INTRAVENOUS IMMUNOGLOBULIN (IVIG) FOR IVF
Intravenous immunoglobulin (IVIG) is a sterile, highly purified immunoglobulin G (IgG) derived from large pools of human plasma. All units of human plasma used to prepare IVIG are provided by FDA approved blood establishments (Red Cross) and tested by FDA-licensed serological tests for infectious agents. Aside from screening for hepatitis, HIV and nucleic acid tests, significant viral reduction is achieved by a combination of processes including Cohn fractionation, pH 4 and solvent detergent treatments. The product is stable for 18 months at room temperature and 24 months in the refrigerator.
The FDA approved indication of IVIG is primarily immune deficiency syndromes such as agammaglobulinemia, Wiscott-Aldrich syndrome, or combined immunodeficiencies (“boy in the bubble”). In the US, 70-80% of IVIG used is off-label use for a variety of diseases. Some of these include but are not limited to rheumatoid arthritis, ITP, Alzheimer’s disease, hemophilias, autism, ulcerative colitis, Crohn’s disease and recurrent pregnancy loss (RPL). The cost of the preparation is approximately $70 per gram. A total of 40-80 grams of IVIG is recommended and divided in two doses for patients with immune problems undergoing IVF treatment. The first dose is administered at least one week prior to the egg retrieval. Patients receive an additional dose once pregnant.
Although IVIG can be associated with certain side effects such as headaches, fever, chills or rash, no seroconversions have been reported since its first use in 1993. Mild reactions are rare, with an incidence of 0.4% reported over 10 years in a long term study. There is currently a worldwide shortage of IVIG; not enough product is available for clinical research. On average 2.6 million grams of IVIG are used annually and this may increase due to its expanding use for different indications.
Whether patients with a history of RPL benefit from IVIG treatment is unknown, and validation of routine administration requires large scale studies. A recent committee opinion by the American Society for Reproductive Medicine (ASRM) based on five randomized controlled trials, reported a potential effect with IVIG treatment in patients with secondary RPL (women who had a history of at least one live birth). Certain subgroups of patients with RPL may benefit from IVIG treatment such as those with increased natural killer cell activity (NKa), an abnormal immunophenotype, presence of anti-thyroid antibodies or those couples with immunological HLA/DQ alpha match. IVIG suppresses NKa in vitro and may improve implantation of the embryo into the uterus and overall pregnancy outcome, although its use is still very much controversial. IVIG empirically has been administered in cases of RPL with no identifiable cause, but the efficacy has not been documented and such a practice is not favored.
Recently, a new solution called Intralipid has been postulated to suppress natural killer cell activity in the laboratory and proposed to replace IVIG. Currently, no large scale clinical trials have shown its benefits in women with immune problems or RPL.