The use of combined heparin/aspirin and immunoglobulin g. therapy in the treatment of ivf patients with antithyroid antibodies


Sher Geoffrey, M.D. * ‡, Maassarani Ghanima, Dr.Med *, Zouves Christo, M.D.,Sohn Sae, M.D., Matzner William, M.D. †§||, Chong Penny, M.D. †§||and Ching Wendell, M.D. †§|| * Pacific Fertility Medical Centers of California† Harbor UCLA Medical Center‡ University of Nevada, School of Medicine§ Reproductive Immunology Associates|| Sepulveda VA Medical Center / UCLA ABSTRACTPROBLEMS: To compare the effect of Heparin Aspirin (H/A) therapy alone vs. H/A in combination with Intravenous Gammaglobulin (IVIg) immunotherapy on IVF outcome in patients who test positive for antithyroid antibodies (ATA).
METHODS: We evaluated 82 women less than 40 years of age whose infertility was exclu- sively related to female causes. All tested positive for organ-specific antithyroid antibodies(antimicrosomal and/or antithyroglobulin antibodies), but negative for antiphospholipid antibodies. Thirty-seven (37) of these women (Group A) received H/A alone, while 45 (Group B) received H/A in combination with IVIg.
RESULTS: Ten (10) or 27% of Group A and 23 (51%) of Group B women, achieved live births following completion of a single IVF/ET cycle (P=0.027).
CONCLUSIONS: We conclude that IVIg therapy significantly improves IVF success ratesin ATA+ women.
AJRI 1998: 39:223-225Copyright Munksgaard, 1998 INTRODUCTION
A relationship between antithyroid antibodies (ATA) and reproductive failure hasbeen established. In 1990, Stagnaro-Green evaluated a selected obstetric popula-tion with a prior history of poor reproductive performance, and was able to show arelationship between antithyroid antibodies and miscarriage. (1). This was subse-quently confirmed by Glinoer, et al. in 1991 (2). It was later demonstrated thatwomen who have an increased concentration of antithyroid antibodies and recur-rent pregnancy loss do not necessarily demonstrate anticardiolipin antibody (3).
Recently, Geva, et al. demonstrated that more than 20% of 78 patients undergoingIVF for mechanical or unexplained infertility tested positive for antithyroid anti-bodies, and 12% were positive for antiovarian antibodies. Of note, is the fact thatall patients in that study were clinically euthyroid with no history of having beenmedicated for hypothyroidism (4). This data suggest that antithyroid antibodiesmay be independent markers for reproductive failure.
It has been suggested that the existence of antithyroid antibodies, before or duringearly pregnancy may reflect activated T cell function, which in turn may be relatedto TH1 lymphocytes (3,5).
In designing this study, we wished to examine the efficacy of only one variable (the use of IVIg) on outcome in IVF patients who demon- stopping solution was added, and the absorbance read at strated thyroid antibodies. Because of the recent contro- 450 nm, using 550 nm as a reference wavelength. The pub- versy over the use of aspirin and heparin in patients under- lished relative sensitivity for this assay is 96.8%, and the going IVF (8, 9), we elected to treat all patients with aspirin and heparin, thereby eliminating the potential that this vari-able could have an impact on outcome results when study- ing the effects of IVIg on these patients.
The number of babies born per transferred embryo, wasdetermined in order to provide a measure of the viable im- MATERIALS AND METHODS
plantation rate. Multiple births and miscarriages were docu-mented. A successful IVF outcome was defined as a live A prospective study was undertaken to evaluate whetherreatment with Heparin/Aspirin alone versus combined H/ A + IVIg would influence IVF success rates.
Data was placed into two – by – two Tables: And analysisbetween and within groups was performed using the Chi Eighty two (82) women < 40 years of age, who tested posi- Squared Test for significance. P values below 0.05 were tive for ATA, but negative for antiphospholipid antibodies considered to indicate statistical significance. Analysis was (APA) were randomly placed into two groups in a non-dis- performed using the CHITEST and CHIINV functions for criminating quasi alternating fashion. Cases of male infer- tility, ovum donation, and gestational surrogacy were ex-cluded. Group A comprised 37 women who received H/A alone while Group B consisted of 45 women who receivedH/A in combination with intravenous immunoglobulin G(IVIg – Gammimune, Bayer Biological or Venoglobulin, Table I compares Groups A&B with regard to demographic Alpha Therapeutic Corp) 7-14 days prior to embryo trans- characteristics and IVF outcome. The IVF birthrate per embryo transferred was significantly greater for Group Bthan Group A [23/45 (51%) vs. 10/37 (27%)] p=0.027. There Patients who had abnormally low plasma levels of IgA wereconsidered to be at risk for the development of anaphylaxis Table I: A Comparison of the Influence of Heparin/Aspirin and were selectively medicated with antihistamines and (H/A) Alone versus Combined H/A and Intravenous Immu-noglobulin G (IVIg) Therapy on IVF Outcome in 82 Women corticosteroids prior to and during the 2-3 hour IVIg infu- Who Tested Negative for Antiphospholipid Antibodies (APA- sion. A second infusion of IVIg was given upon the chemi- ) and Positive for Organ Specific Antithyroid Antibodies cal diagnosis of pregnancy through quantitative serum HCG measurement and a final IVIg infusion was performed uponultrasound confirmation of a viable pregnancy (between the 6th and 7th gestational week). All patients underwent con- trolled ovarian hyperstimulation (COH) using premenstru-ally administered gonadotropin releasing hormone agonist (lupron-Tapp pharmaceuticals), followed by menotropin therapy, as previously described (7). The measurement of APA’s was performed as previously described by Matzner, Antithyroid antibody positivity (ATA+) was defined by the detection of antithyroglobulin and/or antimicrosomal anti- bodies as measured by the QUANTA Lite Thyroid T andThyroid M ELISA assay from INOVA Diagnostics (San Diego, CA). Briefly, 100 microliters of prediluted controls or diluted samples were added to the microwell plates (which were coated with thyroglobulin or microsomal antigen at the factory), and incubated at room temperature for 30 min- utes. The plates were washed in a wash buffer three times,and 100 microliters of HRP Conjugate was added to each * Significant Difference: p = 0.027, chi = 4.8975 well. The plates were then incubated for another 30 min-utes. The plates were again washed three time,s and 100 microliters of TMB Chromogen was added to the wells, and incubated for 30 minutes. At that time, 100 microliters of were no significant differences in the other demographic characteristics noted in Table I. It is notable that 6 (17%)of the 37 women in Group A and 9 (20%) in Group B had Treatment of antithyroid antibody-positive patients with clinical evidence of hypothyroidism.
IVIg significantly improved IVF outcome.
It has long been recognized that women who test positive 1. Stagnaro-Green A, Roman SH, Cohen RH, et al. Detection of for organ specific anti-thyroid antibodies have a high inci- at risk pregnancy by means of a highly sensitive assay for thyroidautoantibodies. Am Med Assoc 1990; 264, 1422-1425 dence of reproductive failure, as evidenced by recurrent 2. Glinoer D, Soto MF, Bordoux P, et al Pregnancy in patients miscarriages and a relatively low pregnancy rate following with mild thyroid abnormalities, maternal and neonatal repercus- advanced fertility treatment (1-4). This also explains the high sions. J Clin Endomcrinal Metab, 1991; 73, 421-427.
IVF failure rate in patients who test positive for organ spe- 3. Pratt DE, Kahavlein G, Dudkiewicz A, et al. The association of cific antithyroid antibodies. In fact, it may be appropriate antithyroid antibodies in euthyroid non-pregnant women with re- to consider such IVF failures as being due to Failed Preg- current first trimester abortions in the next pregnancy. Fertil Steril nancy Recognition (FPR) rather than to poor egg or embryo quality. The distinction between IVF failures due to FPR 4. Geva E, Ammit A, Lerner-Geva L, Azem F, Yovel I , Lessing and those attributable to embryo or gamete insufficiency is JB. Autoimmune disorders: another possible cause for in vitrofertilization and embryo transfer failure. Human Reprod, 1995; important because failure to implant carries with it the im- plication that subsequent placental reserve may be compro- 5. Stagnaro-Green A, Roman SH, Cohen RH, et al. A prospective mised, thereby impacting fetal well being and potentially study of lymphocyte-initiated immuno-supression in normal preg- nancy: Evidence of a T-Cell etiology for post partum thyroid dys-function. J Clin Endocrinol Metab 1992; 74, 645-653.
It is possible that ATA’s, like APA’s directly compromise 6. Sher G, Herbert C, Maassarani G ,Jacobs MH Assessment of trophoblastic development. However, it has been suggested the late proliferative phase endometruim by ultrasonography in that the relationship may be indirect in that the presence of patients undergoing in-vitro fertilization and embryo transfer (IVF/ such antibodies may simply represent a marker for increased ET).Hum Reprod. 1991; 6, 232-237.
7. Sher G, Feinman M, Zouves C, Kuttner G, Maassarani G, Sa- T-Cell activation and toxic cytokine production by lem R, Matzner W, Ching W Chong P. High fecundity rates fol- lowing in-vitro fertilization and embryo transfer in antiphospholipidantibody seropositive women treated with heparin and aspirin.
The anti-idiotype antibodies contained in IVIg, by neutral- izing ATA’s, might mitigate the toxic effects of cytokines.
8. Matzner W, Chong P, Xu G, Ching W. Characterization of Likewise, heparin and aspirin, through antithrombotic and antiphospholipid antibodies in women with recurrent spontane- anticoagulant properties, might prevent vascular thrombo- ous abortions. J Reprod Med. 1994; 39, 27-30.
sis in the choriodecidual vasculature, and promote healthy 9. Denis, A, et. al. Antiphospholipid antibodies and pregnancy rates and outcome in in vitro fertilization patients. Fertil Steril.
Whatever the pathophysiology or mechanism by which theseimmunotherapies operate, it is clear from the results in thisstudy, that IVF patients who test positive for organ specificantithyroid antibodies experience significantly improvedIVF outcomes, when H/A and IVIg are administered priorto egg retrieval.
We cannot say that ATA+ women would or would not ben-efit from aspirin/heparin alone. Further studies are neededto look at outcome using IVIg without aspirin/heparin. Inthis study, aspirin/heparin was deliberately administered toall patients to mitigate the effect that that therapy might haveon outcome while testing the effectiveness of IVIg in ATA+patients., Nevertheless, based upon the data presented inTable I we conclude that: IVIg + H/A-treated ATA+ patients (Group B) had a signifi-cantly higher IVF birthrate as compared to those ATA+women who received H/A alone


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