Eager to improve women's cardiovascular health

Female reproductive characteristics, including menstrual cycle regularity, pregnancy outcomes and ages at menarche and menopause, can serve as a vital sign for overall health.1 For example, it is now well described and increasingly incorporated into clinical screening guidelines that a prior history of pregnancy complications, including hypertensive disorders and preterm or small for gestational age delivery, presages higher lifetime cardiovascular disease (CVD) risk for those affected.2 Polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) commonly track together, and each confers multifold increases in risk for later type 2 diabetes mellitus, especially when both co-occur.1 Each of these reproductive characteristics is highly prevalent, occurring in 5% of women or more. There is also a growing awareness that impaired fecundity, whether because of infertility or pregnancy loss, also confers subsequent health risks.3 Pregnancy loss is an especially common reproductive challenge. Spontaneous loss before 20 weeks of gestation, that is, miscarriage, affects 10%–20% of pregnancies, and a first loss confers a care costs, substantial psychological distress, higher risk for subsequent losses.4 The population prevalence of women who have had one miscarriage is 10.8% (10.3%–11.4%), two miscarriages is 1.9% (1.8%–2.1%) and three or more miscarriages is 0.7% (0.5%–0.8%).4 Although many risk factors have been identified, including foetal aneuploidy, the cause of pregnancy loss in euploid pregnancies is unknown in the majority of cases.4, 5 In the short term, pregnancy loss may be associated with high health care costs, substantial psychological distress and greater risk for serious complications in subsequent pregnancies.4 In the longer term, a history of pregnancy loss is associated with higher risk for CVD.4 Given these multifold downstream consequences, it is no surprise that there has been great interest in trying to prevent sequelae associated with prior pregnancy loss. Daily low-dose aspirin (LDA) is one potential avenue for such prevention. Daily LDA use in pregnancy is considered safe for the mother and foetus.6 The American College of Obstetrics and Gastroenterology and other expert bodies have recommended daily LDA as a preventive medication for pre-eclampsia and its complications to begin after 12 weeks of gestation in persons who are at high risk for pre-eclampsia.6 LDA has also been associated with improvements in outcomes related to in vitro fertilisation success, when initiated either at the start of the cycle or prior to harvesting the eggs.5 The Effects of Aspirin in Gestation and Reproduction (EAGeR) trial, a multicentre, block-randomised, double-blinded, placebo-controlled trial, was established to evaluate the effects of daily LDA (81 mg) from preconception throughout gestation on reproductive outcomes for women who had a history of one or two prior pregnancy losses. The primary trial, conducted in 2007–2011, found a statistically significant difference in live birth between the LDA and placebo group only among women with a single recent loss, but not among all participants. Further analysis suggested that initiating LDA therapy prior to conception may have important impacts in successful establishment, as opposed to maintenance, of pregnancy.5 Given its potential benefit in preventing pregnancy loss and pre-eclampsia, both strong CVD risk factors, as well as the evidence that pregnancy is a sensitive window for later health,1 it is a reasonable question to investigate the extent to which LDA administered in pregnancy may confer longer term benefits for heart health. In addition, prior evidence has suggested that daily LDA may confer a benefit for the prevention of CVD, although recommendations have targeted older, high-risk adults.7 In this issue of PPE, Shaaban et al.8 address this question directly. They report on 9–14-year follow-up of mothers and children previously enrolled in the EAGeR trial. On a brief follow-up survey, administered to participants from the largest recruitment site in 2020–2021, women self-reported their cardiometabolic and respiratory health. Those who achieved a live birth during the trial also reported on the child's asthma symptoms and diagnosis. The results were not suggestive of cardiovascular benefit. More specifically, there was no association of randomization to LDA with lower subsequent risk for hypertension (risk difference [RD] −0.001, 95% confidence interval [CI] −0.05, 0.04), hypercholesterolemia (RD −0.01, 95% CI −0.06, 0.05) or type 2 diabetes mellitus/pre-diabetes (RD −0.01, 95% CI −0.05, 0.03) at 9–14 years follow-up. Diagnosis of CVD itself, or heart disease-related deaths, were not studied, perhaps because participants remained relatively young at outcome assessment, with a mean age of 40.7 years (range 31–54 years). Associations with respiratory symptoms in both mothers and children were also null, perhaps in part related to power, as the point estimate for childhood asthma (risk ratio of 1.3) was consistent with other literature.8 The lack of benefit for maternal cardiovascular risk factors in the EAGeR follow-up aligns with results from an observational analysis of the nuMoM2b Heart Health Study cohort. This study found no association between aspirin use during a first pregnancy and incident cardiovascular-related diagnoses (cardiovascular events, chronic hypertension, metabolic syndrome, prediabetes or type 2 diabetes, dyslipidaemia and chronic kidney disease) 2–7 years following delivery.9 Even considering the strength of this evidence from a randomised trial, the body of evidence remains small and inconclusive. Shaaban et al. assessed only 678 of the 1000 EAGeR trial participants. Only 81 of almost 4500 women in nuMoM2b were exposed to aspirin in pregnancy. Also, participants in both studies were presumably mainly pre-menopausal at follow-up, and CVD risks among women begin to rise steeply during peri- and post-menopause. Although thus not definitive, these studies do not offer any encouragement that aspirin use in pregnancy prevents CVD and related risk factors years later. One possibility is that the duration of preconception and prenatal aspirin use, limited to several months or up to a year, is too brief. Another is that LDA does not, in fact, confer benefit for the outcomes studied, but rather only acute thrombotic events such as myocardial infarction and ischemic stroke.7 Although in recent decades daily LDA has been recommended for the primary prevention of CVD in high-risk older adults, guidelines have recently been revised and downgraded, considering potential risks of bleeding as well as benefits.7 Also of note, 95% of randomised EAGeR trial participants, and 97% of those followed up, were White, although non-White and, in particular, non-Hispanic Black Americans are at the highest risk for both adverse pregnancy outcomes and cardiometabolic diseases.2 Given that one in 10 women will experience a pregnancy loss, and one in five women in the United States will die of heart disease, the population burden is high, disparities are large and the problem of identifying beneficial interventions remains urgent. Fortunately, we already have an answer. Healthful lifestyle behaviours, as outlined in the American Heart Association's 'Life's Essential 8', remain a mainstay of CVD prevention and are associated with improved reproductive health.1, 10 We should invest at least as much in supporting healthy lifestyles as we do in the search for pharmacological treatments. Dr. Oken is solely responsible for the contents of this commentary. Dr. Oken is supported by the US National Institutes of Health (award R01HD096032). None. Emily Oken is Professor and Chair in the Department of Population Medicine at Harvard Medical School and the Harvard Pilgrim Health Care Institute. She trained in internal medicine and paediatrics, and has led longitudinal cohort studies examining associations of perinatal characteristics with longer-term maternal and child health.