Promoting successful PREGNANCIES
Immunomodulation may hold the key in fighting recurrent spontaneous abortions
A familiar saying in obstetrics is that a woman in labor has one foot in the grave--and that it is the health-care professional's duty to keep that foot out of it. The 2004 World Health Report says that one out of every 500 Filipino mothers dies during childbirth.
But it is not only the mother who constantly faces the risk of death; infant mortality remains a serious problem in many developing countries. In the Philippines, one of every 30 live births results in death.
Still, there is also the problem of pregnancy loss. Whether because of preterm delivery, premature rupture of membranes, preeclampsia, or recurrent spontaneous abortion (RSA), a pregnancy out of every five has been documented to result in a miscarriage. Meanwhile, RSA (three or more consecutive pregnancy losses) affects about one percent of all women.
What specialists find especially confounding about pregnancy loss is that in many instances, the etiology is unknown. The usual culprits are chromosomal, hormonal, or structural (viz., uterine abnormalities) problems, among others--but they can only be blamed for about 40 percent of all miscarriages.
In the past few decades the "unexplained" causes of RSA have brought researchers to look into cellular and humoral immunologic factors, starting with studies on antiphospholipid antibodies. However, these can only be associated with three to five percent of RSAs. The more "exciting" focus of research in recent years has been cytokine-mediated pregnancy losses, specifically those related to levels of Th1 and Th2 cytokines.
The challenge of implantation
Through histolytic action, the blastocyst that forms approximately four days from intercourse penetrates the endometrium. The succeeding syncytiotrophoblastic penetration establishes fetomaternal circulation. The blastocyst then leads the mother to release the early-pregnancy factor (EPF), platelet-activating factor (PAF), pregnancy-associated plasma protein, and endometrial proteins to maintain the pregnancy.
Echoing the highlights of a session during the 2002 World Congress on Gynecological Endocrinology, Dr. Susan Nagtalon of the University of the East-Ramon Magsaysay Memorial Medical Center said in a symposium: "For a pregnancy to be successful, there is a need for maternal tolerance to the paternal or fetal antigens. The recognition of the pregnancy of the mother will incite an immunologic reaction in favor of the existence of the fetus in utero."
The trophoblast (which surrounds the blastocyst) helps suppress maternal B-cell and T-cell responses. Trophoblast antigen HLA-G and trophoblast lymphocyte cross-reactive antigens are likewise manifested--with the HLA antigen preventing the natural killer cells from attacking the cytotrophoblast, and lymphocyte cross-reactive antigens helping induce immunologic blocking factors. In abnormal or abortogenic environments, there is little to no production of the trophoblast antigen when the fetus is introduced.
The role of cytokines
Cytokines, aside from being involved in developing humoral and cell-mediated responses, are also involved in cell proliferation, differentiation, and apoptosis; hematopoiesis and wound healing; and the mediation of immune responses.
Type-1 responses (Th1) help induce strong cellular-mediated immune (CMI) responses, while also affecting humoral immune (HI) responses. These responses are seen in cytotoxicity, fighting intracellular pathogens, graft rejection, and delayed-type hypersensitivity. Type-2 responses (Th2), meanwhile, induce strong HI responses while suppressing CMII responses, and respond against extracellular pathogens, as well as mediate allergic and antibody responses. These two responses, obviously, are mutually inhibitory.
Dr. Raj Raghupathy, professor of immunology at the Kuwait University Faculty of Medicine, pointed out recently that there had been anecdotal evidence showing the possible role of Type-2 reactivity in normal pregnancy as seen in some animal and human models. This, he explained, manifests as a downregulation of CMI response while enhancing HI response.
And since Th1 responses are associated with such conditions as allograft rejection, Raghupathy said: "Th1 reactivity was proposed to be antagonistic to successful pregnancy." For instance, TNF alpha, IFN gamma, and IL-2--all involved in mediating Th1 responses--have been shown to induce abortions in rodent models. Similarly, a high expression of IFN gamma and IL-2 has been noticed in women with unexplained recurrent abortions.
This led Raghupathy and his colleagues to investigate the role levels of Th1 and Th2 cytokines play in normal pregnancies and in recurrent abortions. After taking lymphocyte samples from both groups and stimulating them to measure cytokine production, it emerged that recurrent abortions were associated with Th1 reactivity, while successful pregnancies were more closely linked to Th2 stimulation. He added: "Several labs across the world have consistently shown, by a variety of approaches, that normal successful pregnancies seem to be associated with the Th2-type response."
Therefore, the challenge was to try to shift the maternal immune response away from the Th1 type and toward the Th2 type--and thus lead to a successful pregnancy.
Shifting to Th2-type response
Investigators have tried to look for "natural molecules" that could have an effect in modulating the immune response during pregnancy. One of the more widely studied is progesterone. Said Prof. Julia Szekeres-Bartho of the University of Hungary: "It is well known that in most mammalian species, progesterone is indispensable for the maintenance of gestation." As pregnancy progresses, the percentage of progesterone-receptor-positive cells increases; in the peripheral blood of those at risk of premature pregnancy termination, meanwhile, the percentage of these cells is much lower than in that of healthy pregnant women. This then led to studies involving dydrogesterone (Duphaston).
Dydrogesterone is an orally active progestogen that is similar in structure and in pharmacological effect to endogenous progesterone. This, therefore, gives it a high affinity to progesterone receptors.
A 2001 study spearheaded by Prof. Mazen Youself El-Zibdeh of the Islamic Hospital in Amman, Jordan, investigated the possible role of dydrogesterone in improving the outcome of pregnancy in those with RSA. A total of 114 women were divided into three groups--one given 10-mg dydrogesterone twice daily; another given 5,000 IU of human chorionic gonadotropin (HCG) intramuscularly every four days; the third group received no treatment. The treatment period ran between the moment pregnancy was confirmed and the 12th week of gestation. Abortion rate was lowest in the dydrogesterone group (14.6 percent) compared with the HCG (16.6 percent) and no-treatment (20 percent) groups.
As for safety, Dr. Kamala Selvaraj of the GG Hospital Fertility Research Centre in Chennai, India, said that dydrogesterone has been shown to be neither estrogenic nor androgenic. It also does not have any anabolic effect on the fetus. Moreover, it appears to have no effect on body weight, blood pressure, or blood-clotting problems.
J. P. de Guzman
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