An epigenetic association of malformations, adverse reproductive outcomes, and fetal origins hypothesis related...

VACTERL, the prototype for associated congenital anomalies, also has connections with functional issues such as pregnancy losses, prematurity, growth delays, perinatal difficulties, and parental subfertility. This segues into a broader association with similar connections even in the absence of malformations. DNA methylation disturbances in the ovum are a likely cause, with epigenetic links to individual components and to folate effects before conception, explaining diverse fetal and placental findings and providing a link to fetal origin hypothesis-related effects. The association encompasses the following: (1) Pre- and periconceptual effects, with frequent fertility issues and occasional imprinting disorders. (2) Early malformations. (3) Adverse pregnancy outcomes (APOs), as above. (4) Developmental destabilization that resolves soon after birth. This potentiates other causes of association findings, introducing multiple confounders. (5) Long-term fetal origins hypothesis-related risks. The other findings are exceptional when the same malformations have Mendelian origins, supporting a distinct pathogenesis. Expressions are facilitated by one-carbon metabolic issues, maternal and fetal stress, and decreased embryo size. This may be one of the commonest causes of adverse reproductive outcomes, but multifactorial findings, variable onsets and phenotypes, and interactions with multiple confounders make recognition difficult. This association supports VACTERL as a continuum that includes isolated malformations, extends the fetal origins hypothesis, explains adverse effects linked to maternal obesity, and suggests possible interventions.