El-Zibdeh M. J Steroid Biochem Mol Biol 2005; 97: 431-346
This prospective randomised, controlled trial investigated the effect of dydrogesterone, human chorionic gonadotrophin (hCG), or standard supportive therapy in women younger than age 35 years who had had at least three consecutive, unexplained, spontaneous miscarriages. Between 1994 and 2000, a wide range of medical assessments and detailed obstetric history was obtained from 500 women, whose partners were also examined for chromosomal and semen abnormalities. Of these, 180 women were found to have no alternative explanation for their recurrent miscarriage and were randomly assigned (according to the day of the week) to receive treatment with oral dydrogesterone (n=82), hCG (n=50), or no additional treatment (n=48) as soon as possible after confirmation of pregnancy. Most women continued treatment for 8 weeks, or until week 12 of gestation. Fewer women who received dydrogesterone were admitted to hospital for vaginal bleeding during the treatment period compared with untreated controls (5% vs 10%, respectively), and significantly fewer experienced miscarriage (13% vs 29%, respectively, p=0·028; table 3). The frequency of miscarriage in the hCG group was slightly lower than in the dydrogesterone group, but was not significantly different from either the dydrogesterone group or the control group.
Summary :
This study recorded a statistically significant reduction in miscarriage frequency in the dydrogesterone group compared with untreated controls. Strengths of this study include the recruitment of women with a history of three or more consecutive spontaneous miscarriages and the exclusion of women who had an identifiable reason for miscarriage (other than luteal-phase defect). Furthermore, the inclusion of an untreated control group eliminates confounding by indication. Weeks 6-7 of gestation are now considered to be critical for treatment of luteal-phase defect rather than weeks 10-12, on which many earlier studies were based. Most women in this study were treated as early as the 4th gestational week. Limitations of the study include a lack of clarity about the study design, particularly the reason for the difference in treatment-group sizes and the quality of randomisation. For instance, differences in the type of problems experienced by women who attend clinics on different days of the week may result in bias. Of note, women in the dydrogesterone group were marginally older (42% vs 31% of women were older than age 30 years, respectively) and had had more previous miscarriages (36% with four miscarriages vs 29%, respectively).
Oates-Whitehead RM. Progestogen for preventing miscarriage (review). Cochrane Database of Systemic Reviews 2003; 4: CD0035117
In 2003, the Cochrane Collaboration did a meta-analysis of all randomised controlled trials that assessed prophylactic progestogen supplementation on miscarriage frequency in various clinical settings. Studies that were eligible for inclusion were randomised or quasi-randomised trials that compared prophylactic use of progestogens in the first 20 weeks of pregnancy for the prevention of miscarriage with placebo or no treatment. All doses, modes of administration, and treatment durations of natural progesterone and synthetic
progestogens were included in the meta-analysis. 14 studies of 1988 women fulfilled the inclusion criteria. In five studies progestogens were given orally; in four studies they were given intramuscularly; in two studies oral and intramuscular progestogens were used together; in two studies progesterone was given via vaginal suppositories; and in one study progestogen pellets were inserted into gluteal muscle. The duration of treatment varied from 14 days to 36 weeks of gestation, or to miscarriage. In one study patients were required to have had three or more consecutive miscarriages; in four studies women were required to have had two or more consecutive miscarriages; in seven studies women were accepted with threatened imminent miscarriage, irrespective of previous history; in one study women who had had amniocentesis were enrolled; and in the remaining study women who had undergone IVF (in-vitro fertilisation) were recruited. All studies included miscarriage as an outcome. Seven studies accepted women within the first trimester of pregnancy; three accepted women to the 20th gestational week; and in the remaining four studies the gestational cut-off was unclear. Meta-analysis of all studies showed no statistically significant difference in live-birth frequency between progestogen and placebo groups (odds ratio [OR] 1·05 [95% CI 0·83–1·34]). No statistically significant difference in live-birth frequency compared with placebo was observed for progestogen given orally (OR 1·11 [95% CI 0·79–1·56]), intramuscularly (OR 0·77 [95% CI 0·36–1·68]), or vaginally (OR 0·74 [95% CI 0·40–1·35]). The only significant reduction in miscarriage was associated with progestogen administration in women who had had three or more consecutive miscarriages immediately before the studied pregnancy (OR 0·39 [95% CI 0·17–0·91] compared with placebo or no treatment). The authors suggest that there is no evidence to support the routine use of progestogen in the prevention of miscarriage in early to mid pregnancy, but that the trend towards improved live-birth frequency in women with a history of recurrent miscarriage deserves further study.
Summary:
This meta-analysis of randomised controlled trials identified 14 trials published over 50 years that fulfilled the inclusion criteria. Individually, none of the 14 studies achieved significance for the efficacy of progestogen compared with placebo or no treatment. The quality of the studies, as judged by the authors, varied greatly. Four studies accounted for 65% of the total weighting of the meta-analysis. Of these, two observed a trend in favour of placebo, one was neutral, and one observed a trend in favour of progestogen. Such conflicting results may not be surprising in view of the various different progestogen products, control groups, routes and timing of progestogen administration, and the indications for treatment that were included in the meta-analysis. No evidence was found for a role of progestogens in the maintenance of high-risk pregnancies. However, a sub-analysis of three studies of three different progestogens suggested that the administration of progestogens to women who had had at least three previous consecutive miscarriages (ie, recurrent miscarriage) immediately preceding the studied pregnancy significantly increased the chance of successful pregnancy. Individually, none of the studies showed a statistically significant effect for progestogen, but in all cases the trend was towards a reduced miscarriage frequency.
Conclusions on efficacy
There is no good evidence that administration of progesterone or dydrogesterone effectively reduces the frequency of miscarriage in women with threatened miscarriage. Compared with the standard of evidence that is required to support an application to market a new medicine, evidence for the efficacy of progestogens in recurrent miscarriage is extremely limited. However, the data suggest that progesterone and dydrogesterone may have a beneficial effect in women who have had three consecutive, unexplained, spontaneous miscarriages. Further work in this area is necessary.
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