WITHDRAWN: Luteal phase support in assisted reproduction cycles

The aspiration of the granulosa cells that surround the oocyte and the use of gonadotropin releasing hormone agonists (GnRHa) during assisted reproduction technology (ART) treatment can interfere with the production, during the luteal phase, of progesterone, which is necessary for successful implantation of the embryo. Providing hormonal supplementation during the luteal phase with either progesterone itself, or human chorionic gonadotropin (hCG), which stimulates progesterone production, may improve implantation and, thus, pregnancy rates.

To determine (1) if luteal phase support after assisted reproduction increases the pregnancy rate, (2) the optimal hormone for luteal phase support, i.e. hCG, progesterone, or a combination of both, and (3) the optimal route of progesterone administration.

We searched the Cochrane Menstrual Disorders & Subfertility Group trials register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1971 to Dec 2003), EMBASE (1985 to Dec 2003). We handsearched reference lists of relevant articles were scanned, and abstract books from scientific meetings up to December 2003.

Randomized controlled trials of luteal phase support after ART treatment, comparing hCG or progesterone with placebo or no treatment, comparing progesterone with hCG, progesterone plus hCG, or progesterone plus estrogen, or comparing different routes of progesterone administration. Quasi-randomized trials were excluded from the main analyses, but included in a secondary analysis for each comparison.

For each comparison, data on live birth, ongoing and clinical pregnancy per embryo or gamete transfer procedure, miscarriage per clinical pregnancy, ovarian hyperstimulation syndrome (OHSS) per transfer, and multiple pregnancy per clinical pregnancy were extracted into 2 x 2 tables and subgrouped by use of GnRHa in the ovarian stimulation regimen. The odds ratio (OR) and risk difference (RD) were calculated.

Fifty-nine studies were included in the review. Luteal phase support with hCG provided significant benefit, compared to placebo or no treatment, in terms of increased ongoing pregnancy rates (odds ratio (OR) 2.38, 95% confidence interval (CI) 1.32 to 4.29) and decreased miscarriage rates (OR 0.12, 95% CI 0.03 to 0.50), but only when GnRHa was used. The odds of OHSS increased 20-fold when hCG was used in cycles with GnRHa. Progesterone use resulted in a small but significant increase in pregnancy rates (OR 1.34, 95% CI 1.01 to 1.79) when trials with and without GnRHa were grouped together, but no effect on the miscarriage rate was observed. No significant difference was found between progesterone and hCG or between progesterone and progesterone plus hCG or estrogen in terms of pregnancy or miscarriage rates, but the odds of OHSS were more than 2-fold higher with treatments involving hCG than with progesterone alone(OR 3.06, 95% CI 1.59 to 5.86). Comparing routes of progesterone administration, reductions in clinical pregnancy rate with the oral route, compared to the intramuscular or vaginal routes, did not reach statistical significance, but there was evidence of benefit of the intramuscular over the vaginal route for the outcomes of ongoing pregnancy and live birth. No significant difference in pregnancy rate was observed between vaginal progesterone gel and other types of vaginal progesterone.

Luteal phase support with hCG or progesterone after assisted reproduction results in an increased pregnancy rate. hCG does not provide better results than progesterone, and is associated with a greater risk of OHSS when used with GnRHa. The optimal route of progesterone administration has not yet been established.