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Immunology may be key to pregnancy loss (updated) by Carolyn Coulam and Nancy HemenwayLast Updated: July 15, 2005
TREATMENT FOR IMMUNOLOGIC CAUSES OF RECURRENT PREGNANCY LOSS
Effective treatment depends on the cause of the pregnancy loss. If the cause of the pregnancy loss is a problem within the embryo itself, elimination of the problem involves treatments including donor egg, donor sperm or IVF with preimplantation genetic diagnosis (PGD). If, however, the cause is related to activated immune cells and their cytokines, treatments include: Intravenous Immunoglobulin (IVIg), Intralipid, and Phosphodiesterase Inhibitors. If either acquired or inherited thrombophilia is causing clotting of the placental vessel and subsequent pregnancy loss, then heparin and aspirin is the treatment of choice. If the blood clotting is the result of an immune process, then steroids and/or IVIg can be used.
Intravenous Immunoglobulin (IVIg)
IVIg has been used to treat both pre-implantation and post-implantation recurrent pregnancy loss associated with elevated levels of antiphospholipid antibodies, antithyroid antibodies, circulating NK cells and NK cell killing activity and embryotoxins. It has also been used for treatment of unexplained recurrent implantation failure and pregnancy loss. The mechanisms by which IVIg works include:
· IVIg provides antibodies to antibodies (anti-idiotypic antibodies)
· IVIg suppresses B cells production of autoantibodies
· IVIg enhances regulatory T cell activity
· IVIg suppresses NK cell killing activity
Originally, IVIg therapy was used to treat women who had not been successful in pregnancies previously treated with aspirin and prednisone or heparin. The rationale for the use of IVIG in the original studies was the suppression of the lupus anticoagulant in a woman being treated for severe thrombocytopenia. IVIg was often given with prednisone or heparin plus aspirin. The estimated success rate of 71% for women at very high risk for failure with a history of previous treatment failures suggested IVIg treatment was effective. More recently, IVIg therapy alone has been used to successfully treat women with antiphospholipid antibodies as well as women who become refractory to conventional autoimmune treatment with heparin or prednisone and aspirin.
Proinflammatory cytokines at the maternal-fetal surface can cause clotting of the placental vessels and subsequent pregnancy loss. One source of these cytokines is the NK cell. Biopsies of the lining of the uterus from women experiencing repeat pregnancy loss reveal an increase in activated NK cells. Peripheral blood NK cells are also elevated in women with repeat pregnancy loss compared with women without a history of pregnancy loss. Measurement of NK cells in peripheral blood of women with a history of recurrent miscarriage and a repeated failing pregnancy has shown a significant elevation associated with loss of a normal karyotypic pregnancy and a normal level associated with loss of embryos that are karyotypically abnormal. Furthermore, increased NK activity in the blood of nonpregnant women is predictive of recurrence of pregnancy loss. Suppressor T cells with are required for protection against NK cytokine-dependent pregnancy loss. IVIg has been shown to decrease NK killing activity and enhance Suppressor T cell activity. Both of these events are necessary for pregnancy to be successful. IVIg has been used to successfully treat women with elevated circulating levels of NK cells, NK cell killing activity and embryotoxins with live birth rates between 70% and 80%.
IVIg has also been used to treat women with unexplained repeat pregnancy loss. Four randomized, controlled trials of IVIg for treatment of repeat pregnancy loss have been published. A European-based study showed a positive trend but did not achieve statistical significance due to too few patients for adequate statistical power given the magnitude of the effect. However, a US-based trial did show a significant benefit, the difference in live birth rates being 62% among women receiving IVIg and 33% among women receiving placebo. The greater magnitude of effect in the US-based study than the European-based trial could have arisen from the use of a different study design. Patients began IVIg treatment before conception in the US-based trial, but after implantation in the European-based trial. By waiting until 5-8 weeks of pregnancy to begin treatment, women with NK cell-related pathology occurring earlier would have been excluded and those pregnancies destined to succeed would be included, providing an opportunity for selection bias. Indeed, a negative correlation with delay in treatment was significant in this study. A third trial treated only women who had a previous live birth, a group that showed no significant benefit of treatment using leukocyte immunization, but significant benefit from IVIg. The fourth Canadian-based trial had too few patients for adequate statistical power to give significant results but did show a trend toward benefit in women with a history of previous live birth followed by recurrent miscarriage. When the results of all of these trials were combined in a meta-analysis the conclusion showed IVIg to be effective treatment for repeat pregnancy loss. None of the studies took into account the pregnancies lost as a result of chromosomal abnormalities except the US-based trial. Approximately 60% of the pregnancies lost in the clinical trial would be expected to have chromosomal abnormalities that would not be corrected by IVIg.
The usual dosage of IVIg for treatment of repeat implantation failure is 40 gm and repeat post-implantation pregnancy loss is 25 grams but successful pregnancies have been reported using dosages from 20 to 60 grams. The half-life in circulation is 28 days so infusions are usually given every 28days. Depending on the obstetric history, IVIg is continued every 28 days until the end of the first trimester (women with a history of first trimester pregnancy losses) or until 28-32 weeks gestation (women with a history of late pregnancy losses). Pregnancies are monitored with immunologic blood tests and treatment can be modified based on the results of the blood tests.
Side effects of treatment with IVIg include nausea, vomiting, headaches, chills, chest pain, difficulty breathing—all comfort side effects which usually occur during the infusion of IVIg and are related to the rate of infusion. If these side effects occur, the rate of the infusion of IVIg is slowed. Other side effects that have been reported much less frequently are migraine-type headaches and sore or stiff neck occurring from one to four days after the infusion. Last, but not least, while IVIg is a purified protein particulate that is reconstituted in fluid and infused in veins, the protein is extracted from human plasma. Therefore, it runs the same theoretic risks for transmittable disease as other blood products. However, IVIg has been available on the American market under FDA and CDC surveillance since 1981, with no reported instance of HIV transmission. There were reports of cases of hepatitis C after IVIg treatment reported in 1992 and the first part of 1993 for which some manufactures changed the method of extraction and added a detergent solubilization step. Thus the theoretic risk at this time is an unknown risk of transmission of presently unidentified infectious particles. Because of the rigorous screening it must undergo, the cost of IVIg is high. The high cost of IVIg therapy can be a deterrent to treatment for some individuals.
Evidence from both animal and human studies suggest that intralipid administered intravenously may enhance implantation and maintenance of pregnancy. Intralipid is a 20% intravenous fat emulsion used routinely as a source of fat and calories for patients requiring parental nutrition. It is composed of 10% soybean oil, 1.2% egg yolk phospholipids, 2.25% 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. Its likely benefit to IVF patients with immunologic dysfunction is under evaluation.
The phosphodiesterases are 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% of women treated. Successful pregnancy resulted in 42% 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.
Low-dose aspirin (80mg or 1 baby aspirin) alone has used for treatment of both repeat implantation failures and post-implantation pregnancy losses. Aspirin therapy has been reported to enhance implantation rates in women undergoing IVF/ET. In these studies the number of eggs retrieved and number of embryos generated were higher in the aspirin treated group than in the non-treated group making it unclear whether the enhancement in implantation rate was the result of better embryo selection or a direct effect on the lining of the uterus. Among women with increased resistance of blood flow through their uterine arteries who were treated with aspirin for a minimum of two weeks, the pregnancy rate was increased from 17% to 47% and the miscarriage rate decreased from 60% to 15%. As a prostaglandin inhibitor, aspirin would be expected to increase blood flow to the ovary prior to implantation, to the endometrium during implantation and to prevent clotting of the placental vessels following implantation. However, in studies of women experiencing recurrent post-implantation pregnancy loss/miscarriage associated with antiphospholipid antibodies, results of clinical trials have shown aspirin alone to be half as effective as other treatments including heparin and steroids. In two studies women receiving aspirin alone or heparin plus aspirin for treatment of repeat pregnancy loss associated with antiphospholipid antibodies, heparin plus aspirin provided a significantly better outcome that aspirin alone (live birth rate of 80% vs 44%).
A rationale for the use of low-dose aspirin therapy during pregnancy for women with antiphospholipid antibodies is to decrease blood clots from forming in the placental vessels. The mechanisms by which aspirin prevents blood clots are through its antiprostaglandin and antiprostacyclin effects and inhibition of platelet adhesiveness and aggregation.
Heparin has also been used in conjunction with aspirin to prevent blood clotting. The rational for using heparin is that it is a blood thinner and inhibits clot formation by a different pathway that the aspirin. While the effectiveness of heparin and aspirin for treatment of women with elevated circulating antiphospholipid antibodies and a history of recurrent miscarriage is well accepted, the use of heparin with or without aspirin to enhance implantation rates has been controversial. Most clinical trials of women with elevated antiphospholipid antibodies and a history of implantation failure undergoing IVF/ET show no enhancement of implantation rates with heparin and aspirin compared with no treatment. This observation is not surprising since the action of heparin is on the cells lining the blood vessels and pre- and peri- implantation pregnancy loss occurs before placental blood vessels appear. The combination of both heparin and aspirin given to women experiencing repeat pregnancy loss who had antiphospholipid antibodies are associated with a live birth rate of 80% compared with a live birth rate of 44% in women receiving aspirin alone. Live birth rates with heparin, aspirin and a steroid called prednisone are 74%. Thus no enhancement of live birth rates are noticed when prednisone is added to heparin and aspirin therapy for treatment of recurrent miscarriage.
Heparin is usually administered at a dose of 5,000-10,000 units subcutaneous twice a day along with aspirin 80mg each day. In women with a circulating lupus-like anticoagulant, more heparin may be required. The side effects of heparin therapy include bleeding, decreased platelet count and osteoporosis or thinning of the bones. Calcium supplementation (two tablets of Tums a day) is recommended while taking heparin. Low molecular weight heparins such as Lovenox and Fragmin have also been used to treat recurrent pregnancy loss associated with thrombophilias, either acquired or inherited.
Steroid therapy in the forms of prednisone, prednisolone and dexamethasone has been used to prevent both pre-implantation pregnancy failure and post-implantation pregnancy loss. Steroids are routinely administered in many IVF programs. These medications are started prior to initiating ovarian stimulation with gonadotropins and continued until the diagnosis of pregnancy. If the pregnancy test is negative, the dosage is tapered off over the next week and then discontinued. If the pregnancy test is positive, treatment is continued until 8 to 12 weeks of gestation. Steroids are believed to act by inhibiting the cellular immune response. The exact mechanism and the degree to which implantation is enhanced by the use of steroids are not known. Dosages of steroids for treatment of pre-implantation failure vary depending on the preparation. A typical regimen is dexamethasone 0.5mg a day.
Historically, repeat pregnancy loss associated with antiphospholipid antibodies was treated with combinations of prednisone and aspirin. The rationale for prednisone therapy is suppression of autoantibodies such as antiphospholipid and antinuclear antibodies. A study comparing live birth rates in women treated with heparin and aspirin with prednisone and aspirin showed 75% live births in both groups. However, both maternal complications and preterm delivery with premature rupture of membranes and toxemia of pregnancy were significantly higher in pregnant women treated with prednisone and aspirin compared with heparin and aspirin. Other side effects of steroid medication include fluid retention, weight gain, and mood changes. Therefore, the current recommendation for “first attempt” treatment for repeat pregnancy loss associated with antiphospholipid antibodies is heparin and aspirin.
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