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. 2024 Jan 2;7(1):e2351166.
doi: 10.1001/jamanetworkopen.2023.51166.

Mediating Factors in the Association of Maternal Educational Level With Pregnancy Outcomes: A Mendelian Randomization Study

Tormod Rogne  1   2 , Dipender Gill  3 , Zeyan Liew  2   4 , Xiaoting Shi  4 , Vilde Hatlevoll Stensrud  5 , Tom Ivar Lund Nilsen  5   6 , Stephen Burgess  7   8
Affiliations

Mediating Factors in the Association of Maternal Educational Level With Pregnancy Outcomes: A Mendelian Randomization Study

Tormod Rogne et al. JAMA Netw Open. .

Abstract

Importance: Lower educational attainment is associated with increased risk of adverse pregnancy outcomes, but it is unclear which pathways mediate this association.

Objective: To investigate the association between educational attainment and pregnancy outcomes and the proportion of this association that is mediated through modifiable cardiometabolic risk factors.

Design, setting, and participants: In this 2-sample mendelian randomization (MR) cohort study, uncorrelated (R2 < 0.01) single-nucleotide variants (formerly single-nucleotide polymorphisms) associated with the exposure (P < 5 × 10-8) and mediators and genetic associations with the pregnancy outcomes from genome-wide association studies were extracted. All participants were of European ancestry and were largely from Finland, Iceland, the United Kingdom, or the US. The inverse variance-weighted method was used in the main analysis, and the weighted median, weighted mode, and MR Egger regression were used in sensitivity analyses. In mediation analyses, the direct effect of educational attainment estimated in multivariable MR was compared with the total effect estimated in the main univariable MR analysis. Data were extracted between December 1, 2022, and April 30, 2023.

Exposure: Genetically estimated educational attainment. The mediators considered were genetically estimated type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure.

Main outcomes and measures: Ectopic pregnancy, hyperemesis gravidarum, gestational diabetes, preeclampsia, preterm birth, and offspring birth weight.

Results: The analyses included 3 037 499 individuals with data on educational attainment, and those included in studies on pregnancy outcomes ranged from 141 014 for ectopic pregnancy to 270 002 with data on offspring birth weight. Each SD increase in genetically estimated educational attainment (ie, 3.4 years) was associated with an increased birth weight of 42 (95% CI, 28-56) g and an odds ratio ranging from 0.53 (95% CI, 0.46-0.60) for ectopic pregnancy to 0.81 (95% CI, 0.71-0.93) for preeclampsia. The combined proportion of the association that was mediated by the 5 cardiometabolic risk factors ranged from -17% (95% CI, -46% to 26%) for hyperemesis gravidarum to 78% (95% CI, 10%-208%) for preeclampsia. Sensitivity analyses accounting for pleiotropy were consistent with the main analyses.

Conclusions and relevance: In this MR cohort study, intervening for type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure may lead to reductions in several adverse pregnancy outcomes associated with lower levels of education. Such public health interventions would serve to reduce health disparities attributable to social inequalities.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rogne reported receiving grant funding from the National Institutes of Health during the conduct of the study. Dr Gill reported parttime employment by Novo Nordisk A/S outside the submitted work. Ms Shi reported receiving a scholarship from the Yale Graduate School of Arts and Sciences outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Associations Between Genetically Estimated Educational Attainment and Pregnancy Outcomes
Results of inverse variance–weighted 2-sample mendelian randomization analyses are shown. Estimates are odds ratios (ORs) for pregnancy outcomes and grams of birth weight per 1-SD increase of genetically estimated years of education (3.4 years).
Figure 2.
Figure 2.. Associations Between Genetically Estimated Educational Attainment and Cardiometabolic Mediators
Results of inverse variance–weighted 2-sample mendelian randomization analyses are shown. Estimates are the change in the mediator per 1-SD increase of genetically estimated years of education (3.4 years), and the mediators are in log(odds) units for type 2 diabetes (T2D) and in SD units for the other cardiometabolic risk factors. BMI indicates body mass index; HDL-C, high-density lipoprotein cholesterol level; and SBP, systolic blood pressure.
Figure 3.
Figure 3.. Associations Between Genetically Estimated Cardiometabolic Mediators and Pregnancy Outcomes
Results of inverse variance–weighted 2-sample mendelian randomization analyses are shown. Estimates are odds ratios (ORs) for pregnancy outcomes and grams of birth weight per 1-unit increase of the genetically estimated log(odds) of type 2 diabetes (T2D) and 1-SD increase of the other genetically estimated cardiometabolic traits. BMI indicates body mass index; HDL-C, high-density lipoprotein cholesterol level; and SBP, systolic blood pressure.
Figure 4.
Figure 4.. Associations Between Genetically Estimated Educational Attainment and Pregnancy Outcomes After Accounting for Cardiometabolic Mediators
Results of mendelian randomization mediation analyses are shown. Estimates are odds ratios (ORs) for pregnancy outcomes and grams of birth weight per a 1-SD increase of genetically estimated years of education (3.4 years). BMI indicates body mass index; HDL-C, high-density lipoprotein cholesterol level; NA, not applicable; PM, proportion mediated; SBP, systolic blood pressure; and T2D, type 2 diabetes.
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References

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