Recurrent Pregnancy Loss – Does Any Treatment Help? Role of Intravenous Immunoglobulin
S. Daya
Departments of Clinical Epidemiology and Biostatistics and Obstetrics and Gynaecology McMaster University, Hamilton, Ontario, Canada
Miscarriage is a common complication of pregnancy, the frequency of which increases with the number of previous losses. Although accurate data on the prevalence of recurrent miscarriage are limited to a few small studies, it has been estimated to affect 3-5% of couples in the reproductive age. Many factors have been suggested to have a role in the etiology of recurrent miscarriage. Some of these factors are well established but others are supported only by anecdotal evidence. There is now increasing evidence to support immunological mechanisms for this disorder on the basis of maternal rejection of the semi-allogenic conceptus. Unfortunately, there is as yet no definitive diagnostic test that can identify women who have such alloimmune dysfunction.
Despite the lack of immunological diagnostic tests, couples with unexplained recurrent miscarriage are being offered treatments purporting to improve maternal immuno-tolerance. The most popular approach has been immunization of the female with leukocytes form her male partner (1,2). Recently, passive immunization with intravenous immunoglobulin (IVIG) has been proposed as an alternative because of its immunosuppressive properties.
In a recent meta-analysis of four randomized, placebo-controlled trials that have been published, the absolute treatment effect was 10.1% in favour of IVIG (3). However, because it is not always possible to conduct explanatory analyses of such data, the value of the information obtained may be limited. In contrast, by conducting a meta-analysis using individual patient data, more detailed exploration is possible and variables that predict outcome can be identified more reliably. Such an exercise was recently carried out to determine whether IVIG improves the chance of successful pregnancy in women with recurrent miscarriage, and to investigate the effect of clinical variability on pregnancy outcome (4). The details of this study are summarized below.
Study Subjects
There have been six randomized, placebo-controlled trials of IVIG that have now been published. The authors of these trials were contacted to provide additional data on all patients enrolled in their studies unless these data were already presented in their publications. Individual patient data were included in the analysis if the women had had three or more consecutive miscarriages at <20 weeks gestation with the present male partner, had no uterine, endocrinological and autoimmune abnormalities and the karyotypical analysis in the couple was normal. Women with primary and secondary recurrent miscarriage were coded separately in the data base.
Treatment Protocols
Although the individual treatment protocols were quite different, two main approaches to IVIG administration were identified. One strategy was to commence treatment before conception, in the follicular phase of the menstrual cycle, and continue the administration at regular intervals during the pregnancy. The second strategy was to begin treatment after implantation, as soon as the pregnancy was confirmed (i.e. between 5 and 7 weeks gestation) and to continue its administration at regular intervals during the pregnancy.
Results
In total, there were 240 subjects, of whom 125 received IVIG treatment and 115 received placebo. This sample size had at least 80% power to detect an absolute treatment effect of 15% with IVIG over a baseline suc
cess rate of 62% in the placebo group. The overall, pooled estimate of the effect of treatment was summarized by an odds ratio (OR) of 1.08 (95% confidence interval (CI) 0.63 - 1.86, p = 0.78). The respective ORs for primary and secondary recurrent miscarriage subgroups were 1.04 (0.54 - 2.01) and 1.18 (0.43 - 3.21).
The summary statistics in the table show that, although the treatment effects were not statistically significant, the magnitude of the effect in women with primary recurrent miscarriage was much larger when treatment was administered before conception, whereas among those with secondary recurrent miscarriage, the observation was the reverse.
Logistic regression analysis of the data demonstrated that the number of previous miscarriages and female age were both negative prognostic factors; the higher the number of previous losses and the older the female the lower the likelihood of achieving a successful pregnancy.
Conclusions
The results of this meta-analysis of individual patient data demonstrate at present that there is insufficient evidence to indicate that IVIG is an efficacious treatment for unexplained recurrent miscarriage. The urgency of reaching a definitive conclusionin this issue cannot be emphasized enough, given the relatively short supply of IVIG and its expense. A randomized trial of sufficient power and with stratification for primary versus secondary recurrent miscarriage, preconceptional versus postimplantational administration of IVIG, number of previous miscarriages and female age is necessary before one can determine if IVIG is of any benefit to couples with unexplained recurrent miscarriage.
References
1. Daya S, Gunby J, and The Recurrent Miscarriage Immunotherapy Trialists Group. The effectiveness of allogeneic leukocyte immunization in unexplained primary recurrent spontaneous abortion. Am J Reprod Immunol 1994; 32:294-302.
2. Daya S. Immunotherapy for unexplained recurrent spontaneous abortion. Infert Reprod Med Clin N Amer 1997; 8:65-77.
3. Daya S, Gunby J, Clark DA. Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a meta-analysis. Am J Reprod Immunol 1998; 39:69-76.
4. Daya S, Gunby J, Porter F, Scott J, Clark DA. Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage. Hum Reprod Update 1999; 5: (in press).