Pregnancy complications such as miscarriage, pre-eclampsia, diabetes in pregnancy (gestational diabetes) and pre-term birth are linked to a heightened risk of heart disease in later life, suggests an overarching (umbrella) analysis of data by researchers at University of Birmingham, Barts and The London School of Medicine and Dentistry, Queen Mary University of London and Birmingham Health Partners.
Several other factors related to fertility and pregnancy also seem to be associated with subsequent cardiovascular disease, say the researchers, including starting periods early, use of combined oral contraceptives, polycystic ovary syndrome, and early menopause.
However, a longer length of breastfeeding was associated with a reduced risk of cardiovascular disease.
Previous research has suggested that risk factors specific to women may be linked to cardiovascular disease and stroke, but clarity on the quality of the evidence is lacking and on how the findings can be translated into public health and clinical practice.
So, a team of UK researchers searched relevant research databases for published systematic reviews and meta-analyses that investigated links between reproductive factors in women of reproductive age and their subsequent risk of cardiovascular disease.
A total of 32 reviews were included, evaluating multiple risk factors over an average follow-up period of 7-10 years.
The researchers found that several factors, including starting periods early (early menarche), use of combined oral contraceptives, polycystic ovary syndrome, miscarriage, stillbirth, pre-eclampsia, diabetes during pregnancy, pre-term birth, low birth weight, and early menopause were associated with an up to twofold risk of cardiovascular outcomes.
Pre-eclampsia was associated with a fourfold risk of heart failure.
Possible explanations for these associations include family medical history, genetics, weight, high blood pressure and cholesterol levels, and chemical imbalances from use of hormonal contraceptives.
However, no association was found between cardiovascular disease outcomes and current use of progesterone only contraceptives, use of non-oral hormonal contraceptive agents, or fertility treatment.
What’s more, breastfeeding was associated with a lower risk of cardiovascular disease.
The researchers point to some limitations, such as missing data and the fact that reviews were largely based on observational evidence, so they cannot rule out the possibility that other unmeasured (confounding) factors may have had an effect.
Nevertheless, they say the evidence reported in this umbrella review suggests that, from menarche to menopause, the reproductive profile of women is associated with their future risk of cardiovascular disease.
It also provides clarity on the quality of the evidence, identifies gaps in evidence and practice, and provides recommendations that could be incorporated into guidelines, such as incorporating reproductive risk factors as part of the risk assessment for cardiovascular disease, they conclude.
Objective: To consolidate evidence from systematic reviews and meta-analyses investigating the association between reproductive factors in women of reproductive age and their subsequent risk of cardiovascular disease.
Design: Umbrella review.
Data sources: Medline, Embase, and Cochrane databases for systematic reviews and meta-analyses from inception until 31 August 2019.
Review methods: Two independent reviewers undertook screening, data extraction, and quality appraisal. The population was women of reproductive age. Exposures were fertility related factors and adverse pregnancy outcomes. Outcome was cardiovascular diseases in women, including ischaemic heart disease, heart failure, peripheral arterial disease, and stroke.
Results: 32 reviews were included, evaluating multiple risk factors over an average follow-up period of 7-10 years. All except three reviews were of moderate quality. A narrative evidence synthesis with forest plots and tabular presentations was performed. Associations for composite cardiovascular disease were: twofold for pre-eclampsia, stillbirth, and preterm birth; 1.5-1.9-fold for gestational hypertension, placental abruption, gestational diabetes, and premature ovarian insufficiency; and less than 1.5-fold for early menarche, polycystic ovary syndrome, ever parity, and early menopause. A longer length of breastfeeding was associated with a reduced risk of cardiovascular disease. The associations for ischaemic heart disease were twofold or greater for pre-eclampsia, recurrent pre-eclampsia, gestational diabetes, and preterm birth; 1.5-1.9-fold for current use of combined oral contraceptives (oestrogen and progesterone), recurrent miscarriage, premature ovarian insufficiency, and early menopause; and less than 1.5-fold for miscarriage, polycystic ovary syndrome, and menopausal symptoms. For stroke outcomes, the associations were twofold or more for current use of any oral contraceptive (combined oral contraceptives or progesterone only pill), pre-eclampsia, and recurrent pre-eclampsia; 1.5-1.9-fold for current use of combined oral contraceptives, gestational diabetes, and preterm birth; and less than 1.5-fold for polycystic ovary syndrome. The association for heart failure was fourfold for pre-eclampsia. No association was found between cardiovascular disease outcomes and current use of progesterone only contraceptives, use of non-oral hormonal contraceptive agents, or fertility treatment.
Conclusions: From menarche to menopause, reproductive factors were associated with cardiovascular disease in women. In this review, presenting absolute numbers on the scale of the problem was not feasible; however, if these associations are causal, they could account for a large proportion of unexplained risk of cardiovascular disease in women, and the risk might be modifiable. Identifying reproductive risk factors at an early stage in the life of women might facilitate the initiation of strategies to modify potential risks. Policy makers should consider incorporating reproductive risk factors as part of the assessment of cardiovascular risk in clinical guidelines.
Kelvin Okoth, Joht Singh Chandan, Tom Marshall, Shakila Thangaratinam, G Neil Thomas, Krishnarajah Nirantharakumar, Nicola J Adderley