Several epidemiological studies suggest an association between being born too young and abnormal neurodevelopment in early childhood and later in life. However, there is little evidence that these factors are causally related to the harsh intrauterine environment.new research in JAMA Psychiatry Let’s discuss this topic in more detail.
study: Intrauterine growth and child neurodevelopmental characteristics: Mendelian randomization analysis of the Norwegian Mother, Father, and Child Cohort Study (MoBa)). Image credit: Blue Planet Studio / Shutterstock.com
background
The developmental origins of health and disease hypothesis states that health and disease, including cardiometabolic health, are determined by early development: in the womb and early childhood.
Birth weight is often used to represent intrauterine growth and, as a result, has been a variable of interest in multiple neurodevelopmental studies. Previous studies have been primarily observational, increasing the potential for confounding bias. Therefore, many of the observed associations between birth weight and future health outcomes may be noncausal, as the results of these studies are contradictory.
Mendelian randomization (MR) allows researchers to investigate the degree of causality of exposure-outcome associations without the need for randomized controlled trials, the gold standard of clinical research. MR depends on the association between the genetic variation associated with the exposure being studied and the outcome of interest. These factors are less susceptible to confounding and reverse causation than variables typically used in epidemiological studies.
Previous MR-based studies have investigated associations between other offspring traits and exposures during pregnancy and later cardiometabolic health, but not associations with neurodevelopmental outcomes. .
About research
The current study is based on data from the Norwegian Mother and Child Cohort Study (MoBa), a pregnancy cohort based on a population sample. The study was conducted from June 1999 to December 2008 and examined genotype and other characteristics of more than 114,000 children born to more than 95,000 women and 75,000 fathers data was included.
These data were analyzed to identify causal relationships between genetic variants that influence birth weight and were used as a surrogate for intrauterine growth and neurodevelopment of the offspring. Using both maternal and fetal genetic variations, we investigated whether poor intrauterine environment, poor fetal growth, or both influence the risk of abnormal neurodevelopmental disorders.
Testing whether SNPs associated with maternal birth weight are also associated with NDD in the offspring (conditional on the offspring’s genotype at the same locus) would be informative regarding causality.”
Therefore, an unfavorable maternal environment, as indicated by unfavorable maternal genetic mutations, could be used to predict future neurodevelopmental outcomes in offspring.
What did the research show?
Children’s neurodevelopment was examined at five time points from 6 months to 8 years of age. More specifically, the children were evaluated for language problems, motor dysfunction, attention problems, hyperactivity and impulsivity, social communication difficulties, and repetitive behaviors. As expected from earlier studies, multiple negative associations were observed using traditional epidemiological tools.
The causality of the observed epidemiological associations was assessed using MR, which relies on maternal, paternal, and fetal allele or gene mutation scores that are consistently strongly associated with birth weight.
The researchers classified the alleles into different sets. The first set consists of maternal variations associated with child birth weight and neurodevelopmental outcomes, thus suggesting an influence of the intrauterine environment on child neurodevelopment.
The second set includes maternal and fetal alleles associated with birth weight and neurodevelopment. The third set consisted of fetal alleles associated with birth weight and was used to suggest fetal effects on neurodevelopment.
Allele scores for fathers, mothers, and children were associated with significantly increased birth weight.
Autism-related traits increased inversely with birth weight at all time points. These include reduced social communication and restricted or repetitive behaviors at 3 years of age, attention-deficit/hyperactivity disorder (ADHD) characteristics at 18 months and 3 years of age, and characteristics of attention-deficit/hyperactivity disorder (ADHD) at 8 years of age. Disruptive behavioral traits such as ADHD, hyperactive-impulsive behavior, and inattention were included. Movement disorders were also observed at 18 months and 5 years of age.
There has been some limited evidence that fetal genetic variations are associated with these neurodevelopmental risks. No significant relationship was observed between maternal variants associated with intrauterine growth and future effects on neurodevelopment.
What is the impact?
The current influential study failed to identify a causal relationship between maternal genetic influences on birth weight and child neurodevelopmental disorders. Therefore, the maternal intrauterine environment is not considered to be a significant cause of these diseases.
Nevertheless, some evidence suggests that fetal genetic variation may play a limited role in determining the risk of these defects in low birth weight infants, and this describes consistent observations reported in previous epidemiological studies. However, the relevance of these MRs needs to be verified in future studies.
In the current study, we only investigated mutations that affect birth weight and excluded other factors that may cause unfavorable neurodevelopmental outcomes, such as gestational diabetes. Therefore, additional MR studies incorporating different perinatal exposures are needed to elucidate the association between early life exposures and offspring neurodevelopment.
