title: A prospective cohort study of endometriosis and subsequent risk of infertility.
abstract: Is there a temporal relationship between endometriosis and infertility?
  
  
  
  Endometriosis is associated with a higher risk of subsequent infertility, but only among women age <35 years.
  
  
  
  Endometriosis is the most commonly observed gynecologic pathology among infertile women undergoing laparoscopic examination. Whether endometriosis is a cause of infertility or an incidental discovery during the infertility examination is unknown.
  
  
  
  This study included data collected from 58 427 married premenopausal female nurses <40 years of age from 1989 to 2005, who are participants of the Nurses' Health Study II prospective cohort.
  
  
  
  Our exposure was laparoscopically confirmed endometriosis. Multivariate Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for infertility risk (defined as attempting to conceive for >12 months) among women with and without endometriosis.
  
  
  
  We identified 4612 incident cases of infertility due to any cause over 362 219 person-years of follow-up. Compared with women without a history of endometriosis, women with endometriosis had an age-adjusted 2-fold increased risk of incident infertility (HR = 2.12, 95% CI = 1.76-2.56) that attenuated slightly after accounting for parity. The relationship with endometriosis was only observed among women <35 years of age (multivariate HR <35 years = 1.77, 95% CI = 1.46-2.14; multivariate HR 35-39 years = 1.20, 95% CI = 0.94-1.53; P-interaction = 0.008). Risk of primary versus secondary infertility was similar subsequent to endometriosis diagnosis. Among women with primary infertility, 50% became parous after the endometriosis diagnosis, and among all women with endometriosis, 83% were parous by age 40 years.
  
  
  
  We did not have information on participants' intentions to conceive, but by restricting the analytic population to married women we increased the likelihood that pregnancies were planned (and therefore infertility would be recognized). Women in our cohort with undiagnosed asymptomatic endometriosis will be misclassified as unexposed. However, the small proportion of these women are diluted among the >50 000 women accurately classified as endometriosis-free, minimizing the impact of exposure misclassification on the effect estimates.
  
  
  
  This study supports a temporal association between endometriosis and infertility risk. Our prospective analysis indicates a possible detection bias in previous studies, with our findings suggesting that the infertility risk posed by endometriosis is about half the estimates observed in cross-sectional analyses.
  
  
  
  This work was supported by the National Institutes of Health (grant numbers: UM1 CA176726, HD52473, HD57210, T32DK007703, T32HD060454, K01DK103720). We have no competing interests to declare.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA prescott.jennifer@gmail.com.
authors.forename: J
authors.initials: J
authors.lastname: Prescott
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: L V
authors.initials: LV
authors.lastname: Farland
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Tobias
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Gaskins
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: D
authors.initials: D
authors.lastname: Spiegelman
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Chavarro
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA Connors Center for Women's Health and Gender Biology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Rich-Edwards
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Barbieri
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Missmer
mesh_terms: D000328:Adult; D004715:Endometriosis / Q000150:complications* / Q000473:pathology; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000150:complications* / Q000453:epidemiology; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors
keywords: bias; endometriosis; epidemiology; infertility; prospective cohort studies