Use of oral progestogen in women with threatened miscarriage in the first trimester: a randomized double-blind controlled trial.

STUDY QUESTION: Will use of oral progestogen in women with threatened miscarriage in the first trimester reduce the miscarriage rate when compared with placebo? SUMMARY ANSWER: Use of oral progestogen in women with threatened miscarriage in the first trimester did not reduce miscarriage before 20 weeks when compared with placebo. WHAT IS KNOWN ALREADY: Miscarriage is a common complication of pregnancy and occurs in 15-20% of clinically recognized pregnancies. Use of vaginal progestogens is not effective in reducing miscarriage but there is still no good evidence to support use of oral progestogen for the treatment of threatened miscarriage. STUDY DESIGN, SIZE, DURATION: This was a randomized double-blind controlled trial. A total of 406 women presenting with threatened miscarriage in the first trimester were recruited from 30 March 2016 to May 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women attending Early Pregnancy Assessment Clinics because of vaginal bleeding during the first trimester were recruited and randomly assigned to use dydrogesterone 40 mg orally, followed by 10 mg orally three times a day or placebo until 12 completed weeks of gestation or 1 week after the bleeding stopped, whichever was later. The primary outcome was the miscarriage rate before 20 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: The two groups of women had comparable age, BMI, number of previous miscarriages, gestation and ultrasound findings at presentation. The miscarriage rate before 20 weeks of gestation was similar in both groups, being 12.8% (26/203) in the progestogen group and 14.3% (29/203) in the placebo group (relative risk 0.897, 95% CI 0.548-1.467; P = 0.772). The live birth rate was 81.3% in the progestogen group versus 83.3% in the placebo group (P = 0.697). No significant differences were found between the two groups in terms of obstetric outcomes and side effects. LIMITATIONS, REASONS FOR CAUTION: The primary outcome was the miscarriage rate, rather than the live birth rate. Women were recruited from Early Pregnancy Assessment Clinics and those with heavy vaginal bleeding might be admitted into wards directly instead of attending Early Pregnancy Assessment Clinic. The severity of vaginal bleeding was subjectively graded by women themselves. The sample size was not adequate to demonstrate a smaller difference in the miscarriage rate between the progestogen and placebo groups. We did not exclude women with multiple pregnancy, which increased the risk of miscarriage although there was only one set of twin pregnancy in the placebo group. WIDER IMPLICATIONS OF THE FINDINGS: Use of oral progestogen is not recommended in women with threatened miscarriage in the first trimester. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Health and Medical Research Fund, HKSAR (reference number 12132341). All authors declared no conflict of interest. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov with an identifier NCT02128685. TRIAL REGISTRATION DATE: 1 May 2014. DATE OF FIRST PATIENT'S ENROLMENT: 30 March 2016.

A randomized double-blinded non-inferiority trial comparing fentanyl and midazolam with pethidine and diazepam for pain relief during oocyte retrieval.

RESEARCH QUESTION: Is fentanyl and midazolam non-inferior to pethidine and diazepam in pain relief during oocyte retrieval under conscious sedation? DESIGN: A randomized double-blinded non-inferiority trial of 170 infertile women undergoing oocyte retrieval under conscious sedation in an assisted reproduction centre. The women were randomized to receive intravenously either 0.1 mg fentanyl and 5 mg midazolam or 25 mg pethidine and 5 mg diazepam, plus paracervical block with 10 ml 1% lignocaine. The primary outcome was abdominal pain level during retrieval assessed by linear visual analogue scale from 0-10. Secondary outcomes included vaginal pain levels during and after retrieval and postoperative abdominal pain levels and side-effects, satisfaction level, clinical pregnancy and ongoing pregnancy rates. A pre-defined non-inferiority margin of 1 for the difference in pain levels between two groups was set. RESULTS: Vaginal and abdominal pain levels during retrieval were significantly lower in the fentanyl and midazolam group compared with the pethidine and diazepam group (per-protocol analysis, vaginal pain: 1.6 versus 4.3; mean difference: -2.7, 95% CI -3.7, -1.8; P < 0.001; abdominal pain: 2.9 versus 5.2; mean difference: -2.3, 95% CI -3.3 to -1.3; P < 0.001 for non-inferiority). No differences were observed in these pain levels after retrieval. Most women experienced no postoperative side-effects. The fentanyl and midazolam group had better sedation level, satisfaction level on pain relief and satisfaction on the overall retrieval procedure than the pethidine and diazepam group. No significant differences were found in clinical pregnancy and ongoing pregnancy rates between the two groups. CONCLUSION: The fentanyl and midazolam group had significantly lower vaginal and abdominal pain levels during oocyte retrieval than the pethidine and diazepam group.

Attachment of a trophoblastic spheroid onto endometrial epithelial cells predicts cumulative live birth in women aged 35 and older.

OBJECTIVE: To evaluate the attachment rate of a human embryonic stem cell-derived trophoblastic spheroid onto endometrial epithelial cells in predicting the cumulative live birth rate of an in vitro fertilization (IVF) cycle. DESIGN: A prospective observational study. SETTING: University hospital and research laboratory. PATIENT(S): A total of 240 infertile women from 2017-2021. INTERVENTION(S): Infertile women with regular cycles attending for IVF were recruited. An endometrial aspirate was collected from a natural cycle 1 month before IVF to determine the BAP-EB attachment rate. MAIN OUTCOME MEASURE(S): Cumulative live birth rates from a stimulated cycle and its derived frozen embryo transfer cycles within 6 months of ovarian stimulation were obtained. RESULT(S): The BAP-EB attachment rate in women who attained a cumulative live birth was similar to that in those who did not. When women were stratified by age into <35 years and ≥35 years, the BAP-EB attachment rate was significantly higher only in women aged ≥35 years having a live birth when compared with those in the same age group without a live birth. Receiver operating characteristic curve analysis of BAP-EB attachment rate in predicting cumulative live birth showed the areas under the curve of 0.559 (95% confidence interval [CI], 0.479-0.639), 0.448 (95% CI, 0.310-0.585), and 0.613 (95% CI, 0.517-0.710) for all ages, an age of <35 years, and an age of ≥35 years, respectively. CONCLUSION(S): The BAP-EB attachment rate offers only a very modest prediction of the cumulative live birth rate in women aged ≥35 years undergoing IVF. CLINICAL TRIAL REGISTRATION NUMBER: NCT02713854 (https://clinicaltrials.gov/ct2/show/NCT02713854; Date of registration, March 21, 2016; date of enrollment of the first subject, August 1, 2017).

Hyaluronic acid-enriched transfer medium for frozen embryo transfer: a randomized, double-blind, controlled trial.

OBJECTIVE: To compare the effects of hyaluronic acid (HA)-enriched transfer medium versus standard medium on live birth rate after frozen embryo transfer (FET). DESIGN: Randomized, double-blind, controlled trial. SETTING: Two tertiary fertility centers. PATIENT(S): Infertile women aged <43 years at the time of in vitro fertilization undergoing FET. INTERVENTION(S): The women were randomly assigned to 2 groups in a 1:1 ratio. The HA group used EmbryoGlue (Vitrolife, Gothenburg, Sweden) with an HA concentration of 0.5 mg/mL, while the control group used supplemented G-2 (Vitrolife) medium with an HA concentration of 0.125 mg/mL. MAIN OUTCOME MEASURE(S): Live birth rate. RESULT(S): Five hundred fifty women were recruited from April 2016 to April 2018 and included in the intention-to-treat analysis. Eight women in the HA group and 5 women in the control group did not undergo FET because the embryos did not survive on thawing. One woman in the HA group cancelled FET because of fever. One woman in the HA group withdrew and received conventional medium. The 2 groups were similar in demographic characteristics. The live birth rates in the HA group and the control group were comparable (25.5% vs. 25.8%; relative risk 0.99; 95% confidence interval 0.74-1.31). The other clinical outcomes were also similar between the 2 groups. Logistic regression showed that the type of transfer medium was not associated with live birth. CONCLUSION(S): The use of HA-enriched transfer medium does not improve the live birth rate of FET compared with standard medium. TRIAL REGISTRATION NUMBER: NCT02725827 (ClinicalTrials.gov).

Women's age and total motile normal morphology sperm count predict fecundability: a prospective cohort study.

OBJECTIVE: This study investigated the role of women's age, serum anti-Müllerian hormone (AMH) level and semen parameters in predicting fecundability. METHODS: This was a prospective cohort study on couples attending for preconceptional health check. Occurrence of conception at 1 year after ceasing contraception and time to pregnancy were noted by telephone follow-up. The women's age, serum AMH level and total motile normal morphology sperm count (TMNC) were compared between those who conceived and those who did not after 1 year; their independent predictive value on conception at 1 year was analysed by logistic regression. Among those conceiving within 1 year, Spearman's correlations between time to pregnancy and the clinical parameters were studied. RESULTS: Of the 100 couples analysed, we found younger age of the women (p=0.008), higher serum AMH level (p=0.038) and higher TMNC (p=0.015) in those that conceived within 1 year. Multivariate logistic regression found that women's age (OR 0.867, 95% CI 0.761 to 0.988, p=0.032) and TMNC (OR 1.089, 95% 1.001-1.185, p=0.047), but not serum AMH level, significantly predicted conception within 1 year. Among those that conceived within 1 year, none of the parameters analysed were correlated with time to pregnancy within 1 year. CONCLUSIONS: Women's age and TNMC are significant independent predictors of conception within 1 year. No parameter was shown to predict the time to pregnancy within 1 year. This finding can aid preconceptional counselling of couples who are planning for pregnancy.