Preconception stress increases the risk of infertility: results from a couple-based prospective cohort study--the LIFE study.

study questionAre women's stress levels prospectively associated with fecundity and infertility? SUMMARY ANSWER: Higher levels of stress as measured by salivary alpha-amylase are associated with a longer time-to-pregnancy (TTP) and an increased risk of infertility. WHAT IS KNOWN ALREADY: Data suggest that stress and reproduction are interrelated; however, the directionality of that association is unclear. STUDY DESIGN, SIZE, DURATION: In 2005-2009, we enrolled 501 couples in a prospective cohort study with preconception enrollment at two research sites (Michigan and Texas, USA). Couples were followed for up to 12 months as they tried to conceive and through pregnancy if it occurred. A total of 401 (80%) couples completed the study protocol and 373 (93%) had complete data available for this analysis. PARTICIPANTS/MATERIALS, SETTING,

methodsEnrolled women collected saliva the morning following enrollment and then the morning following their first observed study menses for the measurement of cortisol and alpha-amylase, which are biomarkers of stress. TTP was measured in cycles. Covariate data were captured on both a baseline questionnaire and daily journals. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 401 (80%) women who completed the protocol, 347 (87%) became pregnant and 54 (13%) did not. After adjustment for female age, race, income, and use of alcohol, caffeine and cigarettes while trying to conceive, women in the highest tertile of alpha-amylase exhibited a 29% reduction in fecundity (longer TTP) compared with women in the lowest tertile [fecundability odds ratios (FORs) = 0.71; 95% confidence interval (CI) = (0.51, 1.00); P < 0.05]. This reduction in fecundity translated into a >2-fold increased risk of infertility among these women [relative risk (RR) = 2.07; 95% CI = (1.04, 4.11)]. In contrast, we found no association between salivary cortisol and fecundability. LIMITATIONS, REASONS FOR CAUTION: Due to fiscal and logistical concerns, we were unable to collect repeated saliva samples and perceived stress questionnaire data throughout the duration of follow-up. Therefore, we were unable to examine whether stress levels increased as women continued to fail to get pregnant. Our ability to control for potential confounders using time-varying data from the daily journals, however, minimizes residual confounding. WIDER IMPLICATIONS OF THE

findingsThis is the first US study to demonstrate a prospective association between salivary stress biomarkers and TTP, and the first in the world to observe an association with infertility. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3358). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.