Age-related natural fertility outcomes in women over 35 years: a systematic review and individual participant data meta-analysis

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.

Spontaneous pregnancies among infertile couples during assisted reproduction lockdown for COVID‐19 pandemic

“…13 A recent meta-analysis of nine studies considering infertile couples attending ART reported an overall spontaneous pregnancy rate of 9.6% during an average five months of waiting. 14 The spontaneous pregnancy rate extrapolated from our casuistry (ie 7.9%) results comparable to those previously reported.…”

“…On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy.…”

MANAGEMENT OF ENDOCRINE DISEASE: Thyroid and female infertility: more questions than answers?!

“…LT4 treatment was associated with 27-100% chance of live birth compared to 25% in the control group (82,85). These results are in line with most results in spontaneous pregnancies but need to be confirmed in more studies comparing LBR after ART in women with SCH treated with LT4, with corrections for the type of ART (IVF or ICSI), woman's age, cause of infertility, semen parameters, the severity of SCH and the levels of TPO-and TgAb (80,86). Therefore, it is noteworthy mentioning that besides the few patients with SCH and no TAI in the study by Kim et al, the evidence on the treatment of infertile women with SCH and no TAI is almost absent (85).…”

“…A third hypothesis that might go together with the two previous ones is the higher mean age in women with TAI compared with that in TAI -women (72,79). Older age is a known risk factor for an increased MR and infertility (80). However, in the meta-regression analysis by Busnelli et al (72), the increased MR persisted after correction for age.…”

“…Future research should consist of properly designed, randomised studies of euthyroid women with TAI (taking into account both types of antibodies and ultrasound features), treated with LT4 vs placebo. Outcomes should be corrected for age, the type of OS, thyroid antibody levels, thyroid function, and finally the cause(s) of infertility, including a quantification of the sperm quality, and the type of ART treatment (ICSI/IVF) (80,86).…”