Maternal risk factors for theVACTERLassociation: AEUROCATcase–control study

Abstract

Background The VACTERL association (VACTERL) is the nonrandom occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies. Despite suggestions for involvement of several genes and nongenetic risk factors from small studies, the etiology of VACTERL remains largely unknown. Objective To identify maternal risk factors for VACTERL in offspring in a large European study. Methods A case–control study was performed using data from 28 EUROCAT registries over the period 1997–2015 with case and control ascertainment through hospital records, birth and death certificates, questionnaires, and/or postmortem examinations. Cases were diagnosed with VACTERL, while controls had a genetic syndrome and/or chromosomal abnormality. Data collected included type of birth defect and maternal characteristics, such as age, use of assisted reproductive techniques (ART), and chronic illnesses. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) with 95% confidence intervals (95% CI). Results The study population consisted of 329 VACTERL cases and 49,724 controls with recognized syndromes or chromosomal abnormality. For couples who conceived through ART, we found an increased risk of VACTERL (aOR 2.3 [95% CI 1.3, 3.9]) in offspring. Pregestational diabetes (aOR 3.1 [95% CI 1.1, 8.6]) and chronic lower obstructive pulmonary diseases (aOR 3.9 [95% CI 2.2, 6.7]) also increased the risk of having a child with VACTERL. Twin pregnancies were not associated with VACTERL (aOR 0.6 [95% CI 0.3, 1.4]). Conclusion We identified several maternal risk factors for VACTERL in offspring befitting a multifactorial etiology.

A Novel Co-occurrence of VACTERL and Closed Neural Tube Defect

“…A few familial clusters has been reported [12]. Maternal diabetes has been implicated as one of the causative factors [13], however, our patient had normal blood sugar levels.…”

NAD+ deficiency in human congenital malformations and miscarriage: A new model of pleiotropy

“…Diabetic embryopathy overlaps multiple malformation conditions discussed here in the following anomalies: congenital heart defects, vertebral, renal, and limb defects, anal anomalies, caudal dysgenesis, hemifacial microsomia, cleft lip ± cleft palate, neural tube defects, sirenomelia, and urorectal septum malformation (Castori, 2013). Pregestational diabetes is listed as a risk factor for VACTERL anomalies, along with assisted reproductive technologies (ART), and chronic obstructive pulmonary disease, all of which could cause anomalies through diminished NAD+ (Adam et al, 2020; Lubinsky, 2017; van de Putte, van Rooij, Haanappel, et al, 2020). Thus, NAD+ deficiency is a plausible mechanism for diabetic embryopathy.…”

Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus

“…Unlike CDH, EA/TEF is a feature of VACTERL association. Several maternal risk factors, such as conception via assisted reproductive technologies, pregestational diabetes, and chronic obstructive lower pulmonary diseases, are positively correlated with the risk of having a child with VACTERL association (Lubinsky, 2018; van de Putte et al, 2020). Epigenetic factors have also been postulated to contribute to the development of VACTERL association (Lubinsky, 2018; Solomon, 2018).…”