Common risk factors in the shadow of rare pregnancy complications: spotlighting the role of cardiovascular health in placental abruption

Adverse pregnancy outcomes (APOs) are often conceptualised as a window into future cardiovascular disease (CVD) risk. The available evidence for commonly occurring APOs such as hypertensive disorders of pregnancy, gestational diabetes, and preterm birth suggest a two-fold higher risk of CVD following these APOs in the birthing adult.^1,2 In addition, APOs are associated with a higher risk of development of CVD among offspring.^3,4 However, longitudinal data on CVD outcomes following less commonly occurring APOs, such as placental abruption, are limited. Clarifying the unique pathways that link commonly and less commonly occurring APOs with CVD will guide tailored efforts to prevent subsequent pregnancy complications and CVD in birthing people and their offspring. Therefore, the development of large epidemiologic datasets that span several decades of the life course and across generations is needed to capture both pregnancy-related and CVD-related events. In addition, studies promoting our understanding of intergenerational transmission require access to long-term data, not only for the birthing person but for their offspring.

Identifying data sources that fulfill these criteria is challenging, particularly in the US. In the absence of universal health care, birthing people often switch healthcare providers and/or insurers several times throughout their life course. Electronic health records and insurance claims data are often riddled with missing clinical information, limited follow-up, and do not collect data on important confounders and risk factors (e.g., diet quality, physical activity levels). Longitudinal data from observational cohort studies such as the Coronary Artery Risk Development in Young Adults Study (CARDIA), the Women’s Health Initiative, and the Study of Women’s Health Across the Nation offer insights into associations between APOs and CVD, however, are often limited by small sample sizes for APOs and self-reported pregnancy outcomes. Countries with universal healthcare systems and centralised healthcare databases have easier access to large populations with longitudinal data ideal for studying APOs and CVD. In fact, most of the data linking rare APOs (such as placental abruption) with a lifetime risk of CVD have been obtained from healthcare databases outside of the US.¹

In this issue of Paediatric and Perinatal Epidemiology, Ananth and colleagues⁵ describe the methods and baseline characteristics of the Placental Abruption and Cardiovascular Event Risk (PACER) study, one of the first attempts to create a large population-based dataset of birthing people and their offspring with long-term follow-up in the US. The study authors linked data from the New Jersey Vital Records, Hospital Discharge Data Collection System, and Mortality Data from 1993–2020 using a probabilistic record-matching algorithm. Data were successfully linked to hospitalisation records for 92.4% of live birth records and 70.7% of fetal death records, for a total sample of 3,093,241 deliveries that occurred at or after 20 weeks’ gestation. The cohort included a socio-demographically diverse population with 14.3% of deliveries to those who identified as non-Hispanic Black, 22.9% to those who identified as Hispanic, 40% to those with a high school education or less, and 62.5% to those utilizing private insurance.

In the dataset, there were 33,058 (1.1%) cases of placental abruption consistent with national estimates. Prevalence differed by baseline characteristics and CVD-related factors: higher rates were observed among deliveries to older birthing people, multiparas, those who identified as non-Hispanic Black, or did not have prenatal care, as well as to those who smoked during pregnancy, had pregestational diabetes or had a hypertensive disorder of pregnancy. As expected, higher rates of perinatal complications were noted among deliveries complicated by placental abruption including fetal death, fetal distress, and preterm birth.

The PACER cohort represents one of the first attempts to include the birthing person and offspring in a single longitudinal dataset. We applaud the authors on this enormous undertaking, linking data from multiple sources with discrepant coding systems and personal identifiers. As acknowledged by the authors, the cohort does have several limitations. First, approximately 7.5% of all live births and fetal deaths were excluded from the final cohort due to missing data or unsuccessful data linkage. To account for possible selection bias, the authors reweighted the sample prior to analyses, however, the potential for unmeasured bias remains. Second, the PACER dataset is limited to one US state. Therefore, out-of-state CVD events will not be captured, leading to potential underestimation of incident CVD. This may be particularly concerning given rising rates of state-to-state migration within the US; only about half of US citizens currently live in their birth state.⁶ In addition, data will only be representative of one US state. Maternal and infant outcomes vary substantially between US regions and states, reflecting underlying differences in social, structural, and environmental factors influencing disease. Additional linkage of vital data, hospital records, and mortality files both within and between US states will be necessary to accurately describe rates of incident CVD, and their association with APOs in the US.

Despite these limitations, the PACER cohort has the potential to make valuable contributions to our understanding of associations between placental abruption and long-term CVD. The authors emphasize the cohort’s potential to (i) clarify these associations among high-risk individuals including those with recurrent abruption and non-singleton births; (ii) identify the potential mediating effect through preterm delivery and perinatal complications; and (iii) describe the moderating effect of social determinants of health. These are important steps towards unraveling the pathways that link abruption with CVD. Several questions remain, however, specifically regarding the role of other cardiovascular health factors, such as maternal blood pressure elevations, an important risk factor for both abruption and CVD.

First, what is the nature of the relationship between hypertensive disorders of pregnancy (HDP) and placental abruption in predicting later CVD risk? Are HDPs and abruption on a causal pathway to CVD whereby abruption mediates part of the association between HDPs and CVD? Or is there effect modification such that associations between abruption and CVD differ based on HDP status? Furthermore, do these relationships vary based on HDP subtypes (e.g., chronic hypertension, gestational hypertension, preeclampsia)? Given large sample sizes for each of these outcomes, the PACER cohort has the potential to shed light on each of these questions. This epidemiologic work can, in turn, guide preclinical research to clarify the pathophysiologic mechanisms by which HDPs and abruption are associated with each other and with CVD such as maternal vascular malperfusion, microvascular dysfunction, inflammation, and endovascular oxidative stress.

Second, does placental abruption influence long-term blood pressure trajectories after delivery independent of blood pressure during pregnancy? Placental abruption and other APOs related to maternal vascular malperfusion are thought to trigger oxidative stress and the release of endothelial particles leading to vascular injury. Previous work has demonstrated that people with evidence of maternal vascular malperfusion have higher blood pressure in both the short- and long-term after delivery.⁷ However, whether or not the physiologic changes during pregnancy contribute to long-term vascular damage and incident hypertension, independent of underlying risk factors for vascular damage (e.g., chronic hypertension, prehypertension, microvascular dysfunction) remains unclear.

Third, could tighter blood pressure control before and during pregnancy reduce the risk of both abruption and CVD? Outside of pregnancy, robust evidence exists demonstrating a higher risk of CVD even among people with elevated (systolic and diastolic blood pressures 120–129 mmHg and <80 mmHg, respectively) and stage 1 hypertension (SBP 130–139 mmHg or DBP 80–89 mmHg); clinical guidelines recommend lowering blood pressure to <130/80 mmHg for most people with hypertension and CVD risk factors.⁸ During pregnancy, blood pressure goals are higher due to concerns regarding impaired uteroplacental blood flow. Only recently were treatment goals for chronic hypertension reduced from 160/110 mmHg to 140/90 mmHg in light of results from the Chronic Hypertension and Pregnancy (CHAP) trial demonstrating improvement in the composite outcome of preeclampsia with severe features, clinician-initiated indicated preterm, placental abruption, or fetal or neonatal death associated with tighter blood pressure control.^9,10 Although individual associations between tighter blood pressure control and placental abruption were not significant, the total number of abruption events was small. Additional work is needed to investigate the effects of tighter blood pressure control of both chronic and new-onset HDPs on the risk of abruption and long-term risk of CVD.

Regardless of the pathways that link placental abruption and CVD, the promotion of cardiovascular health remains the cornerstone of CVD prevention for all birthing people. Pregnancy can serve as an ideal opportunity to screen for, counsel, and promote healthy lifestyle behaviours given high levels of engagement with the healthcare system and the potential to impact, not only the birthing person but their offspring. Further unraveling the connections between APOs and CVD will inform tailored interventions to ultimately improve maternal health and prevent CVD in the birthing person and offspring.

Biographies

Natalie A. Cameron is an Instructor of Medicine at Northwestern University, Feinberg School of Medicine in the Department of Medicine (Division of General Internal Medicine) and Department of Preventive Medicine (Epidemiology). Dr. Cameron’s research and clinical practice center on women’s preventive cardiovascular health, with a focus on the peripartum period as a window of opportunity for cardiovascular disease prevention across the life course. Her work describing trends in pre-pregnancy hypertension in rural and urban areas in the United States was recognised in the American Heart Association’s Top Heart Disease and Stroke Advances of 2020. She has additionally received several young- investigator awards from the American Heart Association for her work describing trends and disparities in peripartum cardiovascular health.

Sadiya S. Khan is the Magerstadt Professor of Cardiovascular Epidemiology and Associate Professor of Medicine and Preventive Medicine, inaugural Director of the Center of Population Science and Aging in the Potocsnak Longevity Institute, and preventive cardiologist at the Northwestern University Feinberg School of Medicine. Dr. Khan’s clinical expertise and research focus on the epidemiology, risk prediction, and genetics of cardiovascular disease with an emphasis on pregnancy-related risk factors. Dr. Khan’s research efforts are supported by multiple grants from the National Institutes of Health (R01HL159250; R01HL16154; U01HL160279; UG3HL163121; R21HL165376) and the American Heart Association. Dr. Khan has published over 300 peer-reviewed scientific research publications in leading medical journals and has an h-index of 41 (Scopus, January 2024). Her original science has been highlighted by the American Heart Association as among the Top Advances in Heart Disease and Stroke Research for four consecutive years (2020, 2021, 2022, 2023). She is an Associate Editor at JAMA Cardiology and serves in key leadership roles in the American College of Cardiology and the American Heart Association including as a member of the Joint Committee on Clinical Practice Guidelines.