Recurrent Pregnancy Loss and Cardiovascular Disease Mortality in Japanese Women: A Population-Based, Prospective Cohort Study

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Background

This study aimed to examine the association between recurrent pregnancy loss and the risk of cardiovascular disease mortality.

Methods

We identified 54,652 women who were pregnant during the Japan Collaborative Cohort Study. These women were 40-79 years at the date of cohort entry between 1988 and 1990. Participants received municipal health screening examinations and completed self-administered questionnaires. The cause of death was confirmed by annual or biannual follow-up surveys for a median of 18 years. The exposure was the number of pregnancy loss. The outcome was mortality from total cardiovascular disease and its subtypes according to the International Classification of Diseases, 10th Revision. Adjustment variables included age, number of deliveries, education, body mass index, physical activity, smoking status, and drinking status. Kaplan–Meier survival curves were used to estimate the cumulative mortality.

Results

The number of pregnancy loss tended to be inversely associated with the risk of mortality from total stroke, intracerebral hemorrhage, and total cardiovascular disease. The multivariable hazard ratio of total cardiovascular disease for ≥2 pregnancy losses versus no pregnancy loss was .84 (95% confidence interval, .74-0.95). A 2-fold excess risk of mortality from ischemic stroke associated with ≥2 pregnancy losses was observed in women aged 40-59 years, with a multivariable hazard ratio of 2.19 (95% confidence interval, 1.06-4.49), but not in older women.

Conclusions

Recurrentpregnancy loss tends to be associated with a lower risk of mortality from cardiovascular disease at 40-79 years. Younger women have an excess risk of ischemic stroke mortality associated with recurrent pregnancy loss.

Introduction

Pregnancy loss is the most common pregnancy-related complication and represents a significant clinical burden. A history of pregnancy loss may be useful for making a clinical decision to investigate the presence of autoimmune disease or congenital coagulation disorders. We hypothesize that hematological disorders or abnormal vasoconstriction may contribute to the risk of cardiovascular disease (CVD) mortality among women with recurrent pregnancy loss.

The American Heart Association guidelines that were updated in 2011 state that cardiovascular and metabolic stress during pregnancy (e.g., preeclampsia, gestational diabetes) should be regarded as an indicator of the risk of CVD, including ischemic stroke and coronary heart disease, in women.1 Additionally, a careful and detailed history of complications in pregnancy should be taken by a primary care physician or cardiologist.1 However, epidemiological evidence for the risk of complications in pregnancy on long-term CVD is limited in Chinese2 and Japanese populations.3 A Chinese cohort study showed that women with multiple stillbirths or miscarriages did not have an increased risk of ischemic heart disease and ischemic stroke mortality.2 A Japanese cross-sectional study with a much smaller number of subjects, 2733 women aged 35-79 years, reported that single miscarriage and recurrent spontaneous abortion were not associated with a history of ischemic heart disease and stroke.3

Congenital hematological or vascular wall disorders may contribute to the risk of ischemic CVD mortality in younger adults.4, 5, 6, 7 A Danish population-based cohort study showed that the risks of ischemic stroke and myocardial infarction associated with each additional miscarriage were larger in women aged <35 years than in older women.8

Because of the limited available evidence, we examined the association between recurrent pregnancy loss and risk of mortality from total stroke, stroke subtypes, coronary heart disease, and total CVD using data from a large Japanese cohort. In this study, we also analyzed the data based on the age subgroups of 40-59 years and 60-79 years at baseline.

Section snippets

Study Design

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation, the Ethics Boards of the Nagoya University Graduate School and Osaka University Graduate School of Medicine, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

The Japan Collaborative Cohort Study was described previously.9 A total of 110,585

Results

Table 1 shows age-adjusted mean values for clinical parameters and the prevalence of cardiovascular risk factors at baseline according to the number of pregnancy losses. Women with ≥2 pregnancy losses were younger (55.8 versus 58.0 years), had a lower number of deliveries (2.6 versus 2.9), had a slightly higher body mass index (23.1 versus 22.9 kg/m2), had higher alcohol consumption (11.7 versus 9.7 g/d), were more likely to smoke (6.6% versus 4.2%), and had a higher prevalence of diabetes

Discussion

The main findings of the current, large, cohort study are as follows. In women aged 40-79 years, recurrent pregnancy loss was associated with a lower risk of total CVD mortality. Additionally, in younger women aged 40-59 years, recurrent pregnancy loss was associated with a 2-fold higher risk of mortality from ischemic stroke.

Pregnancy loss is a comprehensive term, which includes miscarriage, stillbirth, and medically based termination. Two or more consecutive miscarriages are treated in

Strengths and Limitations

Strengths of our study are that it was a large prospective cohort with long-term follow-up and multiple outcomes. There are some limitations in the current study. First, a self-reported questionnaire consisting of simple questions related to reproduction was used at baseline. The validity and reliability of the question regarding reproductive history could not be evaluated. Reproductive history, including a history of abortion, is particularly sensitive, particularly by consultation. The

Acknowledgments

The authors are grateful to all of the participants in each cohort study. The authors appreciate all of the staff members involved in this study for their help in conducting the baseline survey and follow-up. The authors also thank Dr. Miho Muraji, Dr. Daita Kaneda, and Dr. Takashi Takeda for their professional comments.

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    Grant support: This research was supported by a grant-in-aid from the Health and Labor Sciences research grants of the Ministry of Health, Labour and Welfare, Japan (Research on Health Services: H17-Kenkou-007; Comprehensive Research on Cardiovascular Disease and Life-Related Disease: H18-Junkankitou[Seishuu]-Ippan-012; Comprehensive Research on Cardiovascular Disease and Life-Related Disease: H19-Junkankitou [Seishuu]-Ippan-012; Comprehensive Research on Cardiovascular and Lifestyle Related Diseases: H20-Junkankitou [Seishuu]-Ippan-013; Comprehensive Research on Cardiovascular and Lifestyle Related Diseases: H23-Junkankitou [Seishuu]-Ippan-005, H25-Junkankitou [Seishuu]-Ippan-003, and an Intramural Research Fund [22-4-5] for Cardiovascular Diseases of National Cerebral and Cardiovascular Center; and Comprehensive Research on Cardiovascular and Lifestyle Related Diseases: H26-Junkankitou [Seisaku]-Ippan-001). This research was also supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (Monbusho), and Grants-in-Aid for Scientific Research on Priority Areas of Cancer, as well as Grants-in-Aid for Scientific Research on Priority Areas of Cancer Epidemiology from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Monbu-Kagaku-sho) (Nos 61010076, 62010074, 63010074, 1010068, 2151065, 3151064, 4151063, 5151069, 6279102, 11181101, 17015022, 18014011, 20014026, 20390156, and 26293138).

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