Postnatal Genetic and Neurodevelopmental Assessment in Infants Born at Term With Severely Low Birth Weight of Non-placental Origin

Abstract

ABSTRACT Small for gestational age (SGA) newborns are generally defined as those with a birth weight below the 10th percentile. Fetuses diagnosed with fetal growth restriction (FGR) are usually evaluated to determine if there is a pathological cause and thus a higher risk for adverse outcomes due to being small. Often when this diagnosis is made early in the third trimester, chromosomal microarray analysis is recommended to detect genetic disease. This study was designed to determine the frequency of monogenic disorders in term infants with severely low birth weight but normal Doppler results, as well as to estimate the frequency of neurodevelopmental impairment when a genetic etiology was ruled out. Inclusion criteria for this study were singleton pregnancy; term delivery; birth weight more than 2.5 SDs below the mean; normal Doppler studies of the umbilical artery, fetal middle cerebral artery, cerebroplacental ratio, and uterine artery; no maternal hypertensive disease; and no prenatal fetal structural or identified genetic anomalies or fetal infection. Exclusion criteria included incomplete data. Exome sequencing was completed using saliva sampling and blood sampling, and standard neurodevelopmental assessment techniques were used for children 2 to 3.5 and 6 to 8 years old. Children aged between 3.5 and 6 years were not included because of lack of standardized neurodevelopmental testing. A total of 63 families were contacted, and 7 (11%) reported that a genetic disorder had been diagnosed after birth. In addition, 18 individuals without a known genetic disorder who met all the criteria underwent exome sequencing and neurodevelopmental testing. Of the 7 who reported a postnatally diagnosed genetic syndrome, 5 were Mendelian monogenetic and 2 were epigenetic, including Cockayne syndrome; short stature, microcephaly, and endocrine dysfunction syndrome; Renpenning syndrome; Noonan syndrome; Russell-Silver syndrome; and Prader-Willi syndrome. Median birth weight among the children with genetic disorders was not different from children without. Exome sequencing was normal in the 18 children who were tested and who had not been previously diagnosed with a genetic syndrome. None of the children showed less than average neurodevelopment on overall assessment in the lower age group. In the higher age group, 2 children were classified as having low IQ, with one borderline and one extremely low, with low scores in all other domains as well. In addition, 6 individuals showed a low score in at least 1 of the 5 domains, with the largest deviations showing in the domains of verbal comprehension and working memory. Clinicians should be aware of the potential outcomes of FGR even when other complications are not present. Counseling about genetic analysis prenatally or within a short postnatal timeframe could save a lot of time and effort in evaluating children later. In addition, children should be carefully assessed in later childhood for neurodevelopmental differences that are treatable or that may require different resources. Future research should focus on further homogenizing the population to get more accurate results, as well as dealing with potential biases in this study.