Maternal Hypertension Increases Risk of Preeclampsia and Low Fetal Birthweight: Genetic Evidence From a Mendelian Randomization Study

Abstract

Background: Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing preeclampsia or eclampsia, and low fetal birthweight.

Methods: Uncorrelated single-nucleotide polymorphisms associated systolic blood pressure (SBP), body mass index, type 2 diabetes, LDL (low-density lipoprotein) with cholesterol, smoking, urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate at genome-wide significance in studies of 298 957 to 1 201 909 European ancestry participants were selected as instrumental variables. A 2-sample Mendelian randomization study was performed with primary outcome of preeclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight.

Results: Higher genetically predicted SBP was associated increased risk of PET (odds ratio [OR] per 1-SD SBP increase 1.90 [95% CI=1.45-2.49]; P=3.23×10^-6) and reduced birthweight (OR=0.83 [95% CI=0.79-0.86]; P=3.96×10^-18), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase =1.67 [95% CI=1.44-1.94]; P=7.45×10^-12; and OR per logOR increase type 2 diabetes =1.11 [95% CI=1.04-1.19]; P=1.19×10^-3), but not with reduced birthweight.

Conclusions: Our results provide evidence for causal effects of SBP, body mass index, and type 2 diabetes on PET and identify that SBP is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.

Keywords: birth weight; blood pressure; body mass index; preeclampsia; risk factors.

Figure 1. Data acquisition and analysis flowchart.

Figure 2

Mendelian randomization inverse-variance weighted estimates for effect of genetically-predicted body mass index (BMI), type 2 diabetes (T2DM), systolic blood pressure (SBP), low density lipoprotein cholesterol (LDL-C), smoking, urinary albumin-to-creatinine ratio (uACR) and estimated glomerular filtration rate (eGFR) on the outcome of pre-eclampsia or eclampsia.

Figure 3

Sensitivity analyses for effect of genetically-predicted body mass index (BMI), systolic blood pressure (SBP), low density lipoprotein cholesterol (LDL-C), type 2 diabetes (T2DM), smoking, urinary albumin-to-creatinine ratio (uACR) and estimated glomerular filtration rate (eGFR) on the outcome of pre-eclampsia or eclampsia: Mendelian randomization Egger (MR-Egger), weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) estimates. Odds ratios and 95% confidence intervals (OR [95% CI]) are presented for every 1-SD increase genetically-predicted BMI, SBP, LDL-C, Smoking index, uACR and eGFR; and for every logOR increase in T2DM liability.

Figure 4

Univariable and multivariable Mendelian randomization estimates for effect of body mass index (BMI), type 2 diabetes (T2DM) and systolic blood pressure (SBP), alone and with adjustment for pre-eclampsia or eclampsia (PET) on the outcome of birthweight of first child for mediation analysis. Odds ratios and 95% confidence intervals (OR [95% CI]) are presented for every 1-SD increase genetically-predicted BMI and SBP and for every logOR increase in T2DM liability. Adjusted odds ratio (aOR) and 95% CI is presented for every 1-SD increase genetically-predicted SBP adjusted for the effect of every logOR increase in PET risk on birthweight.