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. Birth Defects Research (Part A), 2013. © 2013 Wiley Periodicals, Inc.
To determine prevalence of prenatal alcohol use in Brazzaville, Congo and to evaluate a prenatal screening tool for use in this population.
A prospective population screening program of 3099 women at 10 prenatal care clinics in Brazzaville, Congo using the 1-Question screen. To validate the 1-Question screen in this population we screened 764 of these women again using the T-ACE as a gold standard for comparison study. The study outcomes were as follows: prevalence of self-reported prenatal alcohol use in Brazzaville using the 1-Question screen, estimation of number of drinking days, drinks per drinking day, most drinks on any one occasion. We also estimated the epidemiologic performance criteria for the 1-Question screen.
The 3099 women screened were classified as follows: no risk 77% (n = 2,384); at risk 3.7% (n = 115); and as high risk 19.3% (n = 600). Of the women reporting drinking during pregnancy, 87.4% reported drinking 4 or more drinks on any occasion. The agreement for detection of alcohol use during pregnancy by the 1-Question Screen and a positive T-ACE score was 94.7%.
23.3% of women attending prenatal care in Brazzaville reported alcohol use during pregnancy and 83% of them continued to drink after recognition of pregnancy. Prenatal alcohol exposure should be the focus of efforts to improve identification of alcohol use prior to and during pregnancy to improve maternal and child health. Birth Defects Research (Part A), 2013. © 2013 Wiley Periodicals, Inc.
BACKGROUND: Previous studies inconsistently suggest that assisted reproduction technology (ART) may increase the risk of birth defects in children. METHOD(S): Live birth infants, conceived by in vitro fertilization fresh embryo transfer (IVF), intracytoplasmic sperm injection fresh embryo transfer (ICSI), or frozen-thawed embryo transfer (FET) in Reproductive Center of Tongji Hospital (Wuhan, China) between 1997 and 2008, were followed up at birth and after 3 years. Preterm pregnancy, multiple pregnancy, sex ratio (male/female), congenital malformation were compared. RESULT(S): A total of 4,236 children were born after ART (IVF 2,543, ICSI 908, FET 785). Compared with IVF, the rate of preterm pregnancy and sex ratio in ICSI were lower (p < 0.05); the rate of multiple pregnancy in ICSI and FET were all lower than IVF (p < 0.05). Congenital defects were comparable in all groups at birth. In total, 2,908 children participated in the second follow-up from 34 months to 60 months with an average of 40 months, and the cases of birth defects had doubled (3 years: 5.16%, birth: 2.22%). The birth defect rate in boys conceived through ICSI was significantly higher than the IVF group after 3-year follow-up (ICSI boys: 8.62%, IVF boys: 5.21% [p < 0.05]), even though there was no significant difference at birth. CONCLUSION(S): Compared with IVF, FET may not increase risk of birth defects. Children conceived through ICSI, especially males, had higher rates of congenital malformations that were inapparent at birth. So longitudinal monitoring may provide insights into the risks of ART. Birth Defects Research (Part A) 2013. © 2013 Wiley Periodicals, Inc.
Environmental factors contribute to the etiology of cleft palate (CP). Identification of genes that are methylated during development of the secondary palate will contribute to a better understanding of the gene-environment link contributing to CP.
Genomic DNA fragments from secondary palate tissue from gestational days (GDs) 12 to 14 were subjected to Selective Enrichment of Methylated DNA (SEMD) and used to probe NimbleGen 2.1M mouse promoter arrays. Input (control) and SEMD samples were labeled with Cy3 and Cy5, respectively, and used for array hybridization (three arrays per GD). Data were analyzed using the Bioconductor package Ringo. Gene methylation was verified by pyrosequencing analysis and expression by quantitative real-time PCR.
A total of 5577 methylated genes were identified during palate development: (1) 74% of genes were methylated on all three GDs; (2) CpG islands accounted for only 30% of methylated regions of interest (MRIs); (3) location of MRIs was more often observed in gene bodies (73%) than in promoters; (4) evaluation of MRIs on GDs 12–14 revealed no significant differentially methylated regions; (5) DAVID analysis of MRIs revealed that the cadherin and Wnt signaling pathways, as well as pathways involved in proteoglycan synthesis, were significantly enriched for methylated genes.
Our prior studies identified differentially expressed mRNAs and microRNAs in the developing palate. The current study complements these studies by identifying genes whose expression may be altered as a result of DNA methylation. Birth Defects Research (Part A) 97:171–186, 2013. © 2013 Wiley Periodicals, Inc.
Down syndrome (DS) and Fetal Alcohol Syndrome (FAS) are two leading causes of birth defects with phenotypes ranging from craniofacial abnormalities to cognitive impairment. Despite different origins, we report that in addition to sharing many phenotypes, DS and FAS may have common underlying mechanisms of development.
Literature was surveyed for DS and FAS as well as mouse models. Gene expression and apoptosis were compared in embryonic mouse models of DS and FAS by qPCR, immunohistochemical and immunoflurorescence analyses. The craniometry was examined using MicroCT at postnatal day 21.
A literature survey revealed over 20 comparable craniofacial and structural deficits in both humans with DS and FAS and corresponding mouse models. Similar phenotypes were experimentally found in pre- and postnatal craniofacial and neurological tissues of DS and FAS mice. Dysregulation of two genes, Dyrk1a and Rcan1, key to craniofacial and neurological precursors of DS, was shared in craniofacial precursors of DS and FAS embryos. Increased cleaved caspase 3 expression was also discovered in comparable regions of the craniofacial and brain precursors of DS and FAS embryos. Further mechanistic studies suggested overexpression of trisomic Ttc3 in DS embyros may influence nuclear pAkt localization and cell survival.
This first and initial study indicates that DS and FAS share common dysmorphologies in humans and animal models. This work also suggests common mechanisms at cellular and molecular levels that are disrupted by trisomy or alcohol consumption during pregnancy and lead to craniofacial and neurological phenotypes associated with DS or FAS. Birth Defects Research (Part A) 97:187–197, 2013. © 2013 Wiley Periodicals, Inc.
Gastroschisis (GS) is usually described as an abdominal wall defect, to the right of a normally inserted umbilical cord, without membraneous covering of the extruded organs. However, precise anatomical descriptions are lacking in the literature. Our aims were to provide evidence that allows reconsideration of its current definition, as well as an explanation for prenatal death, based on detailed observation of stillborn fetuses with GS and a review of the literature.
Prenatal studies, clinical examinations, and histological findings of five stillborn fetuses with isolated GS are described and photographic evidence is provided.
In all five cases, the umbilical cord was only attached to the left side of the umbilical ring, while the right side remained uncovered, allowing evisceration of abdominal organs. Histological evidence of mucoid-like tissue at the free border of the ring suggests that at that site the cord was initially inserted and later detached. Characteristics of the umbilical ring, bowel dilatation, and autopsy findings of acute asphyxia strongly support compression of umbilical vessels as the cause of fetal death.
Based on these findings, on the lack of evidence in the literature demonstrating full-thickness abdominal wall separating the defect from the umbilical cord, and on a critical review of the proposed mechanisms favoring the hypothesis of a defect separate from the umbilical ring, we propose that GS represents a failure in the normal attachment between umbilical cord and umbilical ring. The consistent clinical course of fetuses with prenatal demise suggests careful targeted monitoring during late gestation. Birth Defects Research (Part A) 97:198–209, 2013. © 2013 Wiley Periodicals, Inc.
Maternal smoking during pregnancy has been consistently associated with an increased risk of congenital heart defects (CHDs). However, few studies have reported the association between paternal smoking during pregnancy and CHDs among offspring. This report presents the first case-control study to investigate the possible association between periconceptional paternal smoking and CHDs in China.
From February 2010 through October 2011, 284 case fetuses with nonsyndromic CHDs and 422 control fetuses with no birth defects were recruited. The mothers of cases and controls were interviewed regarding whether the fathers of fetuses smoked and avoided the mothers while smoking during the periconceptional period. An unconditional logistic regression was used to calculate the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) while controlling for potential confounders.
Light paternal smoking increased the risk of isolated conotruncal heart defects (AOR, 2.23; 95% CI, 1.05, 4.73). Medium paternal smoking seemed to be associated with septal defects (AOR, 2.04; 95% CI, 1.05, 3.98) and left ventricular outflow tract obstructions (AOR, 2.48; 95% CI, 1.04, 5.95). Heavy paternal smoking was also associated with isolated conotruncal heart defects (AOR, 8.16; 95% CI, 1.13, 58.84) and left ventricular outflow tract obstructions (AOR, 13.12; 95% CI, 2.55, 67.39). Paternal smoking with no avoidance behavior was associated with an increased risk of these CHDs subtypes.
Periconceptional paternal smoking increased the risk of isolated conotruncal heart defects, septal defects and left ventricular outflow tract obstructions. The avoidance behavior of paternal smokers may decrease the risk of selected CHDs. Birth Defects Research (Part A) 97:210–216, 2013. © 2013 Wiley Periodicals, Inc.
The role of possible environmental factors in the origin of congenital heart defects is unclear in the vast majority of patients. The objective of this study was to describe the birth outcomes and risk factors in isolated atrioventricular canal defect (AVCD) cases.
Medically recorded birth outcomes, maternal age, parity, acute and chronic maternal diseases with related drug treatments and folic acid/multivitamin supplementation were evaluated in isolated AVCD cases. The diagnosis of AVCD was based on the autopsy report or surgical description in the population-based Hungarian Case–Control Surveillance of Congenital Abnormalities, between 1980 and 1996.
The birth outcomes and exposures of 77 isolated AVCD cases were compared with 38,151 controls without defect. Mean gestational age at delivery (38.6 week) and birth weight (2992 g), rate of preterm birth (20.8%) and low birthweight (23.4%) of cases with a female excess (59.7%) differed significantly from the controls. Mothers of cases had higher parity, higher prevalence of conduction disorders/cardiac dysrhythmias and chronic hypertension. The high doses of folic acid in early pregnancy associated with a reduced rate of AVCD.
Conduction disorders/cardiac dysrhythmias and chronic hypertension of mothers may have a role in the origin of AVCD, while high doses of folic acid in early pregnancy may reduce the risk of the development of AVCD. Birth Defects Research (Part A) 97:217–224, 2013. © 2013 Wiley Periodicals, Inc.
The data in the literature suggests that Methimazole (MMI)/Carbimazole (CMZ) embryopathy is rare. This study examined the incidence of CMZ embryopathy in the Hong Kong Chinese population and the factors associated with its development.
Of the 145 pregnant women with hyperthyroidism managed from 2008 to 2010, 29 (20%) had taken CMZ during pregnancy. The presence and details of birth defects, the dosage of CMZ, and the period of exposure during pregnancy were examined in these 29 pregnancies. All cases of CMZ embryopathy in the English literature were reviewed in the same way.
Of the 27 babies (93.1%) with known outcome, 3 had aplasia cutis and 1 had an omphalocele in addition, and 1 affected baby had a sibling with aplasia cutis and patent vitellointestinal duct. The incidence of CMZ embryopathy in our study group is 11.1%. Amongst the 21 cases of CMZ embryopathy in the literature, 85% were exposed to a CMZ dosage of ≥20 mg/day, and the minimum duration of exposure being 7 weeks from last menstrual period. The most common abnormality is ectodermal anomaly (62%), followed by oro-nasal anomaly (48%), facial dysmorphism (38%), gastrointestinal anomaly (33%) and abdominal wall defect (19%). There was no relationship between the type of abnormality and the dosage or duration of exposure to CMZ.
The incidence of CMZ embryopathy in our study group is 11.1%. Critical factors for its development are exposure to a CMZ dosage of ≥20 mg/day before 7 weeks of gestation. Genetic susceptibility may also play a role. Birth Defects Research (Part A) 97:225–229, 2013. © 2013 Wiley Periodicals, Inc.