Background

Physiologic changes and stressors on the cardiovascular system during pregnancy and associated placental dysfunction and hypoxia can precipitate clinical adverse pregnancy outcomes (APOs) and gestational diabetes mellitus (GDM). APOs are associated with accelerated development of cardiovascular disease (CVD) in women with underlying risk.^1-4 APOs include hypertensive disorders of pregnancy (HDP), preterm birth, and small-for-gestational-age birth.

One in four first-time pregnancies result in APOs, which increase CVD risk.⁵ For example, women with APOs have a 2.4-fold higher risk of hypertension 2 to 7 years after delivery.⁵ While APOs confer increased CVD risk, common antecedents may predispose women to both APOs and CVD.^6,7

As approximately 80% of women give birth in their lifetime, pregnancy offers a critical opportunity to screen young women for cardiovascular risk factors. Identifying atherogenic markers and CVD risk factors before or early in pregnancy may guide interventions to prevent APOs and mitigate future CVD risk.^3,8,9 Catov et al. explored the association between first-trimester atherogenic characteristics, APOs/GDM, and hypertension 2 to 7 years after delivery.¹⁰

Methods

This analysis from the Nulliparous Pregnancy Outcomes Study-Monitoring Mothers-to-Be (nuMoM2b) Heart Health Study included 4,471 primiparous women in the US between 2012 and 2015 who provided non-fasting blood samples in the first trimester of pregnancy and followed up in-person 2 to 7 years after birth. Baseline characteristics measured included lipids, glucose, high sensitivity C-reactive protein (hsCRP), insulin, body mass index (BMI), waist circumference, systolic blood pressure (SBP), and diastolic blood pressure (DBP). Diet and physical activity scores were also generated.

Pregnancy outcomes were determined using chart review, including hypertensive disorders of pregnancy (antepartum gestational hypertension, preeclampsia, eclampsia), preterm birth (<37 weeks), small-for-gestational-age birth, and GDM. Study participants had hypertension at 2 to 7 years after birth if during the Heart Health Study in-person visit (median 3.3 years after birth), they had a systolic blood pressure >130, a diastolic blood pressure >80, or were already taking medications for hypertension.

Statistical associations between first-trimester cardiometabolic risk factors and hypertension 2 to 7 years after first delivery were assessed using Poisson regression. The association between first-trimester cardiometabolic characteristics and APO/GDM was also calculated. A four-way decomposition of effects was utilized to estimate relative risk of first-trimester cardiometabolic factors directly versus mediated by APO/GDM on hypertension 2 to 7 years after birth. Secondary analysis looked at subgroups of "latent" profiles, like higher first-trimester BMI, insulin, hsCRP, and blood pressure.

Results

Overall, higher values of first-trimester cardiometabolic characteristics were associated with any APO or GDM. Specifically, higher BMI, glucose, insulin, hsCRP, triglycerides, baseline blood pressure, and atherosclerotic cardiovascular disease (ASCVD) risk score increased risk of any APO or GDM after adjusting for age, race, insurance, smoking, BMI, and baseline blood pressure. The association between these early pregnancy characteristics and individual APOs varied, with a two-fold increase in triglycerides conferring the greatest relative risk of APO/GDM (RR 1.34, CI 1.21–1.48), followed by insulin (RR 1.08, CI 1.04-1.12), hsCRP (RR 1.06, CI 1.02-1.11), and 5mm Hg increase in DBP (RR 1.06, CI 1.02-1.10).

After adjusting for covariates, early pregnancy cardiometabolic factors were also associated with hypertension 2 to 7 years after pregnancy. Specifically, hypertension after delivery was associated with higher BMI, total cholesterol, LDL-C, glucose, insulin, hsCRP, triglycerides, baseline blood pressure and lower HDL-C, diet quality score, and physical activity score in early pregnancy. Many of these associations remained statistically significant in models additionally adjusting for first-trimester BMI, SBP, and DBP and excluding those with chronic hypertension or pre-gestational diabetes mellitus.

The latent profile analysis compared women in categories of elevated cardiovascular risk with women who had low cardiovascular risk, labeled Class 1 (lowest cholesterol, LDL, glucose, insulin, triglycerides, hsCRP, BP, waist circumference, BMI). In particular, the latent profile "total and LDL-C in the top decile" was associated with a 1.28 RR (CI 1.04-1.58) of any APO or GDM versus Class 1, driven primarily through HDP and GDM.

The latent profiles "mostly obese with higher insulin, hsCRP, and BP", "largely non-obese with higher cholesterols", and "total and LDL-C in the top decile", respectively, had a 2.45 (CI 2.11–2.85), 1.29 (CI 1.06-1.55), and 1.98 (CI 1.60-2.44) relative risk of hypertension 2-7 years after delivery versus Class 1.

This study also identified higher rates of hypertension after delivery among those with APOs/GDM. Importantly, APO/GDM explained <15% of the excess risk of early pregnancy atherogenic risk factors on hypertension 2 to 7 years after delivery, suggesting that early cardiovascular risk factors confer an increased risk of hypertension largely independent of an APO or GDM diagnosis.

Discussion

Early cardiovascular risk factors during pregnancy were associated with APO/GDM and hypertension 2 to 7 years after delivery. Most of this risk of hypertension was not mediated by APOs or GDM. In particular, glucose, hsCRP, and triglycerides were strongly associated with risk of hypertension. This is the first study in the US to explore this relationship in a large cohort of young adult women with such a broad set of atherogenic characteristics.

Latent profiles were identified to assess categories of women at greatest risk for developing hypertension, including "mostly obese with higher insulin, hsCRP, and BP", "largely nonobese with higher cholesterols", and "total and LDL-C in the top decile." Risk profiles and baseline atherogenic characteristics can guide development of tools to identify women who may benefit from earlier and more aggressive risk factor modification. Interventions including optimal blood pressure management or targeted diet and physical activity programs can mitigate future CVD risk.

Strengths of this study include a large, multicenter cohort of primiparous women with complete baseline cardiometabolic characteristics. Notably, blood samples obtained in the first trimester were nonfasting and were not measured serially throughout pregnancy. The study further is limited by its observational nature and inclusion of women able to be evaluated in-person within 2 to 7 years after delivery. Additional investigations applying early pregnancy cardiometabolic risk models to other populations may provide further insights.

Clinical Implications

1. Hypertension is a major risk factor for long-term CVD, including atherosclerosis and heart failure. Screening and intervening early when young women connect with healthcare for pregnancy may be an important way to reduce future disease.¹¹
2. Early pregnancy cardiometabolic risk factors may provide clues for which women may experience an APO or GDM, hypertension after delivery, and cardiovascular disease.¹²
3. Further research should explore ways to best identify women at risk of future cardiovascular disease and determine effective strategies to mitigate risk.

References

1. Honigberg MC, Zekavat SM, Aragam K, et al. Long-term cardiovascular risk in women with hypertension during pregnancy. J Am Coll Cardiol 2019;74:2743-54.
2. Leon LJ, McCarthy FP, Direk K, et al. Preeclampsia and cardiovascular disease in a large UK pregnancy cohort of linked electronic health records. Circulation 2019;140:1050-60.
3. Haas DM, Ehrenthal DB, Koch MA, et al. Pregnancy as a window to future cardiovascular health: design and implementation of the nuMoM2b Heart Health Study. Am J Epidemiol 2016;183:519-30.
4. Catov JM, Althouse AD, Lewis CE, Harville EW, Gunderson EP. Preterm delivery and metabolic syndrome in women followed from prepregnancy through 25 years later. Obstet Gynecol 2016;127:1127–34.
5. Haas DM, Parker CB, Marsh DJ, et al. Association of adverse pregnancy outcomes with hypertension 2 to 7 years postpartum. J Am Heart Assoc 2019;8:e013092.
6. Romundstad PR, Magnussen EB, Smith GD, Vatten LJ. Hypertension in pregnancy and later cardiovascular risk. Circulation 2010;122:579-84.
7. Cho GJ, Jung US, Sim JY, et al. Is preeclampsia itself a risk factor for the development of metabolic syndrome after delivery? Obstet Gynecol Sci 2019;62:233-41.
8. El Khouly NI, Sanad ZF, Saleh SA, Shabana AA, Elhalaby AF, Badr EE. Value of first-trimester serum lipid profile in early prediction of preeclampsia and its severity: a prospective cohort study. Hypertens Pregnancy 2016;35:73-81.
9. Catov JM, Parker CB, Gibbs BB, Carper B, Grobman WA. 71: Patterns of physical activity from early pregnancy through five years after delivery and their association with maternal cardiometabolic health. Am J Obstet Gynecol 2017;216:S50.
10. Catov JM, McNeil RB, Marsh DJ, et al. Early pregnancy atherogenic profile in a first pregnancy and hypertension risk 2 to 7 years after delivery. J Am Heart Assoc 2021;10:e017216.
11. Lui NA, Jeyaram G, Henry A. Postpartum interventions to reduce long-term cardiovascular disease risk in women after hypertensive disorders of pregnancy: a systematic review. Front Cardiovasc Med 2019;6:160.
12. Benschop L, Schalekamp‐Timmermans S, Schelling SJC, Steegers EAP, Roeters van Lennep JE. Early pregnancy cardiovascular health and subclinical atherosclerosis. J Am Heart Assoc 2019;8:e011394.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Hypertension

Keywords: Dyslipidemias, Metabolic Syndrome, Pregnancy, Hypertension, Diabetes, Gestational, Cardiovascular Diseases, C-Reactive Protein, Pregnancy Outcome, Triglycerides, Glucose, Risk Factors, Hypertriglyceridemia

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