Early and multicomponent intervention after adverse pregnancy outcomes: an opportunity to win hearts and minds

This editorial refers to ‘Adverse pregnancy outcomes and long-term risk of stroke: a Swedish nationwide co-sibling study’, by C. Crump et al., https://doi.org/10.1093/eurheartj/ehaf366.

Stroke is a major cause of death and disability that may be preceded by distinct risk factors in women vs. men.¹ Understanding earlier life, sex-specific stroke risk factors can help identify high-risk individuals who can be targeted for preventive intervention. The study presented in this issue of European Heart Journal by Crump and colleagues addressed this critical need by rigorously defining the associations between adverse pregnancy outcomes (APOs) and stroke.² Medical Birth Register codes and Swedish Hospital and Outpatient Registers were used to identify APOs and stroke in >2 million women. Hazard ratios (HRs) for ischaemic and haemorrhagic stroke as a combined outcome were determined after five APO types: gestational diabetes, pre-eclampsia, other hypertensive disorders of pregnancy, pre-term birth, and small-for-gestational-age deliveries.² APOs were not rare; 30% of women had experienced at least one APO. All APOs were significantly associated with stroke over 46 years of follow-up; HRs for individual APOs ranged from 1.26 to 1.86.² The highest HR was detected after gestational diabetes, which was largely mediated by type 2 diabetes.²

These associations persisted through a stringent series of analyses. Associations between each APO type and stroke were evaluated after adjustment for all other APOs and pre-pregnancy traditional and stroke-specific cardiovascular disease (CVD) risk factors: hyperlipidaemia, hypertension, diabetes, atrial fibrillation, and body mass index (BMI), confirming independent associations of each individual APO type with stroke.² Both spontaneous (HR 1.55; 95% confidence interval [CI] 1.39–1.73) and medically indicated (HR 1.82; 95% CI 1.64–2.01) pre-term birth were linked to stroke risk, with higher hazards after medically indicated pre-term birth, P = .03.² A co-sibling analysis conducted to tease out the role of shared genetic, social, or lifestyle risk factors dampened the associations by 40%–50%, but they remained significant. A dose-response was observed, as risk increased with the lifetime number of APOs from 0 to ≥3.² Effects were detected at multiple time intervals from 0 to 46 years after delivery and in age-stratified analyses, even in the most adjusted statistical model.² Thus, the associations between APOs and stroke in this study appear independent and real.

What could be driving the higher stroke risk after APOs? The INTERSTROKE Study, designed to define the risk factors of stroke on a population level, concluded that stroke is highly preventable.³ The INTERSTROKE investigators identified 10 modifiable factors that account for ∼90% of the global stroke burden: history of hypertension, current smoking, high waist-to-hip ratio, poor diet risk score, diabetes, high alcohol intake or binge drinking, cardiac causes, apolipoprotein B/A1 ratio, and psychosocial stress and depression.³ Regular physical activity is a reverse risk factor, typically reducing odds of stroke by ∼30%–40%.³

Across subsets of the global population in INTERSTROKE, hypertension is the strongest risk factor for stroke.³ Abdominal obesity, measured with the waist-to-hip ratio, was more closely associated with stroke than BMI and was more strongly related to stroke in women vs. men.³ The population-attributable risk associated with psychosocial stress in women (15.0%; 95% CI 8.5%–25.2%; quantified using questions about work and home stress, life events, and depression) was similar to those associated with poor diet (22.9%; 95% CI 15.3%–32.7%), cardiac causes (11.1%; 95% CI 9.4%–12.9%), and smoking (5.3%; 95% CI% 3.7–7.6%).³ Other investigators concluded that psychosocial stress and depression are stronger or more prevalent risk factors for stroke in women vs. men.¹

Perhaps more attention should be paid to the psychological and emotional toll associated with APOs.^4,5 APOs are linked to higher risk of mood disorders in affected people, including depression, anxiety, and post-traumatic stress disorder.^4,6 In fact, data presented by different authors using a subset of the same Swedish registry cohort described a 36% (adjusted HR = 1.36, 95% CI 1.31–1.42) higher risk of CVDs, including stroke, in women with perinatal depression; results in this analysis were attenuated by 44% but still significant in co-sibling analyses.⁷ In that study, pre-term birth was more common in individuals affected by perinatal depression.⁷ In the analysis by Crump et al., the population-attributable risk for stroke was largest for pre-term birth (5.6%) among all APOs.²

Not only does the complicated pregnancy/birth itself cause stress, but the psychological and/or medical sequelae of the APO can last for months or years.⁸ Babies born after an APO are more likely to be admitted to the neonatal intensive care unit (NICU).⁹ Admission to the NICU, which is itself stressful, can also interfere with lactation, a known modifier of CVD and stroke risk factors for parous women.^9,10 Babies born after APOs are more likely to have short- or longer term medical complications and to be diagnosed with neurodevelopmental disorders.^11–13 Managing medical and neurodevelopmental disorders can lead to months or years of emotional, logistical, and financial strain for parents.⁵

Effects of psychosocial stress may manifest to eventual stroke via two potentially overlapping pathways: direct physiological effects and poor coping behaviours (Graphical Abstract). There are direct physiological responses to stress that are also early events in the development of overt stroke risk factors. Psychosocial stress activates the hypothalamic–pituitary–adrenal axis to increase sympathetic activity, inflammation, blood glucose, coagulation, and overall allostatic load.^5,14 High stress is linked to unfavourable effects on lifestyle and coping behaviours, including smoking, worse medication adherence, poor diet, low physical activity, and higher body weight.¹⁴ These physiological and behavioural pathways may converge on subclinical disease, detectable by endothelial dysfunction, arterial stiffness, insulin resistance, or atherosclerosis.^14,15 In support of this concept, chronic stress was linked to worse endothelial function in a multiethnic cohort in the USA, and the association was largely attenuated after accounting for cigarette smoking in those with higher stress.¹⁵

Graphical Abstract.

HTN, hypertension; WHR, waist-to-hip ratio

Interrupting the cascade from APO to stroke might involve a multifaceted approach to control blood pressure and address modifiable lifestyle habits that influence physical and mental health soon after APOs.³ Exciting data regarding blood pressure management after APOs were reported from a recent clinical trial conducted in 220 post-partum participants in the UK.¹⁶ Participants were randomized 1:1 to self-monitoring of blood pressure and provider-guided titration of antihypertensive medication or standard care after hypertensive APOs.¹⁶ Twenty-four hour mean systolic and diastolic blood pressures were lower in the first nine post-partum months by −6.51 mmHg (95% CI −8.80 to −4.22) and −5.80 mmHg (95% CI −7.40 to −4.20), respectively, in the intervention vs. control group, both P < .001.

A model for improving lifestyle behaviours after a cardiovascular event already exists—traditional cardiac rehabilitation programmes address most or all stroke risk factors. They include supervised or home-based exercise and counselling to support smoking cessation, improvements in diet, and stress management. In other patient groups, outpatient cardiac rehabilitation is delivered in tandem with regular contact with healthcare providers. In individuals with recent APOs, the provider contact might include review of home-measured blood pressure and supportive medication titration.¹⁶ Because poor mental health is associated with poor medication and cardiac rehabilitation adherence in other populations, the inclusion of a mental health component/treatment would be likely to promote success in blood pressure management as well as behavioural goals in individuals with recent APOs.¹⁴ Delivery methods for any post-partum intervention could include home-based or virtual sessions to reduce child care or travel burden, and improve feasibility. As APOs occur in ∼30% of parous people and stroke is ∼90% preventable, implementing a multicomponent, preventive intervention aimed at modifiable stroke risk factors soon after delivery seems like an obvious win.

Declarations

Disclosure of Interest

The author declares no disclosure of interest for this contribution.

Funding

A.D.L. receives funding from the National Institutes of Health (1R01HL167841) and the University of Michigan Women’s Health Innovation Fund.