A diseased placenta can predict premature cardiovascular disease in women: canary out of the coalmine
By Dr. Joel Ray
When a placenta goes bad …
About 60% of the human placenta consists of blood vessels that are critical for transport of nutrients and oxygen to the fetus, while removing waste and carbon dioxide byproducts. Abnormal placental development can disrupt pregnancy and profoundly endanger maternal and infant health. Placental dysfunction may result in adverse maternal clinical outcomes that we broadly call the “maternal placental syndromes” (MPS), the prevalence of which is about 7% of delivered pregnancies.(1 )While MPS—preeclampsia, placental abruption, and placental infarction1,2—pertains to the mother, the ensuing negative effects on the fetus include growth restriction, small for gestational age birthweight, preterm birth, and stillbirth.
The cardiometabolic profile is often the culprit …
We and others have identified a likely association between a woman’s cardiometabolic profile (i.e., number of markers of the metabolic syndrome) before pregnancy, and her risk of MPS, especially preeclampsia.(3,4) After pregnancy the risk of postpartum metabolic syndrome also appears to be higher among those with early-onset MPS. For example, among 849 women with a history of MPS, metabolic syndrome was present in 24.5% of women with early-onset MPS and 11.7% of women with late-onset MPS (adjusted odds ratio [OR] 2.51, 95% confidence interval [CI] 1.66 to 3.80).(5) Women with early-onset MPS exhibited a higher risk of hyperinsulinemia and other individual metabolic syndrome features. Hence, we think that that the cardiometabolic profile of a woman before pregnancy, and which persists after pregnancy, may be the common link between MPS and premature cardiovascular disease in the years that follow.
And premature cardiovascular disease is more likely to follow after pregnancy …
Some common risk factors for placental vascular disease so happen to be common risk factors for the premature-onset cardiovascular disease —coronary artery disease, left ventricular impairment, cerebrovascular disease and peripheral arterial disease—in the affected woman.(6,7) Thus, the systematic evaluation of a woman’s pregnancy outcome (including that of her fetus/newborn), and the pathological integrity of her delivered placenta, may offer an unrealized and efficient means of identifying a subset of women at high risk of cardiovascular disease (and its risk factors) in their post-pregnancy years.(2)
In 2008, McDonald et al examined 5 case-control and 10 cohort studies, totaling 116,175 women with preeclampsia, and 2,259,576 women without preeclampsia.(8) In the cohort studies, women with a history of preeclampsia were at increased future risk of coronary artery disease (relative risk [RR] 2.33, 95% CI 1.95-2.78). Coronary artery disease risk rose with preeclampsia severity: mild (RR 2.00, 95% CI 1.83-2.19, moderate (RR 2.99, 95% CI 2.51-3.58, and severe (RR 5.36, 95% CI 3.96-7.27).(8)
Using population-based administrative data, we previously studied the risk of cardiovascular disease among more than 1 million Ontarian women, who were free of cardiovascular disease prior to their first obstetrical delivery.(1) The adjusted RR for cardiovascular disease was 2.0 (95% CI 1.7-2.2) in the presence of MPS, and was more pronounced when MPS was accompanied by intrauterine growth restriction (RR 3.1, 95% CI 2.2-4.5) or stillbirth (RR 4.4, 95% CI 2.4-7.9). Moreover, the risk of cardiovascular disease was highest in women with MPS and 1-2 (RR 4.5, 95% CI 3.7-5.4) or 3-4 features (RR 11.7, 4.9-28.3) of metabolic syndrome before pregnancy, relative to none. Thus, there may be an additive effect of having MPS in conjunction with worse fetal outcomes, as well as more metabolic syndrome features prior to and following pregnancy.(9) This is important, in that it may enable one to better identify high-risk groups for cardiovascular disease, based on MPS and other common features before and after pregnancy.
We also recently completed the “Heart Failure and Dysrhythmias after Maternal Placental Syndromes: HAD MPS Study”.(10) Therein, among 1.13 million individual deliveries, after a median follow-up of 7.8 years, hospitalization for heart failure occurred at an incidence rate of 1.37 per 10,000 person-years in women with MPS and 0.59 per 10,000 person-years in women without MPS (adjusted RR 1.8, 95% CI 1.4-2.3).(10) The mean age at the onset of a heart failure event was 38 years; the maximum age was 60.5 years.
And we may be able to do something about it – release the canary from the coalmine
There is consistent evidence that MPS—especially preeclampsia—may be a risk factor for premature cardiovascular disease and, perhaps, heart failure. The common link may be partly related to cardiometabolic dysfunction that both predates and persists after pregnancy.(1,11) There is an impetus to develop specific recommendations about the long-term management of women, whose pregnancy was affected by preeclampsia, fetal growth restriction, and/or an intrauterine fetal death attributed to placental vascular disease.(12-14) In 2011 the American Heart Association (AHA) Effectiveness-based guidelines for the prevention of cardiovascular disease in women(14) introduced a new and bold statement:
“Future research should evaluate the potential for exposures, events, or interaction with the medical system during periods of potential vulnerability across a woman’s lifespan such as… pregnancy… to identify women at risk and to determine the effectiveness of diagnostic and preventive interventions during these critical times.”
The work that we and others are generating have and will enhance these recent AHA recommendations, by better elucidating which cardiometabolic risk factors persist after delivery, as well as the degree to which the placenta—a highly vascular and transient organ of pregnancy, and the dysfunction of which often underlies MPS—may offer the most objective assessment (vis-à-vis blood vessel disease) of the impact of pregnancy on future cardiovascular disease risk.
While the focus of our work has been the identification of women at higher risk of cardiometabolic dysfunction, we remain optimistic that pending research by others will show the benefits of a healthy lifestyle in women of reproductive age. Specifically, the identification of the subset of women at highest risk of long-term complications, at a relatively early point in her life, before the overt onset of cardiovascular disease or diabetes, might be shown to be a novel and cost-effective form of primary prevention of these conditions. It is at this point that the “canary may be freed from the coalmine.”
Joel Ray MD MSc FRCPC
Departments of Medicine and Obstetrics and Gynaecology,
Institute of Health Policy, Management and Evaluation,
Institute of Medical Science,
Institute for Clinical Evaluative Sciences,
Li Ka Shing Knowledge Institute, St. Michael’s Hospital and the
University of Toronto, Toronto, Ontario
1. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005; 366:1797-803.
2. Newstead J, von Dadelszen P, Magee LA. Preeclampsia and future cardiovascular risk. Expert
Rev Cardiovasc Ther 2007; 5:283-94.
3. Wolf M, Sandler L, Muñoz K, Hsu K, Ecker JL, Thadhani R. First trimester insulin resistance and subsequent preeclampsia: a prospective study. J Clin Endocrinol Metab 2002; 87:1563-8.
4. Thadhani R, Ecker JL, Mutter WP, Wolf M, Smirnakis KV, Sukhatme VP, Levine RJ, Karumanchi SA. Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia. Hypertension 2004; 43:988-92.
5. Stekkinger E, Zandstra M, Peeters LL, Spaanderman ME. Early-onset preeclampsia and the prevalence of postpartum metabolic syndrome. Obstet Gynecol 2009; 114:1076-84.
6. Ray JG, Vermeulen MJ, Schull MJ, McDonald S, Redelmeier DA. Metabolic syndrome and the risk of placental dysfunction. J Obstet Gynaecol Can 2005; 27:1095-101.
7. Ray JG. Metabolic syndrome and higher risk of maternal placental syndromes and cardiovascular disease. Drug Dev Res 2006; 67: 607-1.
9. Forest JC, Girouard J, Massé J, Moutquin JM, Kharfi A, Ness RB, Roberts JM, Giguère Y. Early occurrence of metabolic syndrome after hypertension in pregnancy. Obstet Gynecol 2005;105:1373-80. 8. 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; 156:918-30.
10. Ray JG, Schull MJ, Kingdom JC, Vermeulen MJ. Heart failure and dysrhythmias after maternal placental syndromes: HAD MPS Study. Heart 2012; 98:1136-41.
11. Romundstad PR, Magnussen EB, Smith GD, Vatten LJ. Hypertension in pregnancy and later cardiovascular risk: common antecedents? Circulation 2010; 122:579-84.
12. Piña IL. Cardiovascular disease in women: challenge of the middle years. Cardiol Rev 2011;19:71-5. 13. Hermes W, Franx A, van Pampus MG, Bloemenkamp KW, van der Post JA, Porath M, Ponjee G, Tamsma JT, Mol BW, de Groot CJ. 10-Year cardiovascular event risks for women who experienced hypertensive disorders in late pregnancy: the HyRAS study. BMC Pregnancy Childbirth 2010; 10:28.
14. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, Newby LK, Piña IL, Roger VL, Shaw LJ, Zhao D, Beckie TM, Bushnell C, D’Armiento J, Kris-Etherton PM, Fang J, Ganiats TG, Gomes AS, Gracia CR, Haan CK, Jackson EA, Judelson DR, Kelepouris E, Lavie CJ, Moore A, Nussmeier NA, Ofili E, Oparil S, Ouyang P, Pinn VW, Sherif K, Smith SC Jr, Sopko G, Chandra-Strobos N, Urbina EM, Vaccarino V, Wenger NK; American Heart Association. Effectiveness-based guidelines for the prevention of cardiovascular disease in women–2011 update: a guideline from the American Heart Association. J Am Coll Cardiol 2011; 57:1404-23.