Few innovations in IVF have evoked the degree of controversy and bad press as has the principle of immunologic factors and their role in infertility. I am at a loss to explain the almost rabid denunciation of immunotherapy as a valid treatment of unexplained IVF failure and recurrent pregnancy loss.

This having been said, the fact remains that there are thousands of women with repeated, unexplained IVF failure or a history of recurrent miscarriage who, following diagnosis and selective immunotherapy, have subsequently gone on to have healthy babies.

So, why this militant obsession to denounce the validity of an immunologic component in reproductive failure? One of the arguments used by those that oppose it is that there are no randomized, controlled studies that support its effectiveness in reproductive medicine. Bear in mind that there is very little that we currently do in the clinical realm of assisted reproductive technology (ART) that is universally supported by such studies. This does not in any way mean that their use is invalidated. Such gold standard statistical testing requires that the influence of all variables, other than the one(s) being evaluated be controlled (kept constant) allowing the one in question to be subjected to randomized testing. Only then can the results be validated.

Such stringent criteria are simply impossible to apply in the IVF setting. That is why virtually every clinical treatment/process currently used in the field gained its acceptance through a process of longitudinal efficacy testing…by trial and error, not through gold standard statistical testing. For example, there are no studies that have even definitively establish a real benefit in choosing IVF over alternatives such as gamete intrafalopian tube transfer (GIFT) or Zygote intrafallopian tube transfer (ZIFT) . Yet no one would argue that IVF is far more effective than either alternative. In fact both GIFT and ZIFT have fallen into disrepute, are hardly ever used, and have been relegated to the pages of history.

Similarly, there are no gold standard randomized statistical studies that have demonstrated a benefit in using adjunct procedures such as assisted hatching (AH), embryo co-culturing, nuclear cytoplasmic transfer, intracytoplasmic sperm injection (ICSI) or the preferential use of one IVF protocol over another. Yet, good and honorable physicians who practice in this arena tout such approaches as being efficacious and even selectively superior, often with “dubious conviction”.

So, why the double standard when it comes to immunotherapy in IVF?
Consider the following: Embryo abnormalities account for roughly 75% of IVF failure, while implantation problems (including immunologic factors) only account for about 25%. It follows that it would be impossible to statistically assess the role of immunologic factors or the effect of selective immunotherapy on IVF outcome unless we could be sure that the embryo(s) transferred were “competent” (i.e. were chromosomally normal and thus upon reaching a receptive uterus, would propagate a viable pregnancy).

The recent introduction of a new genetic test known as Comparative Genomic Hybridization (CGH) performed on embryos makes it possible to evaluate all the chromosomes in an embryo and identify the “competent” embryos (see my recent post on CGH).

Using CGH embryo selection, we will finally be able to control for the important variable of embryo “competence”, and thereby much more reliably evaluate the role of immunologic factors in implantation dysfunction. If we would then demonstrate a significantly improved birth rate with immunotherapy than without it, the controversy of its effectiveness could finally be put to rest.

We are conducting such a study, and while final interpretation must await its completion and full statistical analysis, preliminary findings strongly suggest a benefit through the selective immunotherapy using Intralipid (IL), steroids (e.g. dexamethasone and prednisone) and/or heparin therapy in such cases. Hopefully, this matter can finally be put to rest, and the energy expended opposing its use can be refocused on more pressing issues that affect patient care.