Pathogenesis of Congenital Malformations: Possible Role of Oxidative Stress

Abstract

Objective Congenital anomalies are important causes of morbidity and mortality in children. Oxidative stress (OS) is involved in the physiopathology of pregnancy-related congenital malformations. This review summarizes the role of OS in the pathogenesis of congenital malformations; in particular, its purpose is to describe how OS influences the development of heart congenital malformations, oesophageal atresia, biliary atresia, diaphragmatic hernia, and autosomal dominant polycystic kidney disease. Study Design Systematic review of previous studies about the role of OS in pregnancy and its possible effects in developing of congenital malformations. One electronic database (PubMed) was searched and reference lists were checked. Results An imbalance between the production of reactive oxygen species (ROS) and antioxidant defense can occur early in pregnancy and continue in the postnatal life, producing OS. It may destroy the signaling pathways needed for a correct embryogenesis leading to birth defects. In fact, cell functions, especially during embryogenesis, needs specific signaling pathways to regulate the development. These pathways are sensitive to both endogenous and exogenous factors; therefore, they can produce structural alterations of the developing fetus. Conclusion Because OS plays a significant role in pathogenesis of congenital malformations, studies should be developed in order to better define their OS mechanisms and the beneficial effects of supplemental therapeutic strategies. Key Points

Type of infertility and prevalence of congenital malformations

“…PCOS, the most common ovulatory disorder, is characterised by insulin resistance (distinct from that associated with obesity) and increased oxidative stress, 54 which may be involved in the aetiology of congenital abnormalities. 22,[55][56][57] Our estimate of a 50-60% higher prevalence of malformations among children of mothers with ovulatory disorders is higher than previously reported. 6,7,22,23 However, these studies differed in design, populations and definitions.…”

A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder

“…In this regard, the disruption of mitochondrial redox signaling and control by oxidative stress can also alter signaling pathways and is a known mechanism of congenital malformations 56 . It has notably been involved in the pathogenesis of heart and brain malformations and digestive atresia, reminiscent of the phenotypes we describe 56 , 57 .…”

Cellular, molecular, and metabolic aspects of developing lungs in congenital diaphragmatic hernia

“…Hypoxic environment in CDH causes enhanced production of reactive oxygen species (ROS) leading to remodeling of growing vessels via smooth muscle cell hyperplasia, endothelial dysfunction, and enhanced contractility that eventually manifests as PPHN ( 61 , 62 ). A low level of antioxidant activity with high ROS may destroy the signaling pathways to regulate the growth of developing organs ( 63 ). Supplementation of Vit E as an antioxidant in rat model have shown some lower trend to CDH but does not have any significant effect on lung hypoplasia ( 64 ) Deficient antioxidant activity can be a future therapeutic target for CDH.…”