P-386 The effect of intravenous immunoglobulin versus placebo in patients with recurrent pregnancy loss: a systematic review and meta-analysis of randomized trials
Authors: Kofod L  M , Pedersen M , Andersen M , Christensen E , Pedersen P , Egerup P , Alipour H , Christiansen O  B , Kesmodel U  S 
Published: July 2024

Abstract

Study question
In women with recurrent pregnancy loss (RPL), how does intravenous immunoglobulin (IVIg) compared with placebo affect live birth rate (LBR) in the first subsequent pregnancy?

Summary answer
IVIg significantly improved LBR in the per protocol (PP), but not the intention to treat (ITT) analysis. LBR increased significantly with number of pregnancy losses.

What is known already
RPL is defined as two or more pregnancy losses before 24 weeks of gestation, impacting 1-2% of fertile couples. It results from diverse causes, and immunological factors are increasingly implicated in unexplained RPL cases. IVIg has been studied as a treatment with various proposed mechanisms. Existing research on IVIg in RPL has shown conflicting results, but a recent Japanese randomized controlled trial (RCT) reported a significantly increased LBR when IVIg was administered early and in high-dose.

Study design, size, duration
We conducted a systematic review and meta-analysis of relevant (RCTs, incorporating individual patient data (IPD) to evaluate IVIg’s impact on LBR in RPL patients.

Participants/materials, setting, methods
This study adhered to PRISMA guidelines and was registered in PROSPERO (ID CRD42023375788). We searched PubMed, Embase, and Cochrane libraries for relevant RCTs up to March 20, 2023. We conducted a meta-analysis with predefined primary (live birth and clinical pregnancy rates) and secondary outcomes. Risk ratios with 95% confidence intervals were calculated for dichotomous outcomes, and mean and standard deviation for continuous variables. We contacted the original authors to perform subgroup analyses based on IPD.

Main results and the role of chance
A total of 10 RCTs comprising 594 women were included in the meta-analysis, and IPD were retrieved from six RCTs including 354 women. No statistically significant results in LBR between IVIg and placebo treated women were found in the ITT analysis (RR: 1.02 [95% CI 0.86-1.22] p = 0.78). In the PP analysis, LBR was increased in the IVIg group compared with placebo (RR: 1.23 [1.00-1-50]). A statistically significant increase in clinical pregnancy rate was found in the IVIg group compared with placebo among women receiving high dose (median ³ 77.5 g) IVIg (RR: 1.79, [95% CI 1.21-2.65], p = 0.004). Furthermore, a statistically significant decrease in pregnancy loss rate was found in patients receiving high doses of IVIg (RR: 0.76 [95% CI 0.60-0.96], p = 0.02) compared to placebo. In the IPD analysis, RRs for live birth in the IVIg group compared with placebo increased steadily with the number of previous pregnancy losses. RRs for live birth in patients receiving IVIg compared with placebo were 5.26 (1.58-17.53) and 7.50 [1.20-47.05) in patients with ≥6 and ≥7 consecutive pregnancy losses, respectively. In analyses of IPD data adjusted for maternal age, the RRs for live birth were almost similar.

Limitations, reasons for caution
Limitations in the systematic review include potential bias due to financial support from pharmaceutical companies in half of the studies; potential confounding in subgroup analysis, missing individual patient data; and clinical and methodological heterogeneity among the included RCTs, which all may impact the overall reliability of results.

Wider implications of the findings
The findings highlight the importance of patient selection and personalized treatment. The PP analysis favored IVIg, emphasizing importance of protocol adherence. Secondly, the effectiveness of IVIg seems to increase with number of previous consecutive pregnancy losses. Thirdly, the dose of IVIg seem to impact its effectiveness.

Trial registration number
CRD42023375788