Articles

Intravenous immunoglobulin treatment in womenwith four or more recurrent pregnancy losses: A
double-blind, randomised, placebo-controlled trial
Hideto Yamada,a* Masashi Deguchi,b Shigeru Saito,c Toshiyuki Takeshita,d Mari Mitsui,e Tsuyoshi Saito,f Takeshi Nagamatsu,gKoichi Takakuwa,h Mikiya Nakatsuka,i Satoshi Yoneda,c Katsuko Egashira,j Masahito Tachibana,k Keiichi Matsubara,lRitsuo Honda,m Atsushi Fukui,n Kanji Tanaka,n Kazuo Sengoku,o Toshiaki Endo,f and Hiroaki Yata paCentre for Recurrent Pregnancy Loss, Teine Keijinkai Hospital, 1-40 Maeda 1-jho 12-chome Teine-ku, Sapporo, Japan
Department of Obstetrics and Gynecology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho Chuo-ku, Kobe, Japanc
Department of Obstetrics and Gynecology, the Toyama University, 2630, Sugitani, Toyama, Japand
Department of Obstetrics and Gynecology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japane
Division of Reproductive Medicine and Maternal Care, National Center for Child Health and Development, 2-10-1 Okura,
Setagaya-ku, Tokyo, Japanf
Department of Obstetrics and Gynecology, Sapporo Medical University, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo,Japang
Department of Obstetrics and Gynecology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japanh
Department of Obstetrics and Gynecology, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Japani
Okayama University, Graduate School of Health Sciences, 2-5-1 Shikata, Kita-ku, Okayama, Japanj
Department of Obstetrics and Gynecology, Kyushu University Graduate School of Medicine, 3-1-1 Maidashi, Higashi-ku,
Fukuoka, Japank
Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku,
Sendai, Japanl
Department of Obstetrics and Gynecology, Ehime University School of Medicine, 454, Shitsukawa, Toon, Japanm
Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto,JapannDepartment of Obstetrics and Gynecology, Hirosaki University School of Medicine, 53,Honcho, Hirosaki, Japano
Department of Obstetrics and Gynecology, Asahikawa Medical University, 1-1-1 Midorigaoka-higashi 2-jo, Asahikawa, Japanp
Research & Development Division, Japan Blood Products Organization, 15F Tamachi Station Tower N 3-1-1 Shibaura,
Minato-ku, Tokyo, Japanb

Summary
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) andwomen except those who miscarried due to fetal chromosome abnormality (modified-ITT). This study is registeredwith ClinicalTrials.gov number, NCT02184741.

eClinicalMedicine
2022;50: 101527
Published online 29 June2022
https://doi.org/10.1016/j.
eclinm.2022.101527

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 (OR4¢85, 95% CI 1¢74−13¢49; p = 0¢003) significantly increased in women who received IVIG at 4−5 weeks of gestation*Corresponding author at: Director of Centre for Recurrent Pregnancy Loss, Teine Keijinkai Hospital, 1-40 Maeda 1-jho 12-chome
Teine-ku, Sapporo 006-8555, Japan.
E-mail address: yamada-hideto@keijinkai.or.jp (H. Yamada).

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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 ormore RPLs of unexplained aetiology.
Funding The Japan Blood Products Organization.
Copyright Ó 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Keywords: Abortion; Intravenous immunoglobulin; Pregnancy outcome; Recurrent miscarriage; Recurrent pregnancy loss; Unknown aetiology

Introduction
Research in context
Evidence before this study
We searched PubMed up until May 23, 2022, using thesearch terms “unexplained recurrent pregnancy loss”,“therapy”, and “clinical trials” without language restrictions. No standard therapeutic modality for unexplained
recurrent pregnancy loss (RPL) has been established.
Randomised, double-blind, and placebo-controlled trials(RCTs) found no efﬁcacy of paternal lymphocyte immunisation, prednisone, low dose aspirin and/or heparin,
or vaginal progesterone, in women with unexplained
RPL. Previous RCTs of intravenous immunoglobulin(IVIG) for unexplained RPL used medium-dose (20−50g), but the efﬁcacy of the medium-dose IVIG treatment
remains unproved.
Added value of this study
This RCT enrolled more severe cases of primary RPL
than previous RCTs, who experienced ≥4 miscarriages
and at least one miscarriage of a fetus with normal chromosome karyotype. High dose of IVIG (100 g) was
administered early in pregnancy starting at 4−6 weeks
of gestation. Consequently, this study, for the ﬁrst time,
revealed that high-dose IVIG treatment in women with
≥4 RPLs of unexplained aetiology signiﬁcantly increased
rates of ongoing pregnancy at 22 weeks of gestationand live birth. However, the rates of preterm delivery
and fetal growth restriction increased in the IVIG group.
Implications of all the available evidenceHigh dose of IVIG in very early pregnancy improved
pregnancy outcome in women with ≥4 RPLs of unexplained aetiology. This new treatment will give courageand hope to women with severe unexplained RPL whowish to have children. Women who receive high-dose
IVIG treatment should be carefully monitored for complications throughout their pregnancy periods. Large
scale international clinical trials can be performed to
conﬁrm the efﬁcacy of high-dose IVIG treatment on
unexplained RPL.

2

Recurrent pregnancy loss (RPL) is defined as the loss of≥2 or ≥3 pregnancies and affects 0¢8%−1¢4% of couples
who attempt to have a baby.1-3 A variety of factors are
involved in the pathogenesis of RPL, such as abnormal
uterine morphology, thyroid dysfunction, antiphospholipid syndrome, thrombophilic disorder, and chromosome abnormality. However, the aetiology of >50% of
RPL is unknown and is therefore designated as unexplained RPL.4,5 The mechanism underlying the pathology of unexplained RPL remains poorly understood.
Recent studies have proposed immunological abnormalities, including natural killer (NK) cells,6-8 Th1/Th2
balance,8,9 cytokine,9 and regulatory T cells,8,10 for
pathophysiology underlying unexplained RPL.
No standard therapeutic modality for unexplained
RPL has been established. Randomised, double-blind,and placebo-controlled trials and systematic reviews
have found no efficacy of paternal lymphocyte immunization,11 prednisone,12 low dose aspirin and/or heparin,13 or vaginal progesterone,14 in women with
unexplained RPL. Some studies have indicated that
intravenous immunoglobulin (IVIG) may have therapeutic efficacy for unexplained RPL. Assessment of theefficacy of IVIG treatment in women with ≥2 miscarriages using randomised controlled trials (RCTs) were
performed in the 1990s.15-20 These trials used a
medium dose of IVIG, in which 20−50 g of immunoglobulin was infused once, weekly or every 2−4 weeks
during follicular phase, early or mid-gestation. Conclusions drawn from these IVIG trials are controversial.
Only one study found that IVIG was efficacious;17 however, other studies including RCTs in the 2000s did
not.15,16,18-22 Systematic reviews suggested thatmedium-dose IVIG treatment was effective in womenwith secondary RPL,13 but another RCT refuted its efficacy on secondary RPL.24 There are several studies thatreport beneficial effects of medium-dose IVIG
treatment;17,23 however, as most of the studies are nothomogeneous in terms of the unexplained RPL definition, gestational age in which start and finish the

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treatment, and design, they cannot be used together inmeta-analysis or systematic review to reach an evidencebased level to be recommended in clinical practice.
It is acknowledged that high-dose IVIG treatment iseffective, and this therapy has long been applied toa variety of immune-mediated diseases such as
immune thrombocytopenic purpura, Kawasaki's disease,
Guillain−Barre syndrome, and myasthenia gravis. The
high-dose IVIG treatment (20 g daily for 5 days) in 4−6
weeks of gestation was first reported in 1998,25 and it
yielded a high live birth rate of 89¢8% among womenwith a history of ≥4 miscarriages of unexplained aetiology.26 However, these are observational studies, while no
RCTs have assessed whether high-dose IVIG treatment
improve pregnancy outcome in women with RPL. We
assumed that the immunomodulatory effects of high-dose
IVIG treatment in early pregnancy restore fecundity inwomen with unexplained RPL. Therefore, this multicenter, double-blind, randomised, placebo-controlled trial was
designed to investigate whether high-dose IVIG treatment in 4−6 weeks of gestation can increase therates of ongoing pregnancy at 22 weeks of gestationand live birth among women with primary RPL of
unexplained aetiology who have a history of ≥4 miscarriages including at least one miscarriage of a fetus
with normal chromosome karyotype.

Methods
Study design and participants
The double-blind randomised placebo-controlled trial of
IVIG was conducted at 14 study sites including university hospitals and national centres in Japan, wherein the
study protocol was approved by the institutional review
board of each institution and written informed consent
was obtained from all the participants. The pivotal
Phase II study was performed in accordance with theprinciples of the Declaration of Helsinki. The authors
assume responsibility for the accuracy and completeness of the data and analyses. The study was conductedin accordance with the Good Clinical Practice guidelines. The monitoring services were outsourced to acontract research organization, MEDISCIENCE PLANNING INC., Tokyo, Japan) independent of the medical
institution. Determination of eligibility, reliability of
data, and verification of safety were assured throughmonitoring, including the inspection of source data at
least once every month and interviewing investigatorsand clinical trial collaborators.
Women were eligible to participate if they met all of
the following criteria: women who have 1) primary RPL
and no children; 2) ≥4 RPLs excluding biochemical
pregnancy loss in the count of miscarriages; 3-a) no risk
factors of abnormal uterine morphology, thyroid dysfunction with abnormal levels of free T4 or TSH, chromosome abnormality in a couple, a positive test of

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antiphospholipid antibody (anti cardiolipin antibody,anti b2-GPI antibody, and lupus anticoagulant), or
deficiencies of factor XII, protein S, and protein C, andhave experienced at least one miscarriage of a fetus withnormal chromosome karyotype; or 3-b) have experienced at least one miscarriage of a fetus with normal
chromosome karyotype after having been treated forrisk factors as follows: surgical treatment of septate
uterus, medical therapy for thyroid dysfunction, andcombination therapy with low dose aspirin and heparinfor occasional positive of antiphospholipid antibody
test, deficiencies of factor XII, protein S, and protein C;
and 4) <42 years. Miscarriage was defined as pregnancy
loss before 22 weeks of gestation according to Japaneselaw. At the start of the study in 2014, eligible women
were defined as <40 years, and the number of miscarriages with normal chromosome karyotype had to be atleast two for women with four or five RPLs and at least
one for women with ≥ 6 RPLs. As the number of participants was too small, the protocol was revised in
April 2015.
The exclusion criteria were the following: women
who have 1) chromosome abnormality in a couple,
antiphospholipid syndrome defined according to the
updated Sydney classification criteria,27 or the mostrecent positive test of antiphospholipid antibody; 2) notreatment despite having diabetes mellitus or impaired
glucose tolerance; 3) received IVIG for RPL; 4) a historyof stillbirth at ≥22 weeks of gestation; 5) treatment for
malignancy; 6) thromboembolism; 7) a history of shockor hypersensitivity to immunoglobulin; or 8) IgA deficiency or serum IgA level of <5 mg/dL.
Since no Japanese or South-East Asian has factor V
Leiden or prothrombin gene mutation, this study did
not assess these coagulation abnormalities for participants.

Randomisation and masking
Participants were randomly assigned in a 1:1 ratio toeither the active drug group or the placebo group. The
PLAN procedure in SAS was used to generate randomisation codes, and a seed number was randomly specified by the allocation manager. The vials were wrappedwith an opaque seal to ensure indistinguishability by
pre-assigned physicians or pharmacists who were not
involved in drug distribution, administration, or evaluation. Participants, physicians and nurses were blinded.
To equalize factors affecting miscarriage, randomisation was done by stratifying the participants on the basisof the number of miscarriages (4 or 5 vs. ≥6) using theminimization method for age (≥ 35 years vs. < 35 years).

Procedures
The active drug used was 5% formulation of intact typehuman immunoglobulin G (Kenketsu Venoglobulin

3

ArticlesIHÒ , the Japan Blood Products Organization). Physiological saline was used as placebo. The active drug of
400 mg/kg or placebo of 8 mL/kg was administered byintravenous drip infusion for five consecutive days.
Treatment was initiated at 4 to 6 weeks and 6 days ofgestation after gestational sac was identified by ultrasonography. If miscarriages occurred, chromosome karyotype of the villi was performed wherever possible using
G-banding or microarray methods.

Outcomes
Two populations were analyzed: all women who
received the study drug (intention-to-treat, ITT) andwomen who received the study drug excluding those
who miscarried due to fetal chromosome abnormality(modified-ITT). The primary outcome was the ongoing
pregnancy rate at 22 weeks of gestation. The live birthrate was defined as secondary outcomes.

Statistical analysis
The sample size was calculated based on the results ofan epidemiological survey of RPL in Japan. The live
birth rates in women with four, five, and six prior miscarriages were 65¢0%, 58¢8%, and 34¢2%, respectively.5
The live birth rate was 89.8% when 100 g of immunoglobulin was administered in women with ≥4 miscarriages.26 The sample size was calculated assuming live
birth rates of 42%−48% (placebo) and 75% (IVIG) witha = 0¢05 and b = 0¢20. A study with 40 women pergroup has 80% power. As miscarriages with fetal chromosome abnormality are determined ex post facto,
enrollment was continued until the final number of participants increased by approximately 20%. The ongoing
pregnancy rate at 22 weeks of gestation, live birth rate,
and their 95% confidence interval [CI] were calculated.
Fisher’s exact test was used to compare the two groups.
To estimate ongoing pregnancy rates, Kaplan-Meiercurves were plotted for the pregnancy period. Miscarriage and stillbirth were defined as events, and those
who had a live birth were censored regardless of preterm or full-term delivery. The ongoing pregnancy rates
at 12, 22, 28, and 34 weeks of gestation were estimated,
and the IVIG-to-placebo hazard ratio was calculated.
This study is registered with ClinicalTrials.gov number,
NCT02184741.

Role of the funding sourceThis study was funded by the Japan Blood Products
Organization. The study funder contributed in study
design and data interpretation, but had no role in datacollection, analysis, writing of the manuscript, or thedecision to submit. The study funder remained blinded
to individual treatment allocation throughout the study.
All authors had full access to all the data in the study
and accepted responsibility to submit for publication.

4

Results
From June 3, 2014 to Jan 29, 2020, 104 women wereassessed for eligibility, and 102 women were randomly
assigned to receive IVIG (n = 53) or placebo (n = 49);
three women in the IVIG group withdrew consent or
had an early miscarriage before infusion. Of the remaining 99 women, 50 women received IVIG and 49
women received placebo in the ITT population(Figure 1). These study drugs were started from 4 weeks
and 3 days to 6 weeks and 6 days of gestation. The baseline characteristics and protocol adherence were similarin the two groups (Table 1).
After treatment, 19 women in the IVIG group and 31
in the placebo group had miscarriages. Of the 19 miscarriages in the IVIG group, 12 had normal chromosome karyotype, three had numerical chromosome
abnormality, two were unknown due to inadequate
specimen quality, and two were not analysed due tospontaneous evacuation of the abortus. Of the 31 miscarriages in the placebo group, 20 had normal chromosome karyotype, ten had numerical chromosome
abnormality, and one was unknown.
One pregnancy with fetal anencephaly in the placebogroup was terminated by induced abortion. The remaining 47 women in the IVIG group and 38 in the placebogroup were included in the modified-ITT population(Figure 1).
The ongoing pregnancy rate at 22 weeks of gestation(31/50, 62¢0%) in the IVIG group was higher than that
(17/49, 34¢7%) in the placebo group in the ITT population (odds ratio [OR] 3¢07, 95% CI 1¢35−6¢97;
p = 0.009). The live birth rate (29/50, 58¢0%) in the
IVIG group were higher than that (17/49, 34¢7%) in theplacebo group (OR 2¢60, 95% CI 1¢15−5¢86; p = 0¢03).
The rates of ongoing pregnancy and live birth were notstatistically different between IVIG (47 women) and placebo (38 women) groups in the modified-ITT population (Table 2).
The IVIG-to-placebo hazard ratios for the ongoing pregnancy were 0¢47 (95% CI 0¢26−0¢82; p = 0¢007) in the
ITT population and 0¢52 (95% CI 0¢27−0¢98; p = 0¢04) inthe modified-ITT population, respectively (Figure 2).
Among women who had live births, gestational age
at delivery was earlier in the IVIG group than the placebo group, and the rates of preterm delivery (13/29[44¢8%] vs. 1/17 [5¢9%]) and fetal growth restriction (10/29 [34¢5%] vs. 0/17 [0%]) were higher in the IVIG groupcompared with the placebo group. The number of live
births was 30 including one pair of twins in the IVIG
group and 17 in the placebo group. In the IVIG group
except twins, birth weight was lower, and the rate ofsmall for gestational age (12/28 [35¢7%] vs. 0/17 [0%])was higher compared with the placebo group. The karyotypes of three miscarriages in the IVIG group and tenin the placebo group had numerical chromosome
abnormalities, whereas those of four miscarriages in
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Figure 1. Trial proﬁle. IVIG, intravenous immunoglobulin; ITT, intention-to-treat.

unknown. The rates of normal/abnormal chromosome
karyotypes of miscarriages or congenital anomalies
were not different between the two groups. Four newborns in the IVIG group and none in the placebo group
had congenital anomalies (p = 0¢28). Normal
Participant characteristics

chromosome karyotypes of a total of 32 miscarriages
consisted of 46,XX (n = 23) and 46,XY (n = 9). The disproportion might be derived from contamination ofmaternal tissues to some extent. (Table 3). Although
preeclampsia was observed in four (8¢0%) of 50 womenIVIG
n=50 (%)

Placebon=49 (%)

Age, years

35·2 ± 3·735.0 ± 4.0< 35

21 (42·0)

22 (44·9)≥ 35

29 (58·0)

27 (55·1)

Body weight, kg

56·3 ± 9·0

56·4 ± 11·0

5·1 ± 1·6 (4-11)

5·2 ± 1·7 (4-11)

4 or 5 times

36 (72·0)34 (69·4)

6 times or more

14 (28·0)

15 (30·6)

Number of prior miscarrige (range)

Latest weeks of gestation in past miscarriges< 12 weeks

43 (86·0)

43 (87·8)≥ 12 weeks and < 22 weeks

7 (14·0)

6 (12·2)

5 weeks, 0 day

5 weeks, 1 day

Weeks of gestation when gestational sac was identiﬁed
Weeks of gestation at the start of drug treatment± 3 days± 3 days

5 weeks, 5 days

5 weeks, 4 days

± 4 days± 3 days

4 weeks

3 (6·0)3 (6·1)

5 weeks

31 (62·0)33 (67·3)

6 weeks

16 (32·0)

13 (26·5)

Table 1: Baseline characteristics of study participants.
Plus–minus values are means ± SD. IVIG, intraveous immunoglobulin.

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Intention-to-treat population

Fisher’s exact test
Administration

Ongoing pregnancy at 22
weeks of gestation

Live birth

Ongoing pregnancy at 22 weeks ofgestation– no./total no. (%)

95% CI

p-value

Odds ratio (95% CI)

0·009

3·07 (1·35-6·97)

Placebo

17/49 (34·7)

21·7–49·6

IVIG

31/50 (62·0)

47·2–75·3

Administration

Live births– no./total no. (%)

95% CI

p-value

Odds ratio (95% CI)

Placebo

17/49 (34·7)

21·7–49·6

0·03

2·60 (1·15-5·86)

IVIG

29/50 (58·0)

43·2–71·8

Modiﬁed intention-to-treat population
Administration

Fisher’s exact test
Ongoing pregnancy at 22 weeks of

95% CI

p-value

Odds ratio (95% CI)

0·08

2·39 (0·99-5·77)

gestation– no./total no. (%)
Ongoing pregnancy at 22
weeks of gestation

Live birth

Placebo

17/38 (44·7)

28·6–61·7

IVIG

31/47 (66·0)

50·7–79·1

Administration

Live births– no./total no. (%)

95% CI

p-value

Odds ratio (95% CI)

Placebo

17/38 (44·7)

28·6–61·7

0·13

1·99 (0·83-4·47)

IVIG

29/47 (61·7)

46·4–75·5

Table 2: Pregnancy outcomes.

in the IVIG group and one (2¢0%) of 49 women in theplacebo group (p = 0¢36), there were no thromboembolic events. Twenty-three (46¢0%) of 50 women receiving IVIG had mild adverse events including elevatedliver enzymes in nine (18¢0%), headache in four
(8¢0%), skin rash in four (8¢0%), and fever in two(4¢0%) women, while a total of three (6¢1%) of 49
women in the placebo group had adverse events.
To assess the relationship between the timing of treatment initiation and pregnancy outcomes, the subjects
were divided into women who started treatment at 4 or 5
weeks of gestation and women who started at 6 weeks. In
the ITT population, the rates of ongoing pregnancy at 22
weeks of gestation (OR 6¢27, 95% CI 2¢21−17¢78;
p < 0¢001) and live birth (OR 4¢85, 95% CI 1¢74−13¢49);
p = 0¢003); and the rates of ongoing pregnancy at 22
weeks of gestation (OR 5¢40, 95% CI 1¢79−16¢30;
p = 0¢004) and live birth (OR 4¢03, 95% CI 1¢37−11¢84;
p = 0¢02) in the modified-ITT population, were significantly higher in the IVIG group than the placebo group in
women who started at 4 or 5 weeks of gestation, but not in
women who started at 6 weeks (Table 4).
The subjects were also divided into women with fouror five prior miscarriages and women with ≥6 priormiscarriages to assess the relationship between thenumber of miscarriages and pregnancy outcomes. In
the ITT population, the rates of ongoing pregnancy at
22 weeks of gestation (OR 10¢00, 95% CI 1¢80−55¢36;
p = 0¢009) and live birth (OR 7¢20, 95% CI 1¢35−38¢32;
p = 0¢03); and the rates of ongoing pregnancy at 22
weeks of gestation (OR 8¢33, 95% CI 1¢47−47¢23;
p = 0¢04) and live birth (OR 6¢00, 95% CI 1¢11−32¢55;
p = 0¢05) in the modified-ITT population, were significantly higher in the IVIG group than the placebo groupin women with ≥6 miscarriages (Table 5).

6This study included participants who had experienced at least one miscarriage of a fetus with normal
chromosome karyotype after having been treated forrisk factors as follows: surgical treatment of septate
uterus (IVIG 1/50 vs. placebo 1/49), medical therapy forthyroid dysfunction (IVIG 3/50 vs. placebo 4/49), andcombination therapy with low dose aspirin and heparin for occasional positive of antiphospholipid antibody test (IVIG 0/50 vs. placebo 1/49), deficiencies
of factor XII (IVIG 3/50 vs placebo 0/49), protein S(IVIG 5/50 vs. placebo 3/49), and protein C (none).
The other participants had no risk factors (IVIG 38/
50 vs. placebo 40/49).

Discussion
Previous RCTs for RPL of unexplained aetiology usedmedium-dose IVIG treatment (20−50 g, once,
weekly or every 2−4 weeks) during follicular phase,early or mid-gestation in women with ≥2−≥3,15-20,22
or ≥4 prior miscarriages.21,24 However, the efficacyof these medium-dose IVIG treatments remains
unproved.15-24 The present study enrolled more
severe cases of primary RPL than previous RCTs,
who experienced ≥4 miscarriages and at least one
miscarriage of a fetus with normal chromosome karyotype. To make RPL participants more homogeneous, only primary RPL was enrolled. In addition,
for the first time, high dose of IVIG (20 g daily for 5days) was administered early in pregnancy startingat 4−6 weeks of gestation. Consequently, this RCT
revealed that high-dose IVIG treatment in womenwith ≥4 RPLs of unexplained aetiology significantly
increased rates of ongoing pregnancy at 22 weeks ofgestation and live birth in the ITT population.

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Figure 2. Kaplan-Meier curves of ongoing pregnancy rates. Kaplan-Meier curves of ongoing pregnancy rates for each of the IVIG andplacebo 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, and34 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 logrank test indicates a signiﬁcant difference (p = 0¢04).
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Pregnancy outcomes

IVIG
n=50 (%)

Placebon=49 (%)

p-value

Ongoing pregnancy at 22 weeks of gestation

31 (62·0)17(34·7)

0·009*

Live birth

29 (58·0)

17 (34·7)

0·03*

Gestational age at delivery

36 weeks, 1 day ± 4 weeks, 0 days

39 weeks, 2 days ± 2 weeks, 0 days

0·004**

Mode: Vaginal delivery

12 (41·4)

7 (41·2)

1·00*

Cesarean section

17 (58·6)

10 (58·8)

1·00*Preterm delivery (< 37 weeks)

13 (44·8)

1 (5·9)0·007*

Fetal growth restriction

10 (34·5)

0 (0·0)0·008*

19 (38·0)

31 (63·3)

0·02*

9 weeks, 2 days ± 2 weeks, 6 days

8 weeks, 0 days ± 1 week, 2 days

0·045**< 12 weeks

16 (84·2)30 (96·8)

0·15*≥ 12 weeks and < 22 weeks

3 (15·8)

1 (3·2)0·28*

Normal12 (63·2)

20 (64·5)

0·49*

Abnormal

3 (15·8)

10 (32·3)

Unknown1)

2 (10·5)

1 (3·2)

Not tested2)

2 (10·5)

0 (0·0)-13) (2·0)0 (0·0)

0·39*
1·00*

Miscarriage
Gestational age at miscarriage
Time of miscarriage

Chromosome karyotype of miscarriage

StillbirthUnknown outcome due to discontinuation
Newborns

14) (2·0)15) (2·0)

IVIG

Placebon=286) (%)

n=17 (%)-

p-value

Birth weight, g

2246·4 ± 962·5

3071·6 ± 463·4

0·002**

Apgar score at 5 minutes

8·7 ± 1·1

9·1 ± 0·6

0·13**

Small for gestational age

12 (35·7)

0 (0·0)0·001*

0 (0·0)0·28*

Congenital anomaly7)

4 (14·3)

Table 3: Comparison of pregancy outcomes in intention-to-treat population.
Plus–minus values are means ± SD.
*
Fisher’s exact test.
**
Student’s t-test.
1) Due to inadequate specimen quality.
2) Due to spontaneous evacuation of the abortus.
3) A stillbirth occurred at 25 weeks and 5 days of gestation due to abnormal umbilical cord coiling. The chromosome karyotype was normal.
4) A case discontinued the study at 27 weeks and 0 days of gestation due to adverse events of threatened preterm labor. The follow-up survey of adverse events
confirmed live birth at 34 weeks and 1 day of gestation.
5) A case discontinued the study at 14 weeks and 4 days of gestation due to adverse events of fetal anencephaly, and the pregnancy was terminated by induced
abortion. The chromosome karyotype was normal.
6) One case of twin pregnancy is excluded.
7) One case each of atrial septal defect, cleft lip and palate, congenital hearing loss, ventricular septal defect/cerebral cyst.

The efficacy of IVIG treatment on the rates of ongoing pregnancy at 22 weeks of gestation and live birth
was found in severe cases with ≥6 RPLs in the ITT andmodified-ITT populations. These results suggest thatsevere cases of RPL may have undetermined aetiologies
to a greater extent for which IVIG treatment could be
effective. The time of treatment initiation was also associated with the efficacy of IVIG treatment. The efficacy
on the rates of ongoing pregnancy at 22 weeks of gestation and live birth was more evident in women withadministration started at 4 or 5 weeks of gestation, but
not in women with administration started at 6 weeks ofgestation in the ITT and modified-ITT populations.
This RCT first demonstrated that high-dose IVIG treatment started at 4−5 weeks of gestation is especiallyeffective on women with ≥4 RPLs of unexplained aetiology. A recent meta-analysis of RCTs found that IVIG

8

treatment increased live birth rates when initiated prior
to conception.28
In the present study, high-dose IVIG treatment waswell tolerated in most women, and none of them discontinued the treatment due to adverse effects. However,
the gestational age at delivery was earlier, and the rates
of preterm delivery and fetal growth restriction werehigher in the IVIG group compared with the placebogroup. Similarly, the birth weight was lower, and therate of small for gestational age was higher in the IVIG
group compared with the placebo group. High-dose
IVIG treatment in very early pregnancy may be insufficient to yield full-term birth or normal fetal growthamong severe cases with unexplained RPL in whom thetreatment could be effective in preventing early miscarriages. There could be two main reasons for increased
rates of preterm delivery and fetal growth restriction in

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Articles

Intention-to-treat population
Time at the startof administration

4 or 5 weeks
Ongoing pregnancy at
22 weeks of gestation

6 weeks
Time at the startFisher’s exact test
Administration

Ongoing pregnancy at
22 weeks of gestation–
no./total no. (%)

95% CI

p-value

Odds ratio (95% CI)

Placebo

9/36 (25·0)

12·1–42·2<0·001

6·27 (2·21-17·78)

IVIG

23/34 (67·6)

49·5–82·6

Placebo

8/13 (61·5)

31·6–86·1

0·71

0·63 (0·14-2·76)

IVIG

8/16 (50·0)

24·7–75·3

Administration

Live births– no./total no. (%)

95% CI

p-value

Odds ratio (95% CI)

Placebo

9/36 (25·0)

12·1–42·2

0·003

4·85 (1·74-13·49)

IVIG

21/34 (61·8)

43·6–77·8
0·71

0·66 (0·141-2·76)of administration
4 or 5 weeks
Live birth
6 weeks

Placebo

8/13 (61·5)

31·6–86·1

IVIG

8/16 (50·0)

24·7–75·3

Modiﬁed intention-to-treat population
Time at the startFisher’s exact test
Administrationof administration

Ongoing pregnancy at

95% CI

p-value

Odds ratio (95% CI)

0·004

5·40 (1·79-16·30)

0·23

0·29 (0·05-1·82)

22 weeks of gestation–
no./total no. (%)

4 or 5 weeks
Ongoing pregnancy at
22 weeks of gestation

6 weeks
Time at the start

Placebo

9/28 (32·1)

15·9–52·4

IVIG

23/32 (71·9)

53·3–86·3

Placebo

8/10 (80·0)

44·4–97·5

IVIG

8/15 (53·3)

26·6–78·7

Administration

Live births– no./total no. (%)

95% CI

p-value

Odds ratio (95% CI)

0·02

4·03 (1·37-11·84)

0·23

0·26 (0·04-1·82)of administration
4 or 5 weeks
Live birth
6 weeks

Placebo

9/28 (32·1)

15·9–52·4

IVIG

21/32 (65·6)

46·8–81·4

Placebo

8/10 (80·0)

44·4–97·5

IVIG

8/15 (53·3)

26·6–78·7

Table 4: Time of treatment initiation and pregnancy outcome.

the IVIG group: 1) either the substantial doses of IVIG
in very early pregnancy could negatively affect trophoblast invasion in the uterus, which will only be unveiledin the third trimester, or 2) alternatively, high-dose
IVIG treatment may rescue some fetuses that would
otherwise have been miscarried due to immune disturbances, but the treatment only suppresses the immune
disturbances partially increasing the risk of later
immune injury to the placenta and fetal growth restriction. A previous study also found the high rates of preterm delivery and fetal growth restriction in womenwith unexplained RPL who received high-dose IVIG.26
To clarify the reason for high rates of these adverse
pregnancy outcomes in unexplained RPL women withhigh-dose IVIG treatment, further investigations arenecessary.
High-dose IVIG treatment has long been applied to avariety of immune-mediated diseases. Many distinct but
non-mutually exclusive mechanisms of action, including antiinflammation, suppression of autoantibodies
and complements, blockade of FcRn and FcgRn, up-regulation of inhibitory FcgRIIB, modulation of monocytes, macrophages, dendritic cells, natural NK cells, T
cells, B cells, and endothelial cells, account for the

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immunomodulatory effects of IVIG treatment.29,30
Aberrant immunities of NK cells, Th1/Th2 balance,
cytokine, and regulatory T cells at the fetomaternalinterface and/or in the maternal blood were proposed
for aetiologies of unexplained RPL.6-10 In a mousemodel of miscarriage induced by polyinosinic−polycytidylic acid, a high dose of intact type- immunoglobulin
but not a medium dose or Fab- immunoglobulin
restored fecundity through macrophages together witha reduction of TNF-a and IFN-g expressions in the placenta.31 Similarly, a high dose of intact type- immunoglobulin in an early period reduced miscarriages
through NK cells in a mouse model of miscarriage
induced by lipopolysaccharide.32 High-dose IVIG treatment starting at 4−5 weeks of gestation might effectively restore normal immune environment, while thetreatment starting at 6 weeks of gestation would be toolate to yield the efficacy to restore fecundity. Modification of immune function by a high dose of IVIG during
early pregnancy might reduce the number of miscarriages in humans, but the mechanism is still unknown
and further investigation is required.
In the modified-ITT population, the efficacy of IVIG
treatment on the rates of ongoing pregnancy at 22

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Intention-to-treat population
Number of previous
miscarriages

4 or 5 times
Ongoing pregnancy at
22 weeks of gestation

6 times or more
Number of previous

Fisher's exact test
Administration

Live birth
6 times or more

95% CI

p-value

Odds ratio (95% CI)

0·23

2·00 (0·77-5·18)

0·009

10·00 (1·80-55·63)

Placebo

14/34 (41·2)

24·6–59·3

IVIG

21/36 (58·3)

40·8–74·5

Placebo

3/15 (20·0)

4·3–48·1

IVIG

10/14 (71·4)

41·9–91·6

Live births–

95% CI

p-value

Odds ratio (95% CI)

0·24

1·79 (0·69-4·61)

0·03

7·20 (1·35-38·32)

Administration

miscarriages
4 or 5 times

Ongoing pregnancy at
22 weeks of gestation–
no./total no. (%)

no./total no. (%)
Placebo

14/34 (41·2)

24·6–59·3

IVIG

20/36 (55·6)

38·1–72·1

Placebo

3/15 (20·0)

4·3–48·1

IVIG

9/14 (64·3)

35·1–87·2

Modiﬁed intention-to-treat population
Number of previous

Fisher's exact test
Administration

miscarriages

Ongoing pregnancy at

95% CI

p-value

Odds ratio (95% CI)

0·6

1·38 (0·48-3·98)

0·02

8·33 (1·47-47·23)

22 weeks of gestation–
no./total no. (%)

4 or 5 times
Ongoing pregnancy at
22 weeks of gestation

6 times or more
Number of previous

Placebo

14/25 (56·0)

34·9–75·6

IVIG

21/33 (63·6)

45·1–79·6

Placebo

3/13 (23·1)

5·0–53·8

IVIG

10/14 (71·4)

41·9–91·6

Live births–

95% CI

p-value

Odds ratio (95% CI)

0·79

1·21 (0·42-3·47)

0·05

6·00 (1·11-32·55)

Administration

miscarriages
4 or 5 times
Live birth
6 times or more

no./total no. (%)
Placebo

14/25 (56·0)

34·9–75·6

IVIG

20/33 (60·6)

42·1–77·1

Placebo

3/13 (23·1)

5·0–53·8IVIG

9/14 (64·3)

35·1–87·2

Table 5: Number of previous miscarriages and pregnancy outcome.

weeks of gestation or live birth did not reach statisticalsignificance, since a total of 13 pregnancies were
excluded due to chromosome abnormality of miscarriages. The ratio of miscarriage with abnormal chromosome karyotype in the IVIG group (3/50, 6¢0%) was
lower than that in the placebo group (10/49, 20¢4%,
p = 0¢03). This is potentially a part of IVIG treatment
effect, and the IVIG might have a preventative role inaverting miscarriage with abnormal chromosome karyotype increasing the ratio of live birth, since transferredmosaic embryos with abnormal chromosome karyotype
can develop into healthy euploid newborns in IVF.33
Further investigation is required.
In conclusion, high dose of IVIG in very early pregnancy improved pregnancy outcome in women with ≥4
RPLs of unexplained aetiology. This new treatment will
give courage and hope to women with severe unexplained RPL who wish to bear children. However, thistrial has several limitations and potential bias. To
exclude women who occasionally experienced repeatedmiscarriages of abnormal chromosome karyotype asmuch as possible, this trial enrolled severe cases of primary RPL who experienced ≥4 miscarriages of

10

unexplained aetiology and at least one miscarriage
with normal chromosome karyotype. These inclusion
criteria were most severe compared with previous trials of IVIG. Therefore, it took six years and threemonths to follow up pregnancies of 99 participants;
however, this number was not large. The efficacy ofhigh-dose IVIG treatment was not assessed for secondary RPL. Women who receive high-dose IVIG
treatment in very early pregnancy should be carefully
monitored for complications throughout their pregnancy periods. Large scale international clinical trials
can be performed to confirm the efficacy of highdose IVIG treatment in very early pregnancy onsevere cases of unexplained RPL.

Contributors
H.Y., M.D., S.S., T.T., and H.Y. conceived and designed
the study. M.D., S.S., T.T., M.M., T.S., T.N., K.T., M.N.,
S.Y., K.E., M.T., K.M., R.H., A.F., K.T., K.S., and TE
acquired the data. H.Y., S.S., T.T., and H.Y. analysed andinterpreted the data. H.Y., M.D., S.S., T.T., and H.Y. verified the underlying data. All authors had full access to all

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Articles

the data in the study and accepted responsibility to submit
for publication.

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Data sharing statement
Data from this study will be available after approval of
manufacturing and marketing from the Japanese regulatory authorities or three years after the completion ofthis study, whichever is later. Documentation including
the protocol, statistical analysis plan, and informed consent document will be made available. Data will bemade available to investigators after the proposal for useof the data has been approved. Proposals for the use ofdata should be addressed to the following yata-hiroa
ki@jbpo.or.jp.

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Declaration of interests
We declare no competing interests.

Acknowledgments
Study drugs were packaged and provided by the Japan
Blood Products Organization. We thank all participants
for their contributions to this study and thankTomoyuki Fujii, M.D., Kiyoko Kato, M.D., Hidetaka
Katabuchi, M.D., for study design, study management,
and oversight. The study was funded by The Japan
Blood Products Organization.

Supplementary materials
Supplementary material associated with this article canbe found in the online version at doi:10.1016/j.
eclinm.2022.101527.

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