Human Reproduction Update Advance Access originally published online on November 22, 2007
Human Reproduction Update 2008 14(1):27-35; doi:10.1093/humupd/dmm035
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Progestagen therapy for recurrent miscarriage
1 Department of Medical Microbiology and Immunology, Medical School, Pecs University, H-7643 Pecs, Hungary 2 Institut Clinic of Gynecology, Obstetrics and Neonatology, Faculty of Medicine, University of Barcelona, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/Casanova 143, 08036 Barcelona, Spain
3 Correspondence address. Department of Medical Microbiology and Immunology, Medical School, Pecs University, 12 Szigeti Street, H-7624 Pecs, Hungary. Tel: +3672-536262; Fax: +3672-536253; E-mail: julia.szekeres{at}aok.pte.hu
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Abstract |
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 TOP Abstract IntroductionLuteal phase defect and...Inadequate immunoregulation in...Progesterone treatment of RM-...GlossaryFundingReferences |
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BACKGROUND: Recurrent pregnancy loss (RM) affects 0.5–1% of couples. The pathophysiology of RM is complex. The suggested causes include anatomical, genetic and molecular abnormalities, endocrine disorders, thrombophilias and anti-phospholipid syndrome. In
50% of the cases neither of the above can be identified. We aimed at examining the evidence on the role of progesterone in the pathophysiology of RM, and the clinical evidence on effectiveness of progestogen treatment. METHODS: We searched PubMed and the Cochrane database covering the period of 1968–2007. The search terms progestogens and recurrent miscarriage, NK cells and recurrent miscarriage as well as cytokines and recurrent miscarriage were used.
RESULTS: Progesterone is indispensable for creating a suitable endometrial environment for implantation. RM may be due to subnormal progesterone secretion and retarded endometrial development in the peri-implantation period. Progesterone also acts on the immune system, mainly by affecting cytokine synthesis and the function of NK cells. A recent meta-analysis showed that though progesterone treatment did not affect pregnancy outcome in women with miscarriages in general, separate analysis of three small and dated studies including altogether 91 patients with RM revealed a small but significant effect. It is noteworthy that the design of these 40 years old studies does not meet modern requirements.
CONCLUSION: Standardized laboratory protocols for identifying potential targets of progestogen treatment as well as implementation of well-designed randomized studies are needed to establish the usefulness of progesterone supplementation in the treatment of RM.
Key words: recurrent miscarriage / progesterone / endometrial defect / decidual NK cells / cytokines
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Introduction |
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TOPAbstractIntroductionLuteal phase defect and...Inadequate immunoregulation in...Progesterone treatment of RM-...GlossaryFundingReferences |
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Definition and etiology of recurrent miscarriage
Recurrent miscarriage (RM), which is defined as three or more consecutive miscarriages before the 20th week of gestation (Mills et al., 1988
; Brigham et al., 1999; Nybo Andersen et al., 2000) affects 0.5–1% of couples. Primary RM refers to women with no prior successful pregnancy, whereas secondary RM refers to losses following a live birth.
Both fetal and maternal factors are involved in the pathophysiology of RM. Fetal underlying mechanisms include genetic or developmental abnormalities, while uterine pathology, endocrine dysfunction, anti-phospholipid syndrome and thrombophilic disorders have been identified as maternal factors.
In 50% of the cases neither of the above can be identified, however, since the frequency of normal embryonic karyotypes significantly increases with the number of previous miscarriages (Ogasawara et al., 2000), the higher the number of previous miscarriages, the more likely that the failure is due to constant maternal and not to accidentally occurring fetal factors. Concerning the underlying pathology, primary and secondary miscarriages might form two distinct categories, also suggested by their different responsiveness to therapy (Daya and Gunby and The RM Trialists Group, 1994; Christiansen et al., 2002), and although disputed the prognosis has been reported to be better for secondary than for primary recurrent aborters (Regan et al., 1989).
The prognosis of RM depends on multiple factors. The risk of recurrence increases with the number of successive losses (Risch et al., 1988; Regan et al., 1989; Knudsen et al., 1991; Nybo Andersen et al., 2000). Twenty five to thirty per cent of women with three successive pre-embryonic or embryonic losses experience miscarriage in their next pregnancy (Warburton and Fraser, 1964; FitzSimmons et al., 1983). Maternal age is also a risk factor, irrespective of reproductive history (Nybo Andersen et al., 2000).
There is increasing evidence that progesterone exhibits anti-inflammatory activities (Piccinni et al., 1998, 2000,2001), which might be beneficial in the prevention of pre-term birth (Groom, 2007) and RM. Despite our limited understanding of the pathophysiology of ‘idiopathic’ RM, progesterone supplementation has been widely used to prevent miscarriage (Li, 1998).
The rationale of this treatment is to correct putatively insufficient progesterone production, which could manifest in inappropriate endometrial development or inadequate immune response to fetal antigens. Both of these are likely to contribute to the pathogenesis of spontaneous miscarriage. The objective of this review is to examine the evidence on the role of progesterone in the pathophysiology of miscarriage, and the clinical evidence on whether it is effective.
We searched Pubmed and the Cochrane database covering the period of 19687–2007. The search terms progestogens and recurrent miscarriage, NK cells and recurrent miscarriage, cytokines and recurrent miscarriage were used.
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Luteal phase defect and inappropriate endometrial development |
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TOPAbstractIntroductionLuteal phase defect and...Inadequate immunoregulation in...Progesterone treatment of RM-...GlossaryFundingReferences |
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Endocrine background of normal endometrial development
Progesterone is indispensable for the establishment and maintenance of pregnancy. It prepares the endometrium for blastocyst implantation and controls endometrial development. The pre-ovulatory increase in the secretion of 17β-estradiol (E2) promotes the proliferation and differentiation of uterine epithelial cells. This is followed by the production of progesterone, which induces the proliferation and differentiation of stromal cells (Norwitz et al., 2001). Progesterone acts on the endometrium via specific receptors, the expression of which is controlled by estrogens. By down-regulating estrogen receptors, progesterone leads to a fall of both estrogen and progesterone receptors (Bergeron, 2000). During the luteal phase of the menstrual cycle, the corpus luteum is the only source of progesterone. If pregnancy occurs, the corpus luteum continues to produce progesterone until the trophoblast takes over.
Cyclic secretion of estrogens and progesterone triggers morphological and physiological changes of the endometrium and creates during the implantation window (5–10 days after the LH surge) (Psychoyos, 1973) a suitable endometrial environment for embryo implantation and maintenance of early pregnancy. These changes fail to develop if progesterone production is lower than normal.
RM may be associated with retarded endometrial development in the peri-implantation period, however, not all women who miscarry show the endometrial defect, and only a part of them have lower than normal plasma progesterone concentrations (Li et al., 2000).
The diagnostic value of endometrial dating
In early RM, the prevalence of delayed endometrial development was found to be significantly higher (19/60), whereas that in infertile patients (46/355) did not significantly differ from the controls (1/25) (Balasch et at., 1986; Balasch and Vanrell, 1987).
In a detailed endocrinological investigation of women with unexplained RM, only 27% of the patients had a delayed endometrial development, which was still a significantly higher prevalence than the 11% found among controls. Delayed endometrial development was associated with significantly lower plasma progesterone levels, however, there was a poor association between either delayed endometrial development or low plasma progesterone levels and RM (Li et al., 2000). These findings show that delayed endometrial development is not necessarily due to insufficient progesterone production. A randomized multicentre study involving 619 endometrial biopsies, revealed a high percentage (49.4%) of fertile women with delayed endometrial development and concluded that endometrial dating did not discriminate between fertile and infertile women (Coutifaris et al., 2004). The latter could be due to false positive LH tests (Mc Govern et al., 2004) or observer variation (Myers et al., 2004). Furthermore, the system has its inherent limitations, because though certain post-ovulatory days are characterized by distinctive histological features, the in-between features are less defined and do not allow precise dating. Thus, the diagnostic value of endometrial dating is questionable. This however does not imply that that progesterone deficiency could not—by delaying endometrial development—contribute to the pathophysiology of RM.
Progesterone deficiency and RM
Several studies reported lower than normal serum progesterone concentrations in RM patients with delayed endometrium, compared with those with normal endometrium (Daya, 1989; Babalioglu et al., 1996; Li et al., 2000), whereas others (Vanrell and Balasch, 1986) failed to detect significant differences between the two groups (Table 1).
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If plasma progesterone levels are normal, the endometrium can still be progesterone deficient due to receptor abnormalities. Li et al. (2002)
showed that in the endometrium of 25% of women with RM the spatial expression of progesterone receptors is different from that in normal controls.
Mutations of the progesterone receptor gene could also contribute to impaired reproductive function and consequently to early abortions. Schweikert et al. (2004) reported on a polymorphism within the coding sequence of the human progesterone receptor gene that occurs at a significantly higher frequency in patients with RM than in controls. An inappropriate endometrial development can thus develop on the basis or progesterone receptor defects in the presence of sufficient progesterone concentrations.
These findings support the existence of absolute or relative progesterone deficiency as a biologically significant entity in recurrent first-trimester spontaneous miscarriage. In the former cases progesterone supplementation should potentially be successful. Women suffering form relative progesterone deficiency will probably not benefit from this treatment.
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Inadequate immunoregulation in the absence of progesterone |
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TOPAbstractIntroductionLuteal phase defect and...Inadequate immunoregulation in...Progesterone treatment of RM-...GlossaryFundingReferences |
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The feto–maternal immunological relationship
Fifty per cent of fetally derived antigens are of paternal origin. The presence of anti-fetal, -placental and -paternal antibodies in sera of women with successful pregnancies clearly shows that maternal recognition of fetal antigens does not compromise pregnancy (Billington, 1992); instead, it induces functional changes that allow the fetus to survive and develop.
The immuno-modulating effects of progesterone are well established. High local concentrations of progesterone prolong the survival of xenogeneic and allogeneic skin grafts as well as of xenogeneic tumour cells implanted in hamster uteri (Moriyama and Sugava, 1972). Ovarectomized animals treated with progesterone but not with estrogen develop uterine abscesses after injection with Escherichia coli. During the luteal phase of the ovarian cycle, the immune response is shifted towards a Th2-type response (Faas et al., 2000). In a prospective study Kruse et al. (2003) found generally lower Th1/Th2 cytokine ratios in RM patients with high- than in those with low serum progesterone levels, suggesting that serum progesterone might have an influence on cytokine production. Dydrogesterone treatment of women with pre-term delivery induces a shift in cytokine bias, by inhibiting pro-inflammatory cytokine production and increasing anti-inflammatory cytokine production (Raghupathy et al., 2007).
The effect of progesterone on the immune system of pregnant women is at least in part receptor-mediated (Szekeres-Bartho et al., 1989b,1990; Roussev et al., 1993; Piccinni et al., 1995; Chiu et al., 1996; Van den Heuvel et al., 1996). Following recognition of fetal antigens, activated maternal 
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T cells express progesterone receptors (Szekeres-Bartho et al., 2001; Barakonyi et al., 2002), and upon progesterone binding under the effect of progesterone produce a mediator; named progesterone-induced blocking factor (PIBF) (Szekeres-Bartho et al., 1985,1989a; Polgar et al., 2003).
By signalling via a novel form of the IL-4 receptor (Kozma et al., 2006) this molecule induces a Th2-dominant cytokine response, by facilitating the production of IL-3, IL-4 and IL-10 (Szekeres-Bartho and Wegmann, 1996).
The effect of progesterone on maternal cytokine production
A number of studies suggest that a Th2-dominant cytokine production favours normal pregnancy, whereas an excess of Th1 cytokines leads to pregnancy termination (Wegmann et al., 1993; Raghupathy, 1997).
Women with RM have been shown to have a Thl-dominant cytokine profile (Raghupathy et al., 1999,2000; Rezaei and Dabbagh, 2002; Hossein et al., 2004; Wilson et al., 2004). Conflicting data, i.e. increased IL-4 and IL-10 production together with decreased IFN and TNF
production in RM patients were reported byBates et al. (2002).
In a prospective clinical trial, Raghupathy et al. (2005) investigated the production of Th1 and Th2 cytokines from peripheral blood lymphocytes from RM women challenged in vitro to progestrone, and showed that progestogen induces PIBF production down-regulates peripheral Thl cytokines and stimulates Th2 cytokines, resulting in shift towards Th2-type immunity. Human (Kalinka and Szekeres-Bartho, 2005) and animal (Joachim et al., 2003) studies suggest that inducing PIBF production could be the indirect mechanism by which dydrogesterone improves pregnancy outcome.
The Th1/Th2 concept of normal pregnancy stems from investigating peripheral blood lymphocyte-derived cytokines. Studies on placental cytokine production have differentiated this picture and showed at the same time that—at least in mice—Th1 cytokines are not necessarily detrimental for pregnancy development, some of them, e.g. LIF and IL-11 as well as IFN, are even necessary for implantation of the mouse blastocyst (Stewart et al., 1992; Bilinski et al., 1998; Ashkar et al., 2000).
Practically all cytokines appear in the human endometrium and in the decidua (Vince and Johnson, 1996). A growing body of evidence shows that steroid effects that control both follicular development and uterine receptivity are mediated by locally acting growth factors and cytokines. Progesterone present in the microenvironment of the decidual T cells could be responsible, at least in part, for modulating the cytokine profile (Piccinni et al., 1998, 2000, 2001). Progesterone at concentrations comparable to those present at the materno–fetal interface induce production of Th2-type cytokines, IL-4 and IL-5. Progesterone but neither 17β-E2 or hCG, or progesterone analogues (4-pregnen-20β-ol-3-one, 4-pregnen-20-ol-3-one and 5-pregnen-3β-ol-20-one) favour the development of antigen-specific T cells, into Th0 cell lines and clones capable of producing IL-4 and IL-5 in addition to IFN (Piccinni et al., 1995). Progesterone acts through receptors present on a substantial proportion of T blasts from established T-cell clones (Piccinni et al., 1995).
Two studies on endometrial cytokine expression in women with RM gave seemingly conflicting results, which can be due to the different study design and to the different methods used for cytokine detection. Lim et al. (2000) found that women with RM had higher level of Th1 cytokines mRNA in the peri-implantation endometrium than those with no history of RM. Shimada et al. (2004) reported on less IFN and TNF producing CD4+ endometrial T cells from women with RM compared with the control group. While the second study focused on a subset of T cells only, cytokines produced by all endometrial populations were considered in the first.
The effect of progesterone on maternal NK cells
Through altered cytokine production PIBF inhibits natural killer (NK) mediated killing in an indirect way (Szekeres-Bartho and Wegmann, 1996; Szekeres-Bartho et al., 1996).
NK cells play diverse and important roles during pregnancy. During the secretory phase of the menstrual cycle CD 56bright, CD16 and CD3 negative granulated NK cells appear in the endometrium, and remain there until onset of menses, or if pregnancy occurs, increase in number, to become the predominant uterine lymphocytes of early pregnancy (King et al., 1998). They secrete an array of angiogenic factors and the dynamics of their appearance suggests that one of their functions might be the control of placentation. Decidual NK cells are believed to control trophoblast invasion through the production of immunoregulatory cytokines and angiogenic factors (Hanna et al., 2006; Sargent et al., 2006). Decidual NK cells do not express progesterone receptors (Henderson et al., 2003), however, progesterone affects both the number and function of these cells in an indirect way. The rapid increase of NK cell counts in the early decidua is thought to be due to proliferation of the resident population, and/or recruitment of CD56(bright) lymphocytes from the circulation. Progesterone (together with estrogen and LH) plays a role in potential uterine homing of NK cells (Van den Heuvel et al., 2005). NK cells express chemokine receptors thus can be induced to migrate in response to several chemokines (Campbell et al., 2001). Trophoblast and placenta produce chemokines that may recruit blood NK cells into the decidua during pregnancy (Drake et al., 2001; Hanna et al., 2003). Progesterone induces CXCL10 and 11 production by endometrial cells, and NK cell migration to the endometrium is supported by these sex- hormone-induced chemokines (Sentman et al., 2004).
Hoxa-10, a developmentally regulated homeobox transcription factor is highly expressed in decidualizing stromal cells. Progesterone and, to a lesser extent, estrogen induce Hoxa-10 expression. Hoxa-10 knock-out mice show severe decidualization defects, primarily due to reduced stromal cell responsiveness to progesterone (Lim et al., 1999). Hoxa-10 deficiency interferes with NK cell differentiation without affecting the migration of NK precursors into the decidua (Rahman et al., 2006). Furthermore, gene expression profiling revealed that, at the time of implantation, Hoxa-10 mediates the progesterone-stimulated proliferation of uterine stromal cells (Yao et al., 2003).
Potential cytotoxic mechanisms exerted by NK cells can damage the trophoblast and induce ablation of placenta. In spite of their high perforin content decidual NK cells show a low spontaneous cytotoxic activity (Crncic et al., 2006). The embryonic trophoblast that forms the interface between the maternal and fetal compartments could be the site of fetal antigen presentation, and also the expected target of maternal anti-fetal effector mechanisms. Syncyctiotrophoblast and villous cytotrophoblast are devoid of HLA antigens, whereas extravillous cytotrophoblast cells do express HLA-C and the non-polymorphic molecules; HLA-G and HLA-E (Hedley et al., 1989; Kovats et al., 1990; Le Bouteiller, 1994,1996; Hammer et al., 1997; Billington, 1999).
HLA-G presents antigens and plays a role in the regulation of HLA-E expression (Le Bouteiller et al., 2003; Sala et al., 2004). HLA-G or HLA-E binding by inhibitory receptors of decidual NK cells conveys a negative signal and thus might induce resistance of the trophoblast to NK-mediated lysis (Moretta et al., 1993; Braud et al., 1998; Lee et al., 1998; Llano et al., 1998).
Another mechanism by which HLA-G expressing cells might protect themselves against immune aggression lies in inducing regulatory cells (LeMaoult et al., 2007). Furthermore, soluble HLA-G1 exerts different immunoregulatory functions via different immune targets, including T cells and dendritic cells (Hunt et al., 2005), as well as anti-angiogenic effects (Fons et al., 2006).
Recently, Yie et al. (2006) reported that progesterone up-regulates HLA-G gene expression through a novel progesterone response element. Increased expression of HLA-G—by generating regulatory cells and modulating dendritic cell T cell and NK activity—might contribute to the favourable microenvironment in the decidua. Thus one of the sites of progesterone action in promoting normal gestation is regulation of HLA-G gene expression.
RM is associated with an increased number of endometrial NK cells (Quenby et al., 1999), and decidual lymphocytes from failed pregnancies contain less perforin than those from normal pregnancy deciduas (Gulan et al., 1997), suggesting that an increased rate of degranulation takes place in the former case. Furthermore, a dominant population of TGF-β-producing NK3 type cells in normal decidua is significantly reduced in deciduas from women with RM (Higuma Myojo et al., 2005). Other studies have shown RM patients having fewer CD56-bright NK cells in the preimplantation endometrium than controls (Lachapelle et al., 1996), and patients who miscarried chromosomally normal embryos had decreased percentage of CD56+ decidual NK cells compared with those who miscarried chromosomally abnormal embryos (Yamamoto et al., 1999; Quack et al., 2001). It should however be kept in mind that the changes observed in miscarriage placentae could be due to the necrosis and inflammation following the death of the embryo, thus they might be the result, rather than the cause of miscarriage. Therefore, these findings must be interpreted with caution.
The relative ratio of two putative, functionally distinct decidual NK cell populations might thus determine the fate of the fetus, or alternatively, the loss of control due to progesterone deficiency and consequently impaired HLA-G expression might result in proliferation and activation of decidual NK cells.
In pregnant mice, neutralization of endogenous PIBF activity by specific anti-PIBF antibody causes a significant reduction in the number of viable fetuses, and this is associated with an increased splenic NK activity, together with reduced IL-10 and increased IFN production of the spleen cells (Szekeres-Bartho et al., 1997b). Ninety per cent of pregnancy loss is corrected by treatment of the pregnant animals with anti-NK antibodies (Szekeres-Bartho, 1997a). These data suggest that in mice PIBF contributes to the success of pregnancy and that the major part of its pregnancy-protective effect lies in keeping NK activity under restraint.
RM may also be associated with an adverse immune reaction to progesterone. An interesting study revealed that out of 29 women with RM, 23 and 20 showed an allergic skin reaction to estrogen and progesterone, respectively, whereas no such reaction was observed in the controls (Istekson et al., 2007). The underlying mechanism might be that anti-progesterone immunity that emerges in these patients impairs the physiological functions of progesterone.
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Progesterone treatment of RM—clinical trials |
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TOPAbstractIntroductionLuteal phase defect and...Inadequate immunoregulation in...Progesterone treatment of RM-...GlossaryFundingReferences |
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While there is an accepted causative therapeutic protocol for each group of women with RM of known pathophysiology, there is none for recurrent spontaneous miscarriages of unknown aetiology.
Progesterone treatment could be efficient, if continuation of pregnancy is threatened by insufficient progesterone production, which might result in inappropriate endometrial development, or the failure of the immune system to adapt to the new situation created by the presence of the fetus. The possible sites of action of progesterone are summarized in Fig. 1.
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For more than five decades, progesterone has been administered orally, intramuscularly and vaginally in an attempt to prevent miscarriage in early-to-mid pregnancy. Early studies of progesterone supplementation reported improved pregnancy outcomes in treated women (Tho et al., 1983
; Daya et al., 1988). Two meta-analyses of randomized trials, Goldstein et al. (1989)and Daya (1989) gave conflicting results. The meta-amalysis of Goldstein et al. (1989) showed no benefit when progesterone was used to maintain early pregnancies, whereas Daya (1989) reported that progesterone supplementation significantly improved pregnancy outcome in women with RM. The Goldstein analysis combined the data from 15 very heterogenous studies on ‘high risk’ pregnancies including previous miscarriage, stillbirth or present pre-term labour. Only the pre-term delivery versus the term delivery comparison approached statistical significance. In Daya’s meta-analysis, three controlled trials of progesterone treatment in women with RM have shown small, but not statistically significant, increases in the rates of pregnancies that continued beyond 20 weeks in the treated groups. None of these studies had sufficient statistical power to detect a clinically significant improvement in outcome, but pooling the results of these studies using the principles of meta-analysis have allowed an overall effect of treatment to be calculated. The resulting odds ratio (ORs) for pregnancies reaching at least 20 weeks gestation was 3.09 [95% confidence interval (CI) 1.28, 7.42].
A meta-analysis (Oates-Whitehead et al., 2003) including 14 trials (1988 women) revealed no statistically significant difference in the risk of miscarriage between progestogen and placebo or no treatment groups (OR 1.05, 95% CI 0.83, 1.34), when all women, regardless of gravidity and number of previous miscarriages, were included in the meta-analysis.
On the other hand, in a subgroup analysis of three trials (Swyer and Daley, 1953; Goldzieher, 1964; Le Vine, 1964) involving 91 women who had RM, progestogen treatment showed a statistically significant decrease in miscarriage rate compared with placebo or no treatment (OR 0.39, 95% CI 0.17, 0.91).
In all of the mentioned meta-analyses the same three (>40 years old) placebo-controlled trials were included, and the design of these studies is not acceptable by modern standards (Table 2).
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Two of these studies (Goldzieher, 1964
; Le Vine, 1964) were randomized placebo-controlled and double-blinded, but in both of them the allocation methodology was unclear. The third study (Swyer and Daley, 1953) was not placebo-controlled, the method of randomization is not stated, allocation concealment was clearly inadequate and it was unclear whether any blinding was used. Only one of the three studies (Goldzieher, 1964) was three or more consecutive miscarriages an inclusion criterian. The other two studies included women with two or more consecutive miscarriages. No statistically significant differences were found between the route of administration of progestogen (oral, intramuscular or vaginal) versus placebo or no treatment. No side effects of progesterone were reported.
In a recent study (not included in the meta-analysis) conducted by El Zibdeh (2005), 180 women with a history of recurrent, unexplained spontaneous miscarriage were randomized according to the day of the week the women attended the clinic to receive oral dydrogesterone, intramuscular human chorionic gonadotrophin or no additional treatment. Miscarriages were significantly (P
0.05) less common in the dydrogesterone group (11/82, 13.4%) than in the control group (14/48, 29%); there were no statistically significant differences between the hCG group and the control group. Neither were there any differences between the groups with respect to pregnancy complications or congenital abnormalities. This study was however neither placebo- controlled, nor blinded.
The extensive use of progestational agents during the first and second trimester of pregnancy in attempt to prevent miscarriage showed that this treatment is not associated with adverse effects in the mothers. However, Carmichael et al. (2005) have recently reported that maternal intake of progestins in early pregnancy is associated with an increased risk of hypospadiasis in the male offspring (OR 3.7, 95% CI 2.3, 6.0).
Participants of an international workshop on the evidence-based management of recurrent pregnancy loss called attention to methodological problems threatening the validity of research in this field (Christiansen et al., 2005). The most important of these concerns is patient selection criteria. The validity of research is often hampered by an incorrect diagnosis, due to faulty recall of the pregnancy history, or classification of biochemical pregnancies as miscarriages. The term miscarriage is used to describe a pregnancy that fails to progress, resulting in the death and expulsion of the embryo or fetus. The generally accepted definition stipulates that the fetus or embryo should weigh 500 g (World Health Organization, 1977), a stage that corresponds to a gestational age of 20 weeks. Only patients fulfilling these criteria of RM should be enrolled. Delayed menstruation or biochemical pregnancies should not be included in the studies, since they might have different aetiologies.
The above notwithstanding, the following facts should be considered when analyzing studies on RM. First, the only study design that would be acceptable for such a therapeutic intervention would be a randomized controlled trial, which would exclude any sort of matching. One would expect that random allocation would achieve balance in both number of abortions and age. If the factors were by chance not balanced between the groups, a regression analysis would be necessary to adjust for the imbalance. Of course, stratification is possible for both number of abortions and age (as well as primary versus secondary miscarriage), but power considerations limit the number of stratification factors. Second, it is feasible and acceptable when there is a strong prognostic factor such as primary versus secondary miscarriage, to stratify the random list by that factor in order to ensure balance between the groups and allow for an analysis of the interaction between the treatment and the prognostic factor. Third, it is a principle of randomized trial design that all procedures must be the same for both treatment and control groups. It is to note that samples of human beings are always heterogeneous, even when all patients begin with the same clinical diagnosis. The intervention must be robust enough to overcome this heterogeneity or it will be useless in practice. If we knew which patients would be the responders the trial would not be necessary. Ideally, further studies on progesterone therapy for RM should consider all these potential variables. Finally, double blinding is an indispensable element of a randomized controlled trial to ensure unbiased co-interventions, monitoring, as well as outcome and adverse effect observations.
In conclusion, well-designed randomized studies are needed to provide robust and reliable evidence for the usefulness of progesterone supplementation in the treatment of RM. Laboratory tests including determinations of NK function and cytokine production should be performed on the same patients, according to standardized protocols, to answer the question, whether these parameters are of any value in identifying patients who would respond to progestogen therapy. The usefulness of PIBF measurement in early pregnancy is currently under evaluation (Walch et al., 2005).
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Glossary |
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TOPAbstractIntroductionLuteal phase defect and...Inadequate immunoregulation in...Progesterone treatment of RM-...GlossaryFundingReferences |
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T helper cells (Th cells) like all T cells express the T-cell receptor (TCR)/CD3 complex, as well as the surface protein CD4. They have no cytotoxic or phagocytic activity rather they are involved in activating and directing other immune cells. They are essential in B- cell activation, in the activation and growth of cytotoxic T cells. They act on other cells via cytokines. Th1 cells produce cytokines that promote the development of a cell-mediated response, whereas Th2 cell cytokines act in favour of B cells activation and immunoglobulin production.
Regulatory T cells are a specialized subpopulation of T cells that suppress immune responses of other cells. Their role is to close down immune responses after they have successfully fulfilled their task, e.g. eliminating pathogens.
The majority of peripheral blood T cells express a TCR composed of two glycoprotein chains called - and β-TCR chains. T cells, express another type of receptor composed of a -chain and a -chain. The latter cells constitute a minor subset in peripheral blood, however, they are abundant at the mucosal surfaces and in the skin, and thought to play a major role in mucosal immunity. In contrast to /β T cells, for antigen recognition they do not require antigen processing and MHC presentation of peptide epitopes. Furthermore, T cells are believed to have a prominent role in recognition of lipid antigens. T cells exhibit several characteristics that place them at the border between the rapidly responding innate immune system and the highly specific but slower adaptive immune system.
NK cells are a form of cytotoxic lymphocytes which constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumours and virus-infected cells. NK cells kill by releasing perforin and granzyme that cause lysis or apoptosis of the target cell. In the endometrium and in the decidua there is a specialized population of NK cells. While, 90% of human peripheral NK cells express low density of the CD56 surface marker (CD56dim) and high levels of the FCgRIII (CD16), the majority of decidual NK cells express high density of the CD56 molecule (CD56bright) and no CD16.
Peripheral CD56dim NK cells are granular and known to be cytotoxic, while CD56bright peripheral NK do not contain granules and are non-cytotoxic, but display an imunoregulatory role via cytokine production. Decidual NK cells resemble the CD56bright peripheral NK subset in their CD56bright CD16neg phenotype but, unlike the former, they contain cytotoxic granules. Among the genes selectively over-expressed in decidual NK are secreted proteins with known immunosuppressive activity, suggesting that decidual NK might contribute to the generation of an immunosuppressive environment at the maternal fetal interface.
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Funding |
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The author is the member of a European Network of Excellence on Embryo Implantation Control supported by EU. Contr. No; 512040. This work was supported by grants from Hungarian Natl Research Fund (OTKA T031737), Hungarian Ministry of Health (ETT 045/2003), National Research and Development Program (NKFP 1A-057-2004), Economic Competitiveness Operative Program (GVOP-3.1.1.-2004-05-0329/3.0), and the Hungarian Academy of Sciences.
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