High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss.

The aim was to evaluate whether natural killer (NK) cells and regulatory T (Treg) cells were involved in mechanisms underlying beneficial effects of a high dose of intravenous immunoglobulin (IVIG) on recurrent pregnancy losses (RPL) of unexplained etiology. In a double-blind, randomized, placebo-controlled trial of IVIG (400 mg/kg, for 5 days in 4-6 weeks of gestation) in women with RPL, blood samples were collected pre-infusion, one week after infusion (1 w), and eight weeks of gestation/when miscarried (8 w). Levels of NK and Treg cells in peripheral blood were compared between women with IVIG (n = 50) and placebo (n = 49), and between women with IVIG who gave live birth (n = 29) and those who had miscarriage with normal chromosome (n = 12). Effector Treg cell percentages in IVIG group at 1 w (mean 1.43 % vs. 1.03 %) and at 8 w (1.91 % vs. 1.18 %) were higher than those in placebo group (p < 0.01). Total Treg cell percentages in IVIG group at 1 w (4.75 % vs. 4.08 %) and at 8 w (5.55 % vs. 4.47 %) were higher than those in placebo group (p < 0.05). In women with live birth, total Treg cell percentages increased at 8 w (5.52 %, p < 0.001) compared with pre-infusion (4.54 %) and 1 w (4.47 %), while NK cell activity decreased at 1 w (20.18 %, p < 0.001) compared with pre-infusion (26.59 %). IVIG increased Treg cell percentages and suppressed NK cell activity very early in pregnancy, and these were associated with subsequent live birth. Stimulation of Treg cells and suppression of NK cell activity very early in pregnancy may be a mechanism of pharmacological effects of high dose IVIG.

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

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.