(C40) Implementing Mendelian randomization to assess foetal risk from intrauterine prescriptive drugs for the treatment of glycaemic conditions, hypertension and thyroidism in pregnancy

Publication Number: 984

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. Yet many chronic conditions necessitate maternal medication use during pregnancy, such as diabetes, hypertension, and thyroid disorders.

Objectives: To identify maternal genetic drug targets for the treatment of hypertension, glycaemic and thyroid related conditions.
To predict the potential effects of exposure to medications for these conditions during pregnancy on neonates.

Methods: We conducted a two-sample within-family Mendelian Randomization analysis of the effect of genetically proxied drug targets for treatments of hypertension, glycaemic conditions and thyroid related conditions on neonatal outcomes using 19,365 parent-offspring trios from The Norwegian Mother, Father and Child Cohort Study (MoBa). Genetic proxies for drug targets were identified using DrugBank and expression quantitative trait loci from the Genotype-Tissue Expression (GTEx) Project. Neonatal outcomes included gestational age, birthweight, and pre-eclampsia. Paternal genotype was assessed as a negative control.

Results: 1275 distinct SNPs were identified as potential instruments for drug target exposure.

Our results suggest genetically proxied higher levels of maternal protein targets for treatments of diabetes and hypertension had limited evidence for an effect on neonatal outcomes. Genetic proxies for exposure to antithyroid drug targets increased neonatal apgar scores at 1 minute with an estimated unit increase per SD change in protein target of 0.13 (95% CI: 0.03, 0.24) for maternal exposure and 0.11 (95% CI: 0.00, 0.22) for paternal exposure. These similar estimates suggest that the maternal intrauterine environment does not play a substantial role in this relationship. Effects did not persist for the maternal or paternal exposure when we considered apgar scores at 5 minutes.

Conclusions: Mendelian Randomization 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.