Intralipid or intravenous gamma-globulin (IV-Ig) for implantation failures and repeated miscarriages?

Maternal immune system sometimes needs help with implantation failures or miscarriages, but which kind?

Patients who come to CHR for second opinion consultations frequently have previously identified immune problems, for which various treatments have been recommended by our colleagues. CHR has a long-standing research interest in the immune system which, as repeatedly discussed in the pages of the VOICE, is based on the biological fact that embryos and, after implantation, products of conception represent a semi-allograft (being genetically 50% from the father), which the maternal immune system cannot reject (as it otherwise would any tissue transplant from the male partner) if a pregnancy is to be established.

As we also discussed on many prior occasions, to establish a successful pregnancy, the maternal immune system, therefore, must reprogram itself from rejection to tolerance of the embryo/pregnancy. This reprogramming process, however, does not work as perfectly as it should in women with hyper-active immune systems. Such hyper-active immune systems are characteristic features in women with autoimmunity, inflammation and severe allergies. In such patients, development of immunological tolerance, therefore, is often deficient and, as a consequence, embryo and later pregnancy are still viewed as “foreign” by the maternal immune system and attacked.

Whether autoimmunity, inflammation or allergies are the cause, these attacks are not different form attacks of the immune system of a transplant recipient against the organ he/she receives, a so-called allogeneic immune response. Any preventative treatment, therefore, must be directed at preventing development and/or lowering of an already existing maternal immune response against the embryo/pregnancy, if implantation failure or miscarriage is to be avoided.

This is where this frequently asked question comes into play whether such an immune response is best prevented/treated with intralipid or IV-Ig (intravenous gamma-globulin)?

The honest answer is that nobody knows for sure, and the reason for this answer is that nobody has performed studies to compare these two treatments in their clinical effectiveness. Indeed, no properly conducted studies have established that either really works and some colleagues still argue that neither should be used.

We, therefore, can answer this question only anecdotally, based on using both medications for close to 40 years. Because of the relative rarity of such treatments and patients’ reluctance to be randomized for such studies after repeated implantation failures and/or repeated miscarriages, we, despite a number of attempts over the years, have been unable to complete a proper study. Our here presented opinion, therefore, must be understood in its limitations.

If given the option, CHR’s clear preference in treating women with presumed incomplete tolerance development, is IV-Ig. There are two principal reasons for this answer:

  1. CHR’s clinical experience with IV-Ig has been far superior to the experience with intralipid. At the same time, we, however, fully recognize that the interpretation of CHR’s results we are relying on may be biased because patients who received one or the other treatment, usually, received this treatment for financial rather than medical reasons. Since IV-Ig is significantly costlier, and insurance companies only rarely consider this treatment a covered benefit (intralipid and IV-Ig use in this instance is considered “off-label” and, therefore, “experimental”) our impression about outcomes, clearly, may be biased.
  2. A second reason why CHR prefers IV-Ig over intralipid are its theoretical underpinnings. IV-Ig is not only routinely used in organ transplantation when rejection reactions are observed but also in other clinical situation when hyper-active immune systems require calming down, like in flaring autoimmune states of many autoimmune diseases. How IV-Ig calms down hyper-active immune systems is still not fully understood, but the most-likely explanation is that IV-Ig contains so-called anti-idiotypic antibodies, which neutralize disease-causing antibodies. It is also likely that IV-Ig works through other mechanisms, such a blockage of T-cell activities.

This does not mean that CHR does not use intralipid at all. It is considered a second-best treatment, usually only reserved for patients if observed immune abnormalities are minimal and, therefore, questionable, or if patients simply cannot afford IV-Ig. The minimal dosage of IV-Ig used by CHR is 25 grams, with the standard dosages being 40 grams. Patients with active autoimmune disease usually receive 60 grams in two 30 gram dosages on sequential days. A first dosage of IV-Ig is usually given 4-6 days before embryo transfer.

This is a part of the October 2018 CHR VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.