1 Department of Obstetrics and Gynecology, 2 Department of Transfusion Medicine and Clinical Immunology, University Hospital, S-581 85 Linköping and 3 Department of Obstetrics and Gynecology, Huddinge University Hospital, S-141 86 Huddinge, Sweden
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Abstract |
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Key words: intravenous immunoglobulin/recurrent spontaneous abortion
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Introduction |
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The results of pilot studies were promising. The rate of successful pregnancies was 82% for women with RSA (Mueller-Eckhardt et al., 1989; Christiansen et al., 1992
). In a later study by Mueller-Eckhardt et al. (1991), the success rate for IVIG treatment was 75% in primary and 60% secondary RSA patients.
We report here our results from a double-blind, randomized, placebo-controlled study on i.v. immunoglobulin in the treatment of unexplained RSA.
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Materials and methods |
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The study was run at the Departments of Obstetrics and Gynecology University Hospital, Linköping and Huddinge University Hospital.
Patients
Patients with primary RSA (without a live birth) or secondary (a live birth followed by consecutive spontaneous abortions) were included. RSA was defined as three or more consecutive fetal losses before the 20th gestational week. All previous pregnancy losses were confirmed by ultrasound or by histology. Data were taken from the hospital records. Inclusion criteria are presented in Table I. Women with enrollment in other clinical studies or previous inclusion in this study were excluded.
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IVIG and saline (placebo) could not be distinguished, and the codes were blind for both the patients and the hospital staff. IVIG and placebo were distributed 2 h after request and in identical, non-transparent plastic bags. Women received IVIG (20 g Gammonativ®, 400 ml) or placebo (saline, 400 ml) every 3 weeks on five occasions if a viable pregnancy was confirmed by ultrasound before each treatment. By mistake, one patient with a successful outcome of her pregnancy in the IVIG group received only four infusions.
Study medication
Gammonativ® (Pharmacia & Upjohn Plasma Products, Stockholm, Sweden) is a lyophilized powder of normal serum immunoglobulin of human origin aimed for i.v. use. The content of IgA in Gammonativ® is very low (<0.02% of total protein content) and therefore IgA deficiency is not a contraindication for Gammonativ® treatment. Gammonativ® 20 g in 400 ml sterile water was prepared by the hospital pharmacy within 2 h before it was given to the patient as an i.v. infusion.
Measures of effect
The therapy was defined as successful if the pregnancy resulted in the delivery of a liveborn or stillborn child of either more than 28 weeks gestation or with a birthweight exceeding 999 g.
Statistics
The MantelHaenszel 2 test was used to compare treatment results between IVIG and placebo in the whole group as well as within subgroups. A P value <0.05 was considered as statistically significant. The MannWhitney U-test was used to compare the background data between the IVIG and placebo groups.
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Results |
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In the group of 41 patients that were finally evaluated (Table II), 77% IVIG-treated and 79% placebo-treated women had live births (
2 = 0.016, not significant). In the group of women with primary RSA, 82% of IVIG-treated and 89% of placebo-treated had live births (
2 = 0.184, not significant). In the group with secondary RSA, 73% of IVIG-treated and 70% of placebo-treated women had live births (
2 = 0.018, not significant).
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Background characteristics of the women in the IVIG and placebo groups are presented in Table III. The prevalence of recurrent spontaneous abortion in the IVIG and placebo groups is presented in Table IV
.
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Six women belonging to the IVIG group reported mild skin rashes and itching (n = 1), moderate skin rashes and itching (n = 1), elevated body temperature (n = 2), flush (n = 1) and severe vaginal bleeding (n = 1). Two women in the placebo group reported severe itching (n = 1) and mild vaginal bleeding (n = 1).
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Discussion |
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Due to the result of the half time evaluation, the study was terminated and only half of the planned number of patients was included. This makes the estimate of the true treatment results for IVIG and placebo more uncertain, i.e. the 95% confidence intervals were wide for all groups. Hence, our data are insufficient to test the original hypothesis.
The results of studies published before this study was started were promising (Mueller-Eckhardt et al., 1989, 1991
; Christiansen et al., 1992
). Before this study was completed, three placebo-controlled studies were published. One study showed that IVIG treatment was beneficial (Coulam et al., 1995
) whereas two other studies could not demonstrate that IVIG treatment was efficient (The German RSA/IVIG Group, 1994
; Christiansen et al., 1995
). However, when the results of these placebo-controlled trials were summarized, a significant result was achieved (Christiansen, 1996
). The success rate was 64% in the IVIG group and 47% in the placebo group (P < 0.05). Recently two placebo-controlled studies (Perino et al., 1997
; Stephenson et al., 1998
) have shown no effect of IVIG in RSA patients.
We observed, like other authors (Clifford et al., 1994), that some of the couples had difficulties in becoming pregnant and it is also known that patients who achieve pregnancy more quickly might also have a better prognosis (Clark and Coulam, 1996
). It is therefore not certain that the observed `baby rate' after three consecutive spontaneous abortions is close to 80%.
We used saline as placebo in this study in contrast to most previously published placebo-controlled studies where albumin was used in different concentrations: 5% albumin (The German RSA/IVIG Group, 1994), 1.5% albumin (Christiansen et al., 1995
) and 0.5% (Coulam et al., 1995
). The role of albumin as placebo has been questioned (Rewald et al., 1995
). An immunomodulating effect of albumin in concentrations >0.5% could not be excluded (Coulam et al., 1995
). In a recently published study, saline was used as placebo (Stephenson et al., 1998
).
A pregnancy loss is an emotional event for the couple. The positive role of psychological influence (`tender loving care') has been demonstrated for pregnancy success in women with RSA (Stray-Pedersen and Stray-Pedersen, 1984). The excellent outcome of pregnancy after unexplained recurrent first trimester miscarriage with supportive care alone has been documented recently (Clifford et al., 1997
). We can neither deny nor verify that we have had such an effect in both IVIG and placebo groups in our study.
To conclude, we found that women with RSA have a better prognosis than presumed and that IVIG does not improve the prognosis compared to placebo in a setting where the couples are given extra care.
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Acknowledgments |
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Notes |
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References |
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Submitted on June 29, 1998; accepted on November 12, 1998.