Embryonic hypocellularity, blastogenetic malformations, and fetal growth restriction

Abstract

An association between congenital malformations and fetal growth restriction (FGR) can be largely explained by a relationship with early embryonic hypocellularity. The malformations include the VACTERL association, which is exceptional as a Mendelian syndrome, but is commonly associated with monozygotic twinning, maternal diabetes, and some forms of aneuploidy, all characterized by a small embryo early in development. Parsimony suggests that these different links to VACTERL are related to the hypocellularity as a single common factor, rather than as an expression of three independent pathogenetic processes. A distinct non-genetic pathogenesis is further supported by increased frequencies in the same conditions of a single umbilical artery (SUA), which is also unusual in Mendelian disorders. SUA often involves the atrophy of one artery, which may be facilitated by altered hemodynamics in a smaller embryo, providing a direct link to hypocellularity. Hypocellularity may also explain a possible connection between VACTERL and certain mitochondrial disorders, where reduced energy might slow early cell division and growth, reducing the size of the embryo. © 2016 Wiley Periodicals, Inc.

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

“…Late secondtrimester miscarriages with malformations also occurred about 3 weeks before those without [58]. For typically euploid sirenomelia, 47% of cases were liveborn, 71.2% premature, and 88.2% at under 2500 g, while 8% of informative cases were from multiple gestations, and 5% had diabetic mothers [61], consistent with involvement of the early hypocellularity that is a risk factor for VACTERL [4].…”

“…The atresia probably reflects an early hypocellularity, as seen with conditions such as monozygotic twinning and maternal diabetes. This reduction, although not a direct cause for anomalies, is a predisposition to IBMs [4], and is a likely risk factor for other adverse pregnancy outcomes.…”

“…While physical defects have been the primary focus [3], connections to prematurity, fetal growth restriction (FGR-third trimester weight and length deficiencies here), prenatal lethality, perinatal issues, and parental subfertility will also be shown, supporting an extended disorder. These findings are typically absent when the same malformations occur in Mendelian syndromes [4], indicating a distinct pathogenesis.…”

Relationship between birth weight to placental weight ratio and major congenital anomalies in Japan

“…A possible explanation is that the suboptimal condition of the fetus induced compensatory placental enlargement and a predisposition to preterm birth. Some congenital malformations including those with VACTERL association showed severe fetal growth restriction due to somatic hypocellularity [ 18 ]. In our study, a low BW/PW ratio was identified within the major anomaly subgroups of other anomalies/syndromes and chromosomal abnormality, which may be caused by fetal growth restriction.…”

“…Previous studies have demonstrated that fetal growth restriction was associated with chromosomal abnormality [ 19 ], VACTERL association [ 18 ], congenital heart defects [ 20 ], anencephaly [ 13 ], gastroschisis [ 13 ], esophageal atresia [ 13 ], and renal aplasia [ 13 ]. However, the association between congenital anomalies and the BW/PW ratio remains unknown.…”