Periconceptional Exposure Research Articles

Maternal occupational exposure and oral clefts in offspring

BackgroundPrevious studies suggest that periconceptional maternal occupational exposure to solvents and pesticides increase the risk of oral clefts in the offspring. Less is known about the effect of occupational exposure to metals, dust, and gases and fumes on development of oral clefts.MethodsThis case-malformed control study used data from a population-based birth defects registry (Eurocat) of children and foetuses born in the Northern Netherlands between 1997 and 2013. Cases were defined as non-syndromic oral clefts. The first control group had chromosomal/monogenic defects, and the second control group was defined as non-chromosomal/non-monogenic malformed controls. Maternal occupational exposure was estimated through linkage of mothers’ occupation with a community-based Job Exposure Matrix (JEM). Multivariate logistic regression was used to estimate the effect of occupational exposures. Odds ratios were adjusted (aORs) for relevant confounders.ResultsA total of 387 cases, 1135 chromosomal and 4352 non-chromosomal malformed controls were included in this study. Prevalence of maternal occupational exposures to all agents was 43.9% and 41.0%/37.7% among cases and controls, respectively. Oral clefts had significantly increased ORs of maternal occupational exposure to pesticides (aOR = 1.7, 95% confidence interval [CI] 1.0–3.1) and dust (aOR = 1.3, 95% CI 1.1–1.6) when using non-chromosomal controls. Subgroup analysis for CL(P) stratified by gender showed a significantly increased risk for male infants exposed to ‘other solvents’ and exposure to mineral dust for female infants.ConclusionOur study showed that maternal occupational exposure to pesticides and dust are risk factors for oral clefts in the offspring. Larger studies are needed to confirm this finding.

Influence of Periconception Smoking Behavior on Birth Defect Risk [4OP

INTRODUCTION: The aim of this study is to assess the association of maternal smoking and the timing of periconception exposure with congenital birth defects. METHODS: Population-based retrospective cohort of all live births in Ohio (2006-2015). Rates of major defects were compared between births to non-smoking mothers and those who smoked (1) during the 3 month preconception period and not in the first trimester, and (2) in the preconception period + throughout the first trimester. Multivariate logistic regression quantified the relationship between smoking and birth defects after adjustment for maternal race, age, pregestational diabetes and socio-economic factors. RESULTS: Of 1,436,036 live births in the study period, 23.3% smoked during pregnancy; 6.0% preconception only and 17.3% smoked also through the first trimester. Smoking during the preconception period only, even without first trimester exposure, was associated with a 40% increased risk of gastroschisis (adjRR 1.4, CI 1.1-1.9), but no other individual birth defects. However, smoking through the first trimester was associated with a modest but significantly increased risk of several defects including gastroschisis, omphalocele, congenital diaphragmatic hernia, and cleft palate, even after adjustment for coexisting factors. CONCLUSION: Smoking during the period of fetal organogenesis, during the first trimester of pregnancy, is associated with increased risk of some birth defects. In this study, we provide novel data that smoking during the few months prior to conception, even with cessation in the first trimester, may also pose risk for fetal malformation such as gastroschisis. These findings highlight the importance of preconception women’s public health education efforts and warrant further investigation.

Impact of Periconceptional Exposure to Phthalates on Pregnancy, Birth, and Neonatal Outcomes

Purpose of Review The purpose of this review was to evaluate recent available evidence on exposure to phthalates during pregnancy and the immediate periconceptional period and the health effects in the mother and offspring during the peripartum period. Articles were included if they included biospecimen-based exposure assessment and consideration of quantifiable health effects in either the mother or the offspring.

Modification of the fatty acid composition of an obesogenic diet improves the maternal and placental metabolic environment in obese pregnant mice

Peri-conceptional exposure to maternal obesogenic nutrition is associated with in utero programming of later-life overweight and metabolic disease in the offspring. We aimed to investigate whether dietary intervention with a modified fatty acid quality in an obesogenic high-calorie (HC) diet during the preconception and gestational phases can improve unfavourable effects of an adipogenic maternal environment. In NMRI mice, peri-conceptional and gestational obesity was induced by feeding a HC diet (controls), and they were compared with dams on a fat-modified (Fat-mod) HC diet of the same energy content but enriched with medium-chain fatty acids (MCFAs) and adjusted to a decreased ratio of n-6 to n-3 long-chain polyunsaturated fatty acids (LC-PUFAs). Effects on maternal and placental outcomes at delivery (day 17.5 post coitum) were investigated. Despite comparable energy assimilation between the two groups of dams, the altered fatty acid composition of the Fat-mod HC diet induced lower maternal body weight, weights of fat depots, adipocyte size, and hepatic fat accumulation compared to the unmodified HC diet group. Further, there was a trend towards lower fasting glucose, insulin and leptin concentrations in dams fed the Fat-mod HC diet. Phenotypic changes were accompanied by inhibition of transcript and protein expression of genes involved in hepatic de novo lipogenesis comprising PPARG2 and its target genes Fasn, Acaca, and Fabp4, whereas regulation of other lipogenic factors (Srebf1, Nr1h3, Abca1) appeared to be more complex. The modified diet led to a sex-specific placental response by upregulating PPARG-dependent fatty acid transport gene expression in female versus male placentae. Qualitative modification of the fatty acid spectrum of a high-energy maternal diet, using a combination of both MCFAs and n-3 LC-PUFAs, seems to be a promising interventional approach to ameliorate the adipogenic milieu of mice before and during gestation.

Association between antibiotic use among pregnant women with urinary tract infections in the first trimester and birth defects, National Birth Defects Prevention Study 1997 to 2011.

Previous studies noted associations between birth defects and some antibiotics (e.g., nitrofurantoin, sulfonamides) but not others (e.g., penicillins). It is unclear if previous findings were due to antibiotic use, infections, or chance. To control for potential confounding by indication, we examined associations between antibiotic use and birth defects, among women reporting urinary tract infections (UTIs). The National Birth Defects Prevention Study is a multi-site, population-based case-control study. Case infants/fetuses have any of over 30 major birth defects and controls are live-born infants without major birth defects. We analyzed pregnancies from 1997 to 2011 to estimate the association between maternally reported periconceptional (month before conception through the third month of pregnancy) use of nitrofurantoin, trimethoprim-sulfamethoxazole, or cephalosporins and specific birth defects, among women with periconceptional UTIs. Women with periconceptional UTIs who reported penicillin use served as the comparator. Periconceptional UTIs were reported by 7.8% (2029/26,068) of case and 6.7% (686/10,198) of control mothers. Most (68.2% of case, 66.6% of control mothers) also reported antibiotic use. Among 608 case and 231 control mothers reporting at least one periconceptional UTI and certain antibiotic use, compared with penicillin, nitrofurantoin use was associated with oral clefts in the offspring (adjusted odds ratio, 1.97 [95% confidence interval, 1.10-3.53]), trimethoprim-sulfamethoxazole use with esophageal atresia (5.31 [1.39-20.24]) and diaphragmatic hernia (5.09 [1.20-21.69]), and cephalosporin use with anorectal atresia/stenosis (5.01 [1.34-18.76]). Periconceptional exposure to some antibiotics might increase the risk for certain birth defects. However, because individual birth defects are rare, absolute risks should drive treatment decisions.Birth Defects Research (Part A) 106:940-949, 2016.© 2016 Wiley Periodicals, Inc.

Periconceptional exposure to bisphenol-A and fecundability among couples trying to conceive in a prospective, preconception cohort

Background: Bisphenol-A (BPA) is an endocrine disrupting chemical with nearly ubiquitous exposure. BPA caused reproductive dysfunction in animal models, but data in humans are limited. Objective: Examine couple urinary BPA concentration and fecundability. Methods: A prospective, pre-conception cohort of heterosexual couples (women 18–35, men 18–40) without known infertility or subfertility were recruited, and women observed cervical mucus to identify an estimated day of ovulation and fertile window. Couples collected daily first-morning urine samples during the fertile window and women continued daily collection until the onset of menses or estimated day of ovulation +18 days. Cox proportional hazards models for discrete survival time, adjusting for left truncation for time trying before enrollment, were performed to assess time-varying BPA and fecundability. Models were adjusted for woman’s age and education level, household income, women and men’s BMI, and parity. Fecundability odds ratios (FOR) <1.0 indicate reduced fecundity and longer time to pregnancy, whereas FORs>1.0 indicate enhanced fecundity and shorter time to pregnancy. Results: Women collected mean 16.7±5.2 and men collected mean 5.1±2.1 urine samples per cycle. Among 183 couples, 126 conceived during the study, and 16 early pregnancy losses were observed. There was no association between periconceptional BPA exposure and fecundability either among all pregnancies (FOR 0.995, 95% CI: 0.962, 1.029) or when restricting to live births (FOR 1.002, 95% CI: 0.969, 1.036). Discussion: In this sample of 183 couples, no association between BPA and fecundability was observed. Strengths of this study were the prospective biospecimen collection during the fertile window and serial, daily urine collection to support robust BPA exposure assessment for both men and women.

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 gut and fetal brain connection: Increased anxiety and reduced social interactions in Wistar rat offspring following peri-conceptional antibiotic exposure

BackgroundA growing body of evidence indicates that gut microbiota characteristics may be closely related to mental dysfunctions. However, no studies have investigated fetal brain development in relation to the maternal gut microbiota, despite the extensive use of antibiotics in obstetric practice. ObjectiveTo determine how periconceptional exposure to SuccinylSulfaThiazole (SST), a non-absorbable antibiotic, can affect behavior in rat offspring. This antibiotic drug has previously been shown to substantially perturb the gut microbiota in rats following a 28-day exposure. MethodsFemale Wistar rats were divided in two groups: control, or exposed during one month before breeding until gestational day 15 to a diet containing 1% SST. We administered behavioral tests to offspring, i.e., open field (post-natal day 20), social interactions (P25), marble burying (P30), elevated plus maze (P35), and prepulse inhibition of the acoustic startle reflex (sensory gating) (P45). ResultsBoth male and female offspring exposed peri-conceptionally to SST showed reduced social interactions, with a decrease of about half in time spent in social interactions compared to controls, reduced exploration of the open arm by 20% in the elevated plus maze test indicating increased anxiety and altered sensorimotor gating, with a 1.5–2-fold decrease in startle inhibition. ConclusionMaternal periconceptional exposure to SST provokes alterations in offspring behavior in the absence of maternal infection. Because we administered SST, a non-absorbable antibiotic, only to the dam, we conclude that these neurobehavioral alterations in the offspring are related to maternal gut microbiota alterations.

The Home Observation of Periconceptional Exposures (HOPE) study, a prospective cohort: aims, design, recruitment and compliance.

BackgroundTo examine transient environmental exposures and their relationship with human fecundity, exposure assessment should occur optimally at the time of conception in both members of the couple.We performed an observational, prospective cohort study with biomonitoring in both members of a heterosexual couple trying to conceive. Couples collected urine, saliva, and semen specimens for up to two menstrual cycles on days corresponding to the time windows of fertilization, implantation, and early pregnancy, identified based on the woman’s observations of her cervical fluid.ResultsThree hundred nine eligible couples were screened between 2011 and 2015, of which 183 enrolled. Eleven couples (6.0 %) withdrew or were lost to follow up. The most successful and cost effective recruiting strategies were word of mouth (40 % of participating couples), posters and flyers (37 %), and targeted Facebook advertising (13 %) with an overall investment of $37.35 spent on recruitment per couple. Both men and women collected ≥97.2 % of requested saliva samples, and men collected ≥89.9 % of requested semen samples. Within the periovulatory days (±3 days), there was at least one urine specimen collected by women in 97.1 % of cycles, and at least one by men in 91.7 % of cycles. Daily compliance with periovulatory urine specimens ranged from 66.5 to 92.4 % for women and from 55.7 to 75.0 % for men. Compliance was ≥88 % for questionnaire completion at specified time points.ConclusionsCouples planning to conceive can be recruited successfully for periconceptional monitoring, and will comply with intensive study protocols involving home collection of biospecimens and questionnaire data.

Indoor air pollution and the risk of orofacial clefts in a rural population in Shanxi province, China.

Shanxi Province is a region in China with a high incidence of orofacial clefts (OFCs). Our objective is to investigate the effect of maternal exposure to indoor air pollution (IAP) from coal combustion and tobacco smoke on the risk of an infant being born with orofacial clefts. Data were derived from an ongoing population-based case-control study of major external structural birth defects in Shanxi Province. Subjects included 213 cases with OFCs and 1319 healthy babies born between November 2002 and December 2014 in four rural counties. Exposure information was collected by face-to-face interview with mothers within 1 week of delivery or pregnancy termination. The authors derived an exposure index by integrating a series of IAP-related characteristics concerning dwelling and lifestyle. Increased odds of OFC were associated with IAP exposure from heating (adjusted odds ratio [aOR] = 2.4; 95% confidence interval [CI], 1.2-4.5) and from smoking (aOR = 1.8; 95% CI: 1.3, 2.5), but not with exposure from cooking (aOR = 0.9; 95% CI, 0.6-1.4). Compared with women without IAP exposure, the aORs of OFC for children of women with exposure indices of 1, 2, 3 and ≥ 4 were 1.1 (95% CI, 0.6-1.8), 1.4 (95% CI, 0.8-2.4), 1.8 (95% CI, 1.0-3.2), and 3.4 (95% CI, 1.6-7.4), respectively, demonstrating a clear dose-response trend (p < 0.001). Periconceptional exposure to IAP from coal combustion and tobacco smoking may increase the risk of OFCs in offsprings of women in Shanxi Province. Birth Defects Research (Part A) 106:708-715, 2016. © 2016 Wiley Periodicals, Inc.

Nurturing Nature-Exploring the Possible Role of Epigenetics in Dyslipidemia.

Whereas prior studies have suggested an association between both maternal adiposity and dysglycemia and adult offspring cardiometabolic health, there is a surprising paucity of data examining t h i s s ame a s s o c i a t i on for dyslipidemia. In this issue of JAMA Cardiology, Mendelson and colleagues1 look to start to fill that gap by investigating this association in the Framingham Heart Study. Using the prepregnancy parent low-density lipoprotein cholesterol (LDL-C) levels as a surrogate for peripartum LDL-C levels, they found that maternal, but not paternal, prepregnancy LDL-C level was strongly associated with adult offspring’s LDL-C level. After adjusting for known confounders and 37 known genetic loci related to LDL-C, for each 10-mg/dL higher level of the maternal prepregnancy LDL-C, the adult offspring’s LDL-C level was 3.2 mg/dL higher (to convert to millimoles per liter, multiply by 0.0259). In contrast, the paternal LDL-C was only 1.3 mg/dL higher. What might explain this finding? As the investigators correctly note, this observed association does not prove causality. To that end, in this older Framingham Heart Study cohort, maternal dietary habits might have played a greater role than did paternal habits in setting the dietary habits of the offspring. Moreover, studies2 in the setting of familial hypercholesterolemia have not found any difference between maternal vs paternal carriage of familial hypercholesterolemia and offspring LDL-C levels, both in offspring with and those without familial hypercholesterolemia. However, there is a growing body of evidence that epigenetic regulation of gene expression can be influenced by environmental exposures. To that end, differential DNAmethylation has been observed after periconceptional exposure to famine.3 Determining whether there are epigenetic transmission mechanisms underlying the observations seen in the study by Mendelson and colleagues1 will be an important next step. Regardless, this study should raise awareness of the effect of parental, and specifically maternal, hypercholesterolemia on the cardiovascular risk profile of offspring.

Periconceptional and Gestational Exposure to Antibiotics and Childhood Asthma.

BackgroundPrevious studies suggest that maternal antibiotics exposure during pregnancy may increase the risk of childhood asthma, but the results were inconsistent. Furthermore, most studies did not examine periconception period as an exposure window. We aim to assess the associations between maternal exposure to specific antibiotics before and during pregnancy and the risk of asthma in early childhood.MethodsData from the Collaborative Perinatal Project were used. Maternal exposure to antibiotics before and during pregnancy was recorded at each prenatal visit. A total of 39,907 singleton children were followed up to 7 years of age. Multilevel multiple logistic regression models were used to control for potential confounders and account for multiple pregnancies per woman.ResultsMaternal use of penicillin or chloramphenicol was associated with an increased risk of asthma in the offspring (adjusted odds ratio = 1.21, 95% confidence interval 1.08–1.36 for penicillin; 1.72 [1.14–2.59] for chloramphenicol). The risk was significantly increased if penicillin or chloramphenicol was used in the 1st trimester (1.09 [1.04–1.13] for penicillin and 1.23 [1.01–1.51] for chloramphenicol).ConclusionMaternal exposure to certain antibiotics is associated with childhood asthma by 7 years of age. Early pregnancy may be a sensitive window.

Impact of Periconceptional Use of Nitrosatable Drugs on the Risk of Neural Tube Defects.

Nitrosatable drugs (NSDs) can, in the presence of nitrosating agents and highly acidic conditions, form N-nitroso compounds that have been found to be teratogenic in animal models. Using data from the Slone Epidemiology Center Birth Defects Study collected from 1998 to 2012, we compared maternal periconceptional NSD use between 334 neural tube defect cases and 7,619 nonmalformed controls. We categorized NSDs according to their functional group (secondary amine, tertiary amine, and amide). With logistic regression models, we estimated adjusted odds ratios and 95% confidence intervals. Neural tube defect risk was associated with maternal periconceptional use of secondary (adjusted odds ratio (aOR) = 1.7, 95% confidence interval (CI): 1.1, 2.4) and tertiary (aOR = 1.7, 95% CI: 1.2, 2.5) amines; an association was observed for amides, but the 95% confidence interval included the null (aOR = 1.4, 95% CI: 0.7, 2.5). Within the secondary amine group, elevated adjusted odds ratios were observed for 3 drugs but were null for the remaining medications. Increases in risk were observed for both strata of folic acid intake (<400 µg/day, ≥400 µg/day), with a slightly higher risk in the ≥400-µg/day stratum. Our findings support previously reported positive associations between neural tube defects and periconceptional exposure to NSDs containing a secondary or tertiary amine or amide.

Periconceptional alcohol exposure causes mid-gestational placental growth restriction and alters trophoblast invasion into the decidua.

Periconceptional alcohol exposure causes mid-gestational placental growth restriction and alters trophoblast invasion into the decidua.

Abstract 2763: Maternal folate intake at periconception and genome-wide DNA methylation modifications at birth in children

Abstract Introduction Folate supplementation during pregnancy was previously associated with a lower risk of acute lymphoblastic childhood leukemia (ALL). Folate is involved in the “one-carbon” metabolic cycle necessary for shuttling methyl groups for DNA methylation. Given the observation that aberrant DNA methylation patterns are a characteristic of leukemic cells during ALL oncogenesis, we hypothesized that (1) low folate exposure during fetal development might modify the neonate's DNA genome-wide methylation pattern, and that (2) such a modified pattern can lead to ALL development. Here we investigate the first part of this hypothesis. Methods We analyzed healthy control participants of the California Childhood Leukemia case-control study. Participants’ peri-conception folate exposure was estimated from self-reported maternal folate intake and supplements, which was derived from a food frequency questionnaire on the diet in the year prior to pregnancy, as a surrogate for nutrient “environment” during the peri-conception period. DNA obtained from archived neonatal blood spots was purified, treated with bisulfite and assayed on the Illumina Infinium 450K genome-wide DNA methylation array. After removing cross-reacting probes, SNP-related and polymorphic CpGs, we analyzed the association of folate with methylation intensity of 319,265 CpGs in two independent datasets (n set 1 = 167 and n set 2 = 176). Models were adjusted for cell mixture, sex, gestational age, and race. We used a false discovery rate with random resampling to reduce the number of false-positive findings and we cross-validated the results between sets. Results Maternal folate intake was broadly associated with less child's DNA methylation: with a q-value &amp;lt;0.05, we found more than 122,000 CpG sites associated with folate intake in common in both sets. Because a fraction of these CpGs were sign discordant between sets, we constrained our analysis to the most significant CpGs, in order to avoid false positive associations. The three most significant CpGs found in common in both sets were negatively associated with folate. First, cg21039708 (chr.14) in the gene OTX2OS1 (q &amp;lt;10-14 in both sets) is implicated in facial and eye defects. Second, cg13499966 (chr.2) in the gene CYS1 (q &amp;lt;10-14 in both sets) is implicated in cystic kidney disease and biliary liver fibrosis. Third, cg22664307 (chr.6) in the gene STX11 (q &amp;lt;10-14 in both sets) is associated with lymphohistiocytosis. Conclusions This study was the first to investigate the association between maternal folate intake during the peri-conception period and DNA methylation at birth with a genome-wide approach and it found numerous associations throughout the genome. The relationships between folate-sensitive CpG sites and DNA methylation events critical to childhood leukemogenesis will be considered in our subsequent research. Citation Format: Semira Gonseth, Ritu Roy, E. Andres Houseman, Adam de Smith, Mi Zhou, Seung-Tae Lee, Sébastien Nusslé, Amanda W. Singer, Margaret R. Wrensch, Catherine Metayer, Joseph L. Wiemels. Maternal folate intake at periconception and genome-wide DNA methylation modifications at birth in children. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2763. doi:10.1158/1538-7445.AM2015-2763

Risk factors for Dandy-Walker malformation: a population-based assessment.

Dandy-Walker malformation (DWM) is the most common congenital malformation of the cerebellum, but its causes are largely unknown. An increasing number of genes associated with congenital cerebellar malformations have been identified; however, few studies have examined the potential role of non-genetic, potentially modifiable risk factors. From the National Birth Defects Prevention Study, we examined maternal, paternal, and infant characteristics and maternal conditions and periconceptional exposures (from 1 month before to 3 months after conception) among infants with DWM (n = 160) and unaffected controls (n = 10,200), delivered between 1997 and 2009. Odds ratios, crude (cOR) and adjusted (aOR) were computed using logistic regression. Maternal factors associated with DWM included non-Hispanic black race/ethnicity (aOR = 2.0, 95%CI: 1.3-3.2). Among maternal conditions, a history of infertility increased the risk for DWM (all: aOR = 2.4, 95%CI: 1.3-4.6; multiple: aOR = 3.9, 95%CI: 1.7-8.9). The lack of association with many maternal exposures supports the hypothesis of a major contribution of genetic factors to the risk for DWM; however, the observed associations with maternal non-Hispanic black race/ethnicity and maternal history of infertility indicate that further research into factors underlying these characteristics may uncover potentially modifiable risk factors, acting alone or as a component of gene-environment interactions.

DNA methylation signatures link prenatal famine exposure to growth and metabolism.

Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences. However, a comprehensive assessment of the characteristics of prenatal malnutrition-associated differentially methylated regions (P-DMRs) is lacking in humans. Here we report on a genome-scale analysis of differential DNA methylation in whole blood after periconceptional exposure to famine during the Dutch Hunger Winter. We show that P-DMRs preferentially occur at regulatory regions, are characterized by intermediate levels of DNA methylation and map to genes enriched for differential expression during early development. Validation and further exploratory analysis of six P-DMRs highlight the critical role of gestational timing. Interestingly, differential methylation of the P-DMRs extends along pathways related to growth and metabolism. P-DMRs located in INSR and CPT1A have enhancer activity in vitro and differential methylation is associated with birth weight and serum LDL cholesterol. Epigenetic modulation of pathways by prenatal malnutrition may promote an adverse metabolic phenotype in later life.

Epidemiology of twinning in the National Birth Defects Prevention Study, 1997 to 2007.

Our objective was to evaluate associations between twinning and maternal demographic factors and periconceptional exposures among infants with and without orofacial clefts. We used data from the National Birth Defects Prevention Study; 228 twins and 8242 singletons without birth defects (controls), and 117 twins and 2859 singletons with orofacial clefts, born 1997 to 2007, were included in the analyses. Because of the occurrence of twinning due to the use of assisted reproductive technologies, logistic regression models were computed to estimate odds ratios and 95% confidence intervals for each exposure, stratified by fertility treatment use. To evaluate factors by zygosity, we used sex-pairing data and a simulation approach to estimate the zygosity of like-sex twin pairs for unassisted conceptions. Among control mothers who did not use fertility treatments, predictors of twinning included non-Hispanic black maternal race (adjusted odds ratio, 1.6; 95% confidence interval, 1.0-2.4), and tobacco smoking (adjusted odds ratio, 1.6; 95% confidence interval, 1.1-2.4). Among control mothers who used fertility treatments, older maternal age, higher income, and state of residence were associated with twinning. Associations were generally stronger among mothers of dizygotic (estimated) twins than monozygotic (estimated) twins. Results for mothers of infants with isolated orofacial clefts were similar to those of controls. We observed an increased twinning frequency with increasing maternal age, but factors such as maternal race/ethnicity and socioeconomic status may also contribute. Among women receiving fertility treatments, factors associated with twinning suggested a relation with treatment specifics (e.g., treatment type and number of embryos implanted) and availability of insurance coverage.

The influence of IVF/ICSI treatment on human embryonic growth trajectories.

Is in vitro fertilization treatment with or without intracytoplasmatic sperm injection (IVF/ICSI) associated with changes in first and second trimester embryonic and fetal growth trajectories and birthweight in singleton pregnancies? Embryonic and fetal growth trajectories and birthweight are not significantly different between pregnancies conceived with IVF/ICSI treatment and spontaneously conceived pregnancies with reliable pregnancy dating. IVF/ICSI treatment has been associated with increased risks of preterm birth, fetal growth restriction and low birthweight. Decreased first-trimester crown-rump length (CRL) in the general population has been inversely associated with the same adverse pregnancy outcomes. In a prospective periconception birth cohort study conducted in a tertiary centre, 146 singleton pregnancies with reliable pregnancy dating and nonmalformed live borns were investigated, comprised of 88 spontaneous and 58 IVF/ICSI pregnancies. Serial 3D ultrasound scans were performed from 6 to 12 weeks of gestation. As estimates of embryonic growth, CRL and embryonic volume (EV) were measured using the I-Space virtual reality system. General characteristics were obtained from self-administered questionnaires at enrolment. Fetal growth parameters at 20 weeks and birthweight were obtained from medical records. To assess associations between IVF/ICSI and embryonic growth trajectories, estimated fetal weight and birthweight, stepwise linear mixed model analyses and linear regression analyses were performed using square root transformed CRL and fourth root transformed EV. In 146 pregnancies, 934 ultrasound scans were performed of which 849 (90.9%) CRLs and 549 (58.8%) EVs could be measured. Embryonic growth trajectories were comparable between IVF/ICSI pregnancies and spontaneously conceived pregnancies (CRL: βIVF/ICSI = 0.10√mm; P = 0.10; EV: βIVF/ICSI = 0.03(4)√cm³; P = 0.13). Estimated fetal weight and birthweight were also comparable between both groups (βIVF/ICSI = 6 g; P = 0.36 and βIVF/ICSI = 80 g; P = 0.24, respectively). Variations in embryonic growth trajectories of spontaneously conceived pregnancies with reliable pregnancy dating may partially be a result of less precise pregnancy dating and differences in endometrium receptivity compared with IVF/ICSI pregnancies. The absence of a significant difference in embryonic and fetal growth trajectories suggests safety of IVF/ICSI treatment with regard to early embryonic growth. However, further research is warranted to ascertain the influence of IVF/ICSI treatments in a larger study population, and to estimate the impact of the underlying causes of the subfertility and other periconceptional exposures on human embryonic and fetal growth trajectories. This study was supported by the Department of Obstetrics and Gynaecology of the Erasmus MC, University Medical Centre. No competing interests are declared.

Periconceptional alcohol exposure programs sex specific hyperinsulinemia possibly through dysregulation of placental O-linked glycosylation

Periconceptional alcohol exposure programs sex specific hyperinsulinemia possibly through dysregulation of placental O-linked glycosylation