Maternal obesity and metabolic disorders associate with congenital heart defects in the offspring: A systematic review

Abstract

Background Congenital heart defects (CHDs) are the most common congenital malformations. The aetiology of CHDs is complex. Large cohort studies and systematic reviews and meta-analyses based on these have reported an association between higher risk of CHDs in the offspring and individual maternal metabolic disorders such as obesity, diabetes, hypertension, and preeclampsia, all conditions that can be related to insulin resistance or hyperglycaemia. However, the clinical reality is that these conditions often occur simultaneously. The aim of this review is, in consequence, both to evaluate the existing evidence on the association between maternal metabolic disorders, defined as obesity, diabetes, hypertension, preeclampsia, dyslipidaemia and CHDs in the offspring, as well as the significance of combinations, such as metabolic syndrome, as risk factors. Methods A systematic literature search of papers published between January 1, 1990 and January 14, 2021 was conducted using PubMed and Embase. Studies were eligible if they were published in English and were case-control or cohort studies. The exposures of interest were maternal overweight or obesity, hypertension, preeclampsia, diabetes, dyslipidaemia, and/or metabolic syndrome, and the outcome of interest was CHDs in the offspring. Furthermore, the studies were included according to a quality assessment score. Results Of the 2,250 identified studies, 32 qualified for inclusion. All but one study investigated only the individual metabolic disorders. Some disorders (obesity, gestational diabetes, and hypertension) increased risk of CHDs marginally whereas pre-gestational diabetes and early-onset preeclampsia were strongly associated with CHDs, without consistent differences between CHD subtypes. A single study suggested a possible additive effect of maternal obesity and gestational diabetes. Conclusions Future studies of the role of aberrations of the glucose-insulin homeostasis in the common aetiology and mechanisms of metabolic disorders, present during pregnancy, and their association, both as single conditions and–particularly–in combination, with CHDs are needed.

Molecular Genetics and Complex Inheritance of Congenital Heart Disease

“…The etiology of CHD is heterogeneous, and although the precise environmental contribution to CHD is unknown, environmental factors may contribute to an estimated 10% of CHD. These include, but are not limited to, pre-gestational diabetes, early onset pre-eclampsia, maternal obesity, in-utero exposures to alcohol, maternal Rubella, several medications including aspirin and carbamazepine, and a range of possible environmental exposures [ 23 , 24 , 25 ] ( Figure 1 ). These environmental risk factors could also modify genetic risk in genetically predisposed individuals.…”

“…The contribution of de novo mutations to CHD was first estimated by Zaidi et al [ 8 ], while Jin et al [ 10 ] provided the first model for systematic interrogation of transmitted CHD mutations. Non-genetic etiologies of CHD are reviewed elsewhere [ 23 , 24 , 25 , 26 , 27 ].…”

Metabolomics Signatures and Subsequent Maternal Health among Mothers with a Congenital Heart Defect-Affected Pregnancy

“…Overall, we found that mothers of children with CHDs had metabolomic profiles associated with phospholipid and glutamate metabolism, suggesting that CHD-affected pregnancies may have an influence on the long-term maternal metabolic health. This is particularly notable as CHDs are the most prevalent of birth defects [54] occurring in 8-10 of every 1000 live births in the US [55][56][57][58]. This is one of the first studies to evaluate subsequent maternal health in this population, which provides new insights into disrupted metabolic pathways associated with CHD-affected pregnancies.…”

Prenatal diagnosis of hypoplastic aortic arch without intracardiac malformations: The nevada experience

“…[17][18][19][20] Others have also shown associations with advanced maternal or maternal comorbidities and congenital heart disease. [21][22][23][24] Embedding our fetal cardiologists in all the state's maternal-fetal-medicine clinics provides a population of high-risk pregnancies comprised of both those with maternal comorbidities and abnormal routine obstetric ultrasounds or both. In addition, our previous studies have shown that this nonsiloed system of direct, real-time, onsite collaboration between fetal cardiology and perinatology may result in population-wide, near-universal prenatal detection of critical congenital heart disease.…”