0.38 0.79 0.76 0.95 0.76 (0.59, 0.97) 1.79 (1.11, 2.86)

42/65 80/56 70/47 609/244 213/100 220/84 174/55 37/15 69/59 22/16 281/337 48/31 221/291 12/15 26/71 22/40 25/32 569/684 223/257 45/64 7/18 288/359 229/298 59/61 121/157 49/27

M/F

0.88 (0.48, 1.60) –

0.33 (0.15, 0.75) 0.60 (0.22, 1.67) – 0.97 (0.76, 1.25) 1.18 (0.83, 1.69) – – 0.87 (0.62, 1.22) 0.77 (0.52, 1.12) 1.34 (0.68, 2.64)

– – – 0.75 (0.53, 1.05) – 0.64 (0.44, 0.94) –

Sex ratio (95% CI) 1.45 (0.61, 3.42) 3.01 (1.09, 8.34) – 1.19 (0.76, 1.86) 1.23 (0.69, 2.19) 1.31 (0.63, 2.73) –

Non-Hispanic Black

TABLE II. (Continued )

71/93 21/10

11/20 11/15 10/8 272/309 84/93 7/13 7/10 178/200 114/140 64/60

11/7 28/19 7/6 75/94 21/9 47/75 7/10

M/F 4/5 47/24 43/22 157/64 66/32 68/21 22/11

0.72 (0.52, 0.99) 1.97 (0.92, 4.20)

0.52 (0.25, 1.08) 0.69 (0.31, 1.50) – 0.83 (0.69, 0.99) 0.86 (0.63, 1.18) 0.64 (0.24, 1.71) – 0.83 (0.67, 1.04) 0.76 (0.59, 0.99) 1.00 (0.70, 1.44)

– 1.38 (0.77, 2.49) – 0.75 (0.55, 1.02) 2.19 (1.00, 4.80) 0.59 (0.40, 0.85) –

Sex ratio (95% CI) – 1.84 (1.12, 3.02) 1.83 (1.09, 3.08) 2.30 (1.70, 3.11) 1.93 (1.26, 2.97) 3.04 (1.85, 4.99) 1.88 (0.91, 3.89)

Hispanic

7/8 2/0

3/2 1/0 2/0 35/26 18/8 2/1 0/0 13/15 7/13 6/2

1/0 2/4 1/0 8/11 2/3 6/8 0/0

M/F 2/2 5/4 4/4 13/7 3/3 5/3 4/1

– –

– – – 1.43 (0.82, 2.50) 2.10 (0.87, 5.04) – – 0.92 (0.42, 2.00) – –

– – – – – – –

Sex ratio (95% CI) – – – 1.97 (0.77, 5.09) – – –

Asian/Pacific Islander

AS, aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; CHD, congenital heart defect; CI, confidence interval; COA, coarctation of the aorta; DORV, double outlet right ventricle; LVOTO, left ventricular outflow tract obstruction; NOS, not otherwise specified; OS, other specified; PAPVR, partial anomalous pulmonary venous return; PVS, pulmonary valve stenosis; RVOTO, right ventricular outflow tract obstruction; TAPVR, total anomalous pulmonary venous return; TGA, transposition of the great arteries; VSD, ventricular septal defect. ’–’, not calculated (less than 20 cases total). * *Sex ratios were calculated as odds ratios using NBDPS controls: (Non-Hispanic White: M ¼ 2880, F ¼ 2833; Control counts differed for the following defects: cleft palate M ¼ 2827, F ¼ 2772; VSD conoventricular, VSD OS, Multiple VSDs M ¼ 1977 F ¼ 1947; VSD muscular M ¼ 238 F ¼ 232; PVS M ¼ 2810 F ¼ 2740) (Non-Hispanic Black: M ¼ 546, F ¼ 548; Control counts differed for the following defects: VSD conoventricular, VSD OS, Multiple VSDs M ¼ 371 F ¼ 392; VSD muscular M ¼ 32 F ¼ 47; PVS M ¼ 539 F ¼ 539) (Hispanic: M ¼ 1223, F ¼ 1147; Control counts differed for the following defects: cleft palate M ¼ 1217, F ¼ 1142; VSD conoventricular, VSD OS, Multiple VSDs M ¼ 102 F ¼ 95; VSD muscular M ¼ 10 F ¼ 10; PVS M ¼ 126 F ¼ 139) (Asian/Pacific Islander: M ¼ 142, F ¼ 151; Control counts differed for the following defects: cleft palate M ¼ 141, F ¼ 148; VSD conoventricular, VSD OS, Multiple VSDs M ¼ 102 F ¼ 95; VSD muscular M ¼ 10 F ¼ 10; PVS M ¼ 126 F ¼ 139) Includes only birth defect groups with a minimum of 20 cases. a aEbsteins anomaly is not included in the RVOTO category. Statistically significant results are printed in bold.

Birth defect AVSD APVR TAPVR LVOTO defects Hypoplastic left heart syndrome Coarctation of the aorta Aortic stenosis Common LVOTO associations COA þ AS COA þ VSD COA þ ASD þ VSD RVOTO defectsa Pulmonary atresia Pulmonary valve stenosis Tricuspid atresia Common RVOTO associations PVS þ ASD PVS þ VSD Ebstein anomaly Septal defects VSD, perimembranous VSD, muscular Multiple VSDs ASD secundum or ASD NOS ASD secundum ASD NOS Common septal defect associations VSD þ ASD Single ventricle

Non-Hispanic White

MICHALSKI ET AL. 1077

1078 exposures. These birth defects should be studied for genetic variation and exposures associated with race/ethnicity that may provide clues to etiology. An interesting observation with respect to clinical classification was found for cloacal exstrophy and bladder exstrophy. These defects have been studied to determine whether they should be considered as part of a spectrum. Caton et al. [2007] showed that cloacal exstrophy and bladder exstrophy are associated with female and male sex, respectively suggesting that they should not be combined in clinical classifications. The results of Caton et al. were supported in our study and exemplify the usefulness of examining sex differences when evaluating birth defect groupings.

Comparison With Other Studies Sex differences among cases of a variety of specific birth defects have been addressed previously in several population-based studies of congenital anomalies [Lary and Paulozzi, 2001; Shaw et al., 2003; Rittler et al., 2004; Lisi et al., 2005; Tennant et al., 2011; Sokal et al., 2014]. In Table III, we present odds ratios from the present study and relative risk estimates from the other studies for birth defect categories for which our case definition is similar. Comparison of our study results to other studies is imperfect due to differences in methods and presentation of results, but can provide some useful comparisons. To facilitate evaluation among studies, we also compared sex ratio calculated as an odds ratio (using control infants) with a relative risk calculated using population denominators and found them to be consistently equivalent. A table comparing the two methods can be found in the supplemental material at [wileyonlinelibrary.com/journal/ajmg]. Both of these methods, odds ratios, and relative risk based on prevalence, remove the influence of an underlying male excess in the population. The first population-based study of sex differences in birth defects was conducted by Lary and Paulozzi [2001] using registry data from Metropolitan Atlanta Congenital Defects Program. The methods used are similar to that of the NBDPS and include active surveillance to collect case information and a review of the records by clinicians to confirm accurate coding. They included cases diagnosed up to age 6 (years) while our study used cases diagnosed before the interview deadline of within 24 months after expected due date. Although many of the birth defect categories included do not overlap with the present study, similar results for sex ratio were found for hydrocephalus, diaphragmatic hernia, renal agenesis, and craniosynostosis. Shaw et al. [2003] conducted a descriptive analysis of sex differences among infants with congenital anomalies born in California from 1989 to 1997 and found males to have an overall prevalence of birth defects 28.6% greater than females in their sample. Their unadjusted results presented in Table III are closer to one compared to some of the results shown here. Similar results for sex ratio were found for small intestinal atresia, Ebstein anomaly, atrioventricular septal defect, and cataracts. An opposite sex ratio was found for bladder exstrophy based on a small number of cases. Lisi et al. [2005] conducted a population-based study of infant sex and birth defects using a large sample of births from 24 geographically diverse countries over a period of 30 years. Male proportion and sex ratio were analyzed overall and by contributing registry as well as by isolated versus multiple birth defect status. The study

AMERICAN JOURNAL OF MEDICAL GENETICS PART A found similar results compared to ours with respect to male or female preponderance for the included defects in common. Lisi et al. [2005] presented results comparing the percentage of male cases for isolated and multiple birth defects as well as syndromes. Although not a focus of their study, Lisi et al. [2005] discussed some differences in male proportion by race, specifically of hydrocephaly among blacks in South Africa and Latin America. Our observation of a greater preponderance of male sex among non-Hispanic Black cases of hydrocephaly corroborated their finding. Rittler et al. [2004] conducted a hospital based study of sex ratio and birth defects that focused on sex differences in the associations between birth defects and a variety of characteristics, including race/ethnicity. More than half of the birth defects Rittler et al. [2004] assessed were not included in the NBDPS, which limits the comparability of results to gastroschisis, neural tube defects, hydrocephaly, ventricular septal defects, orofacial clefts, limb deficiencies, and diaphragmatic hernia. Although no categories differed in an opposite direction and the sex differences were smaller for some case groups, we observed similar sex ratios for gastroschisis, hydrocephalus, and limb deficiency. Two racial/ethnic characteristics (black ancestry, native ancestry) were included in Rittler et al. [2004] study as covariates in an unconditional logistic regression analysis. Results for this analysis were not significant and were therefore not reported. A more recent study by Tennant et al. [2011] examined sex differences in congenital anomalies among births occurring in the United Kingdom during 1985–2003. The study included a very large number of defects; yet the overall study population was considerably smaller than the aforementioned studies yielding small counts for the individual defect groups. Their ascertainment and classification were different from our methods (e.g., birth defect cases diagnosed up to age 12). Multiple congenital anomalies were reported as a single overall grouping rather than by each individual defect. The sex ratios reported by Tennant et al. [2011] were similar to those reported here for orofacial clefts, neural tube defects, holoprosencephaly, and diaphragmatic hernia; for heart defects there were more differences in results. The most recent study of sex ratio among infants with congenital anomalies also came from a study population in the United Kingdom. Sokal et al. [2014] conducted a population-based study using data collected from an electronic database of primary care health records and included infants born between 1990 and 2009. Sex-specific prevalences and prevalence ratios were calculated for a large number of birth defects. Multiple congenital anomalies were reported as a single grouping as was done in the other studies discussed above. Notable differences exist in study results for common truncus (truncus arteriosus) and bladder exstrophy, with large male excesses observed by Sokal et al. [2014] and for choanal atresia for which their prevalence ratio was closer to the null. The other cardiac defects in common have more similar results. We recognize that the schema of case classification may have varied greatly between the included studies for some birth defect subtypes and may have contributed to some of the differences observed. Although the degree of skewness varied somewhat, sex ratios were consistently skewed in the same direction for birth defect case groups with the highest sex ratios in our study that were also represented in the other studies. Results were less consistent

Sokal et al. (2014) 0.77 – 0.65 0.83 1.31 – 0.47 0.98 1.13 4.73 2.14 – 0.97 0.73 0.86 1.13 – 2.12 2.76 1.49 0.50 – 0.91 1.63 – – 0.86 1.40 – 3.70 1.77 1.36 0.82 0.97 6.62 –

Current Study (NBDPS)b 0.93 0.91 0.74 0.98 1.28 1.23 0.64 0.80 1.08 0.63 2.34 2.00 0.93 0.82 0.70 1.42 0.67 2.88 1.89 2.51 0.88 0.70 0.45 1.92 1.78 2.01 0.71 1.08 0.94 2.12 1.55 1.31 0.99 1.28 1.52 1.52

1.22 5.92

1.77 1.51 0.97 0.93 1.11

1.37

0.71 1.81 1.73 1.87 0.75

1.82 2.01 2.84 0.95 0.61 0.74 1.28 0.65 2.50 1.45 1.68 1.08 0.80

0.95 1.70

0.84 0.86 0.75 0.83 1.32 – 0.61

Tennant et al. (2011)

– 1.92

– 1.34 1.22 0.97 1.17

1.30 0.92

0.79 1.67 – – 0.73

– 1.91 – – – – 1.20 – – 1.60 1.31 – –

– –

– 0.57 0.72 0.85 1.23 – 0.61

Lisi et al. (2005)c

c

b

– –

– 1.12 – 0.90 1.10

– –

– 1.29 1.39 1.25 0.57

– – – 0.87 – – – – – – – – –

– –

0.66 0.70 0.61 0.72 1.34 – –

Rittler et al. (2004)

aVentricular septal defect estimate includes only perimembranous ventricular septal defects. Atrial septal defect (ASD) estimate includes secundum ASD and ASD, NOS. bCalculated as an odds ratio using isolated cases only. cDenominator data were not reported, risk ratios were calculated using the reported sex ratio of 1.06 in the source population. d dEstimates were calculated using reported case counts and population denominators. e eThis estimate is based on pulmonary valve stenosisfor Tennant et al. and our study; estimates for the other studies may include other pulmonary valve anomalies.

a

Defect Central nervous system Neural tube defects Anencephaly Encephalocele Spina bifida Hydrocephalus Dandy-Walker malformation Arhinencephaly/holoprosencephaly Eye Cataracts Anophthalmous/microphthalmos Cardiovascular system Truncus arteriosus d-Transposition of the great arteries Single ventricle Ventricular septal defecta Atrial septal defecta Atrioventricular septal defect Tetralogy of Fallot Tricuspid atresia/stenosis Aortic valve atresia/stenosis Hypoplastic left heart syndrome Coarctation of the aorta Ebstein anomaly Pulmonary valvee Orofacial Choanal atresia Cleft lip with or without cleft palate Cleft lip Cleft lip and palate Cleft palate Digestive system Esophageal atresia Small intestinal atresia/stenosis Musculoskeletal Craniosynostosis Diaphragmatic hernia Omphalocele Gastroschisis Limb deficiency Genito–Urinary system Bladder extrophy and/or epispadia Bilateral renal agenesis or hypoplasia 0.48 1.00

– – – – 1.08

0.92 0.95

0.91 1.27 1.14 1.34 0.67

0.99 1.61 1.32 0.89 1.00 0.67 1.08 1.10 1.22 1.23 1.29 0.91 1.01

0.86 0.62

0.59 0.83 0.72 1.02 – –

Shaw et al. (2003)d

– 1.74

2.04 1.48 – – –

1.62 –

– – – 1.41 –

– 1.38 – – 0.68 – – 1.16 1.51 1.34 – – –

– –

– 0.48 – 0.77 1.27 0.53 –

Lary and Paulozzi (2001)

TABLE III. Comparison of Sex Ratio (M:F) among Specific Birth Defect Subtypes in the National Birth Defects Prevention Study and Six Other Population Bases Studies

MICHALSKI ET AL. 1079

1080 comparing the lowest sex ratios observed in our study with the results of the other included studies. We observed a male excess for certain CHDs, including coarctation of the aorta, aortic valve stenosis, and d-transposition of the great arteries; however, our estimates were further from the null. Our estimate for isolated truncus arteriosus (also called common truncus or common arterial trunk) differed greatly from the estimates calculated by Tennant et al. [2011] and Sokal et al. [2014]. The estimate of Sokal et al. [2014] was based on an exceptionally small number of cases; however, we have no explanation for the difference observed between studies. The sex ratios for neural tube defects also differ between our results and the other studies. In the NBDPS they are much closer to the null whereas estimates from Shaw et al. [2003], Rittler et al. [2004], and Lary and Paulozzi [2001] show more of a female excess. Lisi et al. [2005] argue that the prevalence may differ geographically due to areas with a history of higher prevalence of neural tube defects as well as areas where selective terminations are more common. Another possible explanation of the differences in the sex ratio of neural tube defects could be due to the inclusion of cases (in the NBDPS) from birth years mostly after the United States began supplementing enriched cereals and grains with folic acid in 1998 [Green, 2002]. Some of the other studies include cases born in earlier years, prior to most efforts to recommend folic acid as a prenatal supplement and fortification of food supplies as means to prevent neural tube defects [Botto et al., 2005; Parker et al., 2014]. Folic acid supplementation is not only important for prevention but it may be tied to the sex ratio of neural tube defects. Recent studies have suggested that since methylation of the inactive X chromosome occurs in female embryos, female embryos have a greater need for the methyl groups provided by folic acid supplementation and are more affected by inadequate sources of methyl groups [Evans, 2012; Juriloff and Harris, 2012].

Strengths and Limitations Our large population-based study allowed us to estimate sex ratios for more than 50 types of birth defects and to present results according to whether the case was isolated or had multiple birth defects and by racial/ethnic group. Other strengths were the detailed and systematic case classification and review by clinical geneticists. A limitation of our study was that our estimates were based on interviewed cases versus all eligible cases; however we were able to compare the percentages of males and females among the interviewed cases and controls with the percentages of non-interviewed cases and controls (see Methods). We found little difference in the sex distribution between the interviewed and non-interviewed cases and controls overall, although differences for specific phenotypes cannot be ruled out. Terminated pregnancies were under-ascertained in our study which could bias our findings if the sex ratio of terminated cases is very different from that among liveborn cases. In addition, some of the sex differences we observed may have been due to chance especially in categories and strata with small numbers. The male:female sex ratio in human populations has been widely studied and shown to be related to many factors including disease, stress, environmental exposures, maternal nutrition, and hormonal influences [James, 1996; Davis et al., 1998; Nicolich et al., 2000;

AMERICAN JOURNAL OF MEDICAL GENETICS PART A Catalano et al., 2006; Bado-Singh et al., 2011; James, 2012; Rosenfeld, 2012]. The “sexome,” the interaction of all sex-linked factors relating to the creation of sex differences in observed phenotypes, may be important to understanding observed sex differences [Arnold and Lusis, 2012]. These factors may increase the risk of certain birth defects differentially by sex and may also reduce the survivability of the malformed fetus resulting in a skewed sex ratio. The sex differences observed here between birth defect subtypes, by race/ethnicity, combined with the knowledge of current hypotheses on sex ratio, may be useful in developing hypotheses about etiologic mechanisms for certain birth defects. In addition, similarities and differences between birth defect subtypes and by isolated/multiple defect status may be useful in guiding analytic grouping strategies in future studies of birth defect etiology.

ACKNOWLEDGMENTS This study was supported by a cooperative agreement from the Centers for Disease Control and Prevention, Centers of Excellence Award No. U01/DD00048702. We thank all the scientists and staff of National Birth Defects Prevention Study and the families who participated in the study. We thank the California Department of Public Health Maternal Child and Adolescent Health Division for providing data. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the California Department of Public Health.

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