Age-related natural fertility outcomes in women over 35 years: a systematic review and individual participant data meta-analysis
Authors: Chua S J , Danhof N A , Mochtar M H , van Wely M , McLernon D J , Custers I , Lee E , Dreyer K , Cahill D J , Gillett W R , Righarts A , Strandell A , Rantsi T , Schmidt L , Eijkemans M J C , Mol B W J , van Eekelen R 
Published: May 2020

Abstract

STUDY QUESTION
What is the rate of natural conception leading to ongoing pregnancy or livebirth over 6–12 months for infertile women of age ≥35 years?

SUMMARY ANSWER
Natural conception rates were still clinically relevant in women aged 35 years and above and were significantly higher in women with unexplained infertility compared to those with other diagnoses.

WHAT IS KNOWN ALREADY
In recent years, increasing numbers of women have attempted to conceive at a later age, resulting in a commensurate increase in the need for ART. However, there is a lack of data on natural fertility outcomes (i.e. no interventions) in women with increasing age.

STUDY DESIGN, SIZE, DURATION
A systematic review with individual participant data (IPD) meta-analysis was carried out. PubMed, MEDLINE, EMBASE, the Cochrane Library, clinicaltrials.gov were searched until 1 July 2018 including search terms ‘fertility service’, ‘waiting list’, ‘treatment-independent’ and ‘spontaneous conception’. Language restrictions were not imposed.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Inclusion criteria were studies (at least partly) reporting on infertile couples with female partner of age ≥35 years who attended fertility services, underwent fertility workup (e.g. history, semen analysis, tubal status and ovulation status) and were exposed to natural conception (e.g. independent of treatment such as IVF, ovulation induction and tubal surgery). Studies that exclusively studied only one infertility diagnosis, without including other women presenting to infertility services for other causes of infertility, were excluded. For studies that met the inclusion criteria, study authors were contacted to provide IPD, after which fertility outcomes for women of age ≥35 years were retrieved. Time to pregnancy or livebirth and the effect of increasing age on fertility outcomes after adjustment for other prognostic factors were analysed. Quality of studies was graded with the Newcastle–Ottawa Scale (non-randomised controlled trials (RCTs)) or the Cochrane Risk of Bias tool (for RCTs).

MAIN RESULTS AND THE ROLE OF CHANCE
We included nine studies (seven cohort studies and two RCTs) (n = 4379 women of at least age 35 years), with the observed composite primary outcome of ongoing pregnancy or livebirth occurring in 429 women (9.8%) over a median follow-up of 5 months (25th to 75th percentile: 2.5–8.5 months). Studies were of moderate to high quality. The probability of natural conception significantly decreased with any diagnosis of infertility, when compared with unexplained infertility. We found non-linear effects of female age and duration of infertility on ongoing pregnancy and tabulated the predicted probabilities for unexplained infertile women aged 35–42 years with either primary or secondary infertility and with a duration of infertility from 1 to 6 years. For a 35-year-old woman with 2 years of primary unexplained infertility, the predicted probability of natural conception leading to ongoing pregnancy or livebirth was 0.15 (95% CI 0.11–0.19) after 6 months and 0.24 (95% CI 0.17–0.30) after 12 months. For a 42-year-old woman, this decreased to 0.08 (95% CI 0.04–0.11) after 6 months and 0.13 (95% CI 0.07–0.18) after 12 months.

LIMITATIONS, REASONS FOR CAUTION
In the studies selected, there were different study designs, recruitment strategies in different centres, protocols and countries and different methods of assessment of infertility. Data were limited for women above the age of 40 years.

WIDER IMPLICATIONS OF THE FINDINGS
Women attending fertility services should be encouraged to pursue natural conception while waiting for treatment to commence and after treatment if it is unsuccessful. Our results may aid in counselling women, and, in particular, for those with unexplained infertility.

STUDY FUNDING/COMPETING INTEREST(S)
S.J.C. received funding from the University of Adelaide Summer Research Scholarship. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437), B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. B.W.M. reports research support by Merck and Guerbet.

PROSPERO REGISTRATION NUMBER
CRD42018096552.