Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial

Hideto Yamada, Masashi Deguchi, Shigeru Saito, Toshiyuki Takeshita, Mari Mitsui, Tsuyoshi Saito, Takeshi Nagamatsu, Koichi Takakuwa, Mikiya Nakatsuka, Satoshi Yoneda, Katsuko Egashira, Masahito Tachibana, Keiichi Matsubara, Ritsuo Honda, Atsushi Fukui, Kanji Tanaka, Kazuo Sengoku, Toshiaki Endo, Hiroaki Yata, Hideto Yamada, Masashi Deguchi, Shigeru Saito, Toshiyuki Takeshita, Mari Mitsui, Tsuyoshi Saito, Takeshi Nagamatsu, Koichi Takakuwa, Mikiya Nakatsuka, Satoshi Yoneda, Katsuko Egashira, Masahito Tachibana, Keiichi Matsubara, Ritsuo Honda, Atsushi Fukui, Kanji Tanaka, Kazuo Sengoku, Toshiaki Endo, Hiroaki Yata

Abstract

Background: There is no effective treatment for women with unexplained recurrent pregnancy loss (RPL). We aimed to investigate whether treatment with a high dose of intravenous immunoglobulin (IVIG) in early pregnancy can improve pregnancy outcomes in women with unexplained RPL.

Methods: In a double-blind, randomised, placebo-controlled trial, women with primary RPL of unexplained aetiology received 400 mg/kg of IVIG daily or placebo for five consecutive days starting at 4-6 weeks of gestation. They had experienced four or more miscarriages except biochemical pregnancy loss and at least one miscarriage of normal chromosome karyotype. The primary outcome was ongoing pregnancy rate at 22 weeks of gestation, and the live birth rate was the secondary outcome. We analysed all women receiving the study drug (intention-to-treat, ITT) and women except those who miscarried due to fetal chromosome abnormality (modified-ITT). This study is registered with ClinicalTrials.gov number, NCT02184741.

Findings: From June 3, 2014 to Jan 29, 2020, 102 women were randomly assigned to receive IVIG (n = 53) or placebo (n = 49). Three women were excluded; therefore 50 women received IVIG and 49 women received placebo in the ITT population. The ongoing pregnancy rate at 22 weeks of gestation (31/50 [62·0%] vs. 17/49 [34·7%]; odds ratio [OR] 3·07, 95% CI 1·35-6·97; p = 0·009) and the live birth rate (29/50 [58·0%] vs. 17/49 [34·7%]; OR 2·60, 95% CI 1·15-5·86; p = 0·03) in the IVIG group were higher than those in the placebo group in the ITT population. The ongoing pregnancy rate at 22 weeks of gestation (OR 6·27, 95% CI 2·21-17·78; p < 0·001) and the live birth rate (OR 4·85, 95% CI 1·74-13·49; p = 0·003) significantly increased in women who received IVIG at 4-5 weeks of gestation as compared with placebo, but these increases were not evident in women who received IVIG at 6 weeks of gestation. Four newborns in the IVIG group and none in the placebo group had congenital anomalies (p = 0·28).

Interpretation: A high dose of IVIG in very early pregnancy improved pregnancy outcome in women with four or more RPLs of unexplained aetiology.

Funding: The Japan Blood Products Organization.

Keywords: Abortion; Intravenous immunoglobulin; Pregnancy outcome; Recurrent miscarriage; Recurrent pregnancy loss; Unknown aetiology.

Conflict of interest statement

We declare no competing interests.

© 2022 The Author(s).

Figures

Figure 1
Figure 1
Trial profile. IVIG, intravenous immunoglobulin; ITT, intention-to-treat.
Figure 2
Figure 2
Kaplan-Meier curves of ongoing pregnancy rates. Kaplan-Meier curves of ongoing pregnancy rates for each of the IVIG and placebo groups in the intention-to-treat population (Panel A) and in the modified intention-to-treat population (Panel B). Miscarriage and stillbirth were defined as events, and pregnant women who had a live birth or an induced abortion due to fetal anomaly were censored and depicted as marks on the curve. IVIG, intravenous immunoglobulin. Panel A: In the intention-to-treat population, Kaplan-Meier estimates of the ongoing pregnancy rates at 12, 22, 28, and 34 weeks of gestation were 38·8%, 36·7%, 36·7%, and 36. ·7% in the placebo group; and 68·0%, 62·0%, 60·0%, and 60·0% in the IVIG group, respectively. The IVIG-to-placebo hazard ratio for the ongoing pregnancy rate was 0·47 (95% CI: 0·26–0·82), and the log-rank test indicates a significant difference (p = 0·007). Panel B: In the modified intention-to-treat population, Kaplan-Meier estimates of the ongoing pregnancy rates at 12, 22, 28, and 34 weeks of gestation were 47·4%, 44·7%, 44·7%, and 44·7% in the placebo group; and 72·3%, 66·0%, 63·8%, and 63·8% in the IVIG group, respectively. The IVIG-to-placebo hazard ratio for the ongoing pregnancy rate was 0·52 (95% CI: 0·27–0·98), and the log-rank test indicates a significant difference (p = 0·04).

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