Interaction between placental efflux transporters and use of antiseizure or antidepressant drugs during pregnancy on birth weight in the Norwegian Mother, Father and Child Cohort Study

Abstract

ABSTRACTBackgroundIntrauterine exposure to antiseizure and antidepressant drugs is associated with adverse pregnancy outcomes, including low birth weight. Gene variants in placental efflux transporter genes may alter foetal exposure to these drugs.MethodsWe investigated whether genetic variants in placental efflux transporters modified the impact of maternal antiseizure and antidepressant drug use on offspring birth weight, using data from the Norwegian Mother, Father and Child Cohort Study and the Medical Birth Registry of Norway (69,828 offspring with their genotype data, 81,189 with maternal genotype data). We systematically searched for gene variants in placental efflux transporters influencing drug exposure [MDR1-ABCB1(7 alleles), MRP1-ABCC1(2), MRP2-ABCC2 (3) and, BCRP-ABCG2(2)] and calculated genetic scores (sum of alleles potentially related to low transporter activity). We assessed the interaction between prenatal drug use and genetic scores on birth weight.FindingsPrenatal antiseizure medication exposure was associated with lower birth weight (-95.5 grams, 95% CI -190 to -0.78). This relationship depended on the offspring’s MRP2-ABCC2genetic score. Birth weight differences between exposed vs. unexposed were 70.3 g (95% CI -494 to 634) in the lowest genetic score category and -306 g (95% CI -361 to -31.8) in the highest (interactionp-value = 0.019; main variant: rs3740066). The antiseizure medication-lower birth weight association also depended on the maternal MDR1-ABCB1genetic score. Birth weight differences between exposed vs. unexposed were -66.8 g (95% CI -225 to 91.2) in the lowest genetic score category and -317 g (95% CI -517 to -117) in the highest (interactionp-value = 0.037; main variants: rs10248420 and rs2235015). Prenatal antidepressant exposure was associated with low birth weight, but no gene-drug interactions were observed.ConclusionsMRP2-ABCC2and MDR1-ABCB1variants may influence prenatal antiseizure medication’s impact on neonatal birth weight.SUMMARYWhat is already known on this topic- Low birth weight increases the risk of neonatal death, morbidity, and lifelong susceptibility to various health conditions, including neurodevelopmental, cardiometabolic, respiratory, and psychiatric disorders.- Previous studies have reported an association between maternal use of centrally acting medication during pregnancy and low birth weight in the offspring, but the underlying causes remain poorly understood.- It is of great concern to identify strategies that can modulate foetal exposure to these medications and enable individualised, safe use since discontinuation may also increase the risk of harm to the mother.What this study adds- Our study uncovered genetic variants in both offspring (rs3740066) and mother (rs10248420 and rs2235015) linked to placental efflux transporters that modulated the association between maternal antiseizure drug use during pregnancy and the risk of low birth weight in the offspring, marking the first exploration of such interactions.- If these findings are confirmed and information about specific drugs is incorporated, this could potentially be used in the development of personalized recommendations for pregnant women undergoing these treatments.