Pharmacologic Interventions in Preventing Ovarian Hyperstimulation Syndrome: A Systematic Review and Network Meta-Analysis

Abstract

Ovarian hyperstimulation syndrome (OHSS) is a severe iatrogenic complication of controlled ovarian stimulation. Randomised controlled trials (RCTs) have proven several pharmacologic interventions to be effective in OHSS prevention, but these trials have seldom compared multiple drugs. We identified randomised controlled trials (RCTs) through June 2015 by searching databases and compared 11 intervention strategies in preventing OHSS (primary outcome) and their influence on pregnancy rate (secondary outcome). A network meta-analysis was used to evaluate the relative effectiveness among treatments and to create a rank probability table. Thirty-one RCTs were identified, including 7181 participants. Five pharmacologic interventions were superior to placebo in decreasing OHSS incidence: aspirin [relative risk (RR) 0.07, 95% credible interval (CrI) 0.01-0.30, p < 0.05], intravenous (IV) calcium [RR 0.11, 95% CrI 0.02-0.54, p < 0.05], cabergoline [RR 0.17, 95% CrI 0.06-0.43, p < 0.05], metformin [RR 0.20, 95% CrI 0.07-0.59, p < 0.05] and IV hydroxyethyl starch (HES) [RR 0.26, 95% CrI 0.05-0.99, p < 0.05]. The rank probability demonstrated aspirin (Rank 1: 36%) and IV calcium (Rank 1: 35%) to be the most efficacious. Additionally, albumin might decrease the pregnancy rate when compared with placebo [RR 0.85, 95% CI 0.74-0.97, p < 0.05]. This conclusion provides a relative standard and objective reference for choosing an OHSS prophylactic agent.

Figure 1. Flow diagram of the identification and selection of publications.

Figure 2

(a) Network figure of the evidence in the network meta-analysis for the primary outcome (OHSS incidence). Each red circle represents a pharmacological intervention. “c = n” represents the clinical trial number (including two 3-arm trials) between each comparator. Solid lines stand for the existence of direct evidence. Dotted lines represent no direct evidence. (b) Pooled relative risk and 95% credible interval (the numbers in parenthesis) of the primary outcome (OHSS incidence) based on the combination of direct and indirect evidence from the network meta-analysis. The longitudinal column interventions are compared with the transverse raw comparators. Bold numbers represents significant differences. (c) Rank probability figure for the interventions of network meta-analysis of the primary outcome (OHSS incidence) of ranks 1–5. A smaller rank number represents a better estimated effect. Each number (expressed in per cent) in this table demonstrates an estimated probability of an intervention to occupy a specific rank. Note. P/N = placebo or no treatment; HES = hydroxyethyl starch.

Figure 3. Forest plot of the direct pair-wise head-to-head comparisons between the interventions and their comparators for primary outcome (OHSS incidence).

“Experiment” in the plot represents intervention, and “control” represents comparator.