Luteal phase support for assisted reproduction cycles

Michelle van der Linden, Karen Buckingham, Cindy Farquhar, Jan A M Kremer, Mostafa Metwally, Michelle van der Linden, Karen Buckingham, Cindy Farquhar, Jan A M Kremer, Mostafa Metwally

Abstract

Background: Progesterone prepares the endometrium for pregnancy by stimulating proliferation in response to human chorionic gonadotropin(hCG) produced by the corpus luteum. This occurs in the luteal phase of the menstrual cycle. In assisted reproduction techniques(ART), progesterone and/or hCG levels are low, so the luteal phase is supported with progesterone, hCG or gonadotropin-releasing hormone (GnRH) agonists to improve implantation and pregnancy rates.

Objectives: To determine the relative effectiveness and safety of methods of luteal phase support provided to subfertile women undergoing assisted reproduction.

Search methods: We searched databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and trial registers. We conducted searches in November 2014, and further searches on 4 August 2015.

Selection criteria: Randomised controlled trials (RCTs) of luteal phase support using progesterone, hCG or GnRH agonist supplementation in ART cycles.

Data collection and analysis: Three review authors independently selected trials, extracted data and assessed risk of bias. We calculated odds ratios (ORs) and 95%confidence intervals (CIs) for each comparison and combined data when appropriate using a fixed-effect model. Our primary out come was live birth or ongoing pregnancy. The overall quality of the evidence was assessed using GRADE methods.

Main results: Ninety-four women RCTs (26,198 women) were included. Most studies had unclear or high risk of bias in most domains. The main limitations in the evidence were poor reporting of study methods and imprecision due to small sample sizes.1. hCG vs placebo/no treatment (five RCTs, 746 women)There was no evidence of differences between groups in live birth or ongoing pregnancy (OR 1.67, 95% CI 0.90 to 3.12, three RCTs,527 women, I2 = 24%, very low-quality evidence, but I2 of 61% was found for the subgroup of ongoing pregnancy) with a random effects model. hCG increased the risk of ovarian hyperstimulation syndrome (OHSS) (1 RCT, OR 4.28, 95% CI 1.91 to 9.6, low quality evidence).2. Progesterone vs placebo/no treatment (eight RCTs, 875 women)Evidence suggests a higher rate of live birth or ongoing pregnancy in the progesterone group (OR 1.77, 95% CI 1.09 to 2.86, five RCTs, 642 women, I2 = 35%, very low-quality evidence). OHSS was not reported.3. Progesterone vs hCG regimens (16 RCTs, 2162 women)hCG regimens included comparisons of progesterone versus hCG and progesterone versus progesterone + hCG. No evidence showed differences between groups in live birth or ongoing pregnancy (OR 0.95, 95% CI 0.65 to 1.38, five RCTs, 833 women, I2 = 0%, low quality evidence) or in the risk of OHSS (four RCTs, 615 women, progesterone vs hCG OR 0.54, 95% CI 0.22 to 1.34; four RCTs,678 women; progesterone vs progesterone plus hCG, OR 0.34, 95% CI 0.09 to 1.26, low-quality evidence).4. Progesterone vs progesterone with oestrogen (16 RCTs, 2577 women)No evidence was found of differences between groups in live birth or ongoing pregnancy (OR 1.12, 95% CI 0.91 to 1.38, nine RCTs,1651 women, I2 = 0%, low-quality evidence) or OHSS (OR 0.56, 95% CI 0.2 to 1.63, two RCTs, 461 women, I2 = 0%, low-quality evidence).5. Progesterone vs progesterone + GnRH agonist (seven RCTs, 1708 women)Live birth or ongoing pregnancy rates were lower in the progesterone-only group and increased in women who received progester one and one or more GnRH agonist doses (OR 0.62, 95% CI 0.48 to 0.81, nine RCTs, 2861 women, I2 = 55%, random effects, low quality evidence). Statistical heterogeneity for this comparison was high because of unexplained variation in the effect size, but the direction of effect was consistent across studies. OHSS was reported in one study only (OR 1.00, 95% CI 0.33 to 3.01, 1 RCT, 300 women, very low quality evidence).6. Progesterone regimens (45 RCTs, 13,814 women)The included studies reported nine different comparisons between progesterone regimens. Findings for live birth or ongoing pregnancy were as follows: intramuscular (IM) versus oral: OR 0.71, 95% CI 0.14 to 3.66 (one RCT, 40 women, very low-quality evidence);IM versus vaginal/rectal: OR 1.24, 95% CI 1.03 to 1.5 (seven RCTs, 2309 women, I2 = 71%, very low-quality evidence); vaginal/rectal versus oral: OR 1.19, 95% CI 0.83 to 1.69 (four RCTs, 857 women, I2 = 32%, low-quality evidence); low-dose versus high-dose vaginal: OR 0.97, 95% CI 0.84 to 1.11 (five RCTs, 3720 women, I2 = 0%, moderate-quality evidence); short versus long protocol:OR 1.04, 95% CI 0.79 to 1.36 (five RCTs, 1205 women, I2 = 0%, low-quality evidence); micronised versus synthetic: OR 0.9, 95%CI 0.53 to 1.55 (two RCTs, 470 women, I2 = 0%, low-quality evidence); vaginal ring versus gel: OR 1.09, 95% CI 0.88 to 1.36 (oneRCT, 1271 women, low-quality evidence); subcutaneous versus vaginal gel: OR 0.92, 95% CI 0.74 to 1.14 (two RCTs, 1465 women,I2 = 0%, low-quality evidence); and vaginal versus rectal: OR 1.28, 95% CI 0.64 to 2.54 (one RCT, 147 women, very low-quality evidence). OHSS rates were reported for only two of these comparisons: IM versus oral, and low versus high-dose vaginal. No evidence showed a difference between groups.7. Progesterone and oestrogen regimens (two RCTs, 1195 women)The included studies compared two different oestrogen protocols. No evidence was found to suggest differences in live birth or ongoing pregnancy rates between a short and a long protocol (OR 1.08, 95% CI 0.81 to 1.43, one RCT, 910 women, low-quality evidence) or between a low dose and a high dose of oestrogen (OR 0.65, 95% CI 0.37 to 1.13, one RCT, 285 women, very low-quality evidence).Neither study reported OHSS.

Authors' conclusions: Both progesterone and hCG during the luteal phase are associated with higher rates of live birth or ongoing pregnancy than placebo.The addition of GnRHa to progesterone is associated with an improvement in pregnancy outcomes. OHSS rates are increased with hCG compared to placebo (only study only). The addition of oestrogen does not seem to improve outcomes. The route of progester one administration is not associated with an improvement in outcomes.