(28) Implementing Mendelian Randomization to Assess Foetal Risk from Intrauterine Prescriptive Drugs for the Treatment of Diabetes, Hypertension and Thyroidism in Pregnancy

Background: Pregnant women are excluded from clinical trials for ethical and practical reasons; thus, little is known about the causal impact of intrauterine medication exposure on developing foetuses. Therefore, concerns about unintentionally inflicting harm to the foetus have increased the vulnerability of mother and child and made it harder to conduct pharmacological research. Yet many chronic conditions necessitate maternal medication use during pregnancy, such as diabetes, hypertension, and thyroid disorders. If left untreated, these conditions have been found to be associated with adverse neonatal outcomes such as preterm birth, intrauterine growth restriction, foetal loss and maternal outcomes. Therefore, the objective of this study is to examine the potential adverse effects of exposure to medications for these conditions during pregnancy on neonates implementing Mendelian Randomization (MR) to discern whether genetic proxies for maternal drug exposures can indicate adverse neonatal drug reactions.

Methods: We conducted a two-sample within-family MR analysis of maternal genetic drug targets on neonatal outcomes using 29,964 parent-offspring trios from The Norwegian Mother, Father and Child Cohort Study (MoBa). We identified genetic proxies for drug targets using DrugBank and the Genotype-Tissue Expression (GTEx) Project. We investigated the association of these maternal genetic variants with neonatal outcomes such as gestational age, birth weight, mode of delivery and apgar score using within family models that included parental genotype to assess intrauterine effects, whilst controlling for environmental confounding. Further, we used the paternal genotype as a negative control to determine whether the SNPs were acting on the offspring via the maternal genotype.

Results: For the relevant treatments indicated by the British National Formulary, we identified and extracted a total of 1064 SNPs as potential instruments for maternal-neonatal intrauterine drug exposure. Our results suggest higher levels of maternal protein targets for antidiabetic drugs decreased head circumference, with an IVW estimated effect of a causal 0.09 cm decrease per SD change (95% CI: 0.01, 0.17). Drug targets for diabetes treatments increased odds of preeclampsia, with estimated odds ratio (OR) 1.41 (95% CI: 1.11, 1.81). Two renin-angiotensin system drug targets increased the odds of a caesarean section, OR of 3.05 (95% CI: 1.13, 8.27) and 2.13 (95% CI: 1.10, 4.14) for the proteins coding for membrane metalloendopeptidase and calcium channel voltage dependent T type alpha 1 I respectively. Yet, the overall renin-angiotensin system maternal protein target estimate was tightly centred around the null, 0.99 (95% CI: 0.81, 1.22) and there was limited evidence from the IVW estimates for an effect of thyroid drug targets on neonatal outcomes. Estimates for the paternal effect of all tested drug targets on offspring outcomes of birth length, gestational age, head circumference and preeclampsia provided little evidence of an effect, indicating a potential maternal drug target effect on the offspring via the intrauterine environment.

Conclusions: Genetic data can provide evidence about the risks to neonates and benefits to mothers of intrauterine medication exposure. Evidence from this study may be used with existing literature, clinical trials, and alternative study types to guide physicians and mothers during pregnancy.