Progesterone supplementation for prevention of preterm birth.

Objective: To study the efficacy of Progesterone supplementation for prevention of preterm birth. Study Design: Descriptive Interventional Study. Setting: Department of Obstetrics and Gynecology at Independent University Hospital, Faisalabad. Period: January 2018 to December 2020. Material & Methods: Data collected by using Non probability consecutive sampling techniques. Total 156 patients were included in study. Data was collected after informed consent, on pre designed proforma. Patient presented in 1st trimester and having previous history spontaneous preterm labour and recurrent miscarriages. We included patient presenting after 24 weeks of pregnancy and patient having threatened or actual preterm labour. Results: Among 156 patients, more than 82% of patient were delivered after 34 weeks of gestation and 18% were delivered before 34 weeks of gestation. Fetal outcome was very good in those patients who were delivered after 34 weeks of gestation with the use of Prophylactic progesterone therapy. Conclusion: Prophylactic use of progesterone helps in prolongation of pregnancy beyond 36 weeks and also help in decreasing the morbidity associated with premature delivery.

“PREGNANCY OUTCOME IN CERVICAL INCOMPETENCE: COMPARISON OF COMBINED USE OF CERCLAGE AND ORAL PROGESTERONE VERSES HIGH DOSE OF VAGINAL PROGESTERONE”

INTRODUCTION- Cervical insufciency, earlier known as cervical incompetence, is the inability of the cervix to maintain pregnancy till term due to structural or functional defects. Approximately 16.25% of second-trimester pregnancy losses and 2% of premature deliveries are due to cervical incompetence. OBJECTIVE- The purpose of this study was to compare the outcome of pregnancy in patients who underwent early (12-16 weeks) cervical cerclage along with oral progesterone supplementation versus those having remedied with high dose intravaginal progesterone supplementation. MATERIAL AND METHODst This retrospective study was conducted in a maternity hospital in Gwalior from 1 January 2018 to th 30 June 2021. Comprehensive history, thorough clinical examination, laboratory investigations, ultrasonography measurement of cervical length, mode of delivery, gestational age at the time of delivery, neonatal outcome, NICU admission, and other parameters were collected from the medical les. patients were divided into two groups. Ÿ Group 1(N-49) – Those who were remedied with high-dose vaginal progesterone supplementation continued uptil 34 wks of gestation. Group 2 (N-49) – Those who underwent Mc Donald type of cervical encerclage at 12-16 weeks along with oral progesterone (10 mg Duphaston twice daily dose) supplementation continued up till 34 weeks of gestation. RESULT- In our study, in the cervical cerclage group, only (4.1%) patients were delivered before 34 weeks while in the vaginal progesterone group (18.4%) patients were delivered before 34 weeks. In the cervical cerclage group (53.1%) patients were delivered between 34-37 weeks while in the vaginal progesterone group, (44.9%) of the patient delivered between 34-37 weeks. In the cervical cerclage group, the cesarean section rate was lower than only the vaginal progesterone group and admission to NICU of babies was also less (22.4%) in this group in comparison to the vaginal progesterone only group (36.7%). CONCLUSION- Our study showed that cervical cerclage plus oral progesterone supplementation in women with extremely shortened cervix signicantly decreased overall spontaneous preterm birth rates, prolonged pregnancy latency, and decreased the overall neonatal morbidity and mortality and is more effective than the vaginal progesterone group.

Pregnancy-related complications and perinatal outcomes following progesterone supplementation before 20 weeks of pregnancy in spontaneously achieved singleton pregnancies: a systematic review and meta-analysis

Background Progesterone supplementation is widely performed in women with threatened miscarriage or a history of recurrent miscarriage; however, the effects of early progesterone supplementation on pregnancy-related complications and perinatal outcomes in later gestational weeks remain unknown. Methods Ovid MEDLINE, the Cochrane Library, Embase and ClinicalTrials.gov were searched until April 3rd, 2021. Randomized controlled trials regarding spontaneously achieved singleton pregnancies who were treated with progestogen before 20 weeks of pregnancy and were compared with those women in unexposed control groups were selected for inclusion. We performed pairwise meta-analyses with the random-effects model. The risk of bias was assessed according to the Cochrane Collaboration tool. The primary outcomes included preeclampsia (PE), and gestational diabetes mellitus (GDM), with the results presented as odds ratios (ORs) with 95% confidence intervals (CIs). Results We identified nine eligible studies involving 6439 participants. The pooled OR of subsequent PE following early progestogen supplementation was 0.64 (95% CI 0.42–0.98, moderate quality of evidence). A lower OR for PE was observed in the progestogen group when the subgroup analysis was performed in the vaginal subgroup (OR 0.62, 95%CI 0.40–0.96). There was insufficient evidence of a difference in the rate of GDM between pregnant women with early progestogen supplementation and unexposed pregnant women (OR 1.02, 95% CI 0.79–1.32, low quality of evidence). The pooled OR of low birth weight (LBW) following oral dydrogesterone was 0.57 (95% CI 0.34–0.95, moderate quality of evidence). The results were affected by a single study and the total sample size of enrolled women did not reach the required information size. Conclusion Use of vaginal micronized progesterone (Utrogestan) in spontaneously achieved singleton pregnancies with threatened miscarriage before 20 weeks of pregnancy may reduce the risk of PE in later gestational weeks. Among spontaneously achieved singleton pregnancies with threatened miscarriage or a history of recurrent miscarriage, use of oral dydrogesterone before 20 weeks of pregnancy may result in a lower risk of LBW in later gestational weeks. However, the available data were not sufficient to reach definitive conclusions, which highlighted the need for future studies.

Progesterone supplementation in mice leads to microbiome alterations and weight gain in a sex-specific manner

BackgroundProgesterone is a steroid hormone produced by the ovaries, involved in pregnancy progression and necessary for successful gestation. We have previously shown that progesterone affects gut microbiota composition and leads to increased relative abundance of Bifidobacterium.ResultsIn non-pregnant female GF mice, levels of progesterone were significantly higher than in SPF mice of the same status. However, no significant differences were observed between GF and SPF males. Females treated with progesterone gained more weight than females treated with a placebo. In contrast to female mice, males treated with progesterone did not gain significantly more weight than males treated with a placebo. Progesterone supplementation led to microbial changes in females but not in males (16S rRNA sequencing). Accordingly, the weight gain observed in female mice treated with progesterone was fully transferable to both male and female germ-free mice via fecal transplantation.ConclusionsWe demonstrate that bacteria play a role in regulating progesterone levels in a female-specific manner. Furthermore, weight gain and metabolic changes associated with progesterone may be mediated by the gut microbiota.

O-198 Progesterone supplementation in women with threatened miscarriage: A randomised placebo-controlled clinical trial

Study question In women with threatened miscarriage, does progesterone supplementation increase the probability of live birth? Summary answer In women with threatened miscarriage, 400 mg progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates. What is known already Women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg. A recently published large randomised clinical trial indicated no overall benefit for progesterone until 16 weeks, although subgroup analysis in women with bleeding and at least one previous miscarriage, progesterone might be of benefit (Coomarasamy et al; N Engl J Med 2019;380:1815-1824). Study design, size, duration We performed a single centre placebo-­controlled randomised clinical trial. After informed consent, women with threatened miscarriage as apparent from vaginal bleeding under 10 weeks, were randomised to 400 mg vaginal micronized progesterone or placebo. The primary endpoint was livebirth. Secondary endpoints were perinatal outcomes, including preterm birth and birthweight. The planned sample size was 386 women. At a planned interim analysis randomisation was halted at 278 women due to lack of effectiveness and slow recruitment. Participants/materials, setting, methods Between February 2012 and April 2019 we randomised 139 women to 400 mg vaginal micronized progesterone and 139 women to placebo. Primary outcome data are available for 134 women in the progesterone arm and 130 women in the placebo arm. Mean age was 30.7 and 30.4 years. The number of women without a previous miscarriage was 68 (51%) and 55 (42%), while 66 (49%) and 75 (58%) women had at least one previous miscarriage. Main results and the role of chance The live birth rates were 113/134 (84.3%) and 112/130 (86.2%), respectively (RR 0.98, 95% CI 0.89-1.08). Among women with at least 1 miscarriage live birth rates were 55/66 (83.3%) and 65/75 (86.7%) (RR 0.96, 95% CI 0.84-1.11). The number of women with more than 1 miscarriage was limited (26 vs 33 in total), but no effect was seen from progesterone in these women. Preterm birth rates were 12.9% and 9.3% (RR 1.38; 95% CI 0.69 to 2.78). There were five pregnancy losses between 20 and 23 weeks, all in the progesterone arm. Mean birth weight was 3310 vs 3300 gram (p=.99). There were also no other differences in obstetric and perinatal outcomes. Anxiety, stress and depression scores did not differ between the groups. Limitations, reasons for caution Our study was single centre and did not reach the planned sample size. We stopped study medication at 12 weeks which might explain the difference between our study and studies that continued progesterone till 16 weeks. Wider implications of the findings In women with threatened miscarriage, 400 mg vaginal progesterone did not improve live birth rates. Trial registration number ACTRN12611000405910

P–672 Higher pregnancy outcomes in patients undergoing embryo transfer-under hormonal replacement therapy where an individualised Progesterone supplementation was applied on the day of β-hCG

Study question Does progesterone-supplementation (PS) from the day of β-hCG assessment improve pregnancy rates in embryo transfer-under hormonal replacement therapy (ET-HRT) in patient with Progesterone (P)<10.6 ng/mL? Summary answer Reduced P on the β-hCG day is associated with lower pregnancy-rates and higher miscarriage-rate. PS from the same day showed significant increase of reproductive outcomes. What is known already Up until now, in ART, very little has been done to understand whether the P intake should be personalized during the luteal phase. Most recent studies on the topic showed that low P levels on the day of ET-HRT or on the day before are associated with decreased pregnancy rates; however, when low P values are supplemented from the day before embryo-transfer (ET), similar results to cases with adequate P are reported. Nevertheless, little is known about the association between low P level, on the day of β-hCG (P- β-hCG) and PS from this day in ET-HRT, and pregnancy outcomes. Study design, size, duration This is a single centre, cohort, retrospective study conducted at a university-affiliated fertility centre between January 2018 and June 2020 where PS took place from the day of positive β-hCG determination when P < 10.6 ng/mL. In total 789 ET-HRT cycles were analysed of which 239 were performed in both fresh and frozen heterologous ET-HRT (het-ET), 336 in homologous ET-HRT (hom-FET) and 214 in euploid ET-HRT (eu-FET) after preimplantation genetic testing for aneuploidies IVF cycles (PGT-A). Participants/materials, setting, methods Women undergoing ET-HRT with normal P (>10.6ng/mL) on the day before ET were screened for P on the day of β-hCG. All women received vaginal P 200 mg/8 hours for the second part of HRT. PS was performed by adding P to the HRT when P- β-hCG was considered low (<10.6 ng/mL). Primary outcome: ongoing-pregnancy-rate (OPR); secondary outcome: miscarriage-rate (MR). Both were evaluated by considering PS on the day of β-hCG as a categorical variable. Main results and the role of chance Patients characteristics were comparable between groups (het-ET, hom-FET and eu-FET) although significantly lower body mass index was found when P- β-hCG>10.6 ng/mL compared to the subgroup with P- β-hCG<10.6 ng/mL and no PS (p = 0.012). Overall clinical pregnancy rate was 52.1% with no-significant differences between groups (48.5% in het-ET, 52.9% in hom-FET and 54.7% in eu-FET). P- β-hCG was considered as adequate in 75.7% (311/411) ET-HRT with positive β-hCG and low in 24.3% (100/411), with no differences between groups. In case of positive β-hCG and P- β-hCG >10.6 ng/mL, OPR was 83.6% and MR was 16.4%, with no-significant differences between groups. Among the 100 low P- β-hCG, 80 ET-HRT received PS. In this subgroup OPR was 96.2% and MR was 3.8%, with no-significant differences between groups. In 20 out of 100 ET with P- β-hCG <10.6 ng/mL, no PS was added for different reasons. This group showed the lowest OPR (30%) and the highest MR (70%), again with no between-group differences according to het-ET, hom-FET or eu-FET. Miscarriage rate was significantly higher (p < 0.001) when P- β-hCG was <10.6 ng/mL and no PS was added to HRT compared to P- β-hCG <10.6 ng/mL but with PS, and also compared to the P- β-hCG >10.6 ng/mL group. Limitations, reasons for caution The main limitation of the study is due to its retrospective nature and the small sample of patients with P- β-hCG<10.6 ng/mL that was not supplemented. Furthermore, the cut-off of P- β-hCG was arbitrarily decided upon previous studies, and lastly different routes of administration were considered for the PS. Wider implications of the findings: The results of this study showed that individualization of Progesterone supplementation in ET-HRT may be a crucial turn point in order to increase the pregnancy rates and decrease the miscarriage rates. An adequate PS should be considered in case of low P- β-hCG levels for both het-ET, hom-FET and eu-FET. Trial registration number Not applicable

P–484 Progesterone supplementation in modified natural frozen embryo transfer (mNC-FET) does not cause mental health adverse effects - A sub-study of a multicenter RCT

Study question Do women undergoing mNC-FET with progesterone supplementation experience mental health adverse effects at a greater rate compared to a control group. Summary answer Progesterone supplementation does not affect mental wellbeing in women undergoing mNC-FET. What is known already Women and men undergoing assisted reproductive treatment more likely to experience stress and other adverse psychological effects than the background population. Various factors such as parental age, cause of infertility and treatment method have been shown to affect patient well-being. Progesterone supplementation is known to cause various physical adverse effects, yet few studies have investigated the potential mental health adverse effects of progesterone supplementation in FET. Study design, size, duration This is a sub-study of an ongoing RCT investigating the effect of luteal phase progesterone supplementation in mNC-FET. The aim is to investigate possible mental health adverse effects of progesterone. From 2019–2021 a total of 164 women were included (n = 84 and n = 82 in the progesterone and control group, respectively). The health and wellbeing self-reporting survey was fulfilled after randomization on hCG trigger + 11 days. Participants/materials, setting, methods A validated, electronic questionnaire in Danish was used to measure mental wellbeing in women aged 18–41 years undergoing mNC-FET with and without use of progesterone supplementation in the luteal phase at seven Danish public hospitals. Women were randomized to either progesterone treatment or no progesterone by a computerized randomization algorithm with minimization for female age > =37 years, previous oocyte retrievals and previous FET. Comparisons of survey responses were performed by chi-square tests. Main results and the role of chance The survey response rate was 68%. We observed no significant differences in any of the three items between the progesterone group and the control group. On the first item “to which degree have you felt sensitive due to treatment”, 56% and 52% responded “to a large degree” or “to some degree” sensitive in the progesterone vs. control group, while 25% and 34% vs. 19% and 13% responded “to a lesser extent” or “not at all” sensitive in progesterone vs. controls (P = 0.35). On the second item, “to which degree have you felt aggressive due to treatment”, 10% and 9% responded “to a large degree” or “to some degree”, 29% and 22% answered “to a lesser degree” and 62% and 70% responded “not at all” in the progesterone vs control group (P = 0.57). On the third item “to which degree have you cried unexpectedly due to treatment” 25% and 18% responded “to a large degree” or “to some degree” in the progesterone vs control group, 20% and 27% answered “to a lesser extent”, while 55% in both groups answered “not at all” (P = 0.44). Limitations, reasons for caution In a self-reported survey selection bias, due to a less than 100% response rate, and reporting bias cannot be excluded. However with the possibility to answer the survey online at leisure, the risk of reporting bias is minimized. Wider implications of the findings: A large concern for clinicians working with ART is patient wellbeing. Our study suggests that luteal phase support does not cause extra emotional distress, though further research is needed. Trial registration number NCT03795220