Ob/gyns should join the fight against quiet killer

Dr. Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South Florida, Tampa.

What do the leading cause of US healthcare costs and adult female mortality, the primary driver of increasing US maternal mortality rates, and the long-term maternal sequelae of spontaneous preterm birth (SPTB), preeclampsia, and fetal growth restriction have in common? The answer is heart disease.

According to the Centers for Disease Control and Prevention (CDC), heart disease is the quiet killer of American women in part because more than half do not recognize that it is the leading cause of mortality.¹ Every year heart disease kills more women than cancer (23.5% vs 22.1% of all US mortality).² In fact, based on the most recent CDC data for both diseases, 7 times as many American women die each year of heart disease as die of breast cancer (292,188 vs 40,931).^1,3 In 2010, the total healthcare bill for cardiovascular disease (CVD) was $444 billion-or about $1 in $6 of all US healthcare spending.⁴

The good news is that ob/gyns are in an ideal position to identify risk factors, implement preventative strategies, and catch incipient disease early enough to prevent death and disability.

Rising maternal mortality rates driven by cardiac disease

Creanga and colleagues employed data from the CDC’s Pregnancy Mortality Surveillance System to identify the evolving etiologies of pregnancy-related mortality.⁵ They focused on the interval between 2006 and 2010 but also made comparisons of these variables with data from 1991 to 1997 and 1987 to 1990 to discern trends. Their findings are disconcerting. During the 2006 to 2010 interval the average pregnancy-related mortality ratio was 16.0 deaths per 100,000 live births. This represents a substantial increase from 11.5 and 9.1 deaths per 100,000 live births for the 2 earlier intervals, respectively.

On the one hand, from 1987 to 2010 maternal deaths due to hemorrhage, hypertension, embolism, and anesthetic complications declined. But, during this same period deaths due to cardiovascular complications increased significantly. Cardiomyopathies and other cardiovascular causes now account for 29% of all pregnancy-related deaths. They also account for a disproportionate share of late-onset maternal deaths. Among women succumbing from cardiomyopathy and other cardiovascular causes, 42.1% and 13%, respectively, died more than 42 days after a live birth.

Sadly, as with so many other adverse health outcomes, there is a profound racial disparity in maternal mortality ratios, with non-Hispanic white versus non-Hispanic black ratios of 12.0 versus 38.9 per 100,000 live births, respectively. When sorted by age, African-American women ≥40 years were at the highest risk, with pregnancy mortality ratios approaching 150 per 100,000. Thus, CVD may be a particular issue among such women.

Many demographic trends help account for the rise in cardiac-associated maternal deaths. The trend toward delayed childbirth clearly plays a role, with women 35 years or older accounting for 15% of live births but 27.4% of deaths. The obesity epidemic-with its attendant early-onset hypertension, diabetes, chronic inflammatory state, and coagulopathy-also likely contributes to the rapid rise in cardiac-associated maternal deaths. Indeed, increasing numbers of American women are entering pregnancy obese and with obesity-associated chronic medical conditions.⁵

Pregnancy complications and CVD

While pregnancy may unmask latent CVD to cause maternal death, seemingly unrelated and relatively common pregnancy complications should alert ob/gyns that affected women are at increased long-term risk of death from ischemic heart disease (IHD). Heida and associates conducted a systematic review and meta-analysis of cohort studies examining the link between SPTB and fatal or nonfatal IHD, stroke, or overall CVD.⁶ The authors identified 10 cohort studies including 3706 to 923,686 women who were followed 12 to 35 years. They noted that SPTB was associated with an increased risk of developing or dying from IHD (hazard ratio [HR] of 1.38; 95% CI: 1.22–1.57) and from any CVD (2.01; 95% CI: 1.52–2.65). They also found an association with stroke (1.71; 95% CI: 1.53–1.91).

Read: Does pregnancy loss mean future CVD risk?

Another meta-analysis has demonstrated a link between preeclampsia/eclampsia and subsequent long-term CVD in the mother. McDonald and associates identified 5 case-control and 10 cohort studies with a total of 116,175 formerly preeclamptic women and 2,259,576 controls with uncomplicated pregnancies.⁷ Compared to control women, those with a history of preeclampsia/eclampsia had an increased risk of eventually developing cardiac disease in both case-control studies (odds ratio [OR] of 2.47; 95% CI: 1.22-5.01) and cohort studies (relative risk [RR] of 2.33; 95% CI: 1.95–2.78), as well as an increased risk of cardiovascular mortality (RR 2.29; 95% CI: 1.73–3.04). Risks of stroke and peripheral arterial disease were also increased, though to a lesser degree. Importantly, the more severe the preeclampsia, the greater the risk of subsequent heart disease. This indicates biological plausibility for the statistical associations. There are also studies linking the birth of a growth-restricted infant to subsequent long-term maternal IHD, also with about a 2-fold increase in risk.⁸

While these associations have been understood for more than a decade, there has been virtually no research conducted to discern whether the pregnancy complication causes the subsequent cardiac disease or whether both the pregnancy complication and long-term CVD reflect a common pathological process-perhaps some combination of an aberrant immune response superimposed on high glucose values and/or elevated low density lipoprotein cholesterol levels and an underlying chronic inflammatory state due to obesity, autoimmune disease, stress, etc.

My colleagues and I have shown that preeclampsia is associated with evidence of chronic decidual inflammation with both an excess of inflammatory macrophages and a deficiency of decidual Natural Killer (NK) cells. Both alterations can contribute to impaired trophoblast invasion and failure of spiral artery remodeling.^9,10 This placental defect together with the presence of vessel wall macrophages or foam cells (ie, acute atherosis) in spiral arteries is observed in many cases of SPTB, and most cases of preeclampsia and idiopathic fetal growth restriction. Remarkably, this pathology is quite similar to that seen in atherosclerotic coronary artery disease (CAD).¹¹  Clearly, far more research is needed to understand this phenomenon.

Take-home message

The rapidly escalating role played by CVD in maternal mortality and the association of SPTB, preeclampsia, and idiopathic fetal growth restriction with long-term cardiovascular mortality in affected women place ob/gyns at the very front line of a much-needed battle to prevent death from heart disease in women. Ob/gyns can likely reduce cardiac-related maternal mortality by extensively counseling at-risk women to optimize their BMI through diet and exercise prior to conceiving, while simultaneously optimizing management of chronic medical conditions and-when necessary-advising against pregnancy in very high-risk and/or nonadherent women.

Similarly, ob/gyns should counsel women whose pregnancies were complicated by SPTB, preeclampsia, and idiopathic intrauterine growth restriction that they are at risk of sub equent CVD, which may not present for several decades. This is especially the case when there are concomitant cardiovascular risk factors (eg, obesity, glucose intolerance, elevated lipids). In such women, encouraging lifestyle changes (diet and exercise), facilitating smoking cessation, initiating early statin therapy for hyperlipidemia, and conducting early surveillance for signs and symptoms of CVD are practical steps to take to reduce long-term risk.

References

1. Centers for Disease Control and Prevention. Women and heart disease fact sheet. http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_women_heart.htm. Accessed February 17, 2015.

2. Centers for Disease Control and Prevention. Leading Causes of Death by Race/Ethnicity, All Females-United States, 2010 http://www.cdc.gov/women/lcod/2010/WomenRace_2010.pdf. Accessed February 17, 2015.

3. Centers for Disease Control and Prevention. Breast cancer statistics. http://www.cdc.gov/cancer/breast/statistics/index.htm. Accessed February 17, 2015.

4. Centers for Disease Control and Prevention. Chronic disease prevention and health promotion: heart disease and stroke prevention. http://www.cdc.gov/chronicdisease/resources/publications/AAG/dhdsp.htm. Accessed February 17, 2015.

5. Creanga AA, Berg CJ, Syverson C, Seed K, Bruce FC, Callaghan WM. Pregnancy-related mortality in the United States, 2006-2010. Obstet Gynecol. 2015;125(1):5–12.

6. Heida KY, Velthuis BK, Oudijk MA, et al; on behalf of the Dutch Guideline Development Group on Cardiovascular Risk Management after Reproductive Disorders. Cardiovascular disease risk in women with a history of spontaneous preterm delivery: A systematic review and meta-analysis. Eur J Prev Cardiol. 2015. pii: 2047487314566758. [Epub ahead of print]

7. McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J. 2008;156(5):918–930.

8. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet. 2001;357(9273):2002–2006.

9. Lockwood CJ, Matta P, Krikun G, et al. Regulation of monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha and interleukin-1beta in first trimester human decidual cells: implications for preeclampsia. Am J Pathol. 2006;168(2):445–452.

10. Lockwood CJ, Huang SJ, Chen CP, et al. Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia. Am J Pathol. 2013;183(3):841–856.

11. Gerszten RE, Tager AM. The monocyte in atherosclerosis-should I stay or should I go now? N Engl J Med. 2012;366(18):1734–1736.