Maternal Periconceptional Exposure Research Articles

Association between maternal peri-conceptional exposures and risk of hypospadias and cryptorchidism in offspring

Objective: To investigate the relationship between maternal exposures to peri-conceptional risk factors and the risk of hypospadias and cryptorchidism in offspring. Methods: Pregnant women who delivered male newborns and participated in the China birth cohort study between February 2018 and December 2020 at the research center of Beijing Obstetrics and Gynecology Hospital, Capital Medical University were selected for the study. All were enrolled at 6-13+6 weeks of their gestation. Baseline risk factor information was collected by questionnaire survey. Information on the outcome of hypospadias and cryptorchidism was obtained by clinical examination at birth and ultrasonography. Logistic regression was used to analyze the Odds Ratio (OR) and 95% Confidence Interval (95%CI) of each factor with respect to the onset of the outcome. Results: A total of 15, 833 pregnant women with an average age of (31.81±3.84) years were included. Among their offsprings, 113 were diagnosed as hypospadias or cryptorchidism (42 hypospadias, 69 cryptorchidism, and 2 both hypospadias and crypterchidism), with an incidence of 7.14‰. The results of multivariate logistic regression analysis showed that mothers with pregnancy history of birth defects (OR=3.01, 95%CI: 1.09-8.35), with preconception Hepatitis B infection (OR=4.74, 95%CI: 1.10-20.42), fetal growth restriction (OR=4.02, 95%CI: 2.10-7.68), multivitamin use since preconception (OR=1.98, 95%CI: 1.12-3.52), and never cook and eat at home (OR=2.17, 95%CI: 1.23-3.82) were risk factors for hypospadias and cryptorchidism (all P<0.05). Conclusions: Obesity in early pregnancy, preconception Hepatitis B infection, pregnancy history of birth defects, fetal growth restriction, multivitamin use before pregnancy, and rarely cook and eat at home were associated with an increased risk of hypospadias or cryptorchidism in their offsprings.

A Comprehensive Investigation on Potential Risk Factors for NSCL/P in a Rural District of Hebei Province, China.

Non syndromic cleft lip with or without palate (NSCL/P), one of the most common birth defects, is closely related to various risk factors. However, information regarding risk factors for NSCL/P in rural districts in China is very limited thus far. The objective of this study was designed to identify the potential risk factors for NSCL/P in rural districts. A comprehensive retrospective investigation including 435 NSCL/P patients and 402 healthy children was carried out in Hebei Province, China. Multiple logistic regression analysis and transmission disequilibrium test (TDT) were respectively used to identify non-genetic and genetic risk factors for NSCL/P, and then PLINK was used to explore the relationship between non-genetic and genetic risk factors. The results showed that maternal periconceptional exposure to pesticides and herbicides, as well as low parental education level were involved in the increased risk of NSCL/P, whereas maternal folic acid and multivitamin supplementation use during preconception period were associated with the reduced risk of NSCL/P. TDT analysis identified 2 single nucleotide polymorphisms (SNPs) (rs7078160 and rs4752028) in VAX1 and one SNP (rs17563) in BMP4 as the genetic risk factors for NSCL/P. Further analysis showed that the genetic risk factors were closely related with the negative non-genetic risk factors. Our study identified the potential risk factors for NSCL/P in rural districts, thus providing a theoretical basis for the prevention of NSCL/P occurrence.

Levels of uranium and thorium in maternal scalp hair and risk of orofacial clefts in offspring

Uranium and thorium are common radioactive elements that exist in the environment. However, few environmental epidemiological studies have focused on their possible effects on congenital malformations. Here, we explored the association between uranium and thorium concentrations in maternal scalp hair grown from 3 months before to 3 months after conception, namely during the periconceptional period and the risk of orofacial clefts (OFCs) in offspring. Our study included 153 women whose pregnancies were affected by OFCs (cases) and 601 women who delivered infants without birth defects (controls) from four provinces in China. Face-to-face interviews were used to collect sociodemographic characteristics with a structured questionnaire. Concentrations of uranium and thorium in maternal scalp hair grown during the periconceptional period were detected using inductively coupled plasma-mass spectrometry. The risk of OFCs in association with higher concentrations of the two radioactive elements was estimated using odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for potential confounding factors. The levels of uranium and thorium in maternal hair were in agreement with the published literature. After adjusting for several confounders, the ORs of thorium in the highest, upper, and lower quartile versus the lowest quartile were 2.63 (95% CI, 1.41–4.92), 1.98 (95% CI, 1.03–3.79), and 2.73 (95% CI, 1.46–5.12), respectively. No association was found between levels of uranium and the risk of OFCs. Maternal periconceptional exposure to thorium may be a risk factor for OFCs in offspring.

T198. A SCHIZOPHRENIA-LIKE BIRTH SEASONALITY AMONG MATHEMATICIANS AND AN OPPOSITE SEASONALITY AMONG BIOLOGISTS: MORE EVIDENCE IMPLICATING BIMODAL RHYTHMS OF GENERAL BIRTHS

BackgroundBased on early-20th century births, a pre-electric illumination time of comparatively normal human exposure to sunlight, studies of schizophrenia (SCZ) found a birth seasonality with two opposite effects: a SCZ-liability peak among subjects born around late-February and an equally significant SCZ-resistance peak among those born six months later, around late-August. We previously investigated this rhythm in connection with a sunlight-dependent bimodal rhythm of general births that, prior to the full advent of electric lighting (but not later), occurred ubiquitously in non-equatorial parts of the world. We found that the SCZ-liability peak coincided with a first, Feb-Mar peak of general-population births (the GP1) while the SCZ-resistance peak coincided with a second, Aug-Sep peak of those births (the GP2). Moreover, in a study of hand and visual-field preferences among professional baseball players, we found the SCZ-liability, GP1-coincident seasonality among players with preferences denoting cerebral asymmetry “deficits” (CADs) and the SCZ-resistance, GP2-coincident seasonality among those with preferences denoting cerebral asymmetry “excesses.” Also, in a study suggested by associations of CADs with artistic abilities, we found the SCZ-liability, GP1-coincident seasonality among groups representing visual, performing and literary art “creators” (VPL-Artists) and the SCZ-resistance, GP2-coincident seasonality among groups representing art critics, historians, curators and other art “observers” (Para-Artists). Together, these findings suggested, as one possibility (but see later), that the SCZ-liability, CAD effects and artistic abilities could all three represent traits genetically or otherwise selected into the GP1 excess population of newborns and out of the GP2 population. The present study of “scientists” was initially aimed at the purported arts/science antithesis.MethodsBirth seasonalities were examined among early-20th century born American scientists and among yet earlier European biologists and mathematicians.ResultsA group representing 1,925 American scientists showed the SCZ-resistance, GP2-coincident seasonality. However, this effect proved to be mostly due to biologists because biochemists, chemists, and physicists showed gradually less seasonality while mathematicians suggested an altogether artist-like, GP1-coincident seasonality. This intimation of a biologist-mathematician antithesis was pursued with an investigation of most major figures in the history of the two sciences from the 15th to the early-20th century. The two groups, numbering 576 mathematicians and 787 biologists, shared the same mean decade of birth, the 1780s, and essentially the same geographic origin in Western Europe. The mathematicians showed a very significant SCZ liability-like, GP1-coincident seasonality while the biologists showed an even more significant SCZ resistance-like, GP2-coincident seasonality. The latter effect was particularly strong among naturalists, anatomists and other groups representing biological “observationalism” as opposed to “experimentalism.”DiscussionThe findings are discussed in light of a) new evidence that the annual photoperiod is indeed alone responsible for both peaks of general births, with the GP1 and the GP2 being caused by maternal periconceptional exposure to, respectively, the summer-solstice sunlight maximum and the winter-solstice minimum, and b) an approach/withdrawal theory of lateralization of basic emotions where the left cerebral cortex would handle external stimuli eliciting complacent emotions towards external realities while the right cortex would handle internal stimuli eliciting disdain for those realities.

Evaluating LINE-1 methylation in cleft lip tissues and its association with early pregnancy exposures.

To pilot investigation of methylation of long interspersed nucleotide element-1 in lip tissues from infants with nonsyndromic cleft lip, and its association with maternal periconceptional exposures. The lateral and medial sides of the cleft lips of 23 affected infants were analyzed for long interspersed nucleotide element-1 methylation by bisulfite conversion and pyrosequencing. The medial side showed 1.8% higher methylation compared with the lateral side; p=0.031, particularly in male infants (2.7% difference; p=0.011) or when the mothers did not take folic acid during periconceptional period (2.4% difference; p=0.011). These results were not statistically significant when Bonferroni adjustment was used. The observed differences in DNA methylation, although nonsignificant after correction for multiple comparisons, suggest that differential regulation of the two sides may impact lip fusion and warrant larger-scale replication.

A Functional Aryl Hydrocarbon Receptor Genetic Variant, Alone and in Combination with Parental Exposure, is a Risk Factor for Congenital Heart Disease.

Recent experimental studies showed that ablation of the aryl hydrocarbon receptor (AhR) as well as its activation by exogenous ligands disrupt the molecular networks involved in heart formation and function, leading to congenital heart disease (CHD). However, no evidence is available about the role of AhR in humans. We assessed the prevalence of a functional AhR genetic variant (p.Arg554Lys) in CHD patients as well as its joint effects with parental exposure. A total of 128 CHD patients (76 males; age 6.2±6.7years) and 274 controls (160 males; age at birth) were genotyped for the AhR polymorphism by using the TaqMan® Drug Metabolism Genotyping assay. Both case and control parents completed a structured questionnaire on demographic, lifestyle and preconception exposures. Genotype (p=0.001) and allele (p<0.0001) distributions of AhR p.Arg554Lys differed significantly between patients and controls. A significant elevated CHD risk was found under dominant (OR=2.9, 95% CI 1.9-4.6, p<0.0001) and additive genetic models (OR=6.2, 95% CI 2-19, p=0.001). There was a significant interaction between 554-Lys allele and paternal smoking exposure (ORsmoking=1.6, 95% CI=0.9-2.9; ORallele=2.6, 95% CI=1.3-5; ORinteraction=4.9, 95% CI=2.4-9.9, p interaction<0.0001). Additionally, 554-Lys allele exacerbated the effect of maternal periconceptional exposure (ORexposure=1.6, 95% CI=0.8-3; ORallele=2.6, 95% CI=1.5-4.5; ORinteraction=5.7; 95% CI=2.6-12, p interaction<0.0001). Our findings showed that the AhR p.Arg554Lys polymorphism, alone and in combination with parental exposures, is associated with the CHD risk, highlighting the significant role of AhR in the cardiovascular development.

Associations between maternal periconceptional exposure to secondhand tobacco smoke and major birth defects

While associations between secondhand smoke and a few birth defects (namely, oral clefts and neural tube defects) have been noted in the scientific literature, to our knowledge, there is no single or comprehensive source of population-based information on its associations with a range of birth defects among nonsmoking mothers. We utilized data from the National Birth Defects Prevention Study, a large population-based multisite case-control study, to examine associations between maternal reports of periconceptional exposure to secondhand smoke in the household or workplace/school and major birth defects. The multisite National Birth Defects Prevention Study is the largest case-control study of birth defects to date in the United States. We selected cases from birth defect groups having >100 total cases, as well as all nonmalformed controls (10,200), from delivery years 1997 through 2009; 44 birth defects were examined. After excluding cases and controls from multiple births and whose mothers reported active smoking or pregestational diabetes, we analyzed data on periconceptional secondhand smoke exposure-encompassing the period 1 month prior to conception through the first trimester. For the birth defect craniosynostosis, we additionally examined the effect of exposure in the second and third trimesters as well due to the potential sensitivity to teratogens for this defect throughout pregnancy. Covariates included in all final models of birth defects with ≥5 exposed mothers were study site, previous live births, time between estimated date of delivery and interview date, maternal age at estimated date of delivery, race/ethnicity, education, body mass index, nativity, household income divided by number of people supported by this income, periconceptional alcohol consumption, and folic acid supplementation. For each birth defect examined, we used logistic regression analyses to estimate both crude and adjusted odds ratios and 95% confidence intervals for both isolated and total case groups for various sources of exposure (household only; workplace/school only; household and workplace/school; household or workplace/school). The prevalence of secondhand smoke exposure only across all sources ranged from 12.9-27.8% for cases and 14.5-15.8% for controls. The adjusted odds ratios for any vs no secondhand smoke exposure in the household or workplace/school and isolated birth defects were significantly elevated for neural tube defects (anencephaly: adjusted odds ratio, 1.66; 95% confidence interval, 1.22-2.25; and spina bifida: adjusted odds ratio, 1.49; 95% confidence interval, 1.20-1.86); orofacial clefts (cleft lip without cleft palate: adjusted odds ratio, 1.41; 95% confidence interval, 1.10-1.81; cleft lip with or without cleft palate: adjusted odds ratio, 1.24; 95% confidence interval, 1.05-1.46; cleft palate alone: adjusted odds ratio, 1.31; 95% confidence interval, 1.06-1.63); bilateral renal agenesis (adjusted odds ratio, 1.99; 95% confidence interval, 1.05-3.75); amniotic band syndrome-limb body wall complex (adjusted odds ratio, 1.66; 95% confidence interval, 1.10-2.51); and atrial septal defects, secundum (adjusted odds ratio, 1.37; 95% confidence interval, 1.09-1.72). There were no significant inverse associations observed. Additional studies replicating the findings are needed to better understand the moderate positive associations observed between periconceptional secondhand smoke and several birth defects in this analysis. Increased odds ratios resulting from chance (eg, multiple comparisons) or recall bias cannot be ruled out.

Maternal exposure to methotrexate and birth defects: a population-based study.

Methotrexate is an anti-folate medication that is associated with increased risk of multiple birth defects. Using data from the National Birth Defects Prevention Study, a case-control study of major birth defects in the United States, we examined mothers exposed to methotrexate. The study population included mothers of live-born infants without major birth defects (controls) and mothers of fetuses or infants with a major birth defect (cases), with expected dates of delivery between October 1997 and December 2009. Mothers of cases and controls were asked detailed questions concerning pregnancy history, demographic information, and exposures in a telephone interview. Approximately 0.06% (n = 16/27,623) of case and 0.04% (n = 4/10,113) of control mothers reported exposure to methotrexate between 3 months prior to conception through the end of pregnancy. Of the 16 case infants, 11 (68.8%) had a congenital heart defect (CHD). The observed CHDs included atrial septal defects, tetralogy of Fallot, valvar pulmonary stenosis, ventricular septal defects (VSDs), and total anomalous pulmonary venous return. One case infant had microtia in addition to a VSD and another had VACTER association. Exposed cases without a CHD had one of the following birth defects: cleft palate, hypospadias, congenital diaphragmatic hernia, or craniosynostosis. Based on a limited number of methotrexate-exposed mothers, our findings support recent case reports suggesting an association between early pregnancy exposure to methotrexate and CHDs. Because of the rarity of maternal periconceptional exposure to methotrexate, long-term, population-based case-control studies are needed to confirm these findings and better evaluate the association between methotrexate and birth defects.

Increased Risk for Congenital Heart Defects in Children Carrying the ABCB1 Gene C3435T Polymorphism and Maternal Periconceptional Toxicants Exposure

BackgroundsThe etiology of congenital heart defect (CHD) is commonly believed to involve the interaction of multiple environmental and genetic factors. This study aimed to explore the joint effects of the ABCB1 gene C3435T polymorphism and maternal periconceptional toxicants exposure on the CHD risk in a Han Chinese population.MethodsAn age and gender matched case-control study with standardized data collection involving 201 pairs was conducted. Periconceptional toxicants exposure was obtained through a structured questionnaire. A job exposure matrix (JEM) was used for toxicants exposure assessment. Genotyping of the ABCB1 C3435T polymorphism was performed by sequencing. Logistic regression analysis was performed to assess the joint effects of the ABCB1 gene C3435T polymorphism and toxicants exposure on the risk of CHD. Placenta tissues and umbilical cords were collected to investigate the impact of C3435T polymorphism on the transcription and translation activities of ABCB1 gene.ResultsMaternal periconceptional exposures to phthalates (adjusted OR: 1.6; 95%CI: 1.0–2.6) and alkylphenolic compounds (adjusted OR:1.8; 95%CI:1.1–3.0) were associated with a higher incidence of CHDs in general. More cases were carriers of the ABCB1 CC/CT genotypes (OR: 2.0, 95%CI: 1.1–3.5, P-value: 0.021). Children carrying the CC/CT genotype and periconceptionally exposed to phthalates and alkylphenolic compounds suffered almost 3.5-fold increased risk of having CHD than non-exposed children with TT genotype (adjusted OR: 3.5, 95%CI: 1.5–7.9, P-value: 0.003), and the OR changed to 4.4 for septal defects (adjusted OR: 4.4,95%CI:1.8–10.9,P-value:0.001). The ABCB1 mRNA expression of the TT genotype was significantly higher than that of the CC genotype (P = 0.03). Compared with TT genotype, lower P-glycoprotein expression was observed for the CC/CT genotypes.ConclusionThe C3435T polymorphism in the ABCB1 gene of fetus increases the risks of CHD in a Han Chinese population when the mothers are exposed to phthalates and alkylphenolic compounds during the periconceptional period, particularly for septal defects.

Folic acid supplementation use and the MTHFR C677T polymorphism in orofacial clefts etiology: An individual participant data pooled‐analysis

This study examines gene-environment interaction between the MTHFR C667T polymorphism and folic acid in the etiology of orofacial clefts (OFC). We used a pooled-analytical approach on four studies that used similar methods. We used logistic regression to analyze the pooled sample of 1149 isolated cases and 1161 controls. Fetal and maternal MTHFR C677T genotypes, and maternal periconceptional exposure to smoking, alcohol, vitamin containing folic acid and folic acid supplements were contrasted between the cleft types [non-syndromic clefts lip or without cleft palate (CL(P)) and non-syndromic cleft palate (CP)] and control groups. There was a reduced risk of CL(P) with maternal folic acid use (p = 0.008; OR = 0.70, 95% CI: 0.65-0.94) and with supplements containing folic acid (p = 0.028, OR = 0.80, 95% CI: 0.65-0.94). Maternal smoking increased the risk of both CL(P) (p < 10 e-3; OR = 1.62, 95% CI: 1.35-1.95) and CP (p = 0.028; OR = 1.38, 95% CI: 1.04-1.83). No significant risk was observed with either maternal or fetal MTHFR C677T genotypes. This individual participant data (IPD) meta-analysis affords greater statistical power and can help alleviate the problems associated with aggregate-level data-sharing. The result of this IPD meta-analysis is consistent with previous reports suggesting that folic acid and smoking influence OFC outcomes.

Maternal periconceptional exposure to cigarette smoking and alcohol consumption and congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a major birth defect that occurs when abdominal organs herniate through a diaphragmatic opening into the thoracic cavity and is associated with high mortality (>50%). The etiology of CDH is not well understood. Using data from the National Birth Defects Prevention Study, we examined associations between CDH and maternal periconceptional exposure (1 month before through the third month of pregnancy) to cigarette smoking and alcohol. Interview reports of exposures were provided by mothers of CDH (n = 503) and unaffected control (n = 6703) infants delivered from October 1997 through December 2005. Any exposure (yes/no), as well as quantity (average number of cigarettes or drinks), type (active/passive smoking; beer, wine, distilled spirits), and duration (e.g., number of months exposed) were examined. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated for all CDH cases combined, selected subtypes (Bochdalek, Morgagni, not otherwise specified), and phenotypes (infants with/without additional major birth defects). The aOR for any smoking was nonsignificantly elevated for all CDH cases combined. Odds of any smoking was significant for isolated Bochdalek CDH (aOR, 1.9; 95% CI, 1.2-3.0). The aORs associated with all measures of alcohol consumption were near unity for each CDH category examined. Stratification of smoking exposure by alcohol consumption and stratification of alcohol consumption by smoking exposure did not appreciably change the aORs. These findings identified periconceptional smoking exposure as a potential risk factor for CDH. Future studies need to confirm our findings and explore possible pathways accounting for the teratogenic effect of smoking.

Maternal periconceptional exposure to cigarette smoking and alcohol and esophageal atresia ± tracheo‐esophageal fistula

Esophageal atresia (EA) is a moderately frequent birth defect that often occurs with tracheo-esophageal fistula (TEF). Etiologic studies for EA+/-TEF have produced inconsistent results. This study used data from the National Birth Defects Prevention Study (NBDPS) to examine the association between maternal periconceptional exposure to cigarette smoking and alcohol and EA+/-TEF. Cases of EA+/-TEF and unaffected controls with an estimated date of delivery from October 1997 through December 2003 were identified, and telephone interview reports for smoking and alcohol exposure were obtained from birth mothers of 334 cases and 4,967 controls. Odds ratios (OR)s and 95% confidence intervals (CI)s, adjusted for several covariates, were calculated to assess associations. ORs were near unity for all EA+/-TEF cases combined and any periconceptional exposure to cigarette smoking (OR = 1.1; CI = 0.8,1.6) or alcohol (OR = 1.2; CI = 0.8,1.8). For cigarette smoking, some elevated ORs were found but varied by type of smoking exposure. No consistent patterns were identified for number of cigarettes smoked per day. For alcohol, ORs were weak to moderately elevated with increasing number of drinks consumed and for binge drinkers compared to non-binge drinkers. ORs were further elevated among mothers who reported active+passive exposure to cigarette smoking and alcohol (OR = 2.5; CI = 1.1,5.6). For both exposures, ORs were higher for cases with additional major defects compared to isolated cases. These results, based on one of the largest published samples of EA+/-TEF cases, suggest a role for these exposures in the etiology of EA+/-TEF, although further study is needed to replicate the observed associations.

Maternal Exposure to Nitrate From Drinking Water and Diet and Risk for Neural Tube Defects

In this population-based case-control study conducted in California between June 1989 and May 1991, the authors investigated the association between maternal periconceptional exposure to nitrate from drinking water and diet and risk for neural tube defects. The mothers of 538 cases and 539 nonmalformed controls were interviewed regarding residential history, consumption of tap water at home, and dietary intake during the periconceptional period. Dietary nitrate exposure was not associated with increased risk for neural tube defects. Exposure to nitrate in drinking water at concentrations above the 45 mg/liter maximum contaminant level was associated with increased risk for anencephaly (odds ratio (OR) = 4.0, 95% confidence interval (Cl): 1.0, 15.4), but not for spina bifida. Increased risks for anencephaly were observed at nitrate levels below the maximum contaminant level among groundwater drinkers only (OR = 2.1, 95% Cl: 1.1, 4.1 for 5-15 mg/liter; OR = 2.3, 95% Cl: 1.1, 4.5 for 16-35 mg/liter; and OR = 6.9, 95% Cl: 1.9, 24.9 for 36-67 mg/liter compared with <5 mg/liter). Adjustment for identified risk factors for anencephaly did not substantially alter these associations, nor did control for maternal dietary nitrate, total vitamin C intake, and quantity of tap water consumed. The lack of an observed elevation in risk for anencephaly in association with exposure to mixed water containing nitrate at levels comparable with the concentration in groundwater may indicate that something other than nitrate accounts for these findings.

Maternal exposure to nitrate from drinking water and diet and risk for neural tube defects.

In this population-based case-control study conducted in California between June 1989 and May 1991, the authors investigated the association between maternal periconceptional exposure to nitrate from drinking water and diet and risk for neural tube defects. The mothers of 538 cases and 539 nonmalformed controls were interviewed regarding residential history, consumption of tap water at home, and dietary intake during the periconceptional period. Dietary nitrate exposure was not associated with increased risk for neural tube defects. Exposure to nitrate in drinking water at concentrations above the 45 mg/liter maximum contaminant level was associated with increased risk for anencephaly (odds ratio (OR) = 4.0, 95% confidence interval (CI): 1.0, 15.4), but not for spina bifida. Increased risks for anencephaly were observed at nitrate levels below the maximum contaminant level among groundwater drinkers only (OR = 2.1, 95% CI: 1.1,4.1 for 5-15 mg/liter; OR = 2.3, 95% CI: 1.1, 4.5 for 16-35 mg/liter; and OR = 6.9, 95% CI: 1.9, 24.9 for 36-67 mg/liter compared with <5 mg/liter). Adjustment for identified risk factors for anencephaly did not substantially alter these associations, nor did control for maternal dietary nitrate, total vitamin C intake, and quantity of tap water consumed. The lack of an observed elevation in risk for anencephaly in association with exposure to mixed water containing nitrate at levels comparable with the concentration in groundwater may indicate that something other than nitrate accounts for these findings.

Risk factors for cytogenetically normal holoprosencephaly in California: A population-based case-control study

Holoprosencephaly is a developmental field defect manifested by a spectrum of abnormalities of the forebrain and midface. Approximately 50% of holoprosencephaly cases are associated with a cytogenetic abnormality or a monogenic syndrome. Suggested risk factors for the remaining 50% of cases have been described in case reports, but have not been confirmed in systematically conducted studies. We report the results of a population-based case-control study of holoprosencephaly. Live births, fetal deaths, and terminations with a diagnosis of cytogenetically normal holoprosencephaly were identified by the California Birth Defects Monitoring Program. Telephone interviews were conducted with the mothers of 58 cases and 107 live born, nonmalformed controls. Women were questioned about their health and reproductive histories, family demographics, and exposures occurring during their pregnancies. Among nonsyndromic cases, increased risks were observed for females (OR=1.8, 95% C.I. 0.9-3.9), foreign-born vs. U.S. or Mexico-born women (OR=3.1, 95% C.I. 1.1-8.6), and women with early menarche (OR=2.3, 95% C.I. 0.9-5.7). Maternal periconceptional exposures associated with increased risks for nonsyndromic holoprosencephaly included alcohol consumption (OR=2.0, 95% C.I. 0.9-4.5), cigarette smoking (OR=4.1, 95% C.I. 1.4-12.0), and combined alcohol and smoking (OR=5.4, 95% C.I. 1.4-20.0), insulin-dependent diabetes (OR=10.2, 95% C.I. 1.9-39.4), medications for respiratory illnesses (OR=2.3, 95% C.I. 0.9-6.0), and salicylate-containing medications (OR=2.5, 95% C.I. 0.8-7.9). These findings are consistent with risk factors identified in some previous reports, and identify several new potential risk factors that require confirmation in future studies.

Does maternal cigarette smoking during pregnancy cause cleft lip and palate in offspring?

To investigate the relationship between maternal cigarette smoking and the risk of oral clefts in offspring, we examined data from the Atlanta Birth Defects Case-Control Study, which included 238 cases of cleft lip with or without cleft palate and 107 cases of cleft palate ascertained by the Metropolitan Atlanta Congenital Defects Program from 1968 through 1980. In all, 2809 infants who served as controls were frequency matched to cases by race, period of birth, and hospital of birth. Maternal periconceptional exposures to smoking were investigated through use of a structured questionnaire. Smoking exposure was defined as reported maternal smoking during the periconceptional period (from 3 months before conception to 3 months after pregnancy began). Offspring of smoking mothers were 1.6 and 2.0 times more likely than offspring of nonsmoking mothers to have isolated cleft lip with or without cleft palate and cleft palate, respectively. On the other hand, offspring of smoking mothers were not at increased risk of having cleft palate or cleft lip with or without cleft palate that are associated with other defects. Adjustment for potential confounding variables did not alter these results. A relatively modest effect of smoking may be explained by the presence of underlying etiologic heterogeneity in oral clefts and differential susceptibility to smoking. Because of the inconsistencies in the literature on the relationship between smoking and oral clefts, these results suggest the need to refine oral clefts into more homogeneous subgroups in epidemiologic studies of these defects.