Individualized Prolonged Luteal Support After Fresh Embryo Transfer in Women With Low Progesterone

Interest of Individualized Prolongation of Subcutaneous Luteal Phase Support up to 8 Weeks for Patients Pregnant After a Fresh Embryo Transfer and With Low Serum Progesterone Level at Pregnancy Test - a Multicentric Randomized Double Blinded Controlled Trial

The goal of this clinical trial is to compare live birth rate in a control group versus an interventional group in subjects aged 18 to 37, pregnant after a fresh embryo transfer and with a serum progesterone level below 17 ng/mL on the day of pregnancy test while using vaginal progesterone as a luteal support. .

This is the first randomized controlled trial to assess the benefit of prolonged subcutaneous progesterone administration in patients with a positive pregnancy test (Bêta chorionique gonadotropic hormone: β-hCG >100 IU/L) after fresh transfer and low progesterone level (<17 ng/mL).

Half the participants will be offered a an extension of luteal phase support , by subcutaneous progesterone supplementation for 6 weeks, the other half will have placebo injections. A double-blind, placebo-controlled, randomized design was chosen to prevent selection bias and ensure the comparability of both study arms.

Introduction:

Progesterone is essential for implantation and early pregnancy maintenance. After ovarian stimulation for In vitro fertilization (IVF), luteal phase insufficiency may occur, requiring luteal phase support (LPS) with exogenous progesterone. Recent data suggest that patients with low serum progesterone levels (<17 ng/mL) at positive pregnancy test after fresh embryo transfer have lower live birth rates and higher miscarriage rates despite standard vaginal LPS.

Aim:

The primary objective of the study is to compare live birth rates between:

• a control group receiving standard luteal phase support with vaginal progesterone until pregnancy test and placebo subcutaneous injections until 8 weeks of gestation, and
• an intervention group receiving prolonged luteal phase support with subcutaneous progesterone until 8 weeks of gestation.

Secondary objectives include comparison of clinical pregnancy rate, ongoing pregnancy rate, miscarriage rate, treatment-related adverse events, obstetrical and neonatal outcomes, gestational age at delivery, birth weight, and cost-effectiveness of the individualized prolonged luteal support strategy.

An ancillary biological sub-study conducted at Montpellier University Hospital will assess serum 17-hydroxyprogesterone and estradiol levels at inclusion.

Methods:

This study is a phase III, multicenter, randomized, double-blind, placebo-controlled trial.

Women aged 18-37 years with positive pregnancy test (Bêta chorionique gonadotropic hormone: β-hCG >100 IU/L) and serum progesterone <17 ng/mL after fresh embryo transfer will be randomized (1:1) to receive either:

• subcutaneous progesterone (PROGIRON®) for 6 weeks, or
• matching placebo for 6 weeks. To ensure adequate progesterone exposure during treatment initiation, vaginal progesterone (PROGESTAN®) will be continued for the first 4 days after randomization in both groups.

Participants will be followed until delivery. A total of 214 participants will be enrolled across multiple In vitro fertilization (IVF) centers.

Inclusion Criteria:

• Patient aged 18 to 37 year-old;
• Patients with a BMI below 34 kg/m2;
• After a fresh embryo transfer following an ovarian hyperstimulation for an IVF with a luteal phase support based on micronized vaginal progesterone;
• With a positive pregnancy test (β-hCG > 100 UI/L);
• With a serum progesterone level below 17 ng/mL on the day of pregnancy test;
• Patient able to self-administer subcutaneous progesterone injections, either alone or with the help of her partner.

Exclusion Criteria:

• Patient undertaking an additional source of progesterone (oral or injected) or a treatment stimulating endogenous progesterone secretion (such as Gonadotropin-Releasing Hormone: GnRH agonist, or chorionique gonadotropic hormone: hCG injections);
• Patients with intolerance or contraindication to subcutaneous progesterone administration;
• Patients with a known 21-hydroxylase deficiency;
• Patients with uterine pathology or untreated hydrosalpinx;
• Patients with a history of recurrent miscarriages (3 or more);
• Patient undergoing pre-implantation genetic testing;
• Patient unavailable or unwilling to participate in future visits or is unable to comply with trial protocol;
• Subjects unable to read or/and write French;
• Failure to obtain the consent;
• Subjects non-beneficiary of the French social security (Government medical aid (AME) excluded);
• Subjects placed under legal protection, under guardianship or under curatorship;
• Patient in an exclusion period determined by a previous study;
• Subjects participating in another interventional research.