The Influence of Oral Dydrogesterone and Vaginal Progesterone on Threatened Abortion: A Systematic Review and Meta-Analysis.
ABSTRACT: To conduct systematic analyses to evaluate the efficacy of progesterone therapy for the prevention of miscarriages in pregnant women experiencing threatened abortion.In November 2016, we performed a systematic literature search and identified 51 articles in PubMed, Embase, and Cochrane databases. We identified nine randomized trials that included 913 pregnant women (including 322 treated with oral dydrogesterone, 213 treated with vaginal progesterone, and 378 control subjects) who met the selection criteria.The incidence of miscarriage was significantly lower in the total progesterone group than in the control group (13.0% versus 21.7%; odds ratio, 0.53; 95% confidence interval (CI), 0.36 to 0.78; P = 0.001; I2, 0%). Moreover, the incidence of miscarriage was significantly lower in the oral dydrogesterone group than in the control group (11.7% versus 22.6%; odds ratio, 0.43; 95% CI, 0.26 to 0.71; P = 0.001; I2, 0%) and was lower in the vaginal progesterone group than in the control group, although this difference was nonsignificant (15.4% versus 20.3%; odds ratio, 0.72; 95% CI, 0.39 to 1.34; P = 0.30; I2, 0%). However, the incidence of miscarriage was not different between the oral dydrogesterone and vaginal progesterone groups.Progesterone therapy, especially oral dydrogesterone, can effectively prevent miscarriage in pregnant women experiencing threatened abortion.
Project description:Threatened miscarriage is a common gynaecological emergency, with up to 25% of women eventually progressing to spontaneous miscarriage. The uncertainty of pregnancy outcomes results in significant anxiety. However, there is currently no acceptable framework for triaging patients presenting with threatened miscarriage. We aim to evaluate the efficacy and safety of a novel clinical protocol using a single serum progesterone level to prognosticate and guide management of patients with threatened miscarriage. 1087 women presenting with threatened miscarriage were enrolled in the study. The primary outcome was spontaneous miscarriage by 16 weeks' gestation. Among the 77.9% (847/1087) of study participants with serum progesterone ? 35 nmol/L who were not treated with oral dydrogesterone, the miscarriage rate was 9.6% (81/847). This did not differ significantly from the 8.5% (31/364) miscarriage rate observed in our prior studies; p?=?0.566. Among women with serum progesterone < 35 nmol/L who were treated with dydrogesterone, the miscarriage rate was 70.8% (170/240). Our novel clinical triage protocol using a single serum progesterone level allowed both effective risk stratification and a reduction in progestogen use with no significant adverse pregnancy outcomes. This protocol, based on a single serum progesterone cutoff, can be readily adapted for use in other healthcare institutions.
Project description:Miscarriage is a common complication of pregnancy occurring in 15-20 % of all clinically recognized pregnancies. Currently, there is still no good scientific evidence to support the routine use of progestogens for the treatment of threatened miscarriage because the existing studies were not large enough to show a significant difference and some of them were not randomized or double-blind.This is a double-blind, randomized controlled trial. A total of 400 patients presenting with first-trimester threatened miscarriage will be enrolled. They will be randomized to take dydrogesterone 40 mg per os, followed by 10 mg per os three times a day or placebo until twelve completed weeks of gestation or 1 week after the bleeding has stopped, whichever is longer. The primary outcome is the percentage of miscarriage before 20 weeks of gestation.We postulate that the dydrogesterone therapy will significantly reduce the risk of miscarriage in women with threatened miscarriage.This study is registered at ClinicalTrials.gov, NCT02128685 . Registered on 29 April 2014.
Project description:The aim of this systematic review and meta-analysis was to conduct a comprehensive assessment of the evidence on the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) for luteal phase support. Embase and MEDLINE were searched for studies that evaluated the effect of luteal phase support with daily administration of oral dydrogesterone (20 to 40 mg) versus MVP capsules (600 to 800 mg) or gel (90 mg) on pregnancy or live birth rates in women undergoing fresh-cycle IVF (protocol registered at PROSPERO [CRD42018105949]). Individual participant data (IPD) were extracted for the primary analysis where available and aggregate data were extracted for the secondary analysis. Nine studies were eligible for inclusion; two studies had suitable IPD (full analysis sample: n = 1957). In the meta-analysis of IPD, oral dydrogesterone was associated with a significantly higher chance of ongoing pregnancy at 12 weeks of gestation (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.08 to 1.61; P = 0.0075) and live birth (OR, 1.28; 95% CI, 1.04 to 1.57; P = 0.0214) compared to MVP. A meta-analysis combining IPD and aggregate data for all nine studies also demonstrated a statistically significant difference between oral dydrogesterone and MVP (pregnancy: OR, 1.16; 95% CI, 1.01 to 1.34; P = 0.04; live birth: OR, 1.19; 95% CI, 1.03 to 1.38; P = 0.02). Safety parameters were similar between the two groups. Collectively, this study indicates that a higher pregnancy rate and live birth rate may be obtained in women receiving oral dydrogesterone versus MVP for luteal phase support.
Project description:<h4>Unlabelled</h4>To compare Crinone vaginal progesterone gel with intramuscularly injected progesterone for luteal phase support in progesterone-supplemented frozen-thawed embryo transfer (FET) cycles, a randomized prospective study of patients qualified for FET was conducted between September 2010 and January 2013 at a hospital in Shanghai, China. From the day of transformation into secretory phase endometrium (day 0), Crinone vaginal gel (90 mg/d) was administered to patients in the Gel Group, while progesterone (40 mg/d) was injected intramuscularly in patients in the Inj Group (n = 750 per group). All patients received oral dydrogesterone (20 mg/d) and estradiol valerate (4–8 mg/d). Day 3 embryos with the highest pre-frozen scores were transferred to patients in the two groups and the clinical outcomes compared. This study comprised 1,500 cycles (750 in each group). Twenty-nine cycles in the Gel Group and 24 in the Inj Group were withdrawn. There were no significant differences between groups in age, endometrial thickness, endometrial preparation time or number of embryos transferred. No significant differences were observed between the Gel Group and Inj Group in the rates of live birth (32.6% vs. 31.7%, P = 0.71), clinical pregnancy (40.1% vs. 40.6%, P = 0.831), implantation (25.8% vs. 25.3%, P = 0.772), abortion (16.3% vs. 18.3%, P = 0.514) or ectopic pregnancy (2.8% vs. 4.4%, P = 0.288). Multivariate logistic regression analysis revealed that the odds ratios (95% confidence intervals) for the rates of live birth, clinical pregnancy, abortion and ectopic pregnancy (Gel Group relative to Inj Group) were 1.036 (0.829–1.295), 0.971 (0.785–1.200), 0.919 (0.595–1.420) and 0.649 (0.261–1.614), respectively. Our study revealed that using Crinone vaginal gel in FET cycles achieved similar pregnancy outcomes to intramuscular progesterone, indicating that vaginal gel is a viable alternative to intramuscular injection.<h4>Trial registration</h4>Chinese Clinical Trial Registry ChiCTR-TRC-14004565.
Project description:Threatened miscarriage is the most common gynecological emergency, occurring in about 20% of pregnant women. Approximately one in four of these patients go on to have spontaneous miscarriage and the etiology of miscarriage still remains elusive. In a bid to identify possible biomarkers and novel treatment targets, many studies have been undertaken to elucidate the pathways that lead to a miscarriage. Luteal phase deficiency has been shown to contribute to miscarriages, and the measurement of serum progesterone as a prognostic marker and the prescription of progesterone supplementation has been proposed as possible diagnostic and treatment methods. However, luteal phase deficiency only accounts for 35% of miscarriages. In order to understand the other causes of spontaneous miscarriage and possible novel urine biomarkers for miscarriage, we looked at the changes in urinary metabolites in women with threatened miscarriage. To this end, we performed a case-control study of eighty patients who presented with threatened miscarriage between 6 and 10 weeks gestation. Urine metabolomics analyses of forty patients with spontaneous miscarriages and forty patients with ongoing pregnancies at 16 weeks gestation point to an impaired placental mitochondrial ?-oxidation of fatty acids as the possible cause of spontaneous miscarriage. This study also highlighted the potential of urine metabolites as a non-invasive screening tool for the risk stratification of women presenting with threatened miscarriage.
Project description:BACKGROUND:Preterm birth accounts for 75% of perinatal deaths and more than 50% of long-term neurological disabilities. For a singleton pregnancy, progesterone treatment is effective in prevention of preterm birth in women with an asymptomatic short cervix or a history of preterm birth. However, a large proportion of preterm births still is not currently preventable. The aim of this study is to determine whether early universal use of oral progesterone before 14?+?0?weeks of gestation can prevent preterm birth better than universal screening of cervical length at 18?+?0 to 23?+?6?weeks of gestation, followed by progesterone treatment in those with a short cervix in singleton pregnancy. METHODS:This is a multicenter, randomized, double-blind, placebo-controlled trial registered with ClinicalTrials.gov on 12 February 2018. Eligible consecutive pregnant women with singleton gestation attending antenatal outpatient clinics will be recruited after receiving counseling and signing the written consent form. Transvaginal cervical length measurement will be performed at recruitment (before 14?+?0?weeks of gestation) and between 18?+?0 and 23?+?6?weeks of gestation. After randomization, women will be randomly assigned to either the treatment group (oral dydrogesterone 10?mg three times daily) or the placebo group, and medication will be started before 14?+?0?weeks of gestation. Assigned groups will be unblinded if the cervical length is ??25?mm between 18?+?0 and 23?+?6?weeks of gestation, and the management option for short cervix will be discussed (oral progesterone, vaginal progesterone, or cervical cerclage). The primary outcome is preterm birth before 37?+?0?weeks of gestation. DISCUSSION:Progesterone is used extensively in part of the in vitro fertilization program as luteal phase support, and it is not associated with teratogenicity. Universal progesterone supplementation may be a better approach to prevent preterm birth. This large, multicenter, randomized, double-blind, placebo-controlled trial will provide the best evidence, leading to the best strategy for the prevention of preterm birth. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03428685. Registered on 12 February 2018.
Project description:Progesterone is a critical hormone in early pregnancy. A low level of serum progesterone is associated with threatened miscarriage. We aim to establish the distribution of maternal serum progesterone in normal pregnancies compared to pregnancies complicated by threatened miscarriage from 5 to 13 weeks gestation.This is a single centre, prospective cohort study of 929 patients. Women from the Normal Pregnancy [NP] cohort were recruited from antenatal clinics, and those in the Threatened Miscarriage [TM] cohort were recruited from emergency walk-in clinics. Women with multiple gestations, missed, incomplete or inevitable miscarriage were excluded from the study. Quantile regression was used to characterize serum progesterone levels in the NP and TM cohorts by estimating the 10th, 50th and 90th percentiles from 5 to 13 weeks gestation. Pregnancy outcome was determined at 16 weeks of gestation. Subgroup analysis within the TM group compared progesterone levels of women who subsequently miscarried with those who had ongoing pregnancies at 16 weeks of gestation.Median serum progesterone concentration demonstrated a linearly increasing trend from 57.5 nmol/L to 80.8 nmol/L from 5 to 13 weeks gestation in the NP cohort. In the TM cohort, median serum progesterone concentration increased from 41.7 nmol/L to 78.1 nmol/L. However, median progesterone levels were uniformly lower in the TM cohort by approximately 10 nmol/L at every gestation week. In the subgroup analysis, median serum progesterone concentration in women with ongoing pregnancy at 16 weeks gestation demonstrated a linearly increasing trend from 5 to 13 weeks gestation. There was a marginal and non-significant increase in serum progesterone from 19.0 to 30.3 nmol/L from 5 to 13 weeks gestation in women who eventually had a spontaneous miscarriage.Serum progesterone concentration increased linearly with gestational age from 5 to 13 weeks in women with normal pregnancies. Women with spontaneous miscarriage showed a marginal and non-significant increase in serum progesterone. This study highlights the pivotal role of progesterone in supporting an early pregnancy, with lower serum progesterone associated with threatened miscarriage and a subsequent complete miscarriage at 16 weeks gestation.
Project description:Is oral dydrogesterone 30 mg daily (10 mg three times daily [TID]) non-inferior to micronized vaginal progesterone (MVP) 600 mg daily (200 mg TID) for luteal support in in vitro fertilization (IVF), assessed by the presence of fetal heartbeats determined by transvaginal ultrasound at 12 weeks of gestation?Non-inferiority of oral dydrogesterone versus MVP was demonstrated at 12 weeks of gestation, with a difference in pregnancy rate and an associated confidence interval (CI) that were both within the non-inferiority margin.MVP is routinely used in most clinics for luteal support in IVF, but it is associated with side effects, such as vaginal irritation and discharge, as well as poor patient acceptance. Dydrogesterone may be an alternative treatment due to its patient-friendly oral administration.Lotus I was an international Phase III randomized controlled trial, performed across 38 sites, from August 2013 to March 2016. Subjects were premenopausal women (>18 to <42 years of age; body mass index (BMI) ≥18 to ≤30 kg/m2) with a documented history of infertility who were planning to undergo IVF. A centralized electronic system was used for randomization, and the study investigators, sponsor's study team, and subjects remained blinded throughout the study.In total, 1031 subjects were randomized to receive either oral dydrogesterone (n = 520) or MVP (n = 511). Luteal support was started on the day of oocyte retrieval and continued until 12 weeks of gestation (Week 10), if a positive pregnancy test was obtained at 2 weeks after embryo transfer.In the full analysis set (FAS), 497 and 477 subjects in the oral dydrogesterone and MVP groups, respectively, had an embryo transfer. Non-inferiority of oral dydrogesterone was demonstrated, with pregnancy rates at 12 weeks of gestation of 37.6% and 33.1% in the oral dydrogesterone and MVP treatment groups, respectively (difference 4.7%; 95% CI: -1.2-10.6%). Live birth rates of 34.6% (172 mothers with 213 newborns) and 29.8% (142 mothers with 158 newborns) were obtained in the dydrogesterone and MVP groups, respectively (difference 4.9%; 95% CI: -0.8-10.7%). Oral dydrogesterone was well tolerated and had a similar safety profile to MVP.The analysis of the results was powered to consider the clinical pregnancy rate, but the live birth rate may be of greater clinical interest. Conclusions relating to the differences between treatments in live birth rate, observed in this study, should therefore be made with caution.Oral dydrogesterone may replace MVP as the standard of care for luteal phase support in IVF, owing to the oral route being more patient-friendly than intravaginal administration, as well as it being a well tolerated and efficacious treatment.Sponsored and supported by Abbott Established Pharmaceuticals Division. H.T.'s institution has received grants from Merck, MSD, Goodlife, Cook, Roche, Besins, Ferring and Mithra (now Allergan) and H.T. has received consultancy fees from Finox, Ferring, Abbott, ObsEva and Ovascience. G.S. has nothing to disclose. E.K. is an employee of Abbott GmbH. G.G. has received investigator fees from Abbott during the conduct of the study; outside of this submitted work, G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, Glycotope, as well as personal fees from VitroLife, NMC Healthcare LLC, ReprodWissen LLC and ZIVA LLC.NCT01850030 (clinicaltrials.gov).19 April 2013.23 August 2013.
Project description:The primary aim of this study was to evaluate the effect of oral dydrogesterone on the recurrent uterine contraction in preterm labor. The secondary aims were to evaluate latency period, gestational age at delivery, pregnancy outcomes, neonatal outcomes, compliance and side effects. A randomized, double blinded, placebo controlled trial was conducted. Forty-eight pregnant women at 24-34 weeks gestation with preterm labor were either randomized to study group receiving tocolytic treatment combined with oral dydrogesterone (20?mg daily) or to placebo group receiving tocolytic treatment combined with oral placebo. Recurrent rates of uterine contraction were comparable between groups (87.5% vs 91.7%, p?=?0.64). Latency periods were not different between dydrogesterone and placebo group (32.7?±?20.2 days vs 38.2?±?24.2 days, p?=?0.39). There were also no differences in gestational age at delivery, pregnancy outcomes, neonatal outcomes, compliance and side effects. Adjuvant treatment with oral dydrogesterone 20?mg/day could not decrease the rates of recurrent uterine contraction and prolong latency period in preterm labor management when compared to placebo.
Project description:CONTEXT:Recurrent miscarriages, the loss of three or more consecutive intrauterine pregnancies before 20 weeks of gestation with the same partner, affect 1%-1.5% of the pregnant population. The inadequate secretion of progesterone in early pregnancy has been proposed as a cause of recurrent miscarriages. AIMS:The aim was to investigate the efficacy of progesterone supplementation in patients with unexplained recurrent miscarriages. SETTINGS AND DESIGN:This was a 9-year cohort study of women with otherwise unexplained recurrent miscarriages who attended a recurrent miscarriage clinic in a tertiary care university hospital. SUBJECTS AND METHODS:Women with at least three unexplained recurrent miscarriages were included in the study. They were divided into three groups according to their initial and 48-h repeat progesterone levels. For women with inadequate endogenous progesterone secretion, natural progesterone vaginal pessaries 400 mg 12-hourly were offered until 12 weeks gestation. STATISTICAL ANALYSIS:Proportions and 95% confidence intervals calculated for categorical variables and the chi-square test were used to show statistical significance. Medians and ranges were calculated for noncontinuous variables. RESULTS:Pregnancy cycles (n = 203) were analyzed to examine the miscarriage rate following progesterone supplementation. Overall live birth and miscarriage rates were 63% and 36%, respectively. When analyzed by the number of previous miscarriages there was a reduction in the miscarriage rate following progesterone supplementation in women with 4 previous miscarriages when compared with historical data. CONCLUSIONS:Progesterone supplementation may have beneficial effects in women with otherwise unexplained recurrent miscarriages.