Julia Szekeres-Bartho
Hungary

Fifty per cent of fetally derived antigens are of paternal origin. There is ample evidence now that pregnancy is recognized by the immune system, furthermore, the maternal immune system might not only recognize pregnancy, but react in a differential way resulting in success or failure.

The immunological relationship between the mother and the fetus is bi-directional, determined - on one hand - by fetal antigen presentation and on the other hand - by recognition and reaction to these antigens by the maternal immune system. Progesterone is a hormone endowed with immunological properties and is essential for the maintenance of pregnancy in humans. Due to chronic allogeneic stimulation by fetal antigens, lymphocytes of pregnant women develop progesterone receptors (PRs). The regulation of lymphocyte PR expression is hormone-independent, and is related to lymphocyte activation. The percentage of PR positive lymphocytes increases throughout gestation. Recurrent abortion, spontaneous abortion and pre-term labour are associated with a decreased number of PR positive cells. The immunologic effects of progesterone are mediated by a 34 kDa protein, named the progesterone Induced Blocking Factor (PIBF). PIBF affects various phases of the immune response, inhibits the release of arachidonic acid and exerts an anti-abortive effect in mice. The immunological effects of progesterone are mediated by cytokines. Pregnancy is a Th2 like phenomenon. Immunoglobulin synthesis in pregnant women is increased, whereas cell mediated responses are decreased. PIBF induces a significant increase in production of Th2 type cytokines, thus it might stimulate antibody synthesis by B cells. There is a population of antibodies which owing to the presence of a mannose rich oligosaccharide residue on one of the Fab arms'of the molecule, posses an asymmetric structure. Due to the asymmetric structure these molecules do not exert effector functions, thus prevent cytotoxic responses to fetal antigens. We found a positive relationship between asymmetric antibody content of pregnancy sera and PIBF expression on lymphocytes of the same women. Blocking of progesterone receptors by RU486, or neutralising endogenous PIBF activity by specific antibody significantly reduces the production of asymmetric antibodies in pregnant mice.

In vitro data in the human system suggest a correlation between the rate of progesterone receptor expression and the success or failure of pregnancy, but provide no direct evidence for their role in maintaining normal gestation. To test the biological significance of our findings, we used animal systems. These in vivo studies revealed that: a) The anti-abortive effect of the PIBF in vivo is manifested via blocking the NK activity: b) A proper stimulation of the maternal immune system is required for the operation of the progesterone-dependent immunomodulatory pathway: c) Neutralization of endogenous PIBF results in pregnancy termination. These data allow the conclusion that the operation of progesterone-dependent immunomodulation is indispensable for the maintenance of normal gestation in mice.

R. Raghupathy and M. Makhseed
Department of Microbiology and  Department of Obstetrics & Gynecology, Faculty of Medicine, Kuwait University, Kuwait

One of the common forms of pregnancy failure in humans is recurrent spontaneous abortion (RSA), but the etiology of up to 60% of recurrent abortions is unknown. Recent years have seen a resurgence of interest in investigating possible cellular immunological effectors of pregnancy loss, and this is partly due to the demonstration that Type 1 or Th 1 type cytokines are injurious to the conceptus and that maternal Type 1 reactivity is generally harmful to murine pregnancy. Successful pregnancy, on the other hand, is biased towards dominance of maternal Type 2 or Th 2 type reactivity. In human pregnancy a strong bias towards Type 2 maternal reactivity has been demonstrated in normal pregnancy.

We have examined unexplained RSA from the perspective of Type 1 and Type 2 cytokines; we investigated the in vitro reactivity of maternal peripheral blood mononuclear cells to (1) a mitogen, (2) autologous placental antigens and (3) trophoblast antigens in women with a history of successful pregnancy and in recurrent aborters.

We find significant differences between normal pregnant women and recurrent aborters, in the levels of cytokines produced by stimulated maternal PBMC. Women with normal pregnancy manifest a higher Type 2 bias, while women with a history of RSA evince a bias towards Type 1 reactivity. We have also demonstrated that recurrent aborters who had yet another abortion have a stronger Type 1-bias as compared to recurrent aborters who went on to have a successful pregnancy. Ratios of Type 1 to Type 2 cytokines are higher in the unexplained pregnancy failure group as compared to the normal pregnancy group. While our studies do not prove a direct cause-and-effect relationship between Type 1 reactivity and pregnancy loss, a strong argument can be made for this, based on the correlation between Type 1 cytokines and RSA and the demonstrated deleterious effects of Type 1 cytokines on the conceptus and on pregnancy. Thus, observations in our laboratory and a few other laboratories indicate that a strong Type 1 reactivity may be antagonistic to pregnancy; besides RSA, a type 1 bias has also been demonstrated in preterm labour, pre-eclampsia and premature rupture of membranes.

Based on these observations, it is interesting to speculate that modalities that suppress Type 1 cytokine bias and redirect maternal reactivity away from a Type 1 predominance may be effective in preventing pregnancy failure. There are suggestions that progesterone may facilitate this redirection of Type 1 responses. Progesterone has been shown to favour the development of Type 2 responses in vitro and has also been shown to reduce the production of Type 1 cytokines by lymphocytes from women with a history of RSA. How progesterone brings about this redirection and its potential therapeutic benefits for recurrent aborters is an extremely interesting and important field of study.

Background: The possible etiological causes of recurrent pregnancy loss (RPL) are numerous and include chromosomal abnormalities of the fetus, infectious etiologies or maternal endocrinologic or anatomic comorbidities. But still, in 40 - 50% of patients with RPL no clinical or laboratory causes can be identified. Recently, a growing body of evidence has been accumulating that an inadequate immune response from the mother may be responsible for a substantial part of these cases and that endogenous progesterone may play a significant role in establishing an adequate immune response during the early stages of pregnancy.

Objective: In this study it was evaluated whether the therapy with dydrogesterone or hCG in early pregnancy will improve the pregnancy outcome in women with recurrent abortions in comparison to no treatment.

Material and Methods: 114 women with history of unexplained recurrent spontaneous abortion were included in this randomized prospective trial. All were under the age of 35 years and had on average 3.3 previous abortions. They were randomly divided into three groups according to the day of the week they attended the clinic. 48 were given dydrogesterone therapy (10 mg dydrogesterone bid per mouth), 36 patients were given hCG (5000 I.U. i.m. every 4 days), and 30 patients did not receive any treatment. Treatment started as early as possible or soon after pregnancy was confirmed and was continued until the 12th gestational week. All patients were given the same instructions regarding bed rest and exercise.

Results: The pregnancy success rate, in terms of viable deliveries was 85.4% in women treated with dydrogesterone and 81.5% in women who received hCG. Abortion occurred in 7 out of 48 women (14.6%) treated with dydrogesterone and in 6 out of 36 women (16.7%) treated with hCG.

In the study group without treatment abortion occurred in 6 out of 30 women (20%). The relative reduction in abortion rate between the dydrogesterone treated and non-treatment group was 27% (p<0.05), and that between the hCG treated and the non-treatment group was 16.6% (p < 0.05). The difference between dydrogesterone and hCG was not significant (P > 0.05).

The administration of dydrogesterone and hCG was found to be well tolerated and safe. Pregnancy complications and congenital abnormalities were similar in the three groups (p> 0.05).

Conclusion: Hormonal imbalance has been recognized as a cause of recurrent abortion. Corpus luteal support with dydrogesterone or with hCG has shown to significantly reduce the incidence of recurrent pregnancy loss. The treatment with dydrogesterone and that with hCG was well tolerated and safe. Future studies will have to show as to what extent a progesterone mediated immunomodulation was responsible for the improved clinical outcome.