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Cited by 94Reproductive Health and TechnologiesAssisted Reproductive Technology and Twin PregnancyOvarian function and disorders

Cardiovascular Risk Following Fertility Therapy

Open access
Dayan, Natalie, Filion, Kristian B., Okano, Marisa, Kilmartin, Caitlin, Reinblatt, Shauna, Landry, Tara, Basso, Olga, Udell, Jacob A.·2017·Journal of the American College of Cardiology
DOI 10.1016/j.jacc.2017.07.753
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Abstract

Background The longer term cardiovascular effects of fertility therapy are unknown.Objectives The aim of this study was to summarize data linking fertility therapy with subsequent cardiovascular outcomes.Methods We systematically searched published reports for studies addressing the question "does fertility therapy increase the risk of longer term cardiovascular outcomes?" We included: 1) human studies; 2) case control, cohort, or randomized designs with 3) exposure to fertility therapy and 4) cardiovascular outcomes clearly reported; 5) presence of comparison group; 6) minimum 1-year follow-up; and 7) adjustment for age. Two independent reviewers screened abstracts, titles, and full texts, and assessed study quality. We used the DerSimonian and Laird random-effects models to pool hazard ratios (HRs) with 95% confidence intervals (CIs) of the following outcomes: acute cardiac event; stroke; venous thromboembolism; hypertension; and diabetes mellitus, comparing women who received fertility therapy with those who did not.Results Six observational studies met inclusion criteria including 41,910 women who received fertility therapy and 1,400,202 women who did not. There was no increased risk of a cardiac event (pooled HR: 0.91; 95% CI: 0.67 to 1.25; I 2 = 36.6%), or diabetes mellitus (pooled HR: 0.93; 95% CI: 0.87 to 1.001; I 2 = 0%). Results were not pooled for hypertension (I 2 = 95.0%) and venous thromboembolism (I 2 = 82.3%). There was a trend toward higher risk of stroke (pooled HR: 1.25; 95% CI: 0.96 to 1.63; I 2 = 0%).Conclusions The small number of studies and significant heterogeneity precludes definitive reassurance about the longer term cardiovascular safety of these treatments, particularly stroke. Future studies are needed to address ongoing knowledge gaps in this area.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review and meta-analysis found no increased risk of acute cardiac events or diabetes mellitus after fertility therapy, but a non-significant trend toward higher stroke risk. The authors conclude that few studies and substantial heterogeneity preclude definitive reassurance about long-term cardiovascular safety.

Key findings

  • Six observational studies included 41,910 women who received fertility therapy and 1,400,202 who did not; median follow-up was 9.8 years (range 1 to >20 years).
  • Pooled risk was not increased for cardiac events (HR: 0.91; 95% CI: 0.67–1.25; I² = 36.6%) or diabetes mellitus (HR: 0.93; 95% CI: 0.87–1.001; I² = 0%).
  • Stroke showed a trend toward higher risk (HR: 1.25; 95% CI: 0.96–1.63; I² = 0%).
  • Results were not pooled for venous thromboembolism (I² = 82.3%) or hypertension (I² = 95.0%) because of substantial heterogeneity; individual estimates were discordant.

Methods

  • Systematic review and meta-analysis following PRISMA and MOOSE guidelines, with an a priori protocol; databases were searched without language restriction through April 2016 and rerun in January 2017.
  • Inclusion criteria required human studies with case-control, cohort, or randomized designs; fertility therapy exposure; cardiovascular outcomes; a comparison group; at least 1-year follow-up; and adjustment for age.
  • DerSimonian and Laird random-effects models pooled hazard ratios with 95% confidence intervals; heterogeneity was assessed with I², and meta-analysis was not performed when I² > 80%.

Limitations

  • The paper states that the small number of studies and significant between-study heterogeneity preclude definitive reassurance, particularly for stroke; confounding by indication, variable exposure classification, possible misclassification, and short follow-up are also noted.
  • The paper states that publication bias was not formally assessed because all analyses included fewer than 10 studies, and pre-specified subgroup and sensitivity analyses were not performed because of the limited number of studies.
  • Evident from the text: only one included study compared infertile women who used fertility therapy with infertile women who did not, and five studies were rated moderate risk of bias while one was rated serious risk of bias.

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

Integrity signals

Registry

Crossref · 10.1016/j.jacc.2017.07.753

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 61 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    There was a trend toward higher risk of stroke (pooled HR: 1.25; 95% CI: 0.96 to 1.63; I2=0%).

    “There was a trend toward higher risk of stroke (pooled HR: 1.25; 95% CI: 0.96 to 1.63; I 2 ¼ 0%).”
    • Also stated in: § STROKE. · hedged
      “Pooled analysis suggested a possible increase in the risk of stroke (HR: 1.25; 95% CI: 0.96 to 1.63; I 2 ¼ 0%) in women who received fertility therapy as compared with women who did not receive fertility therapy”
    Quote in the paperSubstantial claim
  • Findingown data

    Results were not pooled for venous thromboembolism (I2=82.3%).

    “Results were not pooled for hypertension (I 2 ¼ 95.0%) and venous thromboembolism (I 2 ¼ 82.3%).”
    • Also stated in: § VTE. · plain
      “Owing to substantial heterogeneity (I 2 ¼ 82.3%), these results were not pooled”
    Quote in the paperSubstantial claim
  • Findingown data

    There was no increased risk of a cardiac event (pooled HR: 0.91; 95% CI: 0.67 to 1.25; I2=36.6%).

    “There was no increased risk of a cardiac event (pooled HR: 0.91; 95% CI: 0.67 to 1.25; I 2 ¼ 36.6%)”
    • Also stated in: § CARDIAC EVENTS. · plain
      “Overall, the use of fertility therapy was not associated with the risk of a cardiac event (pooled HR: 0.91; 95% CI: 0.67 to 1.25; I 2 ¼ 36.6%).”
    Quote in the paperSubstantial claim
  • Findingown data

    There was no increased risk of diabetes mellitus (pooled HR: 0.93; 95% CI: 0.87 to 1.001; I2=0%).

    “or diabetes mellitus (pooled HR: 0.93; 95% CI: 0.87 to 1.001; I 2 ¼ 0%)”
    • Also stated in: § MELLITUS. · hedged
      “The studies were concordant and the pooled result yielded a neutral effect, with a trend toward possible modest benefit on the development of diabetes mellitus (HR: 0.93; 95% CI: 0.87 to 1.001; I 2 ¼ 0)”
    Quote in the paperSubstantial claim
  • Findingown data

    Results were not pooled for hypertension (I2=95.0%).

    “Results were not pooled for hypertension (I 2 ¼ 95.0%) and venous thromboembolism (I 2 ¼ 82.3%).”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 31
  • May combine two claims. 25

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

    Findingcitation

    One included study was an observational analysis of CV events of a randomized trial evaluating electrocautery of ovaries versus gonadotropins in women with clomiphene-resistant polycystic ovarian syndrome.

    “One included study (35) was an observational analysis of CV events of a randomized trial evaluating electrocautery of ovaries versus gonadotropins in women with clomipheneresistant polycystic ovarian syndrome (36).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] source

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    • cites [36] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Included studies were population-based retrospective cohort studies (n=2), secondary analysis of the Nurses' Health Study II cohort (n=1), and a single nested case-cohort study that resulted in 2 publications (n=2).

    “Studies included were populationbased retrospective cohort studies (n ¼ 2) (28,34), secondary analysis of the longitudinal Nurses' Health Study II cohort (n ¼ 1) (25), and a single nested casecohort study that resulted in 2 publications (n ¼ 2):”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [28]

      Not checked in the free run.

    • cites [34] source

      Not checked in the free run.

    • cites [25] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The included studies comprised 41,190 women who received fertility therapy and 1,400,202 who did not, totaling 1,441,392 women.

    “Our data summary and synthesis included 1,441,392 women: 41,190 women who received fertility therapy and 1,400,202 who did not receive fertility therapy.”
    • Also stated in: § STRENGTHS OF STUDY DESIGN. · plain
      “Despite the limited number of included studies, our review summarized data in more than 1.4 million women (41,190 women who received fertility therapy and 1,400,202 women who did not receive fertility therapy).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Our initial search retrieved 6,007 titles and abstracts after duplicates were removed, of which 62 full-text articles were identified for detailed assessment; 6 studies were ultimately included.

    “Our initial search retrieved 6,007 titles and abstracts after duplicates were removed, of which 62 full-text articles were identified for detailed assessment (Figure 1); 6 studies were ultimately included in our systematic review and metaanalysis.”
    Quote in the paperSubstantial claim

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

    Findingown data

    The median duration of follow-up across included studies was 9.8 years (range 1 to >20 years).

    “The median duration of follow-up across included studies was 9.8 years (range 1 to >20 years).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    IVF was reported in 4 of the 6 included studies.

    “IVF was reported in 4 of the 6 included studies (23,25,27,34).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] source

      Not checked in the free run.

    • cites [25] source

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    • cites [27] source

      Not checked in the free run.

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

    Findingnone given

    All included studies were published between 2013 and 2016.

    “All studies were published between 2013 and 2016.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    A greater proportion of fertility-treated women were nulliparous.

    “A greater proportion of fertility-treated women were nulliparous.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Two studies examined the risk of stroke following fertility therapy, involving 30,477 women who received fertility therapy and 1,296,734 women who did not, followed for a median of 9.7 years and 8.6 years, respectively.

    “Two studies examined the risk of stroke following fertility therapy, involving 30,477 women who received fertility therapy and 1,296,734 women who did not receive fertility therapy followed for a median of 9.7 years (28) and 8.6 years (27), respectively.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28]

      Not checked in the free run.

    • cites [27] source

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

    Findingnone given

    Although only 6 studies were eligible for our analysis, all had been published since 2013, possibly reflecting the growing interest in the assessment of long-term CV health following fertility therapy.

    “Although only 6 studies were eligible for our analysis, all had been published since 2013, possibly reflecting the growing interest in the assessment of long-term CV health following fertility therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    We detected a potential increased risk for stroke among fertility-treated women, although the CIs were wide and crossed the null, given the limited data on this outcome.

    “We detected a potential increased risk for stroke among fertility-treated women, although the CIs were wide and crossed the null, given the limited data on this outcome.”
    • Also stated in: § Conceptual diagram depicting possible link between fertility therapy and cardiovascular disease, accounting for infertility and pregnancy events. · hedged
      “In a systematic review of observational studies of fertility therapy, there was no increased risk of developing a cardiac event, but there was a trend toward an increased risk of stroke, and data were inconclusive regarding risks of hypertension and VTE.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The individual estimates of effect for VTE were discordant, ranging from a possible protective effect (HR: 0.45; 95% CI: 0.21 to 0.94) in the study with a median of 9.7 years of follow-up to a possible harmful effect (HR: 1.29; 95% CI: 0.82 to 2.02) in the study with a 1-year follow-up.

    “The individual estimates of effect were discordant, ranging from a possible protective effect (HR: 0.45; 95% CI: 0.21 to 0.94) in the study with a median of 9.7 years of follow-up to a possible harmful effect (HR: 1.29; 95% CI: 0.82 to 2.02) in the study with a 1-year follow-up.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Both Farland et al. and Udell et al. reported a reduced risk of incident hypertension in fertility-treated women compared with women without such treatment.

    “Both Farland et al. (25) and Udell et al. (28) reported a reduced risk of incident hypertension in fertility-treated women compared with women without such treatment, whereas Westerlund et al. (27) found a significant 27% increase in this risk.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] source

      Not checked in the free run.

    • cites [28]

      Not checked in the free run.

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

    Findingown data

    Most included studies included young women whose average age at delivery ranged from 28.5 years to 34 years.

    “Most of the studies included young women whose average age at delivery ranged from 28.5 years to 34 years (Table 2).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Removing the study of Westerlund et al. (27) resulted in slightly lower heterogeneity.

    “Removing the study of Westerlund et al. (27) resulted in slightly lower heterogeneity.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    This is the first systematic review of the longer term CV safety associated with fertility therapy across a spectrum of women.

    “This is the first systematic review of the longer term CV safety associated with fertility therapy across a spectrum of women.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study was conducted following an a priori protocol.

    “The study was conducted following an a priori protocol (Online Appendix 1).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The risk-of-bias scale was applied separately for cohort and case-control studies by 2 independent reviewers.

    “The scale was applied separately for cohort and case-control studies by 2 independent reviewers (C.K., N.D.).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Studies comparing infertile women who received fertility therapy with other infertile women who did not receive fertility therapy were considered of the highest quality.

    “Studies that compared infertile women who received fertility therapy with other infertile women who did not receive fertility therapy were considered of the highest quality, as opposed to studies using pregnant women who conceived naturally as the reference group.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The CV stress of pregnancy at advanced maternal age might itself contribute to CVD.

    “Furthermore, the CV stress of pregnancy at advanced maternal age might itself contribute to CVD (26).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] source

      Not checked in the free run.

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

    Premisecitation

    The use of fertility therapies to achieve pregnancy in infertile couples is rising in Western countries.

    “The use of fertility therapies to achieve pregnancy in infertile couples is rising in Western countries (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] source

      Not checked in the free run.

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

    Study design and conductcitation

    Risk of bias was assessed using ACROBAT-NRSI, which assesses potential risk of bias in observational studies in 7 domains.

    “Risk of bias was assessed using ACROBAT-NRSI (A Cochrane Risk of Bias Tool: for Non-Randomized Studies of Interventions)”
    • Also stated in: § METHODS · plain
      “which assesses the potential risk of bias in observational studies in 7 domains.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] source

      Not checked in the free run.

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

    Study design and conductnone given

    No study was excluded on the basis of quality alone.

    “No study was excluded on the basis of quality alone.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    We followed PRISMA and MOOSE guidelines for reporting of systematic reviews and meta-analyses of observational studies.

    “We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (29) and Meta-Analysis of Observational Studies in Epidemiology (30) guidelines for reporting of systematic reviews and meta-analyses of observational studies.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29]

      Not checked in the free run.

    • cites [30]

      Not checked in the free run.

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

    Study design and conductnone given

    Each domain and overall risk of bias for each study were rated as low, moderate, serious, critical, or insufficient information.

    “Each domain and the overall risk of bias for each study were rated as low risk, moderate risk, serious risk, critical risk, or as having insufficient information.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    This paper was not included in our systematic review because of the absence of an untreated control group; however, it underscores the importance of an adequate comparison group when evaluating effect of fertility therapy, such as infertile women who were not exposed to fertility therapy.

    “This paper was not included in our systematic review because of the absence of an untreated control group; however, it underscores the importance of an adequate comparison group when evaluating effect of fertility therapy, such as infertile women who were not exposed to fertility therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Studies were summarized using a random-effects model, which considers within- and between-study variance, and therefore provides a conservative estimate of the pooled effect size.

    “Studies were summarized using a random-effects model, which considers within-and between-study variance, and therefore provides a conservative estimate of the pooled effect size (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41]

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

    Study design and conductown data

    Publication bias was not formally assessed by funnel plot and Egger's test for small study effects, as all analyses included fewer than 10 studies.

    “Similarly, publication bias was not formally assessed by funnel plot and Egger's test for small study effects, as all analyses included fewer than 10 studies (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] source

      Not checked in the free run.

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

    Study design and conductnone given

    We searched published and unpublished data without language restriction, and closely followed PRISMA guidelines.

    “We searched published and unpublished data without language restriction, and closely followed PRISMA guidelines in our approach.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    The reason for heterogeneity in hypertension risk is likely multifactorial.

    “The reason for this heterogeneity is likely multifactorial.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The variation in risk estimates across studies of VTE may be at least partly explained by differences in duration of follow-up; heightened risk for VTE dissipates with time.

    “The variation in risk estimates across studies of VTE may be at least partly explained by differences in duration of follow-up (i.e., higher risk of VTE at 1 year postpartum, but not at a median 9.7 years postpartum), suggesting that the heightened risk for VTE dissipates with time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Polycystic ovarian syndrome leads to infertility by anovulatory dysfunction and is also associated with metabolic syndrome and an accelerated atherosclerotic risk profile.

    “For example, polycystic ovarian syndrome leads to infertility by anovulatory dysfunction and is also associated with metabolic syndrome and an accelerated atherosclerotic risk profile (42).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42]

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

    Study design and conductown data

    Several subgroup analyses and sensitivity analyses were pre-specified, but because of the limited number of studies with heterogeneous outcomes, these analyses were not performed.

    “Several subgroup analyses (by study design, study quality, number of treatments, duration since treatment, invasive treatment [IVF vs. non-IVF], or level of adjustment on pooled estimates) and sensitivity analyses (e.g., influence analyses, fill-and-trim method) were pre-specified.However, because of the limited number of studies included in our systematic review with heterogeneous outcomes, these”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Meta-analysis was not performed in the presence of substantial heterogeneity (I2 > 80%).

    “Meta-analysis was not performed in the presence of substantial heterogeneity (I 2 > 80%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The same is not necessarily true of exogenous or supraphysiological doses of estrogens, as demonstrated by conflicting reports about the effects of hormone replacement therapy on the risk of hypertension and incident CVD.

    “However, the same is not necessarily true of exogenous or supraphysiological doses of estrogens, as demonstrated by conflicting reports about the effects of hormone replacement therapy on the risk of hypertension and incident CVD (39).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    In all cases, classification of exposure was unrelated to the outcome, rendering systematic recall bias unlikely.

    “In all cases, classification of exposure was unrelated to the outcome, rendering systematic recall bias unlikely.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both IVF and non-IVF approaches often involve repeated cycles of high-dose hormonal stimulation protocols, which lead to potential fluid shifts, endothelial dysfunction, and a prothrombotic state.

    “Both IVF and non-IVF approaches often involve repeated cycles of high-dose hormonal stimulation protocols, which lead to potential fluid shifts, endothelial dysfunction, and a prothrombotic state (23)(24)(25).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] source

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    • cites [24] source

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    • cites [25] source

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

    Premisecitation

    Failed fertility therapy may increase the risk of heart failure and stroke when compared with successful therapy.

    “A recent population-based cohort study conducted in Ontario, Canada, by our group (43) demonstrated that failed fertility therapy may increase the risk of heart failure and stroke when compared with successful therapy, which indicates that severe infertility may unmask a woman's predisposition toward vascular events.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43]

      Not checked in the free run.

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

    Study design and conductnone given

    In primary analyses, all measures of relative effect were pooled; in sensitivity analyses, inclusion was restricted to studies that reported HRs.

    “In our primary analyses, all measures of relative effect were pooled; in sensitivity analyses, we restricted inclusion to studies that reported HRs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationcitation

    Reproductive factors, such as fertility therapy use, may be a sex-specific risk marker or mediator to appreciate when deciding on risk reduction strategies in women.

    “In an era in which sex-based differences in CVD are increasingly recognized, reproductive factors, such as fertility therapy use, may be a sexspecific risk marker or mediator to appreciate when deciding on risk reduction strategies in women (5,37).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] source

      Not checked in the free run.

    • cites [37] source

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  • May combine two claims.

    Study design and conductreasoning

    Although the small number of studies precluded adequate assessment of publication bias, most studies were large and reported a null effect.

    “Although the small number of studies precluded adequate assessment of publication bias, most studies were large and reported a null effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The limited number of studies in this area precludes further assessment of potential risk according to stroke subtype, or of possible etiologies.

    “The limited number of studies in this area precludes further assessment of potential risk according to stroke subtype, or of possible etiologies.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    The metabolic demands of pregnancy in older women may contribute to a downstream increased risk for cerebrovascular disease.

    “thus, the metabolic demands of pregnancy in older women may contribute to a downstream increased risk for cerebrovascular disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    In analyses estimating rate and risk of hypertension, Westerlund et al. excluded cases with pre-existing hypertension and hypertensive disorders of pregnancy, which may explain the low absolute risk of chronic hypertension (25.8 per 10,000 in women who received IVF and 21.3 per 10,000 in women not treated with IVF).

    “In analyses estimating the rate and risk of hypertension, Westerlund et al. (27) excluded cases with pre-existing hypertension and hypertensive disorders of pregnancy, which may explain the low absolute risk of chronic hypertension (25.8 per 10,000 in women who received IVF and 21.3 per 10,000 in women not treated with IVF).”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Ethnic differences in Sweden versus North America, as well as differences in access to fertility therapy under government health insurance, might further contribute to observed heterogeneity; therefore, we are unable to conclusively summarize the direction of the effect of fertility therapy on future risk of hypertension.

    “Ethnic differences in Sweden versus North America, as well as differences in access to fertility therapy under government health insurance, might further contribute to the observed heterogeneity; therefore, we are unable to conclusively summarize the direction of the effect of fertility therapy on the future risk of hypertension.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    IVF may contribute to CVD risk through the development of hypertensive disorders of pregnancy such as pre-eclampsia, which is itself a potent sex-specific CVD risk factor.

    “Furthermore, IVF may contribute to CVD risk through the development of hypertensive disorders of pregnancy such as pre-eclampsia, which is itself a potent sex-specific CVD risk factor (Central Illustration)(7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] source

      Not checked in the free run.

46 of 46

  • The paper relies on this without support.

    The long-term cardiovascular effects of fertility therapy are unknown or uncertain.

    “The longer term cardiovascular effects of fertility therapy are unknown.”
    “What happens years after pregnancy is less well studied.”
    “its long-term CV safety is unknown.”

  • The paper relies on this without support.

    There is an inevitable selection bias for undergoing fertility therapy.

    “Because there is an inevitable selection bias for undergoing fertility therapy, this apparent benefit on diabetes may simply reflect a healthy user effect rather than an established biological effect.”
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.

  • Sensitivity analysis cites the wrong study number for Nahuis

    Minor

    The cardiac-event sensitivity analysis identifies Nahuis as reference 34, but Table 1 identifies Nahuis as reference 35 and lists reference 34 as Ben-Yaakov.

  • Farland control-group disorder percentage is tenfold too high

    Minor

    Table 2 lists 34 cases among 8,261 women without fertility therapy as 4.0%. That fraction is approximately 0.41%.

    Reported 4 · recomputed 0.411572

  • Nahuis study year differs between the table and reference list

    Minor

    Table 1 dates the Nahuis study to 2016, while its bibliographic entry gives a 2014 publication year.

  • Swedish control-group disorder percentage does not match its count

    Minor

    Table 2 reports 563 cases among 116,960 women without fertility therapy as 0.3%, in both Swedish study columns. The fraction is approximately 0.48%, or 0.5% to one decimal place.

    Reported 0.3 · recomputed 0.481361

4 of 4

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Authors
Dayan, N., Filion, K. B., Okano, M., Kilmartin, C., Reinblatt, S., Landry, T., Basso, O., & Udell, J. A.
Affiliations
  • McGill University Health Centre (CA)
  • Montreal General Hospital (CA)
  • University of Toronto (CA)
Corresponding author
  • Dayan, Natalie
  • Udell, Jacob A.
ORCID
Venue
Journal of the American College of Cardiology
Publisher
Elsevier BV
Published
2017-09
Volume
70
Issue
10
Pages
1203-1213
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/j.jacc.2017.07.753
OpenAlex
W2747626961
Semantic Scholar
249c98a89b065e1e6bdb771c6fd5d13fd90309b7
Cited by
94
References
39
Citations by year
2026: 10 · 2025: 6 · 2024: 15 · 2023: 15 · 2022: 7 · 2021: 9 · 2020: 15 · 2019: 4 · 2018: 11 · 2017: 2
FWCI
10.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Heart and Stroke Foundation of Canada
  • Ontario Ministry of Research and Innovation
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Health and Technologies
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Assisted Reproductive Technology and Twin Pregnancy
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Keywords
cardiovascular risk, stroke, venous thromboembolism, hypertension, diabetes mellitus, cardiac events, long-term safety, assisted reproduction
MeSH terms
Cardiovascular Diseases, Female, Fertility, Humans, Infertility, Female, Global Health, Incidence, Reproductive Techniques, Assisted

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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