Progesterone Luteal Support in Unexplained Infertility Management (PLUIM)

Rationale

Progesterone is a critical hormone in the luteal phase, facilitating endometrial secretory transformation, decidualization, implantation, and early pregnancy maintenance. A previous systematic review suggested that progesterone insufficiency may contribute to reduced implantation potential and lower pregnancy rates in women with unexplained infertility (UI). Additional support for the importance of luteal function in fertility is provided by studies demonstrating improved outcomes following progesterone supplementation in various fertility treatments, including intrauterine insemination (IUI) during mildly stimulated cycles, (natural)-cycle cryoembryo transfers and early gestation.

The present study aims to determine whether progesterone supplementation during the luteal phase in women with UI, managed expectantly through ovulation testing and timed intercourse, can increase live birth rates. A previous pilot randomised controlled trial (the PINC trial) indicated a potential benefit of luteal phase support (LPS) in this population (odds ratio 2.38, 95% CI 0.78-7.24), though the study was underpowered, included only three menstrual cycles, and lacked placebo blinding, thereby limiting the strength of the evidence and supporting the need for a large, high-quality study.

The hypothesis is that the addition of progesterone during expectant management in UI will lead to an absolute increase of 10% in cumulative live birth rate. LPS is expected to be cost-effective, by reducing the need for invasive fertility treatment such as IUI or IVF, thereby shortening time to pregnancy and decreasing the emotional, psychological, and financial burden of infertility care. Given the low cost and ease of home administration, the impact of LPS on total healthcare is expected to be minimal. The overall estimated budget impact of the addition of LPS in UI management is ±11.6 million euros per year.

Trial design

A randomised, controlled, double-blind, multicentre superiority trial will be conducted with two parallel, non-crossover treatment arms: (1) LPS and (2) placebo. All natural cycles occurring within 6 months after randomisation, monitored at home using LH-surge ovulation testing, are included in the study period. The follow up period continues for 12 months after end of the study period (i.e. up to 18 months after randomisation) to assess pregnancy outcomes and confirm live birth.

Trial population A total of 640 patients will be included, with 320 patients allocated to each treatment group.

Couples diagnosed with primary or secondary unexplained infertility, who have a good prognosis for achieving a live birth within the coming year (i.e. Hunault prognostic score ≥30%) and who are assigned to expectant management for at least six months in accordance with Dutch NVOG guidelines, are eligible for inclusion. Female eligibility criteria include an age range of 18-43 years and a body mass index (BMI) below 45kg/m2. A diagnosis of endometriosis will constitute an exclusion criterion.

Interventions

During six consecutive calendar months, participants will perform LH-surge testing via urinary ovulation tests at home, followed by progesterone or placebo treatment during the luteal phase of each menstrual cycle.

A dosage of 300 mg vaginal micronised progesterone twice daily (Utrogestan; Besins Healthcare, Ireland) will be administered in the treatment group, while matching vaginal placebo capsules will be administered in the control group.

Treatment will start on day 3 after a positive urinary LH-surge test and continue until the onset of menstruation, a negative pregnancy test performed 14 days after the positive LH-surge test, miscarriage, or a gestational age of 7+0 weeks. No additional hospital visits or laboratory tests will be required compared with standard care.

Participants are will be asked to use the vaginal capsules as prescribed and complete a medication diary to record compliance throughout the study period. In addition, participants receive short digital questionnaires: at randomisation (Q1, to assess baseline quality of life), at 6 months after randomisation (Q2, quality of life, compliance to therapy, side-effects), and 18 months after randomisation (Q3, determine pregnancy and neonatal outcomes of pregnancies achieved within 6 months after randomisation, determine use of ART treatment and conception during follow up period).

For pregnancies occurring during the six-month study period, the first pregnancy ultrasound will be scheduled at the hospital. Following confirmation of a viable pregnancy, additional antenatal care will be provided within the usual care setting, typically in primary care, unless medical indications require specialist care.