Background Information The current standard work-up for recurrent pregnancy loss only identifies a cause for the problem in 50% of cases. Autoimmune phenomena are currently a leading focus for research into the etiologies of recurrent pregnancy loss. Antibodies are substances produced by the immune system to fight off foreign organisms (such as bacteria) which enter our body. Current immunological thinking assumes that antibody production is also directed toward certain unique regions of the healthy human being. However, this later process is closely regulated in order to prevent damage to vital organs. In some people, these autoantibodies that are generated lack the proper regulatory control and they begin to attack specific parts of their host. The three molecules solely found in the thyroid gland include: thyroglobulin, thyroid peroxidase (previously known as "microsomal antigen"), and the TSH receptor. Thyroglobulin is the protein backbone upon which the thyroid hormones are synthesized. Thyroid peroxidase is an enzyme which helps form T3 and T4 (thyroid hormones). These unique regions seem to generate autoantibodies in certain disease states such as Gravesí disease and Hashimotoís thyroiditis. Whether they are the primary cause for pathology or secondary determinants of chronicity and/or markers of disease exacerbation is unclear at this time. It has been shown that high titers of these autoantibodies are indicative of thyroid injury or lymphocytic infiltration. The presence of antithyroid antibodies in patients without clinical evidence of thyroid dysfunction (i.e. euthyroid) and their link to recurrent pregnancy loss has been discussed in the medical literature since 1990. Anti-thyroglobulin (anti-TG) and anti-thyroid peroxidase (anti-TPO) antibodies have been the two main antibodies associated with recurrent pregnancy loss. The generation of these autoantibodies may be a marker for pregnancy loss either due to: 1) failure of the immunoprotection necessary for normal pregnancy maintenance 2)or immune system hyperfunctioning Review of the Medical Literature Stagnaro-Green et al. 1,2 evaluated 545 (low risk) pregnancies in the first trimester. Women who had thyroid antibodies present in the first trimester had twice the miscarriage rate of women who were thyroid autoantibody negative (17% versus 8%). All women were without a previous history of pregnancy loss. All were euthyroid. The authors also noted that the population with positive antibodies exhibited a decrease in antibody titer during ongoing pregnancy, with a nadir in the 3rd trimester and a postpartum rebound. Giloner et al. 3 evaluated 45 women with thyroid autoantibodies versus 605 controls. A statistically significant increased rate of fetal loss was found in the study group versus controls. Again the authors found that antithyroid antibody titers decreased by more than 50% during gestation such that normalized thyroid peroxidase antibody levels were observed in half of the patients at delivery. More recently, Pratt et al. 4 evaluated the incidence of thyroid autoantibodies in women with recurrent pregnancy loss (defined as 3 or more miscarriages). The incidence of antibodies in the study group (45 patients) versus control (100 patients) was not significantly different. In a follow-up study, Pratt et al. 5 reviewed the association of thyroid autoantibodies in euthyroid nonpregnant women with recurrent first trimester abortion in the next pregnancy. 42 women with a history of 3 or more losses in the first trimester were evaluated; "obvious" causes for miscarriage were ruled out. The uncontrolled study found the presence of antithyroid antibodies had a positive predictive value of 61.5% for recurrent miscarriage, and more importantly a negative predictive value of 86.2%, with a specificity of 83.3%. Who should be tested for the presence of Antithyroid Autoantibodies ? In general,women who have a history of 2 or more pregnancy losses in the first trimester (less than 12 weeks gestation), with an otherwise negative routine work-up for the etiologies of recurrent pregnancy loss, may be offered testing. The standard workup should be discussed with your physician, however, this generally includes evaluation for: genetic causes, anatomic diseases of the reproductive tract, and maternal diseases (including luteal phase deficiency). Studies have shown that even after 3 successive miscarriages of unknown etiology, the risk of subsequent loss is about 30%-35%. Therefore, success rate of viable pregnancy outcome approaches 60%-70% without any treatment in patients with unexplained recurrent pregnancy loss. What is the treatment for Recurrent Pregnancy Loss associated with Antithyroid Autoantibodies ? Prednisone can decrease antibody titers, therefore it may decrease the concentration of antithyroid autoantibodies. Prenidsone is a corticosteroid type of medication. No studies have evaluated the efficacy of treatment of antithyroid autoantibody-associated pregnancy loss. However, it is common practice to prescribe this medicine due to its limited risks and our past experience with its use in treating women with antiphospholipid antibodies and associated pregnancy loss. Women with the following underlying medical problems should take special precautions if steroid medication is to be given for this problem: - h/o Peptic Ulcer Disease - Chronic hypertension - Immunocompromise - Osteoporosis - Rheumatologic disorders - Positive PPD - Diabetes Mellitus - Active Psychological Disorders - Liver Cirrhosis - Renal Insufficiency - Myasthenia Gravis - h/o of Malignant Neoplasia of any kind - Patients on the following medications: rifampin, phenytoin, and phenobarbital What are the risks of treatment ? The risks of prednisone exposure to the mother in the dosages used are minimal. A list of the potential complications follows: 1- Drug-induced secondary adrenocortical insufficiency may occur. 2- Fluid and electrolyte disturbances may occur in susceptible individuals. 3- Osteoporosis leading to vertebral collapse has also been described with chronic steroid administration at higher doses and for greater lengths of time than normally used for this problem 4- Psychogenic derangements may occur in response to corticosteroids, ranging from euphoria, insomnia, mood swings, and personality changes to severe depression or frank psychotic manifestations. Also, any existing emotional instability or psychotic tendencies may be aggravated by these medications. 5- Drugs that induce hepatic enzymes, such as phenobarbital, phenytoin, and rifampin, may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. 6- Minor reversible side effects described with corticosteroid therapy include oropharyngeal candidiasis and facial acne. The risk of prednisone exposure to the fetus : In the first trimester, there are no apparent adverse effects to the developing fetus. 1- In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 to 1992, 236 newborns had been exposed to prednisone in the first trimester.6 The collected data did not support an association between prednisone and congenital defects. 2- In addition, approximately 90% of orally administered prednisone is metabolized in the placenta via the placental enzyme 11-ß steroid dehydrogenase and never reaches the fetus. References 1. Stagnaro-Green A, Roman SH, Cobin RH, El-Harazy E, Wallenstein S, Davies TF. A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction. J Clin Endocrinol Metab 1992;74:645-653. 2. Stagnaro-Green A, Roman SH, Cobin RH, El-Harazy E, Alvarez-Marfany M, Davies TF. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990;264:1422-5. 3. Glinoer D, Fernandez-Soto M, Bourdoux P, Lejeune B, Delange F, Lemone M, Kinthaert J, Robijn C, Grun JP, De Nayer P. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions. J Clin Endocrinol Metab 1991;73:421-427. 4. Pratt DE, Novotny M, Kaberlein G, Dudkiewicz A, Gleicher N. Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss. Am J Obstet Gynecol 1993;168(3):837-841. 5. Pratt DE, Kaberlein G, Dudkiewicz A, Karande V, Gleicher N. The association of antithyroid antibodies in euthyroid nonpregnant women with recurrent first trimester abortions in the next pregnancy. Fertil Steril 1993;60(6):1001-5. 6. Briggs GG, Freeman RK, Yaffe SJ(eds). Drugs in Pregnancy and Lactation, 4th edition. Williams & Wilkins. Baltimore.1994. pgs 713-716. Areas of Current Research ? A prospective study to evaluate oral prednisone treatment for recurrent pregnancy loss in the presence of antithyroid antibodies in euthyroid patients will begin at Yale University School of Medicine in the near future. Attempts will be made to expand the study to a national multicenter trial. If you have any questions regarding this protocol and wish to participate please contact me on the internet at my current mailing address: andrei.rebarber@quickmail.yale.edu Related Web Sites 1. American Thyroid Association
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