O-023 ‘The PiNC Trial’: Progesterone in Natural Cycles for the treatment of unexplained infertility

Abstract

Abstract Study question Does exogenous progesterone for luteal phase support in natural cycles affect the biochemical, clinical pregnancy, livebirth or miscarriage rates in women with unexplained infertility (UI)? Summary answer Progesterone luteal support lead to an increase in livebirth rate from 7% to 15.3% and a decrease in miscarriage rates from 40% to 20%. What is known already Unexplained infertility is a diagnosis likely to encompass a population with varying underlying subtle pathologies. The only treatments currently recommended for treating UI are intrauterine insemination (IUI) and IVF/ICSI which are both expensive and invasive. The evidence for IUI with and without controlled ovarian hyperstimulation (COH) is inconclusive. A recent systematic review and meta-analysis reported a progesterone-mediated reduction in endometrial receptivity as a possible mechanism in the pathogenesis of UI. No trial has been published investigating the effectiveness of exogenous progesterone for luteal support in otherwise natural, unmedicated cycles to improve reproductive outcomes in couples with UI. Study design, size, duration We conducted an open-label, parallel arm, single centre, randomised controlled trial of an investigational medicinal product (cTIMP) from February 2020 to November 2022. We randomised 143 couples with UI to either luteal phase progesterone support or no luteal phase support and analysed the results on an intention-to-treat basis. Each couple participated for 3 menstrual cycles and they were followed up until either the end of a 3rd non-conceptual cycle or any resulting pregnancy. Participants/materials, setting, methods Couples with normal semen analysis (WHO 2020), regular ovulation, bilateral patent tubes, female partner aged ≤42yrs and BMI ≤30 were recruited and randomised following screening and informed consent. Participants timed their luteinising hormone (LH) surge using digital ovulation kits and had timed intercourse for 3 cycles. The treatment group took progesterone suppositories 400mg bd for 14 days after the LH surge. All pregnancies were scanned at 6-7/40 and ongoing pregnancies followed up to delivery. Main results and the role of chance 143 couples were recruited and randomised. Livebirth rates were 11/72 (15.3%) in the treatment group vs. 5/71 (7.0%) in the control group (Odds Ratio (OR) 2.38, 95%CI 0.78-7.24). Biochemical pregnancy rates (defined by a positive urinary pregnancy test) were 15/72 (20.8%) (treatment) vs 10/71 (14.1%) (control) (OR 1.61, 95%CI 0.67-3.86). Clinical pregnancy rates (defined by a gestation sac seen on ultrasound at a minimum of 6/40 gestation) were 14/72 (19.4%) (treatment) vs 9/71 (12.7%) (control) (OR 1.66, 95% CI 0.67-4.13). The miscarriage rate including biochemical losses was 3/15 (20%) of all pregnancies (treatment) vs. 4/10 (40%) (control). One pregnancy in the control group was terminated due to fetal anomalies. There was one ectopic pregnancy in the treatment group. Logistic regression demonstrated that none of the pregnancy outcomes were affected by participant age, BMI, ovarian reserve markers, previous parity or semen analysis parameters. The two participants in the treatment group who experienced miscarriages were both off-protocol. Although the results did not reach statistical significance, the 15.3% livebirth rate and OR of 2.37 for livebirths are clinically significant (equivalent to the success rates of stimulated intrauterine insemination treatment) as is the miscarriage rate of 0/11 clinical intra-uterine pregnancies for women taking progesterone as per protocol.Limitations, reasons for caution Despite the lack of statistical significance, differences in livebirth and miscarriage rates are clinically significant compared with alternative treatments. The trial was unblinded but the objective outcomes are unlikely to be affected by this. A larger trial using the effect size from this study to guide sample size is planned. Wider implications of the findings The treatment investigated here represents a simple, non-invasive and inexpensive option that is acceptable to couples with UI and may increase their chance of pregnancy and livebirth. If this treatment offers similar success rates to stimulated IUI it is likely to become a first-line option for many couple worldwide. Trial registration number 2019-003468-27