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Cited by 416Pregnancy and preeclampsia studiesBirth, Development, and HealthCardiovascular Health and Risk Factors

Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review

Open access
Okoth, Kelvin, Chandan, Joht Singh, Marshall, Tom, Thangaratinam, Shakila, Thomas, G Neil, Nirantharakumar, Krishnarajah, Adderley, Nicola J·2020·BMJ
DOI 10.1136/bmj.m3502PMC PMC7537472
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Abstract

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. Systematic review registration: PROSPERO CRD42019120076.

AI snapshot

Written from the paper’s full text.

TL;DR

This umbrella review consolidates systematic reviews and meta-analyses on reproductive factors in women of reproductive age and later cardiovascular disease. It reports that multiple fertility-related factors and adverse pregnancy outcomes are associated with increased cardiovascular risk, while longer breastfeeding is associated with reduced risk.

Key findings

  • Among 32 included reviews, composite cardiovascular disease associations 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. Longer breastfeeding was associated with reduced cardiovascular disease risk.
  • For ischaemic heart disease, associations were twofold or greater for pre-eclampsia, recurrent pre-eclampsia, gestational diabetes, and preterm birth; 1.5-1.9-fold for current combined oral contraceptive use, recurrent miscarriage, premature ovarian insufficiency, and early menopause; and less than 1.5-fold for miscarriage, polycystic ovary syndrome, and menopausal symptoms.
  • For stroke, associations were twofold or more for current use of any oral contraceptive, pre-eclampsia, and recurrent pre-eclampsia; 1.5-1.9-fold for current combined oral contraceptive use, gestational diabetes, and preterm birth; and less than 1.5-fold for polycystic ovary syndrome. Pre-eclampsia was associated with a fourfold risk of heart failure.
  • 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.

Methods

  • Umbrella review of systematic reviews and meta-analyses; population was women of reproductive age; exposures were fertility-related factors and adverse pregnancy outcomes; outcomes included ischaemic heart disease, heart failure, peripheral arterial disease, stroke, and composite cardiovascular disease.
  • Medline, Embase, and Cochrane databases were searched from inception until 31 August 2019; PRISMA guidelines were followed and the protocol was registered in PROSPERO (CRD42019120076).
  • Two reviewers independently screened, extracted data, and appraised quality with AMSTAR 2; overlapping reviews were assessed with corrected covered area, outdated reviews were excluded, and findings were synthesised narratively with forest plots and tables.

Limitations

  • The paper states that missing metadata, including participant and event numbers, hindered reporting; systematic reviews on endometriosis, pelvic inflammatory disease, first trimester bleeding without miscarriage, and anaemia in pregnancy could not be identified; some reviews were rated low quality and none high quality; and included evidence was observational, with possible residual confounding, imprecise results from few events, cross-sectional designs, heterogeneity, incomplete publication bias assessment, and self-reported data.
  • The paper also states that presenting absolute numbers on the scale of the problem was not feasible, that causality is unclear, and that the exact magnitude of preventable cardiovascular disease attributable to reproductive risk factors is uncertain.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/bmj.m3502

Cites

161 of 161 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 155 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Gestational hypertension is associated with a 1.5-1.9-fold risk of composite cardiovascular disease.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    Stillbirth is associated with a twofold risk of composite cardiovascular disease.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    Preterm birth is associated with a twofold risk of composite cardiovascular disease.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    Gestational diabetes is associated with a 1.5-1.9-fold risk of composite cardiovascular disease.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    Premature ovarian insufficiency is associated with a 1.5-1.9-fold risk of composite cardiovascular disease.

    “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.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 49
  • May combine two claims. 30

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The included reviews evaluated multiple risk factors over an average follow-up period of 7-10 years.

    “32 reviews were included, evaluating multiple risk factors over an average follow-up period of 7-10 years.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    All except three included reviews were of moderate quality.

    “All except three reviews were of moderate quality.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The umbrella review included 32 reviews.

    “32 reviews were included, evaluating multiple risk factors over an average follow-up period of 7-10 years.”
    • Also stated in: § Study characteristics of reviews with non-overlapping associations · plain
      “Of the 32 reviews included in the analyses, 24 conducted meta-analyses as the main form of evidence synthesis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Preterm births were investigated in 3 included reviews.

    “Adverse pregnancy outcomes included miscarriage (n=1), pre-eclampsia (n=2), gestational diabetes (n=2), preterm births (n=3), and multiple adverse pregnancy outcomes (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Breastfeeding was investigated in 1 included review.

    “Factors related to fertility investigated in the included reviews were use of hormonal contraceptive agents (n=9), fertility treatment (n=1), early menarche (n=2), polycystic ovary syndrome (n=3), menopause (n=4), parity (n=2), and breastfeeding (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Miscarriage was investigated in 1 included review.

    “Adverse pregnancy outcomes included miscarriage (n=1), pre-eclampsia (n=2), gestational diabetes (n=2), preterm births (n=3), and multiple adverse pregnancy outcomes (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    One study reviewed risk factors related to fertility and adverse pregnancy outcomes but was limited to heart failure as an outcome.

    “One study reviewed risk factors related to fertility and adverse pregnancy outcomes but was limited to heart failure as an outcome (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The median length of follow-up was about 10 years for studies on risk factors related to fertility.

    “The median length of follow-up was about 10 years for studies on risk factors related to fertility and 7.5 years for studies on adverse pregnancy outcomes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Parity was investigated in 2 included reviews.

    “Factors related to fertility investigated in the included reviews were use of hormonal contraceptive agents (n=9), fertility treatment (n=1), early menarche (n=2), polycystic ovary syndrome (n=3), menopause (n=4), parity (n=2), and breastfeeding (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Menopause was investigated in 4 included reviews.

    “Factors related to fertility investigated in the included reviews were use of hormonal contraceptive agents (n=9), fertility treatment (n=1), early menarche (n=2), polycystic ovary syndrome (n=3), menopause (n=4), parity (n=2), and breastfeeding (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Use of hormonal contraceptive agents was investigated in 9 included reviews.

    “Factors related to fertility investigated in the included reviews were use of hormonal contraceptive agents (n=9), fertility treatment (n=1), early menarche (n=2), polycystic ovary syndrome (n=3), menopause (n=4), parity (n=2), and breastfeeding (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Multiple adverse pregnancy outcomes were investigated in 1 included review.

    “Adverse pregnancy outcomes included miscarriage (n=1), pre-eclampsia (n=2), gestational diabetes (n=2), preterm births (n=3), and multiple adverse pregnancy outcomes (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Pre-eclampsia was investigated in 2 included reviews.

    “Adverse pregnancy outcomes included miscarriage (n=1), pre-eclampsia (n=2), gestational diabetes (n=2), preterm births (n=3), and multiple adverse pregnancy outcomes (n=1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Thirty-two reviews were rated as moderate in quality and seven reviews were rated as low in quality.

    “Thirty two reviews were rated as moderate in quality and seven reviews were rated as low in quality (appendix 7).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Gestational diabetes was investigated in 2 included reviews.

    “Adverse pregnancy outcomes included miscarriage (n=1), pre-eclampsia (n=2), gestational diabetes (n=2), preterm births (n=3), and multiple adverse pregnancy outcomes (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Early menarche was investigated in 2 included reviews.

    “Factors related to fertility investigated in the included reviews were use of hormonal contraceptive agents (n=9), fertility treatment (n=1), early menarche (n=2), polycystic ovary syndrome (n=3), menopause (n=4), parity (n=2), and breastfeeding (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The median length of follow-up was about 7.5 years for studies on adverse pregnancy outcomes.

    “The median length of follow-up was about 10 years for studies on risk factors related to fertility and 7.5 years for studies on adverse pregnancy outcomes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Fertility treatment was investigated in 1 included review.

    “Factors related to fertility investigated in the included reviews were use of hormonal contraceptive agents (n=9), fertility treatment (n=1), early menarche (n=2), polycystic ovary syndrome (n=3), menopause (n=4), parity (n=2), and breastfeeding (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Polycystic ovary syndrome was investigated in 3 included reviews.

    “Factors related to fertility investigated in the included reviews were use of hormonal contraceptive agents (n=9), fertility treatment (n=1), early menarche (n=2), polycystic ovary syndrome (n=3), menopause (n=4), parity (n=2), and breastfeeding (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Of the 32 reviews included in the analyses, 24 conducted meta-analyses as the main form of evidence synthesis.

    “Of the 32 reviews included in the analyses, 24 conducted meta-analyses as the main form of evidence synthesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The risk of myocardial infarction or stroke with combined oral contraceptives is increased in women on higher doses of oestrogen but is not related to the dose, generation, or type of progesterone.

    “The same review55 showed that the risk was increased in women on higher doses of oestrogen but was not related to the dose, generation, or type of progesterone (supplementary table 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The risk of both ischaemic and haemorrhagic stroke is greatest in women on higher doses of oestrogen, who had hypertension, were smokers, or were aged over 35.

    “The risk of both ischaemic and haemorrhagic stroke was greatest in women on higher doses of oestrogen, who had hypertension, were smokers, or were aged over 35 (supplementary table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    When the analysis is limited to women who did not go on to develop diabetes mellitus after gestational diabetes, the risk of composite cardiovascular disease is slightly less but remains statistically significant.

    “When the analysis was limited to women who did not go on to develop diabetes mellitus after gestational diabetes, the risk was slightly less but remained statistically significant (supplementary table 3).62”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Current use of combined oral contraceptives (oestrogen and progesterone), premature ovarian insufficiency, early menopause, and recurrent miscarriage were associated with a 1.5-1.9-fold increased risk of ischaemic heart disease.

    “current use of combined oral contraceptives (oestrogen and progesterone), premature ovarian insufficiency, early menopause, and recurrent miscarriage were associated with a 1.5-1.9-fold increased risk”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Current use of any oral contraceptives (combined oral contraceptives and progesterone only pill), recurrent pre-eclampsia, and pre-eclampsia were associated with a twofold or more increased risk of stroke.

    “Current use of any oral contraceptives (combined oral contraceptives and progesterone only pill), recurrent pre-eclampsia, and pre-eclampsia were associated with a twofold or more increased risk of stroke”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Systematic reviews on endometriosis, pelvic inflammatory disease, first trimester bleeding without miscarriage, and anaemia in pregnancy could not be identified, and therefore these factors were not incorporated in the analyses.

    “Systematic reviews on these exposures could not be identified, however, and therefore these factors were not incorporated in our analyses”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Current use of combined oral contraceptives, use of combined hormonal contraceptive agents in women with dyslipidaemia, use of combined hormonal contraceptive agents in women with hypertension, use of oestrogen containing pills in women with migraine, polycystic ovary syndrome, premature ovarian insufficiency, early menarche, early menopause, menopausal symptoms, parity, pre-eclampsia, recurrent预e

    “Evidence from the umbrella review suggests that current use of combined oral contraceptives, use of combined hormonal contraceptive agents in women with dyslipidaemia, use of combined hormonal contraceptive agents in women with hypertension, use of oestrogen containing pills in women with migraine, polycystic ovary syndrome, premature ovarian insufficiency, early menarche, early menopause, menop”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Maternal delivery of preterm infants, gestational diabetes, and current use of combined oral contraceptives were associated with a 1.5-1.9-fold increase in risk of stroke.

    “maternal delivery of preterm infants, gestational diabetes, and current use of combined oral contraceptives were associated with a 1.5-1.9-fold increase in risk”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Reviews on endometriosis, pelvic inflammatory disease, and anaemia during pregnancy were absent.

    “Reviews on endometriosis, pelvic inflammatory disease, and anaemia during pregnancy were absent”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    A history of maternal delivery of preterm infants, gestational diabetes, pre-eclampsia, and recurrent pre-eclampsia were associated with a twofold or more increase in the risk of ischaemic heart disease.

    “A history of maternal delivery of preterm infants, gestational diabetes, pre-eclampsia, and recurrent pre-eclampsia were associated with a twofold or more increase in the risk of ischaemic heart disease”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingnone given

    This study provides a comprehensive list of factors related to reproduction and adverse pregnancy outcomes and their association with cardiovascular disease.

    “This study provides a comprehensive list of factors related to reproduction and adverse pregnancy outcomes and their association with cardiovascular disease”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The increased risk of composite cardiovascular disease but not stroke was statistically significant (odds ratio 1.67, 95% confidence interval 1.28 to 2.19) in women with gestational hypertension.

    “We reported that the increased risk of composite cardiovascular disease but not stroke was statistically significant (odds ratio 1.67, 95% confidence interval 1.28 to 2.19) in women with gestational hypertension”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    This review reports evidence of an increased risk of cardiovascular disease outcomes in women with stillbirths, small for gestational age offspring, and placental abruption.

    “this review reports evidence of an increased risk of cardiovascular disease outcomes in women with stillbirths, small for gestational age offspring, and placental abruption”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The evidence evaluated reported an increased risk of ischaemic heart disease and cardiovascular disease associated with premature menopause.

    “the evidence we evaluated reported an increased risk of ischaemic heart disease and cardiovascular disease associated with premature menopause”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Early menopause and menopausal symptoms were associated with an increased risk of ischaemic heart disease.

    “early menopause and menopausal symptoms were associated with an increased risk of ischaemic heart disease”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Findingnone given

    The review provides clarity on the quality of the evidence, identifies gaps in evidence and practice, and provides recommendations that could be incorporated into guidelines.

    “The review provides clarity on the quality of the evidence, identifies gaps in evidence and practice, and provides recommendations that could be incorporated into guidelines”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Disagreements in quality assessment were resolved by consulting a third reviewer.

    “In the case of disagreements and failed consensus, a decision was reached by consulting a third reviewer (NJA).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Two reviewers independently carried out study selection and data extraction.

    “Two reviewers (KO and JSC) independently carried out the study selection and data extraction from the eligible studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The study used the data extraction form recommended by the Joanna Briggs Institute.

    “The study used the data extraction form recommended by the Joanna Briggs Institute (appendix 2).42”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Aromataris E Fernandez R Godfrey C Holly C Khalil H Tungpunkom P . Methodology for JBI umbrella reviews. Joanna Briggs Inst Rev Man, 2014:1-34.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    CCA is a validated method of quantifying the degree of overlap between two or more reviews.

    “CCA is a validated method of quantifying the degree of overlap between two or more reviews, and helps the decision process on how to deal with overlap when it is present.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The protocol was registered in PROSPERO (registration No CRD42019120076).

    “The umbrella review followed the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and the protocol was registered in PROSPERO (registration No CRD42019120076).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Two reviewers independently rated the methodological quality of the reviews with the AMSTAR 2 quality appraisal instrument.

    “Two reviewers (KO and JSC) rated the methodological quality of the reviews with the AMSTAR 2 quality appraisal instrument.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The umbrella review followed PRISMA guidelines.

    “The umbrella review followed the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and the protocol was registered in PROSPERO (registration No CRD42019120076).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The review of polycystic ovary syndrome in postmenopausal women was rated as low quality.

    “Results from population based studies suggested that, compared with healthy controls, the risk of cardiovascular events was increased in young women in the reproductive age group with polycystic ovary syndrome (hazard ratio 1.43, 95% confidence interval 1.27 to 1.61); no association was seen in postmenopausal women with polycystic ovary syndrome (supplementary table 3)70 but this review was rated”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Ramezani Tehrani, 2019, Cardiovascular events among reproductive and menopausal age women with polycystic ovary syndrome: a systematic review and meta-analysis, Gynecol Endocrinol

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    A small degree (CCA 5.6%) of overlap was noted between two reviews investigating the association between pre-eclampsia and risk of morbidity from ischaemic heart disease.

    “A small degree (CCA 5.6%) of overlap was noted between two reviews60 61 that investigated the association between pre-eclampsia and the risk of morbidity from ischaemic heart disease (appendix 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] source

      Not checked in the free run.

    • cites [61] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    One review searched for primary studies from 2005 only.

    “One review61 searched for primary studies from 2005 only.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The quality of the newly published breastfeeding studies ranged from low to high.

    “The quality of the studies ranged from low to high (appendix 10).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Methodological rigour in the conduct of the review was achieved by following PRISMA guidelines.

    “Methodological rigour in the conduct of the review was achieved by following PRISMA guidelines”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    With the AMSTAR 2 quality appraisal instrument, some reviews were rated as low quality, and none of the reviews was rated as high in quality.

    “With the AMSTAR 2 quality appraisal instrument, some reviews were rated as low quality, and none of the reviews was rated as high in quality”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    The reviews included were necessarily based on observational evidence; consequently, the possibility of confounding remains because of unknown confounders or lack of adjustment for known confounders.

    “the reviews included were necessarily based on observational evidence; consequently, as noted by Grandi et al,60 the possibility of confounding remains because of unknown confounders or lack of adjustment for known confounders”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The methodological quality of the studies included in the review was assessed with the AMSTAR 2 tool.

    “The methodological quality of the studies included in the review was assessed with the AMSTAR 2 tool”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Misclassification of exposure or outcome status in the studies included in the review is possible.

    “Misclassification of exposure or outcome status in the studies included in the review is also possible”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    For some reproductive factors, including age at first birth, evidence from a systematic review was identified, but because of inherent methodological shortcomings, the review did not meet the inclusion criteria.

    “for some reproductive factors, including age at first birth,122 evidence from a systematic review was identified, but because of inherent methodological shortcomings,40 the review did not meet our inclusion criteria”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [122] source

      Not checked in the free run.

    • cites [40] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Evidence presented in this review on combined hormonal contraceptive agents and combined oral contraceptives is in keeping with findings on the adverse effects of the use of hormonal contraceptive agents reported in current evidence based guidelines.

    “Evidence presented in this review on combined hormonal contraceptive agents and combined oral contraceptives are in keeping with findings on the adverse effects of the use of hormonal contraceptive agents reported in current evidence based guidelines”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] FSRH Clinical Guideline. Combined hormonal contraception (January 2019, amended July 2019) - Faculty of Sexual and Reproductive Healthcare. 2019. https://www.fsrh.org/standards-and-guidance/documents/combined-hormonal-contraception/

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The findings of this review agree with the consensus statement from the European Headache Federation, which reported that the risk of stroke was greater in women with migraine.

    “the findings of this review agree with the consensus statement from the European Headache Federation, which reported that the risk of stroke was greater in women with migraine”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125]

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    Information from some of the primary studies was self-reported, which might lead to potential misclassification and recall bias.

    “Information from some of the primary studies was self-reported, which might lead to potential misclassification and recall bias”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Lack of data, including missing metadata (number of participants and events), hindered the reporting of some elements of the umbrella review.

    “Lack of data, including missing metadata (number of participants and events), hindered the reporting of some elements of the umbrella review”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Insufficient reporting by review authors rather than shortcomings of the review methods could have inadvertently led to a downgrading of the quality of the review.

    “Insufficient reporting by review authors rather than shortcomings of the review methods could have inadvertently led to a downgrading of the quality of the review”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Where eligible, reviews were updated to ensure the evidence was current.

    “Where eligible, reviews were updated to ensure the evidence was current”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The absolute risk of cardiovascular disease associated with the use of combined oral contraceptives is low (about 10 per 100 000 person years for myocardial infarction and 21 per 100 000 person years for stroke).

    “the absolute risk of cardiovascular disease associated with the use of combined oral contraceptives is low (about 10 per 100 000 person years for myocardial infarction and 21 per 100 000 person years for stroke)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A comprehensive search strategy was used to identify relevant reviews.

    “A comprehensive search strategy was used to identify relevant reviews”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Evaluation of CCA and reporting of the highest quality and most current review from reviews with overlapping associations were used to eliminate double counting.

    “Evaluation of CCA and reporting of the highest quality and most current review from reviews with overlapping associations were used to eliminate double counting”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Our previous study found insufficient reporting of gestational diabetes and screening for cardiovascular risk factors in these women.

    “Our previous study found insufficient reporting of gestational diabetes and screening for cardiovascular risk factors in these women”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A meta-analysis published beyond the time line of this review reported that women with gestational hypertension had an increased risk of composite cardiovascular disease (relative risk 1.73, 95% CI 1.43 to 2.09), stroke (1.66, 0.99 to 2.79), coronary heart disease (1.56, 1.35 to 1.81), and heart failure (1.70, 1.43 to 2.02).

    “a meta-analysis,135 published beyond the time line of this review, which reported that women with gestational hypertension had an increased risk of composite cardiovascular disease (relative risk 1.73, 95% confidence interval 1.43 to 2.09), stroke (1.66, 0.99 to 2.79), coronary heart disease (1.56, 1.35 to 1.81), and heart failure (1.70, 1.43 to 2.02)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hospital episodes related to cardiovascular disease occurred in 381 458 women in the financial year 2017-18, indicating an incidence of about 113.4 cardiovascular disease episodes per 10 000 women annually.

    “Hospital episodes related to cardiovascular disease occurred in 381 458 women in the financial year 2017-18,151 indicating an incidence of about 113.4 cardiovascular disease episodes per 10 000 women annually”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] 2019, Heart and circulatory disease statistics 2019, Stat Compend

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Results on the risk of heart failure were based on one cross sectional study that reported imprecise results.

    “Results on the risk of heart failure were based on one cross sectional study that reported imprecise results”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Cross sectional studies cannot be used to infer causality.

    “cross sectional studies cannot be used to infer causality”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Premisenone given

    Clarity on the quality of the evidence is lacking and on how the findings can be translated into public health and clinical practice.

    “Clarity on the quality of the evidence is lacking and on how the findings can be translated into public health and clinical practice”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    A large proportion of unexplained risk of cardiovascular disease in women might be attributable to reproductive risk factors but the exact magnitude of the effect is unclear.

    “A large proportion of unexplained risk of cardiovascular disease in women might be attributable to reproductive risk factors but the exact magnitude of the effect is unclear”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Individual reviews assessing the implications of these risk factors for cardiovascular disease have been published.

    “Individual reviews assessing the implications of these risk factors for cardiovascular disease have been published”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Endothelial dysfunction, which has been found in women with premature menopause and in those with adverse pregnancy outcomes, might trigger pregnancy complications and remain beyond these complications to predispose women to future cardiovascular disease.

    “Endothelial dysfunction, which has been found in women with premature menopause and in those with adverse pregnancy outcomes, might trigger pregnancy complications and remain beyond these complications to predispose women to future cardiovascular disease”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] source

      Not checked in the free run.

    • cites [147] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Guidelines on the prevention of cardiovascular disease recognise perimenopause and menopause as periods when women are vulnerable to cardiovascular disease.

    “Guidelines on the prevention of cardiovascular disease recognise perimenopause and menopause as periods when women are vulnerable to cardiovascular disease”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [128] source

      Not checked in the free run.

    • cites [129] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Risk factors specific to women are associated with cardiovascular disease.

    “Risk factors specific to women are associated with cardiovascular disease”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Families of women with a history of reproductive complications were also at an increased risk of cardiovascular disease and so genetic predispositions could have a role.

    “Families of women with a history of reproductive complications were also at an increased risk of cardiovascular disease and so genetic predispositions could have a role”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [137] source

      Not checked in the free run.

    • cites [138] source

      Not checked in the free run.

74 of 74

  • The paper relies on this without support.

    The associations between reproductive factors and cardiovascular disease observed in the included observational studies are not entirely due to residual confounding.

    “the reviews included were necessarily based on observational evidence; consequently, as noted by Grandi et al,60 the possibility of confounding remains because of unknown confounders or lack of adjustment for known confounders”

  • The paper relies on this without support.

    The included systematic reviews and meta-analyses provide valid estimates of the associations between reproductive factors and cardiovascular disease.

    “This detailed umbrella review synthesised existing systematic reviews and meta-analyses into one user friendly document”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Parity and non-fatal cardiovascular disease have opposite directions in the text and table

    Major

    The text says non-fatal cardiovascular disease risk was increased in ever-parous women, but Table 1 reports a relative risk of 0.79 for non-fatal composite cardiovascular disease under parity.

  • Recurrent pre-eclampsia-stroke association is described as twofold or greater

    Major

    The abstract places recurrent pre-eclampsia in the twofold-or-greater stroke-risk category, but Table 1 reports a relative risk of 1.69.

  • Breastfeeding comparison misstates a cohort study's reference group

    Minor

    The text says all three cited cohorts compared longer breastfeeding with never breastfeeding. Table 2 instead shows that study 114 used breastfeeding for less than four months as its reference group.

  • Gestational diabetes-stroke association is assigned the wrong effect-size category

    Minor

    The abstract places gestational diabetes in the 1.5-1.9-fold stroke-risk category, whereas Table 1 reports a relative risk of 1.25.

4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. 2019, Heart and circulatory disease statistics 2019, Stat Compend, 2019, 94

Cited by

Sorted by citations

Related

Authors
Okoth, K., Chandan, J. S., Marshall, T., Thangaratinam, S., Thomas, G. N., Nirantharakumar, K., & Adderley, N. J.
Affiliations
  • University of Birmingham (GB)
  • Queen Mary University of London (GB)
Corresponding author
Nirantharakumar, Krishnarajah
ORCID
Venue
BMJ
Publisher
BMJ
Published
2020-10-07
Volume
371
Pages
m3502
ISSN
1756-1833 (ISSN-L)
DOI
10.1136/bmj.m3502
PMC
PMC7537472
OpenAlex
W3091804242
Cited by
416
References
161
Citations by year
2026: 38 · 2025: 76 · 2024: 81 · 2023: 90 · 2022: 74 · 2021: 55 · 2020: 2
FWCI
6.51
Type
journal article
Language
en
Update notices
correction (2020-10-14)
Open access
Licence
Locations
  • BMJ (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc)
Funders
National Institute for Health and Care Research (ACF-2018-08-001)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Risk Factors
Keywords
polycystic ovary syndrome, preeclampsia, preterm birth, gestational diabetes mellitus, premature ovarian insufficiency, early menopause, breastfeeding, combined oral contraceptives, progestin-only contraception, heart failure, ischemic heart disease, stroke, peripheral arterial disease, adverse pregnancy outcomes, cardiovascular risk, women's reproductive health
MeSH terms
Systematic Reviews as Topic, Correlation of Data, Cardiovascular Diseases, Female, Fertility, Humans, Pregnancy, Pregnancy Complications, Risk Factors, Meta-Analysis as Topic, Risk Assessment, Reproductive Health

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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