Risk Of Congenital Diaphragmatic Hernia Research Articles

Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.

Maternal dietary intake of vitamin A during pregnancy was inversely associated with congenital diaphragmatic hernia: the Japan Environment and Children's Study.

The pathogenesis of congenital diaphragmatic hernia (CDH) is largely unknown; however, vitamin A seems to play a role in diaphragmatic development. Previous case-control studies reported that maternal dietary vitamin A intake was inversely associated with the risk of CDH. To our knowledge, however, there is no prospective evidence regarding this association. Our aim was to examine whether maternal intake of vitamin A was associated with CDH occurrence. Baseline data, from the Japan nationwide birth cohort study (2011-2014) of 89 658 mothers (mean age at delivery = 31·2 years) who delivered singleton live births, were analysed. We assessed dietary habits using an FFQ focused on the first trimester and estimated the daily intake of total vitamin A (retinol activity equivalents), retinol, provitamin A carotenoids and vegetables. The occurrence of CDH was ascertained from medical records. A total of forty cases of CDH were documented. The adjusted OR of CDH occurrence for the high total vitamin A intake category (median = 468 μg/d) was 0·6 (95 % CI 0·3, 1·2) with reference to the low intake category (230 μg/d). When we restricted to mothers with a prepregnancy BMI of 18·5-24·9 kg/m2, vitamin A intake was inversely associated with the risk of their children being born with CDH (OR 0·5, 95 % CI 0·2, 1·0). Even given the limited number of cases in the study, our findings provide additional evidence to link vitamin A with CDH.

Trends, correlates, and survival of infants with congenital diaphragmatic hernia and its subtypes.

To identify the live-birth prevalence, trends, correlates, and neonatal and 1-year survival rates of congenital diaphragmatic hernia. Using a population-based, retrospective cohort study design, we examined 1,025 cases of congenital diaphragmatic hernia from the 1998-2012 Florida Birth Defects Registry. We used Poisson and joinpoint regression models to compute prevalence ratios and temporal trends, respectively. Kaplan-Meier survival curves and Cox proportional hazards regression were used to describe neonatal and 1-year survival and estimate hazard ratios representing the predictors of infant survival. The birth prevalence of congenital diaphragmatic hernia was 3.19 per 10,000 live births (95% confidence interval [CI]: 3.00-3.39); there was a 4.2% yearly increase among multiple cases only. Among all cases, maternal education less than high school (prevalence ratio: 1.25, 95% CI: 1.02-1.53), high school/associate degree/GED (prevalence ratio: 1.15, 95% CI: 1.01-1.32), multiple birth (prevalence ratio: 1.38, 95% CI: 1.05-1.81), and male sex (prevalence ratio: 1.18, 95% CI: 1.05-1.32) were associated with increased risk for congenital diaphragmatic hernia. The 24-hr, neonatal, and 1-year survival rates were 93.6%, 79.8%, and 71.2%, respectively. The highest hazard ratio of 17.87 (95% CI: 1.49-213.82) was observed for neonatal mortality among cases associated with chromosomal anomalies and born <37 weeks at < 1,500 g. Among isolated cases, multiple birth (hazard ratio: 0.41, 95% CI: 0.20-0.86) was associated with decreased 1-year mortality. Low maternal education and multiple birth may be linked to congenital diaphragmatic hernia. The trends in prevalence, epidemiologic correlates, and predictors of early survival can differ between congenital diaphragmatic hernia subtypes-isolated, multiple, and chromosomal.© 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Dietary vitamin A intake below the recommended daily intake during pregnancy and the risk of congenital diaphragmatic hernia in the offspring

Vitamin A has been related to the etiology of congenital diaphragmatic hernia (CDH). We performed a case-control study to investigate whether maternal dietary vitamin A intake is related to CDH in the offspring. Thirty-one pregnancies diagnosed with CDH and 46 control pregnancies were included during the study. After CDH diagnosis and inclusion of controls by risk set sampling, maternal vitamin A intake was investigated with a food frequency questionnaire. Serum retinol and retinol-binding protein were determined. Univariable and multivariable logistic regression models were used to calculate risk estimates with adjustment for potential confounders. We found no significant differences in the overall nutrient and vitamin A intake between case and control mothers. After stratification in body mass index (BMI) categories, case mothers with normal weight showed a lower energy adjusted vitamin A intake (685 vs. 843 μg retinol activity equivalents [RAEs] / day; p = 0.04) and a slightly lower serum retinol (1.58 vs. 1.67 μmol/L; p = 0.08) than control mothers. Vitamin A intake <800 μg retinol activity equivalents (recommended daily intake) in normal weight mothers was associated with a significantly increased CDH risk (odds ratio [OR], 7.2; 95% confidence interval [CI], 1.5-34.4; p = 0.01). Associations were not significantly different in underweight and overweight mothers. In normal-weight mothers, dietary vitamin A intake during pregnancy below the recommended daily intake is significantly associated with an increased risk of a child with CDH. This finding supports the retinoid hypothesis in human CDH, but warrants further investigation in larger study populations. Birth Defects Research (Part A), 2013. © 2013 Wiley Periodicals, Inc.

Sex and congenital diaphragmatic hernia

Human studies note sex reversal syndromes and sex difference(s) in the incidence of congenital diaphragmatic hernia (CDH). Epidemiology surveys record a higher incidence of CDH in females, whilst other reports cite a higher frequency in males. Nitrofen, a teratogen, produces experimental CDH. This agent is speculated to interfere with retinoid acid-steroid signalling pathways and may also be linked with sexual differentiation. This study was designed therefore to test the hypothesis that nitrofen may influence sexual phenotype and frequency of CDH. Time mated Sprague Dawley rats were dosed with nitrofen at day 9.5 to generate predominantly left sided CDH. Fetuses were delivered by caesarean section on days 20 or 21 of gestation (term=day 22). External genitalia were examined to define external genital phenotype. The abdominal cavity was opened and the genito-urinary system carefully examined. The internal genital organs were assigned a phenotype and findings correlated with external appearances. The diaphragm of each fetus was studied for the absence or presence of CDH and the laterality of defect recorded. Controls (non nitrofen fed) were used for all comparative analysis. Control (n=600) and nitrofen exposed offspring (n=504) had equal frequencies of males and females. CDH occurred with similar incidence in male and female nitrofen treated pups. In all nitrofen exposed fetuses and normal controls, internal and external genitalia concorded without evidence of significant genital tract malformations or intersex states. Prenatal nitrofen exposure is not associated with significant gender differences (or prenatal loss) in the risk of CDH. Genital tract malformations do not appear to accompany CDH in the nitrofen model.