Brinton 2013b.

Methods	Retrospective cohort.
Participants	Cohort of 12193 women ≥ 18 years old, who had sought advice for subfertility between 1965 and 1988 at 5 reproductive endocrinology practices in Boston, MA; Chicago, IL; Detroit, MI; Palo Alto, CA, and New York City, NY. Participants with either primary or secondary subfertility were eligible, but those evaluated for reversal of a tubal ligation were not. An initial follow‐up was pursued during 1998 to 2001 and a second in 2010. After excluding the 1319 participants who requested no additional follow‐up, 8 who were enrolled twice, 6 found to be < 18 years of age, 1 who requested removal from the study and 1 with a missing date of birth, outcome information through 2010 was available for 10018 participants. Excluded from analysis were 15 participants with missing information on a cancer diagnosis date, 111 with < 1 year of follow‐up and 60 with a hysterectomy during the first year of follow‐up, leaving 9832 analytic study subjects, of whom 3933 were exposed to fertility treatments. Mean follow‐up, 26.4 years.
Interventions	Ever use of clomiphene citrate or gonadotropins. Information on clomiphene citrate and gonadotropins included age at first use, treatment cycles, and total cumulative dosage.
Outcomes	Endometrial cancer. Follow‐up procedures included searches for deaths and updated addresses through several publicly available and proprietary databases. Attempts were made to mail a short questionnaire, focusing on the development of cancers and cancer risk factors that might have changed over time, to located subjects who did not expressly indicate that they wanted no further follow‐up. In addition, linkages against cancer registries in the 14 states in which the majority of participants resided were completed. For the 12.4% of participants who resided outside these states, outcome information was dependent on completed questionnaires, with attempts to validate any self‐reports of cancers by requesting records from the participant's treating physicians. Incident cases in total cohort, 118; in exposed cohort, 52.
Notes	Causes of subfertility were endometriosis, anovulation, tubal disease/pelvic adhesions, male factor, cervical disorder, uterine disorder.
Risk of bias
Bias	Authors' judgement	Support for judgement
Selection bias (comparability)	High risk	Quote: "We excluded from analysis 15 patients with missing information on a cancer diagnosis date, 111 with 1 year of follow‐up and 60 with a hysterectomy during the first year of follow‐up". Comment: Outcome not likely to be present at start. Comment: Non‐exposed drawn from the same population as the exposed cohort. Comment: No comparability on cause of subfertility, diabetes mellitus, polycystic ovary syndrome (PCOS), and obesity was ensured.
Selection bias (confounding)	High risk	Quote: "Adjustment for potential confounding factors, [were] obtained using Cox proportional hazards regression with age as the time metric [...] Table III: HRs adjusted for study site, calendar year of the first clinic visit and reproductive status at the first clinic visit". Comment: Analyses inadequately controlling for potential confounders.
Performance bias	High risk	Quote: "Trained staff abstracted data regarding the infertility workup (all procedures and tests), medications prescribed, menstrual and reproductive histories, and other factors that might affect health. Information on the clinical workup was used to define causes of infertility, as previously described". Comment: Exposure to ovary‐stimulation drugs was ascertained by medical records. Blindness regarding the allocated interventions not guaranteed.
Detection bias	High risk	Quote: "In addition to information on cancers identified through death records and completed questionnaires, we completed linkages against cancer registries in the 14 states in which the majority of patients resided. For the 12.4% of patients who resided outside these states, outcome information was dependent on completed questionnaires, with attempts to validate any self‐reports of cancers by requesting records from the patients’ treating physicians". Comment: Outcome was ascertained both by record linkage and questionnaires. No blinding process was reported.
Attrition bias	Low risk	Quote: "Nonetheless, our loss to follow‐up of 7.7% was quite low given the observation time". Comment: Follow‐up is considered to be rather complete.
Selective reporting (reporting bias)	Low risk	Comment: All of the study’s prespecified (primary and secondary) outcomes that were of interest in the review have been reported in the prespecified way.
Other bias	High risk	Quote: "An average of 26.4 years of follow‐up". Comment: Length of follow‐up was considered adequate. Comment: Non‐RCT study.