Natural conception rates in couples with unexplained or mild male subfertility scheduled for fertility treatment: A secondary analysis of a randomized controlled trial

Study Question: What is the natural conception rate over the course of 12 months in couples with unexplained or mild male subfertility who are scheduled for fertility treatment and have a predicted unfavourable prognosis for natural conception? Summary Answer: The natural conception rate over the course of 12 months in couples who were allocated to treatment was estimated to be 24.5% (95% CI: 20-29%). What is Known Already: After starting treatment, couples often perceive unsuccessful cycles as evidence of definitive failure even though they are still able to conceive naturally in between and after treatment. The magnitude of the natural conception rate for couples who chose to commence treatment is unknown, as is whether the calculated prognosis before commencing treatment is still applicable. Study Design, Size, Duration: We performed a secondary analysis of a randomized controlled trial including couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception. Couples were allocated to either three cycles IVF with single embryo transfer (SET), six cycles of IVF in a modified natural cycle (MNC) or six cycles of IUI with controlled ovarian hyperstimulation (IUI-COH). The detailed data collection in this trial allowed us to study the conception rates in periods that couples were not receiving treatment. Participants/Materials, Settings, Methods: We split the dataset into periods during which couples were treated and periods during which they were not treated. Couples could conceive naturally in the periods before, in between and after treatment cycles. The outcome was ongoing pregnancy, thus natural conception rate refers to natural conception leading to ongoing pregnancy. We performed a Cox proportional hazards analysis with female age, duration of subfertility and a time-varying covariate with four categories: IVF-SET, IVF-MNC, IUI-COH and no treatment. We used this Cox model to estimate the natural conception rate over 12 months of no treatment. Main Results and The Role of Chance: Out of 602 included couples, there were 342 ongoing pregnancies, of which 77 (23%) resulted from natural conception. The estimated natural conception rate over 12 months was 24.5% (95% CI: 20-29%) on cohort level. Estimated rates for female age varying between 18 and 38 years and duration of subfertility between 1 and 3 years ranged from 22 to 35%. Limitations, Reasons for Caution: We considered couples at risk for natural conception when not receiving treatment, whereas they might not have had periovulatory sexual intercourse. As couples were scheduled for treatment, it is possible that these couples were less inclined to try to conceive naturally, potentially leading to an underestimation of their natural conception rate if they kept trying to conceive. Wider Implications of the Findings: Couples with unexplained subfertility who are about to start fertility treatment, still have about a one in four chance of ongoing pregnancy due to natural conception over 12 months. This information can add to the counselling of couples who commenced fertility treatment after failed cycles and to emphasize not to cease their natural attempts. Study Funding/Competing Interest(S): The INeS trial was supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (120620027), and a grant from Zorgverzekeraars Nederland, the Dutch association of health care insurers (09-003). The funders had no role in study design, collection, analysis and interpretation of the data. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. No other potential conflicts of interest reported. Trial Registration Number: The INeS trial was registered at the Dutch trial registry (NTR 939).