Cannabis use while trying to conceive: a prospective cohort study evaluating associations with fecundability, live birth and pregnancy loss.

study questionIs cannabis use assessed via urinary metabolites and self-report during preconception associated with fecundability, live birth and pregnancy loss? SUMMARY ANSWER: Preconception cannabis use was associated with reduced fecundability among women with a history of pregnancy loss attempting pregnancy despite an increased frequency of intercourse. WHAT IS KNOWN ALREADY: Cannabis use continues to rise despite limited evidence of safety during critical windows of pregnancy establishment. While existing studies suggest that self-reported cannabis use is not associated with fecundability, self-report may not be reliable. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out including 1228 women followed for up to six cycles while attempting pregnancy (2006 to 2012), and throughout pregnancy if they conceived. PARTICIPANTS/MATERIALS, SETTING,

methodsWomen aged 18-40 years with a history of pregnancy loss (n = 1228) were recruited from four clinical centers. Women self-reported preconception cannabis use at baseline and urinary tetrahydrocannabinol metabolites were measured throughout preconception and early pregnancy (up to four times during the study: at baseline, after 6 months of follow-up or at the beginning of the conception cycle, and weeks 4 and 8 of pregnancy). Time to hCG-detected pregnancy, and incidence of live birth and pregnancy loss were prospectively assessed. Fecundability odds ratios (FOR) and 95% CI were estimated using discrete time Cox proportional hazards models, and risk ratios (RRs) and 95% CI using log-binomial regression adjusting for age, race, BMI, education level, baseline urine cotinine, alcohol use and antidepressant use. MAIN RESULTS AND THE ROLE OF CHANCE: Preconception cannabis use was 5% (62/1228), based on combined urinary metabolite measurements and self-report, and 1.3% (11/789) used cannabis during the first 8 weeks of gestation based on urinary metabolites only. Women with preconception cannabis use had reduced fecundability (FOR 0.59; 95% CI 0.38, 0.92). Preconception cannabis use was also associated with increased frequency of intercourse per cycle (9.4 ± 7 versus 7.5 ± 7 days; P = 0.02) and higher LH (percentage change 64%, 95% CI 3, 161) and higher LH:FSH ratio (percentage change 39%, 95% CI 7, 81). There were also suggestive, though imprecise, associations with anovulation (RR 1.92, 95% CI 0.88, 4.18), and live birth (42% (19/45) cannabis users versus 55% (578/1043) nonusers; RR 0.80, 95% CI 0.57, 1.12). No associations were observed between preconception cannabis use and pregnancy loss (RR 0.81, 95% CI 0.46, 1.42). Similar results were observed after additional adjustment for parity, income, employment status and stress. We were unable to estimate associations between cannabis use during early pregnancy and pregnancy loss due to limited sample size. LIMITATIONS, REASONS FOR CAUTION: Owing to the relatively few cannabis users in our study, we had limited ability to make conclusions regarding live birth and pregnancy loss, and were unable to account for male partner use. While results were similar after excluding smokers, alcohol use and any drug use in the past year, some residual confounding may persist due to these potential co-exposures. WIDER IMPLICATIONS OF THE

findingsThese findings highlight potential risks on fecundability among women attempting pregnancy with a history of pregnancy loss and the need for expanded evidence regarding the reproductive health effects of cannabis use in the current climate of increasing legalization. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract numbers: HHSN267200603423, HHSN267200603424, HHSN267200603426, HHSN275201300023I). Jeannie G. Radoc has been funded by the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the National Institutes of Health and generous contributions to the Foundation for the National Institutes of Health from the Doris Duke Charitable Foundation (DDCF Grant # 2014194), Genentech, Elsevier, and other private donors. The authors report no conflict of interest in this work and have nothing to disclose. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00467363.