Comparison of the effect of dydrogesterone and natural micronized progesterone for luteal-phase support in assisted reproductive technology cycles: A single-blind randomized clinical trial study.

Background and Aims: One of the causes of preterm labor and recurrent abortion is progesterone deficiency in the luteal phase. The aim of the study was a comparison of the effect of oral dydrogesterone and vaginal progesterone for luteal-phase support (LPS) in assisted reproductive technology cycles (ART). Methods: This randomized clinical control trial study was conducted on 207 infertile women. Samples were randomly divided into two groups. The first group received a natural micronized vaginal progesterone (MVP) of 400 mg once daily and the second group received dydrogesterone (Duphestone) 20 mg twice daily. Then chemical pregnancy, abortion, and live births were compared in two groups. Results: The results of the study showed that the vaginal form of the drug could increase the chance of pregnancy (positive ß-human chorionic gonadotropin) versus the oral form. According to the results of multiple logistic regression analysis after adjusting for other variables, the live birth rate in the vaginal group was more than five times that of the oral group (odds ratio = 5.07; 95% confidence interval = 1.24-20.65; p = 0.023). Conclusion: The vaginal form of the progesterone could increase the chance of pregnancy and the outcome of fertility (live birth). Thus, vaginal progesterone is effective for LPS in women undergoing fresh embryo transfer.

SMFM Consult Series #70: Management of short cervix in individuals without a history of spontaneous preterm birth.

Most deliveries before 34 weeks of gestation occur in individuals with no previous history of preterm birth. Midtrimester cervical length assessment using transvaginal ultrasound is one of the best clinical predictors of spontaneous preterm birth. This Consult provides guidance for the diagnosis and management of a short cervix in an individual without a history of preterm birth. The following are Society for Maternal-Fetal Medicine recommendations: (1) we recommend that all cervical length measurements used to guide therapeutic recommendations be performed using a transvaginal approach and in accordance with standardized procedures as described by organizations such as the Perinatal Quality Foundation or the Fetal Medicine Foundation (GRADE 1C); (2) we recommend using a midtrimester cervical length of ≤25 mm to diagnose a short cervix in individuals with a singleton gestation and no previous history of spontaneous preterm birth (GRADE 1C); (3) we recommend that asymptomatic individuals with a singleton gestation and a transvaginal cervical length of ≤20 mm diagnosed before 24 weeks of gestation be prescribed vaginal progesterone to reduce the risk of preterm birth (GRADE 1A); (4) we recommend that treatment with vaginal progesterone be considered at a cervical length of 21 to 25 mm based on shared decision-making (GRADE 1B); (5) we recommend that 17-alpha hydroxyprogesterone caproate, including compounded formulations, not be prescribed for the treatment of a short cervix (GRADE 1B); (6) in individuals without a history of preterm birth who have a sonographic short cervix (10-25 mm), we recommend against cerclage placement in the absence of cervical dilation (GRADE 1B); (7) we recommend that cervical pessary not be placed for the prevention of preterm birth in individuals with a singleton gestation and a short cervix (GRADE 1B); and (8) we recommend against routine use of progesterone, pessary, or cerclage for the treatment of cervical shortening in twin gestations outside the context of a clinical trial (GRADE 1B).

Progesterone therapy for prevention of recurrent spontaneous preterm birth in a minority patient population: a retrospective study.

BACKGROUND: Preterm birth is a leading cause of infant morbidity and mortality worldwide. The burden of prematurity underscores the need for effective risk reduction strategies. The purpose of this study is to evaluate the efficacy of progesterone therapy, both intramuscular 17-α-hydroxyprogesterone caproate (IM 17-OHPC) and vaginal progesterone, in the prevention of recurrent spontaneous preterm birth (sPTB). The co-primary outcomes included: recurrent spontaneous PTB < 37 and < 34 weeks' gestation. METHODS: This retrospective cohort study included 637 pregnant patients that delivered at any of the three hospitals within the Los Angeles County healthcare system between October 2015 and June 2021. We compared frequencies of measured variables between each of the progesterone treated groups to no treatment using Pearson chi-squared tests and independent t-tests for categorical and continuous variables, respectively. We estimated crude and adjusted associations between each specific treatment (versus no treatment) and primary outcomes using logistic regression. RESULTS: Recurrent sPTB < 37 weeks' gestation occurred in 22.3% (n = 64) of those in the no treatment group, 29.1% (n = 86, p = .077) in the 17-OHPC group, and 14.3% (n = 6, p = 0.325) in the vaginal progesterone group. Recurrent sPTB < 34 weeks' gestation was 6.6% (n = 19) in the no treatment group, 11.8% (n = 35, p = .043) in the 17-OHPC group, and 7.1% (n = 3, p = 1) in the vaginal progesterone group. Among all participants, neither 17-OHPC nor vaginal progesterone was significantly associated with a reduction in recurrent sPTB at any time point. Among those with a short cervix, IM 17-OHPC was positively associated with recurrent sPTB < 37 weeks' gestation (aOR 5.61; 95% CI 1.16, 42.9). CONCLUSIONS: Progesterone therapy of any type did not reduce the risk of recurrent sPTB < 34 or < 37 weeks' gestation compared to no progesterone therapy.

Effects of vaginal progesterone and placebo on preterm birth and antenatal outcomes in women with singleton pregnancies and short cervix on ultrasound: a meta-analysis.

Background: Vaginal progesterone in preterm birth and adverse outcomes caused by cervical insufficiency remains controversial. To address it, the effect of vaginal progesterone on preterm delivery and perinatal outcome of single pregnancy women with short cervix (less than 25 mm) was systematically evaluated by meta-analysis. Methods: "Vaginal progesterone," "placebo," "ultrasound," "cervix," "singleton pregnancy," "preterm birth," and "antenatal outcomes" were entered to screen clinical studies PubMed, Embase, and the Chinese Biomedical Literature Database (CBM). The study population consisted of women with singleton pregnancies and a short cervix on ultrasound, and were assigned into the progesterone group (n = 1,368) and the placebo group (n = 1,373). Treatment began after the patient was diagnosed with short cervix until delivery. Neonatal survival rate, Neonatal Intensive Care Unit (NICU) admission rate, respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), neonatal mortality, and birth weight <1,500 g were analyzed. Results: A total of 8 articles, totaling 2,741 study subjects, were enrolled. The progesterone group exhibited an obvious reduced rate of preterm birth at <34 weeks (OR = 0.67, 95% CI: 0.53∼0.84; Z = 3.53, P = 0.004), preterm birth at <32 weeks (OR = 0.46, 95% CI: 0.28∼0.77; Z = 2.99, P = 0.003), NICU admission rate (OR = 0.45, 95% CI: 0.30∼0.66; Z = 0.15, P < 0.0001), RDS rate (OR = 0.42, 95% CI: 0.28∼0.63; Z = 4.25, P < 0.0001), IVH incidence rate (OR = 0.40, 95% CI: 0.17∼0.95; Z = 2.08, P = 0.04), neonatal mortality (OR = 0.25, 95% CI: 0.13∼0.46; Z = 4.39, P < 0.0001), and proportion of neonates with birth weight < 1,500 g (OR = 0.45, 95% CI: 0.32∼0.64; Z = 4.50, P < 0.0001). Conclusion: Vaginal progesterone lowered the incidences of preterm birth and adverse pregnancy outcomes in women with singleton pregnancies and a short cervix.

Can we improve the outcome of pregnancies with low serum PAPP-A in the first trimester?

OBJECTIVE: This study aimed to assess the impact of micronized progesterone (VMP4) supplementation on pregnancies with low serum pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) values during first-trimester screening. METHODS: Out of 8933 patients evaluated, 116 pregnant women with low PAPP-A concentrations in their blood and no fetal chromosomal anomalies (CAs) were included. Three groups were formed: group 1 received VMP4 from 11 to 16 weeks (29 women, 25%), group 2 received VMP4 from 11 to 36 weeks (25 women, 21.5%), and group 3 (62 women, 53.5%) served as controls without receiving progesterone. RESULTS: Results indicated that group 3 had higher rates of complications, including miscarriages (16.37%), preterm delivery (17.8%), and fetal developmental abnormalities (19.4%). Birthweight variations were elevated in pregnancies without progesterone, contrasting with lower variations in VMP4 groups. Group 2, receiving VMP4 until 36 weeks, reported the lowest incidence of abortion and preterm birth (PB), along with the highest mean birth weight. CONCLUSIONS: The conclusion suggests that 200 mg per day of VMP4 up to 36 weeks of supplementation led to fewer placental-related complications in women with very low PAPP-A at first-trimester screening (0.399 MoM). By reporting lower rates of miscarriages, PBs, and fetal developmental abnormalities in the micronized progesterone-treated groups, the study suggests a potential reduction in complications.

Comparison between oral dydrogesterone versus micronized vaginal progesterone gel in clinical outcome within the first HRT-FET cycle: a retrospective analysis.

OBJECTIVE: The purpose of this study is to compare the clinical efficacy of oral dydrogesterone and micronized vaginal progesterone (MVP) gel during the first HRT-FET cycle. METHODS: A retrospective cohort study based on a total of 344 women undergoing their first HRT-FET cycles without Gonadotropin-Releasing Hormone agonist (GnRH-a) pretreatment was conducted. All the cycles were allocated to two groups in the reproductive medical center at the University of Hong Kong-Shenzhen Hospital. One group (n = 193) received oral dydrogesterone 30 mg/d before embryo transfer, while the other group (n = 151) received MVP gel 180 mg/d. RESULTS: The demographics and baseline characteristics of two groups were comparable. We found no statistically significant difference in live birth rate (24.35% vs. 31.13%, P = 0.16), clinical pregnancy rate (34.72% vs. 36.42%, P = 0.74), embryo implantation rate (25.09% vs. 28.36%, P = 0.43), positive pregnancy rate (42.49% vs 38.41%, P = 0.45), miscarriage rate (9.33% vs 3.97%, P = 0.05), or ectopic pregnancy rate (0.52% vs. 0.66%, P = 0.86) between the oral dydrogesterone group and MVP gel group. In the multivariate logistic regression analysis for covariates, medication used for luteal support was not associated with live birth rate (OR = 0.73, 95% CI: 0.32-1.57, P = 0.45). And the different luteal support medication did not have a significant positive association with the live birth rate in the cycles with day 2 embryo transferred (OR = 1.39, 95% CI:0.66-2.39, P = 0.39) and blastocyst transferred (OR = 1.31 95% CI:0.64-2.69, P = 0.46). CONCLUSION: 30 mg/d oral dydrogesterone and 180 mg/d MVP gel revealed similar reproductive outcomes in HRT-FET cycles in the study.

Luteal phase support using micronized vaginal progesterone as pessaries or capsules in artificial cycles: is there any difference?

RESEARCH QUESTION: Is there a difference between the proportion of patients with serum progesterone <8.8 ng/ml on the day of embryo transfer when micronized vaginal progesterone (MVP) for luteal phase support (LPS) is given as pessaries versus capsules? DESIGN: This retrospective, matched-cohort, single-centre study compared pessaries (Cyclogest) versus capsules (Utrogestan, Progeffik) for LPS in hormone replacement treatment-embryo transfer (HRT-ET) cycles. Patients under 50 years old with a triple-layer endometrial thickness of ≥6.5 mm underwent transfer of one or two blastocysts. Serum progesterone concentrations were measured on the day of transfer; patients with concentrations <8.8 ng/ml received a single 'rescue' dose of additional progesterone by subcutaneous injection. RESULTS: In total 2665 HRT-ET cycles were analysed; 663 (24.9%) used pessaries for LPS and 2002 (75.1%) used capsules. Mean serum progesterone concentrations with standard deviations on the day of embryo transfer were significantly higher in the group using MVP pessaries compared with those using capsules (14.5 ± 5.1 versus 13.0 ± 4.8 ng/ml; P = 0.000). The percentage of participants with suboptimal serum progesterone concentrations on the day of embryo transfer (<8.8 ng/ml) was significantly lower in the pessary group than the capsule group (10.3%, 95% confidence interval [CI] 7.9-12.6% versus 17.9%, 95% CI 16.2-19.6%; adjusted odds ratio 0.426, 95% CI 0.290-0.625; P = 0.000). No differences in pregnancy outcome were observed between the groups. CONCLUSIONS: Using MVP pessaries rather than capsules for LPS resulted in significantly fewer patients having suboptimal serum progesterone concentrations on the day of embryo transfer. Consequently, almost 50% fewer patients in the pessary group needed rescue treatment.

Intra-individual variability of serum progesterone levels on the day of frozen blastocyst transfer in hormonal replacement therapy cycles.

STUDY QUESTION: Is there a significant intra-individual variability of serum progesterone levels on the day of single blastocyst Hormone Replacement Therapy-Frozen Embryo Transfer (HRT-FET) between two consecutive cycles? SUMMARY ANSWER: No significant intra-individual variability of serum progesterone (P) levels was noted between two consecutive HRT-FET cycles. WHAT IS KNOWN ALREADY: In HRT-FET cycles, a minimum P level on the day of embryo transfer is necessary to optimise reproductive outcomes. In a previous study by our team, a threshold of 9.8 ng/ml serum P was identified as significantly associated with the live birth rates in single autologous blastocyst transfers under HRT using micronized vaginal progesterone (MVP). Such patients may benefit from an intensive luteal phase support (LPS) using other routes of P administration in addition to MVP. A crucial question in the way towards individualising LPS is whether serum P measurements are reproducible for a given patient in consecutive HRT-FET cycles, using the same LPS. STUDY DESIGN, SIZE, DURATION: We conducted an observational cohort study at the university-based reproductive medicine centre of our institution focusing on women who underwent at least two consecutive single autologous blastocyst HRT-FET cycles between January 2019 and March 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients undergoing two consecutive single autologous blastocyst HRT-FET cycles using exogenous oestradiol and vaginal micronized progesterone for endometrial preparation were included. Serum progesterone levels were measured on the morning of the Frozen Embryo Transfer (FET), by a single laboratory. The two measurements of progesterone levels performed on the day of the first (FET1) and the second FET (FET2) were compared to evaluate the intra-individual variability of serum P levels. Paired statistical analyses were performed, as appropriate. MAIN RESULTS AND THE ROLE OF CHANCE: Two hundred and sixty-four patients undergoing two consecutive single autologous blastocyst HRT-FET were included. The mean age of the included women was 35.0 ± 4.2 years. No significant intra-individual variability was observed between FET1 and FET2 (mean progesterone level after FET1: 13.4 ± 5.1 ng/ml vs after FET2: 13.9 ± 5.0; P = 0.08). The characteristics of the embryo transfers were similar between the first and the second FET. Forty-nine patients (18.6%) had discordant progesterone levels (defined as one progesterone measurement > and one ≤ to the threshold of 9.8 ng/ml) between FET1 and FET2. There were 37/264 women (14.0%) who had high intra-individual variability (defined as a difference in serum progesterone values >75th percentile (6.0 ng/ml)) between FET1 and FET2. No specific clinical parameter was associated with a high intra-individual variability nor a discordant P measurement. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design. Moreover, only women undergoing autologous blastocyst HRT-FET with MVP were included, thereby limiting the extrapolation of the study findings to other routes of P administration and other kinds of endometrial preparation for FET. WIDER IMPLICATIONS OF THE FINDINGS: No significant intra-individual variability was noted. The serum progesterone level appeared to be reproducible in >80% of cases. These findings suggest that the serum progesterone level measured on the day of the first transfer can be used to individualize luteal phase support in subsequent cycles. STUDY FUNDING/COMPETING INTEREST(S): No funding or competing interests. TRIAL REGISTRATION NUMBER: N/A.

Nationwide status of progestogen treatment to prevent spontaneous preterm birth: A questionnaire survey for childbirth healthcare facilities in Japan.

AIM: This study aimed to investigate the current status of progestogen treatment for pregnant women at a high risk for preterm birth (PTB) in childbirth healthcare facilities in Japan. METHODS: A web-based nationwide questionnaire survey regarding progestogen use for prevention of PTB was conducted among childbirth healthcare facilities from 2019 to 2021. RESULTS: Valid responses were obtained from 528 facilities (25.2% of those surveyed), including 155 tertiary perinatal facilities (making up 92.3% of all tertiary perinatal care facilities). In the survey period, progestogen treatment was implemented in 207 facilities (39.2%) for PTB prevention. Regarding types of progestogens, 17α-hydroxyprogesterone caproate was used in 170 facilities (82.1%), with a low dose (125 mg/week) administered in 62.9% of the facilities to comply with the regulations of the national health insurance system, although 250 mg/week is considered the best dose. Vaginal progesterone was used in 36 facilities (17.4%), although the cost of vaginal progesterone was not covered by health insurance. Of the facilities not administering progestogen treatment, approximately 40% expressed that vaginal progesterone would be their first choice for PTB prevention in daily practice if it would be covered by health insurance in the future. CONCLUSIONS: Due to the current regulations of the Japanese health insurance system, 17α-hydroxyprogesterone caproate, rather than vaginal progesterone, was mainly used for PTB prevention. Despite global evidence supporting vaginal progesterone as the approach with the highest efficacy, only a limited number of facilities have utilized it due to the current drug use regulations in Japan.

The combination of dydrogesterone and micronized vaginal progesterone can render serum progesterone level measurements on the day of embryo transfer and rescue attempts unnecessary in an HRT FET cycle.

PURPOSE: To evaluate the role of serum progesterone (P4) on the day of embryo transfer (ET) when dydrogesterone (DYD) and micronized vaginal progesterone (MVP) are combined as luteal phase support (LPS) in a hormone replacement therapy (HRT) frozen ET (FET) cycles. METHODS: Retrospective study, including single euploid HRT FET cycles with DYD and MVP as LPS and P4 measurement on ET day. Initially, patients with P4 levels < 10 ng/ml increased MVP to 400 mg/day; this "rescue" was abandoned later. RESULTS: 560 cycles of 507 couples were included. In 275 women, serum P4 level was < 10 ng/ml on the ET day. Among those with low P4 levels, MVP dose remained unchanged in 65 women (11.6%) and was increased in 210 women (37.5%). Women with P4 levels ≥ 10 ng/ml continued LPS without modification. Overall pregnancy rates in these groups were 61.5% (40/65), 54.8% (115/210), and 48.4% (138/285), respectively (p = n.s.). Association of serum P4 levels with ongoing pregnancy rates was analyzed in women without any additional MVP regardless of serum P4 levels (n = 350); multivariable analysis (adjusted for age, BMI, embryo quality (EQ)) did not show a significant association of serum P4 levels with OPR (OR 0.96, 95% CI 0.90-1.02; p = 0.185). Using inverse probability treatment weights, regression analysis in the weighted sample showed no significant association between P4 treatment groups and OP. Compared to fair EQ, the transfer of good EQ increased (OR 1.61, 95% CI 1.22-2.15; p = 0.001) and the transfer of a poor EQ decreased the odds of OP (OR 0.73, 95% CI 0.55-0.97; p = 0.029). CONCLUSION: In HRT FET cycle, using LPS with 300 mg/day MVP and 30 mg/day DYD, it appears that serum P4 measurement and increase of MVP in patients with P4 < 10 ng/ml are not necessary.

A pragmatic evaluation of the implementation and acceptance of a universal second trimester cervical length screening program in an un-selected population.

PURPOSE: To evaluate patients' acceptance of a universal transvaginal ultrasound cervical length (CL) screening program and the feasibility of initiating treatment with progesterone in a clinical setting in women found to have a short cervix. METHODS: An observational, pragmatic cohort study was conducted at one tertiary care facility from 2012-2015, involving eligible women with singleton pregnancies who accepted and underwent second-trimester CL screening. The primary outcomes were the percentage of women who were eligible and accepting of screening, compliance with progesterone treatment, and the screening value of TVCL in predicting SPTB. Secondary outcomes were the number of women who received progesterone treatment and the rates of SPTB. RESULTS: Overall cervical length screening acceptance rate was found to be 82.5%. Of the 797 women that underwent screening, 21 women (2.6%) had a TVCL < 25 mm, of whom nine had a TVCL < 20.0 mm. Nineteen of the 21 women with a TVCL < 25 mm were treated with progesterone, with a 94.7% compliance rate. Delivery outcomes were obtained for 767 women. Of those with a TVCL < 25 mm, there was a 35% rate of SPTB as opposed to a 6.3% SPTB rate in those with TVCL > 25 mm. The negative predictive value for SPTB with a TVCL 25 mm or greater was 94.0%. CONCLUSION: Universal cervical length screening was successfully implemented in 82.5% of the patient population with a high compliance rate with progesterone treatment. Furthermore, there was a higher rate of SPTB in those with a shorter cervix. Based on our outcomes obtained in an observational and pragmatic manner, we showed that incorporating second trimester transvaginal cervical length screening into routine clinical practice is readily accepted and, with the addition of vaginal progesterone treatment, may reduce the rate of prematurity.

Oral micronized progesterone versus vaginal progesterone for luteal phase support in fresh embryo transfer cycles: a multicenter, randomized, non-inferiority trial.

STUDY QUESTION: Does oral micronized progesterone result in a non-inferior ongoing pregnancy rate compared to vaginal progesterone gel as luteal phase support (LPS) in fresh embryo transfer cycles? SUMMARY ANSWER: The ongoing pregnancy rate in the group administered oral micronized progesterone 400 mg per day was non-inferior to that in the group administered vaginal progesterone gel 90 mg per day. WHAT IS KNOWN ALREADY: LPS is an integrated component of fresh IVF, for which an optimal treatment regimen is still lacking. The high cost and administration route of the commonly used vaginal progesterone make it less acceptable than oral micronized progesterone; however, the efficacy of oral micronized progesterone is unclear owing to concerns regarding its low bioavailability after the hepatic first pass. STUDY DESIGN, SIZE, DURATION: This non-inferiority randomized trial was conducted in eight academic fertility centers in China from November 2018 to November 2019. The follow-up was completed in April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1310 infertile women who underwent their first or second IVF cycles were enrolled. On the day of hCG administration, the patients were randomly assigned to one of three groups for LPS: oral micronized progesterone 400 mg/day (n = 430), oral micronized progesterone 600 mg/day (n = 440) or vaginal progesterone 90 mg/day (n = 440). LPS was started on the day of oocyte retrieval and continued till 11-12 weeks of gestation. The primary outcome was the rate of ongoing pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In the intention-to-treat analysis, the rate of ongoing pregnancy in the oral micronized progesterone 400 mg/day group was non-inferior to that of the vaginal progesterone gel group [35.3% versus 38.0%, absolute difference (AD): -2.6%; 95% CI: -9.0% to 3.8%, P-value for non-inferiority test: 0.010]. There was insufficient evidence to support the non-inferiority in the rate of ongoing pregnancy between the oral micronized progesterone 600 mg/day group and the vaginal progesterone gel group (31.6% versus 38.0%, AD: -6.4%; 95% CI: -12.6% to -0.1%, P-value for non-inferiority test: 0.130). In addition, we did not observe a statistically significant difference in the rate of live births between the groups. LIMITATIONS, REASONS FOR CAUTION: The primary outcome of our trial was the ongoing pregnancy rate; however, the live birth rate may be of greater clinical interest. Although the results did not show a difference in the rate of live births, they should be confirmed by further trials with larger sample sizes. In addition, in this study, final oocyte maturation was triggered by hCG, and the findings may not be extrapolatable to cycles with gonadotropin-releasing hormone agonist triggers. WIDER IMPLICATIONS OF THE FINDINGS: Oral micronized progesterone 400 mg/day may be an alternative to vaginal progesterone gel in patients reluctant to accept the vaginal route of administration. However, whether a higher dose of oral micronized progesterone is associated with a poorer pregnancy rate or a higher rate of preterm delivery warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant from the National Natural Science Foundation of China (82071718). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the number ChiCTR1800015958. TRIAL REGISTRATION DATE: May 2018. DATE OF FIRST PATIENT'S ENROLMENT: November 2018.

Rectal progesterone administration secures a high ongoing pregnancy rate in a personalized Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) protocol: a prospective interventional study.

STUDY QUESTION: Can supplementation with rectal administration of progesterone secure high ongoing pregnancy rates (OPRs) in patients with low serum progesterone (P4) on the day of blastocyst transfer (ET)? SUMMARY ANSWER: Rectally administered progesterone commencing on the ET day secures high OPRs in patients with serum P4 levels below 35 nmol/l (11 ng/ml). WHAT IS KNOWN ALREADY: Low serum P4 levels at peri-implantation in Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) cycles impact reproductive outcomes negatively. However, studies have shown that patients with low P4 after a standard vaginal progesterone treatment can obtain live birth rates (LBRs) comparable to patients with optimal P4 levels if they receive additionalsubcutaneous progesterone, starting around the day of blastocyst transfer. In contrast, increasing vaginal progesterone supplementation in low serum P4 patients does not increase LBR. Another route of administration rarely used in ART is the rectal route, despite the fact that progesterone is well absorbed and serum P4 levels reach a maximum level after ∼2 h. STUDY DESIGN, SIZE, DURATION: This prospective interventional study included a cohort of 488 HRT-FET cycles, in which a total of 374 patients had serum P4 levels ≥35 nmol/l (11 ng/ml) at ET, and 114 patients had serum P4 levels <35 nmol/l (11 ng/ml). The study was conducted from January 2020 to November 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients underwent HRT-FET in a public Fertility Clinic, and endometrial preparation included oral oestradiol (6 mg/24 h), followed by vaginal micronized progesterone, 400 mg/12 h. Blastocyst transfer and P4 measurements were performed on the sixth day of progesterone administration. In patients with serum P4 <35 nmol/l (11 ng/ml), 'rescue' was performed by rectal administration of progesterone (400 mg/12 h) starting that same day. In pregnant patients, rectal administration continued until Week 8 of gestation, and oestradiol and vaginal progesterone treatment continued until Week 10 of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: Among 488 HRT-FET single blastocyst transfers, the mean age of the patients at oocyte retrieval (OR) was 30.9 ± 4.6 years and the mean BMI at ET 25.1 ± 3.5 kg/m2. The mean serum P4 level after vaginal progesterone administration on the day of ET was 48.9 ± 21.0 nmol/l (15.4 ± 6.6 ng/ml), and a total of 23% (114/488) of the patients had a serum P4 level lower than 35 nmol/l (11 ng/ml). The overall, positive hCG rate, clinical pregnancy rate, OPR week 12, and total pregnancy loss rate were 66% (320/488), 54% (265/488), 45% (221/488), and 31% (99/320), respectively. There was no significant difference in either OPR week 12 or total pregnancy loss rate between patients with P4 ≥35 nmol/l (11 ng/ml) and patients with P4 <35 nmol/l, who received rescue in terms of rectally administered progesterone, 45% versus 46%, P = 0.77 and 30% versus 34%, P = 0.53, respectively. OPR did not differ whether patients had initially low P4 and rectal rescue or were above the P4 cut-off. Logistic regression analysis showed that only age at OR and blastocyst scoring correlated with OPR week 12, independently of other factors like BMI and vitrification day of blastocysts (Day 5 or 6). LIMITATIONS, REASONS FOR CAUTION: In this study, vaginal micronized progesterone pessaries, a solid pessary with progesterone suspended in vegetable hard fat, were used vaginally as well as rectally. It is unknown whether other vaginal progesterone products, such as capsules, gel, or tablet, could be used rectally with the same rescue effect. WIDER IMPLICATIONS OF THE FINDINGS: A substantial part of HRT-FET patients receiving vaginal progesterone treatment has lowserum P4. Adding rectally administered progesterone in these patients increases the reproductive outcome. Importantly, rectal progesterone administration is considered convenient, and progesterone pessaries are easy to administer rectally and of low cost. STUDY FUNDING/COMPETING INTEREST(S): Gedeon Richter Nordic supported the study with an unrestricted grant as well as study medication. B.A. has received unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA and Marckyrl Pharma. P.H. has received honoraria for lectures from Gedeon Richter, Merck, IBSA and U.S.K. has received grant from Gedeon Richter Nordic, IBSA and Merck for studies outside this work and honoraria for teaching from Merck and Thillotts Pharma AB and conference expenses covered by Merck. The other co-authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER (25): EudraCT no.: 2019-001539-29.

Vaginal progesterone for the prevention of recurrent spontaneous preterm birth.

After the United States Food and Drug Administration pulled 17-alpha hydroxyprogesterone caproate from the market for its use in prevention of recurrent spontaneous preterm birth, national societies have had mixed recommendations regarding the management of patients with a singleton pregnancy and previous spontaneous preterm birth. Herein we highlight the randomized trial data and translational evidence supporting the use of vaginal progesterone for prevention of recurrent spontaneous preterm birth in singleton pregnancies. Prophylactic vaginal progesterone starting at 16 weeks and 0 days every night should be offered to patients with singletons and previous singleton spontaneous preterm birth regardless of cervical length, and continued along with placement of cerclage if a transvaginal ultrasound cervical length ≤25 mm is detected at <24 weeks.

Low serum progesterone on day of transfer adversely impacts ongoing pregnancy rates in hormonally prepared single blastocyst frozen embryo transfer cycles.

OBJECTIVE: To evaluate if serum progesterone (P) levels on the day of transfer influence ongoing pregnancy rate (OPR) in hormonally prepared single blastocyst frozen embryo transfer (FET) cycles? STUDY DESIGN: Single center prospective cohort study conducted between June 2021 and August 2022 analyzed 217 single good quality blastocyst FET cycles hormonally prepared with oral estradiol valerate and micronized vaginal progesterone 400 mg twice daily. RESULTS: Mean serum P on the day of embryo transfer (ET) was 9.76 ± 5.19 ng/ml. Receiver operator curve (ROC) showed a significant predictive value of serum P levels on the day of ET for OPR, with an area under curve (AUC) (95 %CI) = 0.58 (0.49-0.66). Optimal serum P threshold for OPR was 7.7 ng/ml (Sensitivity 76.8%, Specificity 43.7%). 35.9% patients had serum P below this threshold. BMI was significantly higher (26.8 ± 3.7 vs 25.6 ± 4.3; p = 0.048) in patients with serum P < 7.7 ng/ml vs ≥ 7.7 ng/ml. OPR was significantly lower (24.4% vs 45.3%; p = 0.002) and clinical miscarriage rates significantly higher (37.9% vs 19.2%; p = 0.042) if serum P < 7.72 ng/ml vs ≥ 7.7 ng/ml. CONCLUSION: This study found that serum P level on the day of transfer in hormonally prepared FET cycles was a significant predictor of OPR.

Serum progesterone concentration on pregnancy test day might predict ongoing pregnancy after controlled ovarian stimulation and fresh embryo transfer.

Progesterone (P4) is essential for pregnancy. A controlled ovarian stimulation (COS) leads to a iatrogenic luteal defect that indicates a luteal phase support (LPS) at least until pregnancy test day. Some clinicians continue the LPS until week 8 or later, when P4 is mainly secreted by syncytiotrophoblast cells.Measuring serum P4 on pregnancy test day after a fresh embryo transfer could help to identify women who might benefit from prolonged LPS. In women with LPS based on P4 administered by the rectal route, P4 concentration on pregnancy test day was significantly higher in patients with ongoing pregnancy than in patients with abnormal pregnancy.This monocentric retrospective study used data on 99 consecutive cycles of COS, triggered with human chorionic gonadotropin, followed by fresh embryo transfer resulting in a positive pregnancy test (>100 IU/L) (from November 2020 to November 2022). Patients undergoing preimplantation genetic screening or with ectopic pregnancy were excluded. All patients received standard luteal phase support (i.e. micronized vaginal progesterone 600 mg per day for 15 days). The primary endpoint was P4 concentration at day 15 after oocyte retrieval (pregnancy test day) in women with ongoing pregnancy for >12 weeks and in patients with miscarriage before week 12 of pregnancy.The median P4 concentration [range] at pregnancy test day was higher in women with ongoing pregnancy than in women with miscarriage (55.9 ng/mL [11.6; 290.6] versus 18.1 ng/mL [8.3; 140.9], p = 0.002). A P4 concentration ≥16.5 ng/mL at pregnancy test day was associated with higher ongoing pregnancy rate (OR = 12.5, 95% CI 3.61 - 43.33, p <0.001). A P4 concentration ≥16.5 ng/mL at pregnancy test day was significantly associated with higher live birth rate (OR = 11.88, 95% CI 3.30-42.71, p <0.001).After COS and fresh embryo transfer, the risk of miscarriage is higher in women who discontinue luteal support after 15 days, as recommended, but with P4 concentration <16.5 ng/mL. The benefit of individualized prolonged luteal phase support should be evaluated.

New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline.

BACKGROUND: There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product profiles (TPPs) for medicines to prevent spontaneous preterm birth and manage preterm labor. The objectives of this study were to 1) analyse the research and development pipeline of medicines for preterm birth and 2) compare these medicines to target product profiles for spontaneous preterm birth to identify the most promising candidates. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched to identify candidate medicines (including drugs, dietary supplements and biologics) and populate the Accelerating Innovations for Mothers (AIM) database. This database was screened for all candidates that have been investigated for preterm birth. Candidates in clinical development were ranked against criteria from TPPs, and classified as high, medium or low potential. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 178 candidates. Of the 71 candidates in clinical development, ten were deemed high potential (Prevention: Omega-3 fatty acid, aspirin, vaginal progesterone, oral progesterone, L-arginine, and selenium; Treatment: nicorandil, isosorbide dinitrate, nicardipine and celecoxib) and seven were medium potential (Prevention: pravastatin and lactoferrin; Treatment: glyceryl trinitrate, retosiban, relcovaptan, human chorionic gonadotropin and Bryophyllum pinnatum extract). 107 candidates were in preclinical development. CONCLUSIONS: This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals.

Changes in use of 17-OHPC after the PROLONG trial: a physician survey.

OBJECTIVES: To determine if 17α-hydroxyprogesterone caproate (17OHPC) or vaginal progesterone use for patients at risk for preterm birth has changed since the publication of the 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG) trial, and to assess which organizations' (Food and Drug Administration's [FDA], American College of Obstetrics and Gynecology's [ACOG] or Society of Maternal Fetal Medicine's [SMFM]) statements most influenced change. METHODS: Through a vignette-based physician survey, we sought to measure (by Likert scale) how counseling tendencies regarding 17OHPC and vaginal progesterone have changed since the PROLONG trial publication. Participants were also asked which organizations' statements most influenced change. RESULTS: With response rate of 97 % (141/145), a pre-to-post PROLONG trial comparison revealed significant changes in counseling for progesterone. Respondents were less likely to recommend 17OHPC (p<0.001) and more likely to recommend vaginal (p<0.001). The FDA statement most influenced the decision not to recommend 17OHPC for the prevention of preterm birth (r=-0.23, p=0.005). CONCLUSIONS: Providers have made significant changes in their counseling regarding progesterone use for patients at risk for preterm birth after the publication of the PRLONG trial.

The association between the type of progesterone supplementation and miscarriage risk in women who have had a positive pregnancy test following embryo transfer: a retrospective cohort study.

PURPOSE: The purpose of this study was to identify if switching from intramuscular (IM) to vaginal progesterone compared to staying on IM progesterone after a positive pregnancy test following embryo transfer (ET) is associated with miscarriage risk. METHODS: A retrospective cohort study was performed in a private university-affiliated fertility clinic and included women aged 18-50 years with a positive pregnancy test following ET. The two groups studied were: women who stayed on IM progesterone following a positive pregnancy test and those who switched to vaginal progesterone after a positive test. The main outcome measured was risk of miscarriage < 24 weeks gestation as a proportion of non-biochemical pregnancies. RESULTS: 1988 women were included in the analysis. Among the baseline characteristics, the presence of prior miscarriages as well as prior failed ETs, and frozen cycles (vs fresh) as type of transfer were associated with IM progesterone use (p values ≤ 0.01). As per miscarriage risk < 24 weeks, 22.4% (274/1221) of patients in the IM progesterone group experienced a miscarriage compared with 20.7% (159/767) in the vaginal progesterone group (OR 0.90; 95% CI 0.73-1.13). A multivariable logistic regression model revealed an adjusted OR (aOR) of 0.97 (95% CI 0.77-1.22). CONCLUSION: This study suggests that switching from IM to vaginal progesterone after a positive pregnancy test following an ET is not associated with miscarriage risk. Considering that IM progesterone imposes substantial discomfort, this study offers reassurance and some flexibility in treatment protocols. Further prospective studies are necessary to corroborate the results of this study.

Combined vaginal progesterone and cervical cerclage in the prevention of preterm birth: a systematic review and meta-analysis.

OBJECTIVE: Vaginal progesterone and cervical cerclage are both effective interventions for reducing preterm birth. It is currently unclear whether combined therapy offers superior effectiveness than single therapy. This study aimed to determine the efficacy of combining cervical cerclage and vaginal progesterone in the prevention of preterm birth. DATA SOURCES: We searched Medline (Ovid), EMBASE (Ovid), PsycINFO (Ovid), CINAHL (EBSCOhost), Cochrane Library (Wiley), and Scopus (from their inception to 2020). STUDY ELIGIBILITY CRITERIA: The review accepted randomized and pseudorandomized control trials, nonrandomized experimental control trials, and cohort studies. High risk patients (shortened cervical length <25mm or previous preterm birth) who were assigned cervical cerclage, vaginal progesterone, or both for the prevention of preterm birth were included. Only singleton pregnancies were assessed. METHODS: The primary outcome was birth <37 weeks. Secondary outcomes included birth <28 weeks, <32 weeks and <34 weeks, gestational age at delivery, days between intervention and delivery, preterm premature rupture of membranes, cesarean delivery, neonatal mortality, neonatal intensive care unit admission, intubation, and birthweight. Following title and full-text screening, 11 studies were included in the final analysis. Risk of bias was assessed using the Cochrane Collaboration tool for assessing the risk of bias (ROBINS-I and RoB-2). Quality of evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) tool. RESULTS: Combined therapy was associated with lower risk of preterm birth at <37 weeks than cerclage alone (risk ratio, 0.51; 95% confidence interval, 0.37-0.79) or progesterone alone (risk ratio, 0.75; 95% confidence interval, 0.58-0.96). Compared with cerclage only, combined therapy was associated with preterm birth at <34 weeks, <32 weeks, or <28 weeks, decreased neonatal mortality, increased birthweight, increased gestational age, and a longer interval between intervention and delivery. Compared with progesterone alone, combined therapy was associated with preterm birth at <32 weeks, <28 weeks, decreased neonatal mortality, increased birthweight, and increased gestational age. There were no differences in any other secondary outcomes. CONCLUSION: Combined treatment of cervical cerclage and vaginal progesterone could potentially result in a greater reduction in preterm birth than in single therapy. Further, well-conducted and adequately powered randomized controlled trials are needed to assess these promising findings.