The migration of the embryo into the uterine lining is accomplished by proliferation of the invading cells of the embryo and the ability of these cells to digest a path through the uterine tissue. Proliferation of the invading cells is stimulated by proteins called growth factors secreted by cells within the uterine lining. Digestion of the path through the uterine tissues is accomplished by the same enzymes that are involved in dissolving clots (fibrinolysis). Thus, defects in production of growth factors or fibrinolysis result in peri-implantation pregnancy loss. Once the embryo has migrated into the uterus, two events need to occur to ensure success of pregnancy. The embryo must not be rejected by the maternal immune cells and the embryo must induce its own blood supply to get enough nutrients to continue to grow.
Since the embryo contains proteins contributed by the father, they will be foreign to the mother. Therefore, the mother must adapt her immune response so as to not reject or destroy the pregnancy. At the same time the maternal immune system has to “tolerate” the paternal contribution to the pregnancy, it must maintain anti-infectious immune responsiveness to protect both the mother and the embryo. Pregnancy has, thus, been thought of as a state of immunologic tolerance. This tolerance is induces by signals from the embryo to maternal immune cells. Such signals include secretion of a protein called soluble HLA G. Deficiencies in induction in tolerance can lead to pregnancy loss. Thus, immunologic causes for peri-implantation pregnancy loss include inadequate embryonic signaling for tolerance or inappropriate response of the maternal immune cells to proper embryonic signaling.
Pregnancy loss during implantation can result from lack of established blood supply to the pregnancy so that insufficient nutrients are available to support further growth of the embryo. From studies of cancer cells, we know that groups of cells can grow to a size of approximately 3 mm nourished by diffusion alone. But to exceed the 3mm size, the cells must recruit host blood vessels to provide nourishment for growth. The pregnancy reaches a size of 3 mm approximately 2 week after fertilization. If blood vessels are not induced, the pregnancy does not continue to grow. Lack of recruitment of blood vessels results from a defect in a process called angiogenesis. Angiogenesis is the formation of new blood vessels from preexisting vessels and is induced by proteins called cytokines. If cytokines do not stimulate angiogenesis so that the pregnancy can have its own blood supply, peri-implantation pregnancy loss will ensue.
Treatment of recurrent pregnancy loss during implantation is dependent on the cause. The treatments for recurrent pregnancy loss during implantation at our Chicago-area centers are the same as those for pre-implantation pregnancy loss, intravenous immunoglobulin and intralipid.
- Intravenous Immunoglobulin (IVIg) – the only medication that has been shown in randomized placebo controlled trials to be effective in the treatment of implantation failure. IVIg was shown to benefit those women experiencing implantation failure after IVF/ET who were good embryo producers (fertilized at least 50 percent of eggs retrieved and generated at least 3 embryos for transfer). Implantation rates increased from 7 percent with placebo to 18 percent with IVIg in one randomized trial and from 9 percent to 40 percent in another randomized trial. IVIg is usually administered at least 6 to 7 days prior to embryo transfer. The usual dosage for implantation failure is 40mg prior to embryo transfer and 40mg after the first positive pregnancy test. In some instances it may be necessary to repeat IVIg infusions every three to four weeks until the end of the first trimester of pregnancy. Overall, the pregnancy rate per cycle in women with a history of previous implantation failure after IVF/ET who are treated with IVIg is 50 percent and live birth rate is 70 percent.
- Intralipid – Evidence from both animal and human studies suggest that intralipid administered intravenously may enhance implantation. Intralipid is a 20 percent intravenous fat emulsion used routinely as a source of fat and calories for patients requiring parental nutrition. It is composed of 10 percent soybean oil, 1.2 percent egg yolk phospholipids, 2.25 percent gylcerine and water. Intralipid stimulated the immune system to remove “danger signals” that can lead to pregnancy loss. The appeal of Intralipid lies in the fact that it is relatively inexpensive and is not a blood product.
- Phosphodiesterase Inhibitors – responsible for enzymatic degradation of molecules within the cells involved in generating energy for the cell to function. They have anti-inflammatory effects. Two phosphodiesterase inhibitors—Sildenfil (Viagra) and Pentoxiphylline (Trental) have been shown to increase blood flow to the uterus. Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. Significant improvement of the thickness of the uterine lining in about 70 percent of women treated. Successful pregnancy resulted in 42 percent of women who had previously experienced repeated IVF failures and who responded to the Viagra. Similar results were obtained when Trental was used in 400mg twice a day doses alone with vitamin E to treat women experiencing implantation failure associated with thin endometrium and elevated uterine NK cells. Animal studies have demonstrated that pentoxifylline prevents miscarriages in abortion-prone mice. Efficacy of pentoxifylline for treatment of recurrent pregnancy loss in human beings remains to be established.