Risk of Cardiovascular Disease Among Postmenopausal Women With Prior Pregnancy Loss: The Women's Health Initiative

Donna R. Parker, ScD; Bing Lu, DrPH; Megan Sands-Lincoln, PhD; Candyce H. Kroenke, MPH, ScD; Cathy C. Lee, MD, MS; Mary O'Sullivan, MD; Hannah L. Park, PhD; Nisha Parikh, MD; Robert S. Schenken, MD; Charles B. Eaton, MD, MS


Ann Fam Med. 2014;12(4):302-309. 

In This Article

Abstract and Introduction


Purpose. Metabolic, hormonal, and hemostatic changes associated with pregnancy loss (stillbirth and miscarriage) may contribute to the development of cardiovascular disease (CVD) in adulthood. This study evaluated prospectively the association between a history of pregnancy loss and CVD in a cohort of postmenopausal women.

Methods. Postmenopausal women (77,701) were evaluated from 1993–1998. Information on baseline reproductive history, sociodemographic, and CVD risk factors were collected. The associations between 1 or 2 or more miscarriages and 1 or more stillbirths with occurrence of CVD were evaluated using multiple logistic regression.

Results. Among 77,701 women in the study sample, 23,538 (30.3%) reported a history of miscarriage; 1,670 (2.2%) reported a history of stillbirth; and 1,673 (2.2%) reported a history of both miscarriage and stillbirth. Multivariable-adjusted odds ratio (OR) for coronary heart disease (CHD) for 1 or more stillbirths was 1.27 (95% CI, 1.07–1.51) compared with no stillbirth; for women with a history of 1 miscarriage, the OR = 1.19 (95% CI, 1.08–1.32); and for 2 or more miscarriages the OR = 1.18 (95% CI, 1.04–1.34) compared with no miscarriage. For ischemic stroke, the multivariable odds ratio for stillbirths and miscarriages was not significant.

Conclusions. Pregnancy loss was associated with CHD but not ischemic stroke. Women with a history of 1 or more stillbirths or 1 or more miscarriages appear to be at increased risk of future CVD and should be considered candidates for closer surveillance and/or early intervention; research is needed into better understanding the pathophysiologic mechanisms behind the increased risk of CVD associated with pregnancy loss.


Cardiovascular disease (CVD) is the leading cause of mortality for women in the United States, with 24% of female deaths attributed to CVD in 2009.[1,2] Although traditional risk factors for CVD, are associated with increased CVD risk in both men and women, unique risk factors for women related to reproductive history have only recently been considered as potentially important.[2] Growing evidence suggests that the metabolic, hormonal, and hemostatic pathway alterations that are associated with pregnancy loss may contribute to the development of coronary heart disease in adulthood.[3–5] Women with adverse pregnancy outcomes, such as preeclampsia, preterm delivery, low birth weight, intrauterine growth restriction, and pregnancy loss (including miscarriage and stillbirth), may be at risk of metabolic and vascular diseases later in life.[6,7] Additionally, genotypes and phenotypes underlying vascular disease may also underlie fetal programming.[5]

At present, the mechanisms underlying the association of miscarriage and stillbirth with CVD are unclear, although there appears to be a relationship between the metabolic syndrome, abnormal implantation, and endothelial dysfunction.[8,9] Specifically, it has been suggested that the endothelial dysfunction resulting from systemic inflammatory processes may be involved.[10] The resulting vascular pathology may thus contribute to both poor placentation during pregnancy (resulting in pregnancy loss) and an increased likelihood of CVD.[10] Recently the 2011 American Heart Association guidelines have incorporated pregnancy complications as a risk factor for CVD in women based on the growing evidence suggesting an association.[2] These guidelines, however, did not address the long-term cardiovascular implications of miscarriage.

A limited number of studies have evaluated pregnancy loss and risk of development of future CVD, but the findings have been inconsistent, with some finding no clear association[11,12] and others suggesting an increased risk between pregnancy loss and CVD.[3,10,13,14] The Women's Health Initiative (WHI) population provides a unique opportunity to be able to examine the association of miscarriage and stillbirth in a diverse, geographically dispersed cohort of women with adjudicated cardiovascular events, including fatal and nonfatal myocardial infarctions and stroke outcomes.