Background Pregnancy complications are influenced by a complex interplay of socioeconomic and reproductive factors. Observational studies have suggested associations with socioeconomic traits—such as educational attainment (EDU), household income (INC), and physically demanding work (PDW)—as well as reproductive traits including age at first sexual intercourse (AFS) and age at first birth (AFB). However, observational findings are prone to confounding and reverse causation, making it difficult to establish causality. Therefore, this study applies Mendelian randomization (MR) to investigate the causal relationships between reproductive and socioeconomic traits and the risk of pregnancy complications. Methods We conducted univariable and multivariable MR analyses to assess the causal effects of reproductive traits and socioeconomic traits on pregnancy complications. Genetic instruments reaching genome-wide significance (P < 5 × 10⁻8) were selected from large-scale genome-wide association studies (GWAS) involving 263,615 to 766,345 participants for socioeconomic traits (EDU, INC, PDW) and 214,547 to 418,758 participants for reproductive traits (AFS, AFB). Outcome data were derived from GWAS based on biobank datasets for eight pregnancy complications: spontaneous abortion (SA), postpartum depression (PD), gestational diabetes (GD), Pre-eclampsia or eclampsia (PE), premature rupture of membranes (PRM), premature separation of placenta (PSP), intrahepatic cholestasis of pregnancy (ICP), and hyperemesis gravidarum (HG). Sample sizes ranged from 294 to 9,113 cases and 59,610 to 117,892 controls. Results Univariable MR analysis identified significant associations, including AFB–PD(OR = 0.90, 95% CI: 0.81–0.98, P = 0.024 ), AFS–SA(OR = 0.77, 95% CI: 0.62–0.96, P = 0.020 ), AFS–PD(OR = 0.46, 95% CI: 0.36–0.59, P < 0.001 ), AFS–GD(OR = 0.62, 95% CI: 0.48–0.82, P < 0.001 ), AFS–PRM (OR = 0.68, 95% CI: 0.48–0.94, P = 0.020 ), EDU–SA (OR = 0.83, 95% CI: 0.71–0.97, P = 0.020 ), EDU–PD (OR = 0.55, 95% CI: 0.46–0.67, P < 0.001 ), EDU–GD (OR = 0.68, 95% CI: 0.56–0.83, P < 0.001 ), EDU–PRM (OR = 0.72, 95% CI: 0.56–0.94, P = 0.010 ), INC–PD (OR = 0.58, 95% CI: 0.48–0.70, P < 0.001 ), INC–GD (OR = 0.65, 95% CI: 0.43–0.97, P = 0.030 ), PDW–PD (OR = 2.00, 95% CI: 1.06–3.77, P = 0.030 ), and PDW–PE (OR = 2.80, 95% CI:1.09–7.18, P = 0.030 ). Multivariable MR analysis confirmed independent protective effects of higher EDU on PD (OR = 0.58, 95% CI: 0.37–0.91, P = 0.020 ), GD (OR = 0.58, 95% CI: 0.35–0.96, P = 0.030 ), and PRM (OR = 0.44, 95% CI: 0.24–0.81, P = 0.010 ). AFS was independently associated with an increased risk of PSP(OR = 1.86, 95% CI: 1.03–3.36, P = 0.040).Two-step MR mediation indicated that AFS partially mediates the EDU–outcome relationship for SA, PD, GD, and PSP (proportions mediated ~ 55–65% ), while the reverse pathway (EDU as mediator of AFS) showed smaller but directionally consistent mediation (~ 24–29% ). Conclusion Lower EDU is causally associated with increased risks of PD, PE, and PRM. Educational level may influence reproductive timing, such as AFS, which in turn affects the likelihood of pregnancy complications. These findings highlight the potential benefits of targeted educational and social interventions in mitigating adverse pregnancy outcomes.

Mendelian randomization study on the effects of women’s reproductive traits and socioeconomic traits on pregnancy complications

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2026年6月17日

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Liwen Zhang,
Yu Xia,
Weidi Wang

摘要

Background

Pregnancy complications are influenced by a complex interplay of socioeconomic and reproductive factors. Observational studies have suggested associations with socioeconomic traits—such as educational attainment (EDU), household income (INC), and physically demanding work (PDW)—as well as reproductive traits including age at first sexual intercourse (AFS) and age at first birth (AFB). However, observational findings are prone to confounding and reverse causation, making it difficult to establish causality. Therefore, this study applies Mendelian randomization (MR) to investigate the causal relationships between reproductive and socioeconomic traits and the risk of pregnancy complications.

Methods

We conducted univariable and multivariable MR analyses to assess the causal effects of reproductive traits and socioeconomic traits on pregnancy complications. Genetic instruments reaching genome-wide significance (P < 5 × 10⁻⁸) were selected from large-scale genome-wide association studies (GWAS) involving 263,615 to 766,345 participants for socioeconomic traits (EDU, INC, PDW) and 214,547 to 418,758 participants for reproductive traits (AFS, AFB). Outcome data were derived from GWAS based on biobank datasets for eight pregnancy complications: spontaneous abortion (SA), postpartum depression (PD), gestational diabetes (GD), Pre-eclampsia or eclampsia (PE), premature rupture of membranes (PRM), premature separation of placenta (PSP), intrahepatic cholestasis of pregnancy (ICP), and hyperemesis gravidarum (HG). Sample sizes ranged from 294 to 9,113 cases and 59,610 to 117,892 controls.

Results

Univariable MR analysis identified significant associations, including AFB–PD(OR = 0.90, 95% CI: 0.81–0.98, P = 0.024 ), AFS–SA(OR = 0.77, 95% CI: 0.62–0.96, P = 0.020 ), AFS–PD(OR = 0.46, 95% CI: 0.36–0.59, P < 0.001 ), AFS–GD(OR = 0.62, 95% CI: 0.48–0.82, P < 0.001 ), AFS–PRM (OR = 0.68, 95% CI: 0.48–0.94, P = 0.020 ), EDU–SA (OR = 0.83, 95% CI: 0.71–0.97, P = 0.020 ), EDU–PD (OR = 0.55, 95% CI: 0.46–0.67, P < 0.001 ), EDU–GD (OR = 0.68, 95% CI: 0.56–0.83, P < 0.001 ), EDU–PRM (OR = 0.72, 95% CI: 0.56–0.94, P = 0.010 ), INC–PD (OR = 0.58, 95% CI: 0.48–0.70, P < 0.001 ), INC–GD (OR = 0.65, 95% CI: 0.43–0.97, P = 0.030 ), PDW–PD (OR = 2.00, 95% CI: 1.06–3.77, P = 0.030 ), and PDW–PE (OR = 2.80, 95% CI:1.09–7.18, P = 0.030 ). Multivariable MR analysis confirmed independent protective effects of higher EDU on PD (OR = 0.58, 95% CI: 0.37–0.91, P = 0.020 ), GD (OR = 0.58, 95% CI: 0.35–0.96, P = 0.030 ), and PRM (OR = 0.44, 95% CI: 0.24–0.81, P = 0.010 ). AFS was independently associated with an increased risk of PSP(OR = 1.86, 95% CI: 1.03–3.36, P = 0.040).Two-step MR mediation indicated that AFS partially mediates the EDU–outcome relationship for SA, PD, GD, and PSP (proportions mediated ~ 55–65% ), while the reverse pathway (EDU as mediator of AFS) showed smaller but directionally consistent mediation (~ 24–29% ).

Conclusion

Lower EDU is causally associated with increased risks of PD, PE, and PRM. Educational level may influence reproductive timing, such as AFS, which in turn affects the likelihood of pregnancy complications. These findings highlight the potential benefits of targeted educational and social interventions in mitigating adverse pregnancy outcomes.