Dr. Carolyn Coulam is one of the world’s most renown experts in the area of Reproductive Immunology including Recurrent Pregnancy Loss. Dr. Coulam is board certified in the specialty of obstetrics and gynecology and in the subspecialty of reproductive endocrinology. Prior to joining Team RMI, Dr. Coulam graduated from the University of Utah College of Medicine in 1967 with a degree in medicine and a masters degree in biochemistry. She completed a rotating internship at Mary Hitchcock Memorial Hospital at Dartmouth College, and her residency at the Mayo Clinic, where she remained for 17 years. While on the staff of the Mayo Clinic, Dr. Coulam was chair of the Division of Reproductive Endocrinology and established the first in vitro fertilization (IVF) program at this institution, in 1983.
On the topic of this case, and others like it, Dr. Coulam had this to say…
Pregnancy loss is a distressful experience. When the losses are repetitive, it is especially devastating and can be frustrating to both the patient and physician. Successful therapy for recurrent pregnancy loss depends on being able to identify the cause and target it specifically. The two major causes for repeated pregnancy losses are defects within the pregnancy itself or problems within the uterine environment that do not allow an otherwise normal pregnancy grow properly. Chromosome analysis of the pregnancies that are lost will help to differentiate between these two major causes. Depending on maternal age, the frequency of loss of chromosomally normal pregnancies occurs in 50%-30% of abortuses. Until recently, couples losing chromosomally normal pregnancies were relegated to “go home and try again”. New research is providing more insight into the causes of the 30% to 50% heretofore unexplained pregnancy losses. These causes have been classified as anatomic, hormonal, immunologic and thrombophilic.
While anatomic abnormalities have been associated with late pregnancy losses and hormonal abnormalities have been associated with implantation failures, their roles in post-implantation early pregnancy losses have been controversial. The mechanism of the losses in post-implantation pregnancy failures seems to involve clotting off the small placental vessels so that the pregnancy “withers on the vine”. Clotting of these vessels can be caused by cytokines that are produced by immunologic cells (most notably natural killer or NK cells) within the endometrium, antiphospholipid antibodies or a genetic predisposition contributed by thrombophilia genes. Tests available to diagnose which of the above risk factors are contributing to the recurrent pregnancy losses include evaluation of NK cells with the Reproductive Immunophenotype and NK activity assay, measurement of serum concentrations of antiphospholipid antibodies as well as lupus-like anticoagulant and determination of polymorphisms or mutations in thrombophilia genes. Other test that can detect clotting as a result of an inflammatory process included the measurement of antinuclear and antithyroid antibodies as well as the embryotoxicity assay. A description of each of these tests follows:
· Antinuclear Antibodies- The presence of ANA indicates there may be an underlying autoimmune process that affects the clotting off of the placenta and can lead to early pregnancy loss.
· Antiphospholipid Antibodies- Antiphospholipid antibodies have a direct action on the blood vessel to cause clotting. About 17% of women experiencing recurrent pregnancy losses display positive antiphospholipid antibodies. Since some women do not test positive until they are pregnant or have suffered a pregnancy loss, repeat testing during early pregnancy is highly recommended when there is a history of recurrent post0implantation pregnancy loss.
· Antithyroid Antibodies- Women with thyroid antibodies face double the risk of miscarriage as women without them. Increased levels of thyroglobulin and thyroid microsomal (thyroid peroxidase) autoantibodies show a relationship in an increased miscarriage rate, and as many as 31 percent of women experiencing RSA are positive for one or both antibodies. Chances of a loss in the first trimester of pregnancy increase to 20 percent, and there is also an increased risk of post-partum thyroid dysfunction.
· Embryotoxicity Assay- The embryotoxicity assay (ETA) is looking measures substances in blood that kill embryos. Embryotoxic factors have been identified in as many as 60 percent of women with recurrent, unexplained miscarriage, and also reported among women endometriosis-associated infertility.
- Lupus-like Anticoagulant- About four percent of women with recurrent miscarriage test positive for lupus-like anticoagulant, and nine percent of individuals diagnosed with SLE have a positive lupus anticoagulant test, or activated partial thromboplastin time (APTT). APTT is an adequate screening test for lupus-like anticoagulant antibodies, but there is a high incidence of false positives. Women who have a positive APTT should also have more specific tests, such as Kaolin clotting time, Russel viper venom assay and the platelet neutralization assay a to confirm the presence of lupus anticoagulant antibody activity.
- Natural Killer Activity- Natural Killer cell activity or activation assay (NKa) measures the killing activity (cytotoxicity) within each cell. Increased killing activity is associated with implantation failure and pregnancy loss. A value of greater than 10% killing with a target to effector ratio of 1:50 is considered abnormal. The NKa also measures the ability of IVIg and intralipid to suppress the killing activity. Patients with high NK cell activity that suppress with IVIg or intralipid in the NKa will respond very well to treatment
- Reproductive Immunophenotype- White blood cells that belong to the innate or primitive immune system kill anything perceived as foreign. Some types of NK cells produce a substance called tumor necrosis factor (TNF), which might be described as your body's version of chemotherapy, and is toxic to a developing fetus. Patients who have high levels of these cells are at risk for implantation failure and miscarriage. The proportion of NK cells is determined by a reproductive immunophenotype (RIP) test, which looks for cells that have the CD56+ marker. An NK (CD56+) cell range above 12 percent is abnormal.
- Thrombophilia Panel - A number of genes involved in blood clotting have been shown to be associated with abnormal clotting and a history of thrombosis. Deficiencies of antithrombin III, protein S or C are usually associated with a previous history of blood clots or thromboses. Other gene mutations or “changes” are not associated with such a high risk of blood clots, but are associated with recurrent pregnancy loss. These include Factor V von Leiden, Factor II Prothrombin, Fibrinogen, Factor XIII), fibrinolysis (PAI-1) and thrombosis (Human Platelet Antigen-1, Methylenetetrahydrofolate reductase gene mutations. All of these mutations have been associated more with second and third trimester loss than first trimester loss. However, it appears the more mutations you have, the higher the risk for early pregnancy loss. In one study, about 8 percent of women with a history of recurrent miscarriage had combined thrombophilic defects compared with 1 percent of controls.
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) or Intralipid. 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 may be added to the treatment regimen. If the cause of the recurrent pregnancy loss resides within the uterine environment and if that cause cannot be corrected as was the case in the recent newspaper article, then a host uterus may be a final solution for treatment. In this particular situation, the grandmother was physically and emotionally fit and did an unquestionably loving and generous deed for her daughter.