Progestogen for treating threatened miscarriage.
Topic: Hormone Therapy

Miscarriage is a common complication encountered during pregnancy. The role of progesterone in preparing the uterus for the implantation of the embryo and its role in maintaining the pregnancy have been known for a long time. Inadequate secretion of progesterone in early pregnancy has been linked to the aetiology of miscarriage and progesterone supplementation has been used as a treatment for threatened miscarriage to prevent spontaneous pregnancy loss.

PICO
Population: Pregnant women with threatened miscarriage
Intervention: Progestogen supplementation
Comparison: Placebo or no treatment
Outcomes: Prevention of spontaneous pregnancy loss

Included studies:
title: Sonography of pregnancies with first-trimester bleeding and a viable embryo: a study of prognostic indicators by logistic regression analysis.
abstract: The objective of our study was to investigate the relationship between sonographic findings and the occurrence of abortion in pregnancies complicated by first-trimester bleeding in which fetal cardiac activity was documented upon admission. A prospective study of transvaginal sonography was performed in 270 pregnant patients with bleeding between 5 and 12 weeks' gestation. The study group included 149 cases in which a singleton fetus with cardiac activity was initially documented. The outcome variable was pregnancy loss prior to 20 weeks. The influence of sonographic findings on admission was studied by univariate analysis and logistic regression. The prevalence of abortion was 23/149 (15%). A significant relationship (p < 0.05) was found between the occurrence of abortion and the following: fetal bradycardia (heart rate less than -1.2 SD from the mean), a discrepancy between the diameter of the gestational sac and crown-rump length less than -0.5 SD from the mean, and a discrepancy between menstrual and sonographic age of more than 1 week. According to the logistic regression equation that was obtained, the probability of abortion in first-trimester bleeding with documented fetal cardiac activity upon admission varied between a minimum of 6% when none of the above risk factors were present and a maximum of 84% when all were present. The presence of any of the above factors identified 84% of all subsequent abortions.
title: Double-blind controlled trial of progesterone substitution in threatened abortion.
abstract: Between 1983 and 1984 a double-blind randomized study with progesterone substitution in threatened abortion was carried out. Fifty-six patients with vaginal bleeding during the first trimester of pregnancy, the internal cervical os being closed, were referred to the hospital. Twenty-five women (5th and 6th week of gestation) with positive serum concentrations of beta-hCG were admitted to the study without regard to sonogram results. In other 25 women (7th-10th week of pregnancy) and 6 women (greater than or equal to 11th week of pregnancy) fetal heart action and movement could be demonstrated by ultrasound. The patients were prescribed bed rest and vaginal suppositories twice daily, containing either 25 mg progesterone or only polyethylene glycol. The code was not broken until after completion of the study. Serial serum determinations of beta-hCG, estradiol-17 beta (E2), progesterone, and ultrasound were performed. Four patients had to be omitted from final analysis (two tubal pregnancies, one intrauterine infection, one sectio parva). Three of 26 patients progesterone (11%) and five of 26 patients with placebo (19%) had an abortion, which represented no significant difference. Frequency of abortion was increased in women more than 30 years old, in women with previous abortions and after ovulation induction. Progesterone treatment resulted in a significant elevation of serum progesterone concentrations (p less than 0.01), while beta-hCG and E2 were unchanged. The results of this study confirm that pregnancy outcome is favorable in women with bleeding and normal hormone concentrations without hormonal treatment and unfavorable in women with reduced beta-hCG and E2-concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
title: [The treatment of threatened abortion (author's transl)].
abstract: In a prospective study 265 patients with threatened abortions were divided into 2 groups. One group of 134 patients received treatment with Oestradiol benzoat and hydroxyprogesterone capronat. The other group of 131 patients received no hormonal treatment. Of the group treated with hormones 40.7% of the women had an abortion. Of the group treated with placebos 39.7% of the patients had an abortion. There was therefore no difference in the success rate of the treatment of threatened abortion irrespective of the administration of hormones or placebos. The value of hormonal therapy in the treatment of threatened abortion is therefore questionable.
title: Progesterone and threatened abortion: a randomized clinical trial on endocervical cytokine concentrations.
abstract: The purpose of this study was to investigate the effect of vaginal progesterone on endocervical cytokine concentration in women at risk of threatened abortion. One hundred and sixty pregnant women with clinical symptoms of threatened abortion before the 20th week of pregnancy were randomly assigned to receive vaginal progesterone or placebo. Cervical fluids were collected and endocervical concentrations of different cytokines (IFNγ, TNFα, IL-8, IL-10 and IL-12) were analyzed before and one week after progesterone or placebo treatment. A significant decrease in IFNγ and increase in IL-10 in endocervical fluid was seen when the values were compared before and after progesterone treatment. However, there were no significant differences in pregnancy outcomes between the placebo and progesterone groups. We conclude that despite the failure of vaginal progesterone treatment to improve pregnancy outcomes, progesterone can induce a shift in the concentration of cytokines in endocervical secretions.
title: A randomised trial of progesterone prophylaxis after midtrimester amniocentesis.
abstract: Midtrimester amniocentesis to investigate fetal karyotype carries a small risk of fetal loss.
title: 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.
abstract: Presented herein is a randomized prospective study performed to evaluate the efficacy of the addition of lymphocyte immunotherapy (LI) to progesterone (P) therapy (LI/P) for the prevention of spontaneous abortion (SAB) in primary aborters with a history of three SABs. The incidence of intrauterine pregnancies in four cycles was 23 of 35 (65.7%) patients for LI/P vs. 14 of 31 (45.1%) patients treated with progesterone alone. SABs occurred in 6 of 23 (26.0%) LI/P-treated patients compared to 8 of 14 (57.1%) given progesterone alone. The mean number of previous abortions in both groups was 3.9. The mean age of the LI/P group was 34.1 vs. 33.6 years for the group treated with progesterone alone. These data could be interpreted to show that progesterone therapy and LI independently inhibit SAB or that LI/P acts synergistically to inhibit immune destruction. LI/P therapy was found to be more effective than progesterone therapy alone.
title: Therapeutic value of indomethacin in threatened abortion.
abstract: One hundred cases of threatened abortion were randomly allocated to four lines of treatment namely, long acting progesterone, antispasmodic, indomethacin and placebo. The lowest success rate was encountered in the indomethacin treated group; symptoms of intolerance were common and three cases out of sixteen turned into missed abortion. Indomethacin does not offer any advantage over other lines of treatment in threatened abortion.
title: Progesterone supplementation during early gestations after IVF or ICSI has no effect on the delivery rates: a randomized controlled trial.
abstract: The aim was to study whether prolongation of luteal support during early pregnancy influences the delivery rate after IVF.
title: Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
abstract: Women who have had a spontaneous preterm delivery are at greatly increased risk for preterm delivery in subsequent pregnancies. The results of several small trials have suggested that 17 alpha-hydroxyprogesterone caproate (17P) may reduce the risk of preterm delivery.
title: [A randomized prospective study comparing supplementation of the luteal phase and early pregnancy by natural progesterone administered by intramuscular or vaginal route].
abstract: Deficiency in the luteal phase has been shown during stimulated cycles using a protocol involving a GnRH agonist. The authors undertook a randomised prospective trial of supplementation by progesterone of the luteal phase and of early pregnancy in two hundred and seventy two patients requiring fertilisation in vitro (FIV), gamete inter-fallopian transfer (GIFT) or zygote inter-fallopian transfer (ZIFT). Either progesterone in solution in oil (50 mg/day) administered by intramuscular injection or micronized progesterone administered intra-vaginally (600 mg/d) were used as support for the luteal phase. Administration of progesterone in association with estradiol valerate was started on the day prior to oocyte puncture and was continued until the 12th week of pregnancy. The implantation rate was very close to the threshold of significance (P = 0.07) in favour of the patients given vaginal progesterone. There was a higher rate of clinical pregnancies (33.6 versus 26.7 p. cent) in the latter group, though this was not significant. While plasma progesterone (Pg) levels were lower in patients using vaginal progesterone, the abortion rate during the first three months was lower in this group (P < 0.05). Micronized progesterone administered vaginally was well tolerated by all patients. During stimulated cycles, notably by GnRHa, it thus proved to be more effective than Pg administered by intramuscular injection with regard to implantation and abortion rates.
title: Endocrine effects of 17 alpha-hydroxyprogesterone caproate during early pregnancy: a double-blind clinical trial.
abstract: The clinical and endocrine effects of progestogen therapy in early pregnancy were investigated using a double-blind randomized trial in 64 patients who had a viable fetus at 6 weeks gestation and had an increased risk of miscarriage. The patients were randomly allocated to receive either 17 alpha-hydroxyprogesterone caproate or a placebo between 7 and 12 weeks gestation. Four fetal ultrasonographic variables and 17 maternal endocrine variables were studied in each woman. Only four maternal serum variables (17 alpha-hydroxyprogesterone, prolactin, thyroxin and thyroxin binding globulin) rose significantly. The serum progesterone levels in the hormone supplemented group were on average 20% higher than in the placebo group but the difference was not statistically significant. However, the relation between the progesterone levels and the fetal outcome was not clear. Therefore it is not advisable to prescribe 17-OHP-C during early pregnancy to prevent a miscarriage.
title: A prospective, randomized, placebo-controlled trial on the use of mifepristone with sublingual or vaginal misoprostol for medical abortions of less than 9 weeks gestation.
abstract: A combination of mifepristone and misoprostol provides an effective method of medical abortion for early pregnancy. This is the first randomized trial comparing the use of sublingual misoprostol with vaginal misoprostol in combination with mifepristone for termination of early pregnancies up to 63 days.
title: Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone.
abstract: To compare the influence of vaginal micronized progesterone and oral dydrogesterone supplementation on uteroplacental circulation in early pregnancy that is complicated by threatened abortion.
title: Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice.
abstract: To estimate the miscarriage rate in a cohort of pregnant women and the final outcome of pregnancy.
title: Fetal loss following ultrasound diagnosis of a live fetus at 6-10 weeks of gestation.
abstract: To examine prospectively the value of demographic characteristics and ultrasound findings in the prediction of subsequent fetal loss in pregnancies with live fetuses at 6-10 weeks of gestation.
title: A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage.
abstract: Recurrent miscarriage is a difficult clinical problem occurring in approximately 1-2% of fertile women. Following investigation, most cases fail to reveal an identifiable cause and are therefore classified as idiopathic. The aim of this study was to identify important gestational milestones for pregnancy success prediction in women following idiopathic recurrent miscarriage. A total of 325 consecutive patients with idiopathic recurrent miscarriage was involved in a prospective longitudinal observational study. Patients were identified from a miscarriage database of 716 patients. Preconceptual presentation and investigation excluded patients from the study sample with known associations of recurrent pregnancy loss, such as antiphosholipid syndrome, oligomenorrhoea, mid-trimester loss and other rare causes, e.g. abnormal parental karyotype. Following early presentation in a subsequent pregnancy, all patients followed a standard clinic protocol including fetal viability ultrasonography on a fortnightly basis throughout the first trimester. Kaplan-Meier curves were constructed for pregnancy outcome. Out of 325 idiopathic cases, 70% (n = 226) conceived, with a 75% success rate. Of 55 miscarriages, longitudinal assessment showed that six losses occurred following detection of fetal cardiac activity (3%). Data from this large study group have enabled accurate prediction of future pregnancy success and have established important gestational milestones for women with idiopathic recurrent miscarriage.
title: Dydrogesterone support in threatened miscarriage.
abstract: The aim of this study was to determine whether dydrogesterone helps to preserve pregnancy in women with threatened miscarriage.
title: [Is hormonal therapy still justified in imminent abortion? (author's transl)].
abstract: In a prospective study, 300 women were treated during 1976 to 1978 alternatingly with hormones or placebo, the comparability of both groups being established in respect of certain influencing factors. No statistically confirmed difference was found in the total success rates of both types of treatment. The age of the pregnant women, and any previous abortions, did not represent any risk factor for imminent abortion. A better success rate was obtained with gestagen therapy, depending on the gestation period. (= 9th week of pregnancy).
title: Randomised trial comparing expectant with medical management for first trimester miscarriages.
abstract: To compare the efficacy of antiprogesterone (mifepristone) in combination with a synthetic prostaglandin E1 analogue (misoprostol) for outpatient treatment of miscarriages.
title: Dydrogesterone in threatened miscarriage: a Malaysian experience.
abstract: Threatened miscarriage is a common problem during pregnancy.
title: A double-blind study of progestogen treatment in spontaneous abortion. (Preliminary report).
title: Dydrogesterone in threatened abortion: pregnancy outcome.
abstract: To determine whether therapy with dydrogesterone in threatened abortion during the first trimester of pregnancy will improve pregnancy outcome.
title: Effect of medroxyprogesterone acetate upon the duration and characteristics of human gestation and labor.
title: Dydrogesterone in the reduction of recurrent spontaneous abortion.
abstract: One hundred and eighty women with a history of recurrent, unexplained spontaneous abortion (mean 3.5 abortions) were randomised to receive oral dydrogesterone (10 mg b.i.d.), intramuscular human chorionic gonadotrophin (hCG; 5000 IU every 4 days) or no additional treatment (controls). Treatment was started as soon as possible after confirmation of pregnancy and continued until the 12th gestational week. All women received standard supportive care. Abortions were significantly (p < or = 0.05) less common in the dydrogesterone group (13.4%) than in the control group (29%); there were no statistically significant differences between the hCG group and the control group. There were no differences between the groups with respect to pregnancy complications or congenital abnormalities. In conclusion, hormonal support with dydrogesterone can increase the chances of a successful pregnancy in women with a history of recurrent spontaneous abortion.
title: Effects of vaginal progesterone on pain and uterine contractility in patients with threatened abortion before twelve weeks of pregnancy.
abstract: Fifty women with previous diagnosis of inadequate luteal phase and threatened abortion underwent a prospective, randomized, double-blind study in one medical center carried out with a parallel trial. The primary objective was to establish the effects of vaginal progesterone (Crinone 8%) in reducing both pain and uterine contractions (UCs). The gel with or without (placebo) vaginal progesterone was administered once a day since the diagnosis of threatened abortion and for 5 days. The efficacy on pain symptom amelioration was evaluated by a 5-score intensity gradation, while the UCs were evaluated by ultrasound. The secondary objective of the study was to evaluate the outcome of the pregnancies. The use of progesterone was effective both on pain relief and on the frequency of the UCs that decreased after 5 days of vaginal progesterone administration (P < 0.005). The evaluation of the ongoing pregnancy and spontaneous abortion in both study groups after 60 days showed that 4 patients of group A and 8 patients of group B miscarried (P < 0.05). In conclusion, patients with threatened abortion benefit from vaginal progesterone by a reduction of UCs and pain. The use of vaginal progesterone improved the outcome of pregnancies complicated by threatened abortion and previous diagnosis of inadequate luteal phase.