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Intravenous immunoglobulin in the prevention of recurrent miscarriage

Sir, The randomised trial of intravenous immunoglobulin G for prophylaxis of recurrent miscarriage by the German RSA/IVIG Group (December, Vol. 101 1994) is most welcome. Although the groups were small (a total of 57 pregnancies that could be evaluated), it is clear that there is little or no benefit of immunoglobulin over the human albumin which was used as a placebo. Nevertheless, the reasonable conclusion that no specific benefit is obtained from immunoglobulin therapy may not be correct. When the trial was initiated, intravenous albumin seemed a sensible choice as placebo, but, with hindsight, saline might have been more appropriate. There is now some evidence that intravenous infusions of human albumin can influence the regulation of ovarian hormones and antagonise the changes associated with polycystic ovary syndrome (Asch et al. 1993; Shahata et al. 1994). Polycystic ovaries and a high level of leutinising hormone are associated with miscarriage, and indeed it has been claimed that this hormone abnormality is the commonest single cause of recurrent miscarriage (Clifford et al. 1994). It seems possible, therefore, that both immunoglobulin and albumin may help prevent spontaneous abortion in a minority of patients. This possibility is consistent with the statistically significant association between onset of treatment and successful pregnancy with either immunoglobulin or albumin. It also becomes a possibility that the subgroup benefiting from albumin may be different from the subgroup benefiting from immunoglobulin. The 70% or greater success rate with serum or placebo in patients with three or more previous miscarriages is rather high and is consistent with specific effects of both blood products or a psychological benefit from entering the trial, or both. However, the circumstance that admission to the trial took place only after confirmation of pregnancy (including patients at up to eight weeks of pregnancy) might mean the trialists were inadvertently excluding some potential patients who experienced very early abortions, and thereby introduced a bias in favour of successful outcome. Certainly, I have little doubt that the very variable rates reported in the literature for live births: abortions with similar patients without specific treatment are largely a reflection of the selection criteria used for the patients. For that reason, it is not valid to assume that immunoglobulin (or albumin) is just as effective as active immunotherapy with allogeneic lymphocytes. A recent meta-analysis of data obtained from randomised trials appeared to indicate a modest benefit from allogeneic lymphocyte vaccination (Recurrent Miscarriage Immunotherapy Trialists Group 1994). To assess the relative merits of immunoglobulin and leukocytes it would be essential to conduct a large trial with patients randomised three ways to receive autologous cells or saline (placebo), paternal mononuclear cells, or intravenous immunoglobulin. This German immunoglobulin trial has made a valuable contribution to the literature, but it has raised as many questions as it has answered.