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Observational Study
. 2025 Apr 15;85(14):1488-1500.
doi: 10.1016/j.jacc.2025.02.015.

Genetic Risk and First-Trimester Cardiovascular Health Predict Hypertensive Disorders of Pregnancy in Nulliparous Women

Vineetha Mathew  1 , Raiyan R Khan  2 , Amanda R Jowell  3 , Qi Yan  2 , Itsik Pe'er  2 , Buu Truong  4 , Pradeep Natarajan  5 , Lynn M Yee  6 , Sadiya S Khan  7 , Garima Sharma  8 , Aniruddh P Patel  5 , So Mi Jemma Cho  4 , Maria A Pabon  9 , Rebecca B McNeil  10 , Jillyn Spencer  11 , Robert M Silver  12 , Lisa D Levine  13 , William A Grobman  14 , Janet M Catov  15 , David M Haas  16 , Michael C Honigberg  17
Affiliations
Observational Study

Genetic Risk and First-Trimester Cardiovascular Health Predict Hypertensive Disorders of Pregnancy in Nulliparous Women

Vineetha Mathew et al. J Am Coll Cardiol. .

Abstract

Background: Hypertensive disorders of pregnancy (HDPs) (preeclampsia/eclampsia and gestational hypertension) are a leading cause of maternal and perinatal morbidity and mortality and are associated with long-term maternal cardiovascular disease. High genetic risk and poor cardiovascular health (CVH) are each associated with HDPs, but whether genetic risk for HDP is modified by CVH status in early pregnancy is unknown.

Objectives: In this study, the authors sought to test the independent and joint associations of genetic risk and first-trimester CVH with development of HDP.

Methods: We examined genotyped participants from the nuMoM2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be), a prospective observational cohort that enrolled nulliparous individuals with singleton pregnancies from 2010 to 2013 at 8 U.S. clinical sites. Genetic risk was calculated according to a validated genetic risk score for HDP. A first-trimester CVH score was closely adapted from the American Heart Association Life's Essential 8 model. Genetic risk and CVH were each categorized as low (bottom quintile), intermediate (quintile 2-4), or high (top quintile). The primary outcome was development of HDP. Multivariable-adjusted logistic regression was used to test the independent and joint associations of genetic risk and CVH with development of HDPs.

Results: Among 7,499 participants (mean age 27.0 years), the median first-trimester CVH score was 77.1 (Q1-Q3: 67.1-85.7). Overall, 1,032 participants (13.8%) developed an HDP (487 [6.5%] preeclampsia, 545 [7.3%] gestational hypertension). Genetic risk and CVH were each independently and additively associated with HDP (high vs low genetic risk: adjusted OR [aOR]: 2.21 [95% CI: 1.78-2.77; P < 0.001]; low vs high CVH: aOR: 2.92 [95% CI: 2.28-3.74; P < 0.001]). There was no significant interaction between genetic risk and CVH regarding risk of HDPs (Pinteraction > 0.05). HDP incidence ranged from 4.5% (low genetic risk, high CVH) to 25.7% (high genetic risk, low CVH). Compared with low CVH, high CVH was associated with 53%-74% lower risk of HDP across genetic risk strata. Findings were consistent when examining preeclampsia/eclampsia and gestational hypertension separately.

Conclusions: Lower genetic risk and higher first-trimester CVH were independently and additively associated with lower risk of developing HDPs in nulliparous individuals. Favorable CVH in early pregnancy may mitigate high genetic risk for HDP.

Keywords: cardiovascular health; hypertension; hypertensive disorders of pregnancy; polygenic risk scores; preventive cardiology.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Honigberg is supported by the National Heart, Lung, and Blood Institute (NHLBI; K08HL166687), American Heart Association (940166, 24RGRSG1275749), and Patient-Centered Outcomes Research Institute. The nuMoM2b cohort was supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; U10 HD063036, U10 HD063072, U10 HD063047, U10 HD063037, U10 HD063041, U10 HD063020, U10 HD063046, U10 HD063048, and U10 HD063053) and the Clinical and Translational Science Institutes (UL1TR001108 and UL1TR000153). The nuMoM2b Heart Health Study was supported by cooperative agreement funding from the NHLBI and the NICHD (U10-HL119991; U10-HL119989; U10-HL120034; U10-HL119990; U10-HL120006; U10-HL119992; U10-HL120019; U10-HL119993; U10-HL120018, and U01HL145358), the National Center for Advancing Translational Sciences (UL-1-TR000124, UL-1-TR000153, UL-1-TR000439, and UL-1-TR001108), the Barbra Streisand Women’s Cardiovascular Research and Education Program, and the Erika J. Glazer Women’s Heart Research Initiative, Cedars-Sinai Medical Center, Los Angeles, with supplemental support for NHLBI U10-HL119991 from the Office of Research on Women’s Health and the Office of Disease Prevention. DNA extraction and genome-wide association studies of nuMoM2b specimens were supported by the Indiana University Grand Challenges Precision Diabetes Project. Dr Natarajan has received research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche, and Novartis; has received personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis; is a scientific advisory board member for Esperion Therapeutics, Preciseli, and TenSixteen Bio; is a scientific co-founder of TenSixteen Bio; has equity in MyOme, Preciseli, and TenSixteen Bio; and his spouse is employed by Vertex Pharmaceuticals (all unrelated to the present work). Dr Honigberg has received consulting fees from Comanche Biopharma; has served on an advisory board for Miga Health; has worked as site principal investigator for Novartis; and has received research support from Genentech. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

FIGURE 1
FIGURE 1. Adjusted Odds of Developing a Hypertensive Disorder of Pregnancy in the nuMoM2b Study by Genetic Risk and First-Trimester Cardiovascular Health
(A) Analysis in the full cohort (n = 7,499). (B) Analysis in the Heart Health Study subcohort with first-trimester cholesterol levels (n = 3,492). The first-trimester cardiovascular health (CVH) score for the full cohort included diet, physical activity, sleep, nicotine exposure, body mass index, blood pressure, and prepregnancy diabetes. The first-trimester CVH score in the Heart Health Study subcohort additionally incorporated first-trimester non–high-density lipoprotein cholesterol. CVH was categorized as low (bottom quintile), intermediate (middle 3 quintiles), or high (top quintile). Similarly, genetic risk was categorized as low (bottom quintile), intermediate (middle 3 quintiles), or high (top quintile). Models were adjusted for age, education, and marital status.
FIGURE 2
FIGURE 2. Odds of Developing a Hypertensive Disorder of Pregnancy Associated With Individual Components of First-Trimester Cardiovascular Health
The full cohort included 7,499 pregnant women from the nuMoM2b study, of whom 1,032 (13.8%) developed a hypertensive disorder of pregnancy in the index nuMoM2b pregnancy: 487 (6.5%) with preeclampsia/eclampsia and 545 (7.3%) with gestational hypertension. Components of cardiovascular health (CVH) are categorized in accordance with the American Heart Association Life’s Essential 8 framework. Models are adjusted for age, education, and marital status. AHEI = Alternative Healthy Eating Index; BMI = body mass index.
FIGURE 3
FIGURE 3. Population-Attributable Risk for Hypertensive Disorders of Pregnancy Associated With Suboptimal Metrics of First-Trimester Cardiovascular Health in the nuMoM2b Study
The population-attributable risk proportion for hypertensive disorders of pregnancy was calculated for “nonoptimal” values of each component of the cardiovascular health score, as defined by the American Heart Association Life’s Essential 8 framework in the full study cohort (n = 7,499). Abbreviations as in Figures 1 and 2.
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