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Cited by 55Reproductive Health and TechnologiesBlood Pressure and Hypertension StudiesPregnancy and preeclampsia studies

Infertility, fertility treatment, and risk of hypertension

Open access
Farland, Leslie V., Grodstein, Francine, Srouji, Serene S., Forman, John P., Rich-Edwards, Janet, Chavarro, Jorge E., Missmer, Stacey A.·2015·Fertility and Sterility
DOI 10.1016/j.fertnstert.2015.04.043PMC PMC4522333
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Abstract

Objective To evaluate the association between infertility and fertility treatments on subsequent risk of hypertension. Design Cohort Study Setting Nurses’ Health Study II Patients 116,430 female nurses followed from 1993 to June 2011 as part of the Nurses' Health Study II cohort. Intervention None Main Outcome Measures Self-reported, physician diagnosed hypertension Results Compared to women who never reported infertility, infertile women were at no greater risk of hypertension (multi-variable adjusted relative risk (RR) = 1.01 95% confidence interval [0.94–1.07]). Infertility due to tubal disease was associated with a higher risk of hypertension (RR=1.15 [1.01–1.31]) but all other diagnoses were not associated with hypertension risk compared to women who did not report infertility (ovulatory disorder: RR=1.03 [0.94–1.13], cervical: RR=0.88 [0.70–1.10], male factor: RR= 1.05 [0.95–1.15], other reason: RR=1.02 [0.94–1.11], reason not found: RR=1.02 [0.95–1.10]). Among infertile women there were 5,070 cases of hypertension. No clear pattern between use of fertility treatment and hypertension was found among infertile women (Clomiphene: RR =0.97 [0.90–1.04], Gonadotropin alone: RR=0.97 [0.87–1.08], IUI: RR=0.86 [0.71–1.03], IVF: RR=0.86 [0.73–1.01]). Conclusion Among this relatively young cohort of women, there was no apparent increase in hypertension risk among infertile women or among women who underwent fertility treatment in the past.

AI snapshot

Written from the paper’s full text.

TL;DR

In the Nurses’ Health Study II, infertility overall and fertility treatment were not associated with increased long-term risk of hypertension. Tubal infertility was associated with a modestly higher risk versus women who never reported infertility, but not when compared with male-factor infertility.

Key findings

  • Compared with women who never reported infertility, ever reporting infertility was not associated with hypertension risk (multivariable-adjusted RR = 1.01, 95% CI 0.94–1.07). Tubal disease was associated with higher risk (RR = 1.15, 95% CI 1.01–1.31), while other diagnoses were not: ovulatory disorder RR = 1.03 (0.94–1.13), cervical RR = 0.88 (0.70–1.10), male factor RR = 1.05 (0.95–1.15), other reason RR = 1.02 (0.94–1.11), reason not found RR = 1.02 (0.95–1.10).
  • Among infertile women, there were 5,070 cases of hypertension, and no clear pattern was found between fertility treatment and hypertension: clomiphene RR = 0.97 (0.90–1.04), gonadotropin alone RR = 0.97 (0.87–1.08), IUI RR = 0.86 (0.71–1.03), IVF RR = 0.86 (0.73–1.01).
  • Comprehensive fertility treatment history also showed no significant differences, e.g., clomiphene only RR = 0.97 (0.90–1.04), gonadotropin/IUI alone RR = 1.02 (0.83–1.24), clomiphene + gonadotropin/IUI RR = 0.93 (0.83–1.04), IVF only RR = 0.82 (0.55–1.22).
  • When male-factor infertility was used as the reference group, no infertility type was associated with increased hypertension risk, including tubal infertility (RR = 1.07, 95% CI 0.87–1.32).

Methods

  • Prospective cohort study within the Nurses’ Health Study II: 116,430 female nurses followed from 1993 to June 2011; follow-up rate from the original cohort was 92%.
  • Exposures were self-reported infertility and fertility treatment (clomiphene, gonadotropin alone, IUI, IVF); the outcome was self-reported, physician-diagnosed hypertension.
  • Cox proportional hazard models estimated incident hypertension risk, with sequential multivariable adjustment for age, calendar time, BMI, race, smoking, income, parity, diet, BMI at age 18, state-mandated insurance coverage, alcohol, physical activity, oral contraceptive use, analgesic use, breastfeeding, and additional infertility/treatment covariates.

Limitations

  • The paper states that all variables were self-reported, which may cause non-differential misclassification, though validation studies showed high reliability and validity for fertility treatment, ovulatory disorder infertility, and hypertension.
  • The paper states the cohort was homogeneous in race and education, so results should be generalized with caution, especially to under-represented racial and ethnic groups.
  • The paper states it could not identify acute or temporary effects of fertility treatment on hypertension risk, and that tubal infertility findings differed by comparison group, possibly due to sample size, residual/unmeasured confounding, measurement error, or differences between male-factor and non-infertile comparison groups.
  • Evident from the text: the observational design cannot establish causality, and residual confounding remains possible despite extensive adjustment.

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

Integrity signals

Registry

Crossref · 10.1016/j.fertnstert.2015.04.043

Cites

27 of 27 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 20 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Compared to women who did not report infertility, infertility due to ovulatory disorder, cervical mucus factor, male factor, other reason, or reason not found was not associated with hypertension risk (RRs ranged 0.88-1.05, all 95% CIs included 1.0).

    “all other diagnoses were not associated with hypertension risk compared to women who did not report infertility (ovulatory disorder: RR=1.03 [0.94–1.13], cervical: RR=0.88 [0.70–1.10], male factor: RR= 1.05 [0.95–1.15], other reason: RR=1.02 [0.94–1.11], reason not found: RR=1.02 [0.95–1.10]).”
    • Also stated in: § Results · hedged
      “Compared to women who did not report infertility, women with most infertility diagnoses did not appear to have an increased risk for hypertension after adjustment for confounding factors (ovulatory disorder: RR=1.03 CI:0.94–1.13, cervical mucus: RR=0.88 CI:0.70–1.10, male factor: RR= 1.05 CI:0.95–1.15, other reason: RR=1.02 CI:0.94–1.11, reason not found: RR=1.02 CI:0.95–1.10).”
    Quote in the paperSubstantial claim
  • Findingown data

    Compared to women who never reported infertility, women who reported ever experiencing infertility were not at higher risk of hypertension during follow-up (multivariable adjusted RR=1.01, 95% CI 0.94-1.07).

    “Compared to women who never reported infertility, infertile women were at no greater risk of hypertension (multi-variable adjusted relative risk (RR) = 1.01 95% confidence interval [0.94–1.07]).”
    • Also stated in: § Results · plain
      “Compared to women who did not report infertility, women reporting having ever experienced infertility were not at higher risk of hypertension during follow-up (relative risk [RR]=1.01 95% confidence interval [CI]:0.94–1.07).”
    Quote in the paperSubstantial claim
  • Findingown data

    When using women with male factor infertility as the comparison group, tubal infertility was not associated with increased risk of hypertension (RR=1.07, 95% CI 0.87-1.32).

    “When utilizing a comparison group of women reporting male factor infertility, there was no increased risk for any infertility type (ovulatory disorder: RR=1.11 CI:0.95–1.28, tubal: RR=1.07 CI:0.87–1.32, cervical mucus: RR=0.96 CI:0.76–1.22, other reason: RR=0.93 CI:0.80–1.07, reason not found: RR=0.88 CI:0.73–1.06).”
    • Also stated in: § Discussion · plain
      “Tubal infertility was not associated with hypertension when compared to male factor infertility”
    Quote in the paperSubstantial claim
  • Findingown data

    When using women with male factor infertility as the comparison group, no infertility type was associated with increased risk of hypertension (ovulatory disorder RR=1.11, 95% CI 0.95-1.28; tubal RR=1.07, 95% CI 0.87-1.32; cervical mucus RR=0.96, 95% CI 0.76-1.22; other reason RR=0.93, 95% CI 0.80-1.07; reason not found RR=0.88, 95% CI 0.73-1.06).

    “When utilizing a comparison group of women reporting male factor infertility, there was no increased risk for any infertility type (ovulatory disorder: RR=1.11 CI:0.95–1.28, tubal: RR=1.07 CI:0.87–1.32, cervical mucus: RR=0.96 CI:0.76–1.22, other reason: RR=0.93 CI:0.80–1.07, reason not found: RR=0.88 CI:0.73–1.06).”
    Quote in the paperSubstantial claim
  • Findingown data

    Compared to women who did not report infertility, women with infertility due to tubal disease had a higher risk of hypertension (multivariable adjusted RR=1.15, 95% CI 1.01-1.31).

    “Infertility due to tubal disease was associated with a higher risk of hypertension (RR=1.15 [1.01–1.31])”
    • Also stated in: § Results · hedged
      “Women with tubal infertility appeared at slight increased risk for hypertension (RR=1.15 CI:1.01–1.31).”
    • Also stated in: § Discussion · plain
      “The sole exception was women with a diagnosis of infertility due to tubal disease who had a 15% greater risk of hypertension than women without a history of infertility.”
    Quote in the paperSubstantial claim
  • May combine two claims. 8
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingown data

    The association between tubal infertility and hypertension differed by comparison group: it was significant compared to women who never reported infertility but not compared to women with male factor infertility.

    “Our findings for the association between tubal infertility and hypertension differed depending on the group to whom the tubal infertility was compared. Tubal infertility was not associated with hypertension when compared to male factor infertility, however tubal infertility was significantly associated with hypertension when compared to women who never reported infertility.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The multivariable models adjusted for a priori confounders including age, BMI, race, smoking, income, parity, diet, alcohol, physical activity, oral contraceptive use, analgesic use, and breastfeeding.

    “Many high blood pressure risk factors and risk factors for fertility treatment and infertility were considered a priori confounders and included in the multivariable models.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The follow-up rate from the original Nurses' Health Study II cohort is 92%.

    “The follow-up rate from the original cohort is 92%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A prior validation study found that 93% of women reporting ovulatory disorder infertility reported diagnostic test results and/or indicative treatment, and 95% of reviewed medical records confirmed the diagnosis.

    “In a supplemental questionnaire mailing to these women, 93% of women who responded reported diagnostic test results and/or indicative treatment for ovulatory disorder infertility. Additionally, 40 participant’s medical records were reviewed, with 95% confirmation by diagnostic test and/or treatment.(20)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Rich-Edwards, 1994, Adolescent body mass index and infertility caused by ovulatory disorder, Am J Obstet Gynecol 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 conductown data

    Analyses of tubal infertility additionally adjusted for history of sexual abuse, finer race/ethnicity, household income, and endometriosis.

    “Since tubal infertility has several specific risk factors, we conducted analyses of tubal infertility adjusting for additional potential confounding variables. We also adjusted for history of sexual abuse.(23) We also more finely adjusted for race/ethnicity (white (ref), Hispanic, black, other) and household income (<$15,000, $15–19,999, $20–29,999, $30–39,999, $40–49,999, $50–74,999, $75–99,999,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Riley, 2010, Hypertension in adult survivors of child abuse: observations from the Nurses' Health Study II, J Epidemiol Community Health source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Among this relatively young cohort of women, there was no apparent increase in hypertension risk among infertile women or among women who underwent fertility treatment in the past.

    “Among this relatively young cohort of women, there was no apparent increase in hypertension risk among infertile women or among women who underwent fertility treatment in the past.”
    • Also stated in: § Discussion · hedged
      “In sum, women who are infertile or who have utilized fertility treatments do not appear to be at longer-term increased risk of hypertension.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Self-reported hypertension was found to have high validity compared with medical records; of 51 women who reported hypertension and had medical records, hypertension (blood pressure >140/90) was confirmed in all cases.

    “Of 85 women we sampled from NHS who had reported high blood pressure and responded to a validation questionnaire, only one denied elevated blood pressure (reporting that she in fact had hypotension).(21) Self reported hypertension was found to have high vaildity compared to the medical records. Of 51 women who reported hypertension for whom we were able to obtain medical records, hypertension (bl”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Colditz, 1986, Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women, Am J Epidemiol source

      Not checked in the free run.

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

    Interpretationown data

    The study population was homogeneous in terms of race and education level, so results should be generalized with caution, especially to under-represented racial and ethnic groups.

    “The population under study was homogenous in terms of race and education level thus these results should be generalized with caution, especially to under-represented racial and ethnic groups who often have differential risks of hypertension compared to Caucasians.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study has several strengths including its large sample size, temporal evaluation of predictors and outcome, high follow-up rate, and information on both infertility and treatment.

    “This study has several strengths including its large sample size, temporal evaluation of predictors and outcome, high follow-up rate, and information on both infertility and treatment.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Infertility due to tubal disease has been positively associated with risk of type 2 diabetes.

    “In addition, we have previously found positive associations between infertility due to tubal disease and risk of other cardio-metabolic conditions including gestational diabetes (24) and type 2 diabetes (Tobias, under review for publication).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tobias, under review for publication

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Current oral contraceptive use is associated with temporary increased blood pressure and a potentially elevated risk of developing vascular disease later in life.

    “Additionally, current oral contraceptive use, which also alters the hormonal milieu, is associated with temporary increased blood pressure, as well as a potentially elevated risk of developing vascular disease later in life.(3–5)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Rosenthal, 2000, Hypertension in women, J Hum Hypertens source

      Not checked in the free run.

    • cites [4] Chasan-Taber, 1996, Prospective study of oral contraceptives and hypertension among women in the United States, Circulation source

      Not checked in the free run.

    • cites [5] Tanis, 2001, Oral contraceptives and the risk of myocardial infarction, N Engl J Med source

      Not checked in the free run.

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

    Premisecitation

    Infertility due to tubal disease has been positively associated with risk of gestational diabetes.

    “In addition, we have previously found positive associations between infertility due to tubal disease and risk of other cardio-metabolic conditions including gestational diabetes (24) and type 2 diabetes (Tobias, under review for publication).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Tobias, 2013, History of infertility and risk of gestational diabetes mellitus: a prospective analysis of 40,773 pregnancies, Am J Epidemiol source

      Not checked in the free run.

12 of 12

  • The paper relies on this without support.

    No prior studies have examined the relation between infertility, fertility treatment, and development of hypertension.

    “To our knowledge, no studies have examined the relation between infertility, fertility treatment, and development of hypertension.”

  • The paper relies on this without support.

    Gonadotropin injections used alone and in combination with IUI and IVF raise endogenous levels of estrogen and progesterone, and IVF cycles involve high doses of progesterone after embryo transfer.

    “Gonadotropin injections utilized alone and in combination with IUI and IVF raise endogenous levels of estrogen and progesterone, and in an IVF cycle, high doses of progesterone are administered for the two weeks subsequent to embryo transfer.”
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?

  • Subfertility itself has been associated with metabolic syndrome and CVD in later life.

    “Subfertility itself has been associated with metabolic syndrome and CVD in later life (22).”

    From Cardiovascular Risk Following Fertility Therapy (2017) · cites this paper as [22]

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.

  • Follow-up end date differs by one month

    Minor

    The abstract says follow-up ended in June 2011, whereas the methods say the current analysis covered follow-up through May 2011.

1 of 1

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Related

Authors
Farland, L. V., Grodstein, F., Srouji, S. S., Forman, J. P., Rich-Edwards, J., Chavarro, J. E., & Missmer, S. A.
Affiliations
  • Harvard University (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Farland, Leslie V.
ORCID
Venue
Fertility and Sterility
Publisher
Elsevier BV
Published
2015-08
Volume
104
Issue
2
Pages
391-397
ISSN
0015-0282 (ISSN-L)
DOI
10.1016/j.fertnstert.2015.04.043
PMC
PMC4522333
OpenAlex
W2141488693
Semantic Scholar
381c2974b0c638fed57b844d3cadba707a8f8d96
Cited by
55
References
27
Citations by year
2026: 7 · 2025: 5 · 2024: 6 · 2023: 8 · 2022: 6 · 2021: 7 · 2020: 4 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 3 · 2013: 1
FWCI
2.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Fertility and Sterility (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UM1-CA-176726, CA176726)
  • National Cancer Institute (UM1CA176726)
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD59955, R21HD059955, T32HD060454)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Health and Technologies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
Keywords
infertility, infertility treatment, hypertension, tubal disease, ovulatory dysfunction, male factor infertility, clomiphene citrate, gonadotropins, intrauterine insemination, in vitro fertilization, Nurses' Health Study II
MeSH terms
Adult, Female, Follow-Up Studies, Humans, Hypertension, Infertility, Female, Middle Aged, Pregnancy, Prospective Studies, Cohort Studies, Reproductive Techniques, Assisted

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