Gravidity modifies the associations of age and spousal age difference with couple’s fecundability: a large cohort study from China
Authors: Zhang Yue , Zhang Hongguang , Zhao Jun , Zhao Yueshu , Zhang Junhui , Jiang Lifang , Wang Yuanyuan , Peng Zuoqi , Zhang Ya , Jiao Kailei , He Tianyu , Wang Qiaomei , Shen Haiping , Zhang Yiping , Yan Donghai , Ma Xu 
Published: October 2023

Abstract

STUDY QUESTION
Do couple’s age ranges for optimal fecundability, and the associations with fecundability of couple’s age combinations and age differences differ with gravidity?

SUMMARY ANSWER
The couple’s age range of optimal fecundability and age combinations differed with gravidity, and gravidity might modify the associations of age and spousal age difference with couple’s fecundability.

WHAT IS KNOWN ALREADY
Age is one of the strongest determinants of fecundability, but the existing studies have certain limitations in study population, couple’s extreme age combinations and age differences, and have not explored whether the association between age and fecundability differs with gravidity.

STUDY DESIGN, SIZE, DURATION
Retrospective cohort study. 5 407 499 general reproductive-aged couples (not diagnosed with infertility) participated in the National Free Pre-conception Check-up Projects during 2015–2017. They were followed up for pregnancy outcomes through telephone interviews every 3 months until they became pregnant or were followed up for 1 year.

PARTICIPANTS/MATERIALS, SETTING, METHODS
The main outcome was time to pregnancy, and the fecundability odds ratios and 95% CIs were estimated using the Cox models for discrete survival time. The associations of age and spousal age difference with fecundability were evaluated by restricted cubic splines.

MAIN RESULTS AND THE ROLE OF CHANCE
In this large cohort of general reproductive-aged population, the age of optimal fecundability of multigravida couples was older than that of nulligravida couples, but their subsequent fecundability declined more sharply with age. The decline in female fecundability was more pronounced with age, with fecundability dropping by ∼30% in both nulligravida and multigravida couples whose female partners aged ≥35 years. In the nulligravida group, the fecundability of couples who were both ≤24 years with the same age was the highest, which decreased steadily with the increase of spousal age difference, and younger male partners did not seem to contribute to improving couple’s fecundability. In the multigravida group, couples with female partners aged 25–34 years and a spousal age difference of −5 to 5 years showed higher fecundability, and the effect of spousal age difference on couple’s fecundability became suddenly apparent when female partners aged around 40 years. Young male partners were unable to change the decisive effect of female partner’s age over 40 years on couple’s reduced fecundability, regardless of gravidity.

LIMITATIONS, REASONS FOR CAUTION
Lacking the time for couples to attempt pregnancy before enrollment, and some couples might suspend pregnancy plans during follow-up because of certain emergencies, which would misestimate the fecundability. Due to the lack of information on sperm quality and sexual frequency of couples, we could not adjust for these factors. Moreover, due to population characteristics, the extrapolation of our results required caution.

WIDER IMPLICATIONS OF THE FINDINGS
The couple’s age range of optimal fecundability, age combinations, and spousal age difference on fecundability varied with gravidity. Female age-related decline in fecundability was more dominant in couple’s fecundability. Targeted fertility guidance should be provided to couples with different age combinations and gravidities.

STUDY FUNDING/COMPETING INTEREST(S)
This research received funding from the Project of National Research Institute for Family Planning (Grant No. 2018NRIFPJ03), the National Key Research and Development Program of China (Grant No. 2016YFC1000307), and the National Human Genetic Resources Sharing Service Platform (Grant No. 2005DKA21300), People’s Republic of China. The funders had no role in study design, analysis, decision to publish, or preparation of the manuscript. The authors report no conflict of interest.

TRIAL REGISTRATION NUMBER
N/A.