Recurrent miscarriage and embryonic loss

Jerome H. Check

Professor Obstetrics and Gynecology, Division Head of Reproductive Endocrinology & Infertility, Robert Wood Johnson Medical School at Camden, 7447 Old York Road, Melrose Park, PA 19027, USA

Email: laurie{at}ccivf.com

Sir,

I read with interest the publication by Morikawa et al. (2004)Go concluding that women with a history of recurrent miscarriages are more likely to have an embryonic loss rather than a fetal loss when compared to control patients without such a history who subsequently abort. In their discussion they imply that since this difference in loss pattern occurs especially in the recurrent miscarriage group where chromosome analysis of the fetal products of the last miscarriage was normal, there may be some condition that may be remedial so that early institution of some treatment may prevent a subsequent miscarriage. As an example they refer to a previous publication from their group showing the benefits of high-dose immunoglobulin therapy (Morikawa et al., 2001Go).

There are data suggesting that the production of an immunomodulatory protein expressed by {gamma}/{delta} T cells can inhibit natural killer cell cytolytic activity and cause a shift from TH1 to TH2 cytokines (Szekeres-Bartho et al. 1989aGo, 1996Go). The production of this immunomodulatory protein requires the de novo induction of progesterone receptors in the gamma/delta T cells by an allogeneic stimulus and requires the interaction of a high concentration of progesterone with these receptors (Szekeres-Bartho et al., 1989bGo). The protein has been termed the progesterone induced blocking factor (PIBF) (Szekeres-Bartho et al., 1985Go).

Low levels of PIBF expression have been found in pathological pregnancies compared to healthy normal pregnancies (Szekeres-Bartho et al., 1995Go). We found, however, that in progesterone-treated women there was no difference in PIBF expression in those who abort versus non-aborters (Check et al., 1997aGo). The possibility exists therefore that women with recurrent miscarriage may have a need for a greater amount of progesterone to stimulate sufficient PIBF to suppress immune rejection. Progesterone therapy has been demonstrated to reduce the frequency of miscarriage (Check et al., 1987Go). Possibly progesterone therapy may be one method to allow pregnancies to progress from the embryo to fetal stage in women with recurrent miscarriages. To test this hypothesis, we evaluated the percentage of embryonic losses compared to fetal losses in women undregoing IVF who had an isolated sporadic miscarriage compared to women with recurrent losses. Both groups were supplemented with progesterone. The percentage of embryonic losses in 104 women with recurrent miscarriages was 30.8 versus 31.0% in women with sporadic miscarriages.

Morikawa et al. (2004)Go suggested that possibly high-dose immunoglobulin therapy may be one treatment that could inhibit early embryonic losses. However, progesterone therapy seems to completely reverse the embryo loss pattern in women with recurrent miscarriages. I am curious to know what was the percentage of embryonic loss in the small number of patients that the authors treated with immunoglobulin therapy? Even if this therapy was effective, progesterone therapy is a lot less expensive.

Theoretically, in some instances the fetal semi-allograft may prove insufficient to induce progesterone receptors in {gamma}/{delta} T cells (if one uses the proposed model) and a more potent immune stimulus may be needed in addition to progesterone treatment (Check et al., 1995Go, 1997bGo). However, it may be that the majority of patients with recurrent miscarriage just need extra progesterone at least to progress from the embryo to the fetus stage.

References

Check JH, Chase JS, Nowroozi K, Wu CH and Adelson HG (1987) Progesterone therapy to decrease first-trimester spontaneous abortions in previous aborters. Int J Fertil 32, 192–199.[ISI][Medline]

Check JH, Tarquini P, Gandy P and Lauer C (1995) A randomized study comparing the efficacy of reducing the spontaneous abortion rate following lymphocyte immunotherapy and progesterone treatment versus progesterone alone in primary habitual aborters. Gynecol Obstet Invest 39, 257–261.[ISI][Medline]

Check JH, Ostrzenski A and Klimek R (1997a) Expression of an immunomodulatory protein known as progesterone induced blocking factor (PIBF) does not correlate with first trimester spontaneous abortions in progesterone supplemented women. Am J Reprod Immunol 37, 330–334.[ISI][Medline]

Check JH, Arwitz M, Gross J, Peymer M and Szekeres-Bartho J (1997b) Lymphocyte immunotherapy (LI) increases serum levels of progesterone induced blocking factor (PIBF). Am J Reprod Immunol 37, 17–20.[ISI][Medline]

Morikawa M, Yamada H, Kato EH, Shimada S, Kishi T, Yamada T, Kobashi G and Fujimoto S (2001) Massive intravenous immunoglobulin treatment in women with four or more recurrent spontaneous abortions of unexplained etiology: down-regulation of NK cell activity and subsets. Am J Reprod Immunol 46, 399–404.[CrossRef][ISI][Medline]

Morikawa M, Yamada H, Kato EH, Shimada S, Yamada T and Minakami H (2004) Embryo loss pattern is predominant in miscarriages with normal chromosome karyotype among women with repeated miscarriage. Hum Reprod 19, 2644–2647.[Abstract/Free Full Text]

Szekeres-Bartho J, Kilar F, Falkay G, Csernus V, Torok A and Pacsa AS (1985) Progesterone-treated lymphocytes of healthy pregnant women release a factor inhibiting cytotoxicity and prostaglandin synthesis. Am J Reprod Immunol Microbiol 9, 15–18.[Medline]

Szekeres-Bartho J, Autran B, Debre P, Andreu G, Denver L and Chaouat G (1989a) Immunoregulatory effects of a suppressor factor from healthy pregnant women's lymphocytes after progesterone induction. Cell Immunol 122, 281–294.[CrossRef][ISI][Medline]

Szekeres-Bartho J, Csernus V and Hadnagy J (1989b) The blocking effect of progesterone on lympchotye responsiveness is receptor-mediated. Biol Immunol Reprod 15, 36.

Szekeres-Bartho J, Faust Zs and Varga P (1995) The expression of a progesterone-induced immunomodulatory protein in pregnancy lymphocytes. Am J Reprod Immunol 34, 342–348.[ISI][Medline]

Szekeres-Bartho J, Faust Zs, Varga P, Szereday L and Kelemen K (1996) The immunological pregnancy protective effect of progesterone is manifested via controlling cytokine production. Am J Reprod Immunol 35, 348–351.[ISI][Medline]

Submitted on January 28, 2005; accepted on February 25, 2005.





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