By Rebecca H. Allen, MD, MPH
Assistant Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck, a Liletta trainer for Actavis, and on the advisory board for Bayer, Actavis, and Vermillion.
SYNOPSIS: In this Scottish retrospective cohort study of 60,000 women, two or more miscarriages were found to increase the risk of future ischemic heart disease by two- to three-fold.
SOURCE: Wagner MM, et al. Association between miscarriage and cardiovascular disease in a Scottish cohort. Heart 2015;101:1954-1960.
The authors of this retrospective cohort study extracted data from the Aberdeen Maternity and Neonatal Databank to examine all women with at least one singleton live birth or miscarriage from 1950 to 2010. These women were then linked to the Scottish Morbidity Record to identify hospital admissions for cardiovascular conditions and to the National Register of Scotland for deaths using probabilistic record linkage. Women were sorted into four groups: no miscarriage, non-consecutive miscarriage, two consecutive miscarriages, and three or more consecutive miscarriages. The miscarriages could have occurred before or after a live birth. Women without miscarriage who had a least one live birth formed the unexposed control group. The primary outcomes were arterial cardiovascular disease including ischemic heart disease and stroke. Women with pre-existing cardiovascular disease, hypertension, type 1 diabetes mellitus, kidney disease, and any disease of the circulatory system were excluded. Other data collected included age, gravidity, parity, self-reported smoking (ever/never), social class (based on husband/partner’s occupation), and body mass index.
A total of 60,105 women were analyzed in the study, with the majority having at least one live birth and no miscarriage (49,579/82.5%), followed by the non-consecutive miscarriage group (9,419/15.7%), the two consecutive miscarriage group (940/1.6%), and the three or more consecutive miscarriage group (167/0.3%). Median follow-up time was 17 years (range 0 to 62 years). The absolute number of ischemic cardiac events in the control group was 1440 (2.9%) compared to women with nonconsecutive miscarriages (272 [2.9%]), women with two or more consecutive miscarriages (30 [3.2%]), and women with three or more consecutive miscarriages (7 [4.2%]). After controlling for age, body mass index, social class, and smoking, women with non-consecutive miscarriage had no increased risk of ischemic heart disease (hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.87-1.13), women with two consecutive miscarriages had about double the risk (HR, 1.75; 95% CI,1.22-2.52), and women with three or more miscarriages had triple the risk (HR, 3.18; 95% CI, 1.49-6.8). A sensitivity analysis performed to examine groups by number of miscarriages, regardless of whether they were consecutive, confirmed these findings, with women experiencing two miscarriages or more having an increased risk of future ischemic heart disease.
COMMENTARY
The relationship between obstetric events and future cardiovascular disease is an emerging and fascinating area of study. Already, a history of preeclampsia, pregnancy-induced hypertension, and gestational diabetes are named as risk factors for the development of cardiovascular disease in women in national guidelines.1 Women with this history are considered “at risk” for cardiovascular disease and placed in the same category as women who smoke or have current hypertension. Cardiologists may view pregnancy as a “stress test” that can possibly unmask early or preexisting endothelial dysfunction and vascular or metabolic disease. The American Heart Association recommends that obstetricians refer patients with a history of preeclampsia, pregnancy-induced hypertension, or gestational diabetes to a primary care physician or cardiologist postpartum so that their other risk factors for cardiovascular disease can be carefully monitored and controlled.1 Whether miscarriage should be added to the list of obstetric conditions that predisposes women to heart disease is still under study. Several previous studies have suggested a link between these two conditions, and this study adds information about whether consecutive or non-consecutive miscarriages carry the most risk.2
Why miscarriage would predispose to cardiovascular disease is debatable. While approximately 15% of pregnant women experience sporadic loss of a clinically recognized pregnancy, only 2% experience two consecutive pregnancy losses and ≤ 1% will have three consecutive pregnancy losses.3 These numbers are well reflected in the Scottish cohort. It is not known whether miscarriages cause downstream events that increase the risk of cardiovascular disease in women or if both conditions share an underlying pathology. This study is interesting because it addressed both recurrent and sporadic miscarriages. Biologically, it makes more sense that recurrent miscarriages would share an underlying pathology with cardiovascular disease. With recurrent miscarriages, there is more likely to be a maternal component, whether genetic or related to metabolic or immunologic syndromes (e.g., antiphospholipid antibody syndrome). It is difficult to tease this out because many risk factors for miscarriage overlap with risk factors for cardiovascular disease, such as obesity, smoking, and diabetes. Sporadic miscarriages, on the other hand, are usually due to embryonic or fetal genetic abnormalities. Therefore, I would think they would be associated with less future maternal cardiovascular disease risk. Nevertheless, at least two or more nonconsecutive miscarriages in this study also conferred an increased risk of cardiovascular disease in a subgroup analysis. I am skeptical of this result without further studies but it is intriguing. Weaknesses of this study include the fact that type 2 diabetes was not available for use as a variable, and I am not sure of the accuracy of the social class variable. I also found the lack of specificity regarding what trimester the miscarriage occurred troubling, as first and second trimester pregnancy losses tend to have different etiologies. Data were missing for some variables for which sophisticated statistical techniques had to be utilized. But the results do concur with a meta-analysis on the subject.2 There were too few cerebrovascular events for the study to make a conclusion about the association between miscarriage and future stroke risk.
So what are we supposed to do with this information? It is important to remember that heart disease is the leading cause of death among women in the United States. What threshold of miscarriage history would make a clinician proceed with a cardiovascular disease risk evaluation? I am not sure this study definitively answers that question, but I would not be surprised to see recurrent miscarriage in the next iteration of the American Heart Association guidelines for stratifying women into risk groups for cardiovascular disease.
REFERENCES
- Mosca L, et al. 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;57:1404-1423.
- Oliver-Williams CT, et al. Miscarriage and future maternal cardiovascular disease: A systematic review and meta-analysis. Heart 2013;99:1636-1644.
- American Society of Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: A committee opinion. Fertil Steril 2012;98:1103-1111.
In this Scottish retrospective cohort study of 60,000 women, two or more miscarriages were found to increase the risk of future ischemic heart disease by two- to three-fold.
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