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Immunoglobulin Therapy in Recurrent Pregnancy Loss

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Journal of Islamabad Medical & Dental College (JIMDC);2013;2(4):64-68

Original Article

Immunoglobulin Therapy in Recurrent Pregnancy Loss

Wajiha Mahjabeen1, Salma Kafeel2, Saeed Alam3, and Riffat Bibi4
1AssisstantProfessor, Department of Pathology, Islamabad Medical and Dental College, Islamabad
2Consultant Gynaecologist and Obstetrician, Salma and Kafeel Medical Centre, Islamabad
3Professor, Department of Pathology, Islamabad Medical and Dental College, Islamabad
4Scientist, Salma & Kafeel Medical Centre, Islamabad

(1,3Bahria University, Islamabad)

Abstract About 1-2% of couples face the problem of recurrent

Objective: Recurrent pregnancy loss is a global issue. miscarriages (RM) and it is well known disturbing and
This study was planned in order to evaluate the effects of distressing dilemma for them. RM also known as
high dose intravenous immunoglobulin (IV Ig) in primary recurrent pregnancy loss (RPL) or habitual abortion is
and secondary unexplained miscarriages in patients of defined as loss of 03 or more continuous pregnancies
recurrent pregnancy loss. before 20 weeks of gestation.2 RPL is further classified
Patients and Methods: Total 168 couples having as either primary (never achieved a live birth) or
history of primary or secondary recurrent pregnancy loss secondary RPL (normal pregnancy followed by
were included in the study. They were divided into IVIg recurrent abortions).3 There are multiple causes of RPL
group and control group. IVIg group was given 50 gm of like cervical incompetence, uterine problems,
IVIg on monthly basis. Control group was provided with chromosomal abnormalities, endocrinological
normal saline drip at same intervals. Statistical package
problems, autoimmune defects such as anti-
for social sciences 19(SPSS 19) was used to analyze the
data. phospholipid syndrome and microbial infections.4,5
Although a large number of autoantibodies to cells
Results: Women receive IVIg treatment (primary +
secondary recurrent pregnancy loss) shows significantly and tissue components particularly anticardiolipin
higher percentage of live birth as compare to control group antibodies and others like antithyroglobulin, anti-
(81%; p<0.000). Percentage of full term live birth is also phosphatidylserine, antiphos-phatidylethanolamine,
significantly increased in IVIg group in comparison with antiphosphatidylinositol, anti-phosphatidylglycerol
control group (76.2%; p < 0.000). In primary recurrent and antiphosphatidic acid and anticoagulant
pregnancy loss total percentage of live births and full term antibodies have been found in many patients having
live births were 85.3 and 79.4% in IVIg group while in
control group it was 26.9% and 19.2% (p<0.000). In
problem of RPL. But still presence of these antibodies
secondary recurrent pregnancy loss percentage of total does not clearly indicate that whether these are the
number of live birth and full term live births in IVIg causes or consequences of pregnancy loss. That’s why
group is 78% and 74% in comparison with control group besides the postulation of immunological etiology, the
32% and 26% respectively (p<0.000). cause of RPL is still unknown and pregnancy loss is
Conclusion: High dose intravenous immunoglobulin often described as idiopathic, spontaneous or
has a beneficial role in patients of primary and secondary unexplained RPL .6
recurrent miscarriages. In order to avert the RPL, multiple treatment options
Key words: High dose immunoglobulin, Primary like IVIgs, low molecular weight heparin with or
recurrent miscarriage, Secondary pregnancy loss. without aspirin, prednisolone and progestin, paternal
lymphocyte immunization have been studied.7,8
Introduction Purified human plasma collected from thousands of
Spontaneous pregnancy loss (SPL) is a common healthy donors is used in order to make IVIg
worldwide problem. It is an emotional and physical preparation. Being a therapeutic immunomodulatory
trauma for couples. About 15% of all clinically agent it contains a wide variety of natural antibodies,
recognized pregnancies end up in spontaneous loss. non pathogenic natural autoantibodies, antibodies
Many pregnancies terminated even before their against exogenous antigens (bacteria, viruses, etc.), Fab
clinical recognition. Live births results in only about fragments of IgG, immunomodulating peptides (CD4,
30% of all conceptions.1

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Journal of Islamabad Medical & Dental College (JIMDC);2013;2(4):64-68

CD8, CD95, etc.), and various cytokines (interleukin Results

[IL]–2, IL-4, IL-10, transforming growth factor–ß, etc.).9
Although different studies depicted the encouraging Patients of RPL who participated into study were
effects of IVIg in patients of RPL but there is still divided into IVIg group (n=84) and control group
ambiguity regarding patients selection criteria and (n=84). Base line characteristics of all participants were
dosage of IVIg.10,11,12 That’s why we planned this study measured (Table 1). The outcome of pregnancies is
in order to evaluate the effects of high dose IVIg in shown in table 2. Women who received IVIg treatment
primary and secondary unexplained miscarriages in showed significantly higher percentage of live births
patients of RPL. (81%) as compared to control group (31%) (p<0.000)
(OR 9.481, 95%CI 4.64-19.37). Percentage of full term
Material and Methods live birth is also significantly increased in IVIg group
(76.2%) in comparison with control group (23.8%) (OR
Subjects: This retrospective study was performed at
10.24, 95% CI 5.03-20.83). Total percentage of fetal loss
Salma and Kafeel Medical Centre Islamabad from
upto and after 13 weeks is significantly high in control
January 2012 to December 2012. Couples with history
group 28.6% and 26.2% as compare to IVIg group 7.1%
of 3 or more recurrent abortions and unexplained
and 4.8% (OR 0.19, 95%CI 0.07-0.50) (OR 0.141, 95% CI
etiology were recruited and their pelvic ultrasound,
0.05-0.43) respectively.
hysterosalpingography, endometrial biopsy,
Couples were then divided in to two groups according
hormonal analysis including LH, FSH, Prolactin,
to type of miscarriage (primary or secondary). Baseline
Progesterone, Estrogen, Thyroid stimulating hormone,
characteristics of individuals having primary RPL are
TORCH profile, liver, kidney function tests and
depicted in table 3. These women also show greater
antiphospholipid antibodies in some cases were done.
treatment response to IVIg group. Total percentage of
A total of 168 patients having normal TORCH profile
live births and full term live births were 85.3 and
and hormonal levels were included in this study.
79.4% in IVIg group while in control group it was
Treatment: Patients were divided into two groups.
26.9% and 19.2% (OR 15.74, 95%CI 4.35-56.92) (OR
One was labeled as IVIg group and the other one was
16.20, 95% CI 4.50-58.35) respectively. In control group
categorized as control group. IVIg group was given 50
total percentage of fetal loss up to and after 13 weeks
grams of intravenous immunoglobulin (IVIg). It was
is significantly high (26.9%) and (23.1% ) as compared
started within 2 weeks of attempted conception. After
to IVIg group ( 2.9%) and (2.9%) (OR 0.082, 95% CI
establishment of pregnancy, same dose of IVIg was
0.009-0.720) (OR 0.101; 95%; CI 0.011-0.901)
continued on monthly basis up to term. Control group
respectively.
was provided with normal saline drip at same
Baseline characteristics of women having history of
intervals.
secondary RPL are shown in table 5. Percentage of
Statistical analysis: Statistical package for social
total number of live birth and full term live births in
sciences 19(SPSS 19) was used to analyze the data.
IVIg group is 78% and 74% in comparison with
Baseline characteristics of participants were measured
control group 32% and 26% respectively (OR 7.534,
as mean ± SD. In order to compare the percentages
95% CI3.08-18.44) (OR 8.10, 95%CI 3.31-19.80).
between IVIg and control group Chi-square test was
Percentage of fetal loss upto 13 weeks in control group
applied. p<0.05 was considered significant.

Table 1: Baseline characteristics of participants

S No. Characteristics of participants IVIG Group (n=84) Control Group (n=84)
1. Maternal age at enrolment (mean ± SD) 29.21 ± 6.38 32.69 ± 7.25
2. Paternal age at enrolment (mean ± SD) 33.86 ± 7.80 36.28 ± 6.46
3. No of previous miscarriages (mean ± SD) 3.62 ± 0.88 3.67 ± 1.02
4. Cumulative number of previous pregnancies 366 376
5. Cumulative number of previous miscarriages 304 308
6. Primary recurrent miscarriages (n) 34 28
7. Secondary recurrent miscarriages (n) 50 56

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Journal of Islamabad Medical & Dental College (JIMDC);2013;2(4):64-68

Table 2: Index pregnancy outcome in women who received IVIG treatment and in controls
S No. Out come IVIG Group Control Group p-value*
1. Total number of pregnancies (n) 84 84
2. Total number of live births, n (%) 68(81) 26(31) 0.000**
3. Total number of full term live births, n (%) 64(76.2) 20(23.8) 0.000**
4. Total number of pre term live births, n (%) 04(4.8) 06(7.1) 0.514
5. Total number of first trimester fetal loss upto 13 wks (n %) 06(7.1) 24(28.6) 0.000**
6. Total number of fetal loss after 13 wks, n (%) 04(4.8) 22(26.2) 0.000**
7. Total number of intrauterine deaths 06(7.1) 12(14.3) 0.134
8. In case of live births, Total number of SVD, n (%) 52(61.9) 10(11.9) 0.000**
9. In case of live births, Total number of C-section, n (%) 16(19) 16(19) 1.000
*Chi-square test was applied, ** p<0.05 was considered significant

Table 3: Baseline characteristics of participants having primary recurrent miscarriages

S No. IVIG Group (n 34) Control Group (n 26)
1. Maternal age at enrolment (mean ± SD) 28.09±5.43 33.15±7.70
2. Paternal age at enrolment (mean ± SD) 31.79±5.20 35.42±6.00
3. No of previous miscarriages (mean ± SD) 3.65±0.95 3.38±0.85
4. Cumulative number of previous pregnancies(n) 146 110
5. Cumulative number of previous miscarriages (n) 124 88

Table 4: Index pregnancy outcome in women receiving IVIG and in control group in case of primary recurrent
abortions
S No. Out come IVIg Group Control Group p-value*
1. Total number of pregnancies (n) 34 26
2. Total number of live births, n (%) 29(85.3) 07(26.9) 0.000**
3. Total number of full term live births, n (%) 27(79.4) 05(19.2) 0.000**
4. Total number of pre term live births, n (%) 02(5.9) 02(7.7) 0.781
5. Total number of first trimester fetal loss upto 13 wks, n (%) 01(2.9) 07(26.9) 0.007**
6. Total number of fetal loss after 13 wks, n (%) 01(2.9) 06(23.1) 0.016**
7. Total number of intrauterine deaths 03(8.8) 06(23.1) 0.125
8. In case of live births, Total number of SVD, n (%) 19(55.9) 01(3.8) 0.000**
9. In case of live births, Total number of C-section, n (%) 10(29.4) 06(23.1) 0.582
*Chi-square test was applied. **p<0.05 was considered significant

Table 5: Baseline characteristics of participants having secondary recurrent miscarriages

S No. IVIg Group (n=50) Control Group (n=50)
1. Maternal age at enrolment (mean ± SD) 29.98 ± 6.90 31.38 ± 6.59
2. Paternal age at enrolment (mean ± SD) 35.2 6 ± 8.93 35.90 ± 6.46
3. No of previous miscarriages (mean ± SD) 3.58 ± 0.83 3.68 ± 1.02
4. Cumulative number of previous pregnancies(n) 220 222
5. Cumulative number of previous miscarriages (n) 179 184

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Journal of Islamabad Medical & Dental College (JIMDC);2013;2(4):64-68

Table 6: Index pregnancy outcome in women receiving IVIg and in control in case of secondary recurrent
abortions
S No. Out come IVIG Group Control Group p-value*
1 Total number of pregnancies (n) 50 50
2 Total number of live births, n (%) 39(78) 16(32) 0.000**
3 Total number of full term live births, n (%) 37(74) 13(26) 0.000**
4 Total number of pre term live births, n (%) 02(4) 03(6) 0.646
5 Total number of first trimester fetal loss upto 13 wks, n (%) 05(10) 14(28) 0.022**
6 Total number of fetal loss after 13 wks, n (%) 03(6) 14(28) 0.003**
7 Total number of intrauterine deaths 03(6) 06(12) 0.295
8 In case of live births, Total number of SVD, n (%) 34(68) 08(16) 0.000**
9 In case of live births, Total number of C-section, n (%) 06(12) 08(16) 0.564
Chi-square test was applied **p<0.05 was considered significant

and IVIg group is 28% and 10% respectively (OR 0.29, published. One study revnealed that IVIg treatment
95%CI 0.09-0.87) while fetal loss after 13 weeks in was effective whereas two other studies demonstrated
control group and IVIg group is 28% and 6% that IVIg treatment was not beneficial.16,17,18 However,
respectively (OR 0.16, 95% CI 0.04-0.615). after summarizing the results of these placebo
controlled trials, a significant result was achieved19
Discussion and it was suggested that IVIg could be more effective
in women having the history of secondary RM or
Intravenous immunoglobulin being a safe preparation repeated second trimester intrauterine fetal deaths.20
is considered to be an effective therapy in spontaneous In the largest randomized controlled trial (RCT) in
miscarriages. In general, the purpose of IVIg treatment which IVIg was evaluated in women with idiopathic
is to enhance passive immunity in women suffering secondary RM; no treatment benefit was found. The
from RPL. This treatment may have valuable effect by meta-analysis, which combined this study results with
improving the person’s antibody levels and antigen- two prior RCTs, also showed no significant effect of
antibody reaction potential. Our study demonstrated treatment with IVIg for idiopathic secondary RM.21 A
the significantly (p<0.05) high birth rate of 81% computerized search in Medline, Embase, Central,
(68/84) after giving the high dose IVIg treatment. Ovid Medline In-Process, and Other Non-Indexed
While in control group it was 31% (26/84). Our results Citations Databases and randomized controlled trial
are in accordance with a recent study conducted by registries was performed. Abstracts of the American
Yamada in 2012. Results revealed that after giving Society of Reproductive Medicine and European
daily infusion of 20 g of intact type immunoglobulin Society of Human Reproduction and Embryology
for 5 days during early gestation live birth rate was annual meetings and reference lists of identified
73.3% (44/60). While after exclusion of pregnancies reports were searched. IVIg was not found to be
with abnormal chromosome karyotype live birth rate beneficial when women with combined or with
increased upto 89.8% (44/49).12 primary and secondary RM were analyzed
The results of use of IVIg in different studies are separately.22 This also signifies the treatment therapy
controversial. Primarily the results of IVIg regarding primary and secondary miscarriages. In
administration in pregnancy loss were encouraging. In primary recurrent abortions results were 85.3%
a study conducted on twenty women with history of (29/34) as compared to control group 26.9% (7/26). In
spontaneous recurrent abortions the therapeutic effect secondary RPL rate of live births in IVIg group was
of IVIg was significant. After IVIg treatment the 78% (39/50). In control group it was 32% (16/50). A
overall success rate was 82-86%.13 At that time it was systematic review of eight trials involving 442 women
proposed that passive IVIg therapy can be used in evaluates the medium dose IVIg therapy to treat
patients of RPL as a substitution of providing active recurrent miscarriage. It shows a significant increase in
immunity by allogenic leukocytes.14 In a study live births following IVIg use in women with
conducted by Mueller-Eckhardt et al. (1991) the secondary RM, while those with primary miscarriage
success rate for IVIg treatment was 75% in primary did not experience the same benefit.10 The meta-
and 60% secondary recurrent spontaneous abortion analysis of 5 RCTs indicate a higher proportion of
patients.15 Later three placebo-controlled studies were successful pregnancies with medium dose IVIg in

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Journal of Islamabad Medical & Dental College (JIMDC);2013;2(4):64-68

secondary recurrent SPL. IVIg treatment was not Autoimmune Diseases, Cancer, and Recurrent Pregnancy
Loss. Ann. N.Y. Acad. Sci 2005; 1051:743–778
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receiving IVIg therapy, pregnancy rate (93.3%) and immunoglobulin for treatment of recurrent miscarriage: a
live birth rate (87.5%) was highly significant as systematic review.: International Journal of Obstetrics &
Gynaecology 2007; 114: 134–142
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immunoglobulin therapy in women with RSA of medicine. Intravenous immunoglobulin and recurrent
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conducted in 2012 demonstrated the beneficial effect 227.
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(HIVIg) (daily infusion of 20 gms of intact type Immunoglobulin Therapy for Women with Four or More
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