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IVF and Immunotherapy can Prevent Multiple Miscarriages

Society for Assisted Reproductive Technology (SART) data has shown that the per-cycle success rate for in-vitro fertilization (IVF) has remained at 24%. Although there has been an increase in success when the cause is male factor infertility and intra-cytoplasmic sperm injection (ICSI) is implemented, the rate for women whose etiology is female organic pelvic disease has not changed. The reproductive autoimmune failure syndrome (RAFS), first described in 1988, is the association of pregnancy wastage, infertility and endometriosis with circulating autoantibodies. Patients with RAFS have polyclonal B-cell activation; that is, their antibody producing cells including those that manufacture autoantibodies are very active.

The pathophysiologic mechanisms that cause in-vitro fertilization failures are complex. Antiphospholipid antibodies (APA) play a central role in this process. Phospholipids are adhesion molecules -- they help cells stick to each other. At a very basic level, they help the fetus "stick" to the uterus. Antiphospholipid antibodies interfere with this process, so that the transferred fetus has difficultly implanting, i.e., attaching to the uterus. Furthermore, APA cause problems with uterine and placental blood flow, making the uterus unhealthy for successful implantation.

Antinuclear antibodies (ANA) cause inflammation in various tissues, including the uterus. This inflammatory process prevents the uterus from being able to host a proper implantation. CD56+CD16+ natural killer cells (NK) cells normally kill cancer cells before they grow into large tumors. These cells may misinterpret the implanting fetus as a cancer and kill it too. It is believed that antithyroid antibodies are markers for polyclonal B-cell activation and do not have a direct effect on implantation or the fetus. Any patient who has antithyroid antibodies should be carefully evaluated for APA, ANA and increased NK cell number and/or activity.

There are many studies that recognize the role of and/or support the use for immunotherapy. A small sampling follows:

  • Patients that suffer from failed IVF, 11/12 studies have revealed an increased prevalence of APA.
  • Three controlled studies, two of which were randomized, have demonstrated a significant increase in pregnancy outcome when intravenous immune globulin (IVIg) was administered to patients with a previous history of multiple failed IVFs.
  • A recent randomized prospective study concluded that up to 54% of patients with failed IVFs had successful pregnancies when given prednisone and aspirin prior to the IVF if they have antinuclear antibodies.
  • Women who have received immunotherapy prior to IVF were twice as likely to have multiple births.

All of these observations provide evidence that immune problems can affect implantation and that immunotherapy can positively modulate this problem, resulting in IVF success.

Reproductive Immunology Associates conducted five studies that demonstrated the utility of measuring immune markers in this group and the results are as follows:

  1. Over 50% of the women who have female pelvic organic diseases that required IVF had APAs. If the women took a baby aspirin each day, and injected themselves with a small amount of the anticoagulant heparin, there was a 45% fecundity rate versus 26% for the untreated group.
  2. Patients who did not respond to aspirin and heparin, and had antibodies to phosphatidylserine or phosphatidylethanolamine could increase their rate of success with the addition of IVIg.
  3. IVIg was also recommended if a woman had any APA and suffered four or more IVF failures.
  4. Women with antithyroid antibodies benefited from IVIg.

Immune testing is prudent, and when recommendations are followed, the combined IVF success rate is between 40% and 50%, twice the national average!

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