Impaired fecundity as a marker of health and survival: a Danish twin cohort study.

study questionIs fecundity, measured as self-reported time to first pregnancy (TTP), a marker for subsequent health and survival? SUMMARY ANSWER: Long TTP was a marker for increased mortality among women and higher hospitalization rates for both women and men. WHAT IS KNOWN ALREADY: Poor semen quality has been linked to increased mortality and morbidity from a wide range of diseases. Associations among fecundity, health and survival among women are still uncertain and studies on actual measures of fecundity and health outcomes are rare. STUDY DESIGN, SIZE, DURATION: We performed a prospective cohort study of 7825 women and 6279 men, aged 18 and above with measures on first TTP, who participated in one of the Danish nation-wide twin surveys in 1994 (twins born 1953-1976) and 1998 (twins born 1931-1952). They were followed-up for mortality and hospital admissions from the interview until 2018. PARTICIPANTS/MATERIALS, SETTING,

methodsTwins were identified in the Danish Twin Registry and linked to Danish registers. TTP was restricted to the first pregnancy as a categorical outcome with cut-off points at 2, 10 and 18 months. We analysed the association between TTP and survival using a Cox proportional hazards model estimating hazards ratios (HRs) with 95% confidence intervals (CIs). Fine-Gray survival models were used to estimate sub-hazard ratios for specific causes of death allowing for competing risks. Using negative binomial regression, we estimated incidence rate ratios (IRRs) with 95% CIs for all-cause and cause-specific hospitalizations. All analyses were stratified by sex and adjusted for age at interview, birth cohorts, age at first attempt to become pregnant, smoking, years in school and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: In the total study population, 49.9% of women and 52.7% of men reported a TTP of less than 2 months, 30.8% of women and 29.6% of men reported a TTP of 2-9 months, 6.6% of women and 5.7% of men reported a TTP of 10-17 months, and 13.3% of women and 12.0% of men reported a TTP of 18 months or more. Among 1305 deaths, we found a higher mortality for women (HR = 1.46; 95% CI 1.15, 1.87) with a TTP of ≥18 months relative to those with a TTP of <2 months, while the highest mortality was indicated for men with a TTP of 10-17 months (HR = 1.31; 95% CI 0.98, 1.74). Among 53 799 hospitalizations, we found an increased hospitalization rate among women (HR = 1.21; 95% CI 1.0-1.41) and men (HR = 1.16; 95% CI 1.00-1.35) with a TTP of ≥18 months, and for men with a TTP of 2-9 months (HR = 1.14; 95% CI 1.01-1.30). A dose-response relationship was found for women regarding both mortality (P = 0.022) and hospitalizations (P = 0.018). Impaired fecundity was associated with a wide range of diseases and some causes of death, indicating a multi-factorial causal influence on fecundity, especially among women. LIMITATIONS, REASONS FOR CAUTION: A major limitation was that fecundity depends on both partners, which was not considered in this study. Moreover, we could not obtain information on a number of potential confounders. WIDER IMPLICATIONS OF THE

findingsFecundity seems positively correlated with overall health and may be a universal marker of future health and survival. These results add knowledge to the limited findings showing that reduced fecundity in women and poor semen quality in men may reflect worse health and a shorter life, particularly among women. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by NIH grant HD096468 (M.L.E., T.K.J. and R.L.J.). The authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: N/A.