Vaginal Progesterone Administration Research Articles

Does the route of administration matter? Systematic review and meta-analysis of randomized clinical trials between vaginal versus intramuscular progesterone administration in the prevention of preterm birth

Does the route of administration matter? Systematic review and meta-analysis of randomized clinical trials between vaginal versus intramuscular progesterone administration in the prevention of preterm birth

Cervical elastography in predicting spontaneous preterm birth in singleton pregnancy with a short cervix receiving progesterone treatment at 18 to 24 weeks’ gestation

Background A short cervix in the second trimester is known to increase the risk of preterm birth, which can be reduced with the administration of vaginal progesterone. However, some studies have suggested that a significant number of cases still experience preterm birth despite progesterone treatment. Objective This study was aimed to investigate the potential value of transvaginal cervical elasticity measured by E-Cervix as a predictor for spontaneous preterm birth (sPTB) in singleton pregnancies receiving progesterone treatment for a short cervix (CL ≤ 2.5 cm) diagnosed at 18 to 24 weeks’ gestation. Study design This prospective study was conducted at a single center premature high-risk clinic from January 2020 to July 2022. Singleton pregnancies with a short cervix at 18 to 24 weeks’ gestation were enrolled. Cervical elastography using E-Cervix was performed, and maternal and neonatal demographic characteristics, cervical length (CL), elasticity contrast index (ECI), cervical hardness ratio, mean internal os strain (IOS), and mean external os strain (EOS) were compared before and after progesterone treatment in sPTB and term birth groups. Multivariate logistic regression was used to analyze the association between elasticity parameters and spontaneous preterm birth. The screening performance of CL and optimal cervical elasticity parameters in predicting sPTB was evaluated using receiver-operating characteristic (ROC) curve analysis. Results A total of 228 singleton pregnant women were included in the study, among which 26 (11.4%) had sPTB. There were no significant differences in maternal characteristics and gestational age at enrollment between women with and without sPTB. At the start of progesterone treatment, there were no significant differences in cervical elasticity parameters between the two groups. After two weeks of progesterone treatment, women who had sPTB showed significantly higher levels of ECI, IOS, EOS (p = 0.0108, 0.0001, 0.016), and lower hardness ratio (p = 0.011) compared to those who had a full-term birth. Cervical length did not show significant differences between the two groups, regardless of whether progesterone treatment was administered before or after. Among the post-treatment cervical elasticity parameters, IOS and EOS were associated with a 3.38-fold and 2.29-fold increase in the risk of sPTB before 37 weeks (p = 0.032, 0.047, respectively). The AUROC of the combined model including CL, IOS, and EOS (0.761, 95% CI0.589–0.833) was significantly higher than the AUROC of CL alone (0.618, 95% CI 0.359–0.876). At a fixed false-positive of 13%, the addition of IOS and EOS in the CL model increased sensitivity from 34.6% to 57.6%, PPV from 25.7% to 36.5%, and NPV from 91.1% to 94.1%. Conclusion When assessing the risk of sPTB in singleton pregnancies with a short cervix receiving progesterone therapy, relying solely on cervical length is insufficient. It is crucial to also evaluate cervical stiffness, particularly the strain of the internal and external os, using cervical elastography.

Circadian serum progesterone variations on the day of frozen embryo transfer in artificially prepared cycles

Research questionWhat is the intra-day variation of serum progesterone related to vaginal progesterone administration on the day of frozen embryo transfer (FET) in an artificial cycle? DesignA prospective cohort study was conducted including 22 patients undergoing a single blastocyst artificial cycle (AC)–FET from August to December 2022. Endometrial preparation was achieved by administering oestradiol valerate (2 mg three times daily) and consecutively micronized vaginal progesterone (MVP; 400 mg twice daily). A blastocyst FET was performed on the 6th day of MVP administration. Serum progesterone concentrations were measured on the day of transfer at 08:00, 12:00, 16:00 and 20:00 hours. The first and last blood samples were collected just before MVP was administered. ResultsThe mean age and body mass index of the study population were 33.95 ± 3.98 years and 23.10 ± 1.95 kg/m2. The mean P-values at 08:00, 12:00, 16:00 and 20:00 hours were 11.72 ± 4.99, 13.59 ± 6.33, 10.23 ± 3.81 and 9.28 ± 3.09 ng/ml, respectively. A significant decline, of 2.41 ng/ml (95% confidence interval 0.81–4.00), was found between the first and last progesterone measurements. ConclusionA statistically significant intra-day variation of serum progesterone concentrations on the day of FET in artificially prepared cycles was observed. This highlights the importance of a standardized procedure for the timing of progesterone measurement on the day of AC–FET. Of note, the study results are applicable only to women using MVP for luteal phase support; therefore it is necessary to confirm its validity in comparison with the different existing administration routes of progesterone.

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.

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)? Rectally administered progesterone commencing on the ET day secures high OPRs in patients with serum P4 levels below 35 nmol/l (11 ng/ml). 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. 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. 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. 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). 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. 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. 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. EudraCT no.: 2019-001539-29.

P-511 Prolonging the time of vaginal progesterone supplementation does not improve pregnancy outcomes after day 6 blastocyst transfer

Abstract Study question Does the administration of vaginal progesterone for 6 days improve pregnancy outcomes when transferring day 6 blastocysts, as opposed to 5 days of progesterone treatment? Summary answer We observed similar pregnancy outcomes after 5 and 6 days of vaginal progesterone supplementation following day 6 blastocyst transfer in oocyte recipient cycles. What is known already Progesterone administration promotes the final phase of endometrial preparation for embryo transfer. However, the optimal duration of progesterone transformation still remains unknown. The implantation potential of blastocysts formed at different timepoints is also contentious, as blastocysts on day 6 have been linked to poorer clinical outcomes compared to their day 5 counterparts. It is unclear whether this effect stems from an intrinsic impaired implantation capacity of slow-developing blastocysts, or a displaced window of implantation (WOI). It has been hypothesized that 6 days of progesterone administration may improve clinical outcomes after frozen day 6 blastocyst transfer. Study design, size, duration Retrospective cohort study of oocyte recipients undergoing single day 6 blastocyst transfer, between January 2020 and December 2022. This study compared two groups: day 6 blastocysts transferred after 5 days of progesterone administration (n = 284) and day 6 embryo transfers performed after 6 days of progesterone administration (n = 69). Participants/materials, setting, methods Our study included oocyte recipients who underwent a single embryo transfer of a day 6 blastocyst and hormonal replacement treatment for endometrial preparation with vaginal external progesterone administration (800mg/24h) for either 5 or 6 days prior to embryo transfer. Outcomes were analyzed using unpaired t-test or Fisher’s test and logistic regression. Multivariate models were adjusted for oral or transdermal estrogen administration and endometrial thickness on the day of embryo transfer. P-values &amp;lt;0.05 were considered significant. Main results and the role of chance Mean maternal age was 43.5 years, while patients had a mean BMI of 25.1. Mean days of estrogen therapy prior to embryo transfer were 22.4, with 75.3% of patients using transdermal estrogen administration, and achieving a mean endometrial thickness of 9.6 mm on the day of transfer. Mean progesterone levels on the day of transfer were 11.9 ng/ml. Thirty-seven percent of the day 6 blastocysts were of high quality. None of the demographic or cycle characteristics were significantly different between the study groups. When considering outcomes of day 6 blastocyst transfers, we found no significant differences in biochemical (26.33% vs 20.13%, p = 0.343), clinical (22.06% vs 17.46%, p = 0.49) and ongoing (14.64% vs 9.52%, p = 0.41) pregnancy rates between 5 and 6 days of progesterone administration. Our adjusted analysis further corroborated these results. Limitations, reasons for caution The retrospective nature of the study and low number of transfers performed after 6 days of progesterone treatment warrant careful interpretation. This study only evaluated endometrial preparation by vaginal progesterone administration in oocyte recipients and cannot be extrapolated to other routes of progesterone administration or other patient populations. Wider implications of the findings Poorer reproductive outcomes associated with the transfer of day 6 blastocysts appear to be related to a reduced implantation capacity of slow-developing embryos rather than a displaced WOI due to rising progesterone. WOI appears wider than assumed, as prolonged progesterone transformation times had no effect on pregnancy outcomes. Trial registration number Not applicable

P-596 Rectal progesterone administration secures high ongoing pregnancy rate in a personalized Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) protocol - a prospective interventional study

Abstract Study question Can supplementation with additional rectal administration of progesterone secure high ongoing pregnancy rates (OPR) in patients with low serum progesterone (P4) at blastocyst transfer (ET)? Summary answer Rectally administered progesterone starting on the blastocyst transfer day secures high OPR in patients with serum P4 levels lower than 35 nmol/l (11ng/ml). What is known already Low serum P4 levels at peri-implantation in 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 (LBR) comparable to patients with optimal P4 levels if they receive additional subcutaneous progesterone, starting close to 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, although progesterone is well absorbed and serum P4 levels reach a maximum level after approximately two hours. Study design, size, duration This prospective interventional study included a cohort of 488 patients treated with single blastocyst HRT-FET, in which a total of 374 patients had a serum P4 level ≥35nmol/l (11ng/ml) at ET, and 114 patients had a serum P4 level &amp;lt;35nmol/l (11ng/ml). The study was conducted from January 2020 to November 2022. Participants/materials, setting, methods Patients undergoing HRT-FET in a public Fertility Clinic. Endometrial preparation included oral oestradiol (6mg/24hours), followed by vaginal micronized progesterone, 400mg/12hours. Single blastocyst transfer and P4 measurements were performed on the 6th day of progesterone administration and patients with serum P4 &amp;lt;35nmol/l (11ng/ml) additional rectal administration of progesterone (400mg/12hour) was started the same day. In pregnant patients, vaginal and rectal administration continued until week 8, and oestradiol and vaginal progesterone treatment continued until week 10. 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 blastocyst transfer was 48.9 ±21.0 nmol/l (15.4 ±6.6ng/ml), and a total of 23% (114/488) of the patients had a serum P4 level lower than 35nmol/l (11ng/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 neither OPR week 12 nor total pregnancy loss rate between patients with P4 ≥35nmol/l (11ng/ml) and patients with P4 &amp;lt;35nmol/l, who received rescue in terms of rectally administered progesterone, 45% vs. 46%, p = 0.77 and 30% vs. 34%, p = 0.53, respectively. OPR did not depend on 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 progesterone (Cyclogest®), a solid pessary with progesterone suspended in vegetable hard fat, was used vaginally as well as rectally. It is unknown whether other vaginal progesterone products could be used rectally as easily with the same rescue effect. Wider implications of the findings A substantial part of HRT-FET patients receiving vaginal progesterone treatment has low serum P4. Adding rectally administered progesterone in these patients increases the reproductive outcome. Importantly, rectal progesterone administration is considered convenient by the majority of patients; moreover, progesterone pessaries are easy to administer rectally and of low cost. Trial registration number EudraCT no.: 2019-001539-29

P-595 What to expect from “standard vaginal progesterone regimen” in Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) – do different products result in different serum levels?

Abstract Study question Do luteal serum progesterone levels (P4) vary in relation to time of blood sampling, the type and dosing of vaginal progesterone products used for HRT-FET? Summary answer Significant differences in luteal serum P4 levels exist between time of blood sampling as well as between different vaginal progesterone products and the administration regimen. What is known already Mid-luteal P4 levels below 9-11 ng/ml have been shown to negatively affect reproductive outcomes in HRT-FET cycles. Formulations of vaginal progesterone products differ as progesterone can be suspended in vegetable hard fat, in a vegetable lipophile liquor, be prepared in an oil-in-water emulsion carrier, or mixed in a tablet. Moreover, dosing regimens vary from one to three times daily, and BMI, age, and parity affect serum P4 levels; importantly, no consensus exists in terms of optimal time point to measure P4 in relation to administration, the specific serum P4 cut-off level to use or the most optimal vaginal progesterone product. Study design, size, duration Cohort study including 488 HRT-FET blastocyst transfers performed from January 2020 to November 2022 in patients undergoing a “standard vaginal progesterone regimen”. Each patient participated only once in the study. To compare the vaginal progesterone product used in the present study, we reviewed the most recent literature, including data from six studies, using three different products in six different regimens; all studies were cohort studies, including between 227 -1150 patients undergoing a “standard” HRT-FET protocol. Participants/materials, setting, methods A total of 488 patients in a public Fertility Clinic underwent HRT-FET, including endometrial preparation with oral oestradiol (6mg/24hours), followed by vaginal micronized progesterone, 400mg/12hours (Cyclogest®). Blood sampling on the blastocyst transfer day was standardised to two to four hours after progesterone administration. In contrast, P4 was measured randomly on the day of pregnancy testing. For comparison a review of the literature from six HRT-FET cohort studies using either Crinone®, Utrogestan® or “PIVET”-pessaries was performed. Main results and the role of chance The mean serum P4 (2-4 hours after administration) on the day of blastocyst transfer in our cohort was 15.4 ±6.6ng/ml. On the day of pregnancy testing (random time points) serum P4 levels were divided into four groups, depending on the time from progesterone administration to blood sampling: &amp;lt;2hours, &amp;gt;2&amp;lt;4hours &amp;gt;4&amp;lt;6hours and &amp;gt;6hours.The mean P4 levels were 14.7 ±6.3ng/ml, 15.6 ±5.8ng/ml, 14.3 ±4.9ng/ml and 12.9 ±6.4, respectively, and a significant difference was seen, between P4 levels measured 2-4 hours and &amp;gt;6 hours after vaginal administration (p = 0.03). As regards the product, the mean P4 levels in this study (Cyclogest®) was significantly different from the reviewed P4 levels of other “standard” HRT-FET cohorts, using three different products (Uterogestan®, Crinone® and the “PIVET-pessary”) 12.1 ±7.0ng/ml (p &amp;lt; 0.001), 7.6 ±3.2ng/ml (p &amp;lt; 0.001) and 29.3 ±20.3ng/ml (p &amp;lt; 0.001), respectively. As regards the dose, a significant difference in P4 levels was seen between dosing regimens in two cohorts when using the same product (Crinone®) 90mg x 3 vs. 90 mg x 2; 11.3 ±4.7ng/ml and 7.6 ±3.2ng/ml, respectively, p &amp;lt; 0.001. Interestingly, when comparing another product (Utrogestan®) used in different dosing regimens, 400mg x 2 vs. 200mg x 3, no difference in P4 levels was seen, 12.1 ±7.0ng/ml and 11.3 ±5.1ng/ml, P = 0.09. Limitations, reasons for caution In HRT-FET serum P4 levels reflect the exogenous administration, only, and P4 fluctuations depend on the route and number of administrations, as well as absorption and metabolization. The reviewed data used for this comparison between different progesterone products and regimens derive from cohorts with different characteristics and blood sampling timings. Wider implications of the findings Luteal serum P4 measurement is important, however, standardization of blood sampling in relation to the latest vaginal progesterone administration is mandatory to obtain correct levels. Clinicians should be aware of the significant differences in P4 levels related to dose and vaginal absorption between different types of vaginal progesterone products. Trial registration number EudraCT no.: 2019-001539-29

P-649 Circadian serum progesterone variations on the day of frozen embryo transfer in artificially prepared cycles

Abstract Study question What is the intra-day variation of serum progesterone related to vaginal progesterone administration on the day of frozen embryo transfer (FET) in an artificial cycle? Summary answer We observed a statistically significant intra-day variation of serum progesterone (P) levels on the day of FET in artificially prepared cycles (AC). What is known already The use of FET cycles has increased enormously. In an attempt to further optimize pregnancy outcomes after FET, recent studies have focused on the importance of correct serum luteal P levels in both natural and AC-FET cycles. Despite the different cut-off values proposed to define low serum P, it is generally accepted that lower serum P values(&amp;lt;8.8 ng/ml) around the day of FET are associated with lower live birth rates and higher miscarriage rates. However, a single luteal serum P measurement can be misleading given the diurnal variation and the impact of patient characteristics such as age, BMI, parity, ethnicity. Study design, size, duration A prospective cohort study was conducted at a tertiary university-based hospital encompassing twenty-two patients undergoing a single blastocyst transfer in an AC from August to December 2022. Sample size calculation was performed using a paired t-test resulting in twenty-two patients required to detect a difference of 15% between the first and the last daily progesterone value with a false-positive rate of 5%(two-sided),a power of 80%,assuming a standard deviation of change in the outcome of 0.250. Participants/materials, setting, methods Patients with a normal BMI,aged between 18 and 40 years old, were included. Endometrial preparation was achieved by administering estradiol valerate(6 mg/day) until an adequate endometrial thickness was reached. Consecutively, micronized vaginal progesterone(MVP, 800 mg/die) was started five days prior to blastocyst transfer. P levels were evaluated on the day of FET at 08:00h, 12:00h, 16:00h, and 20:00h. The first and last blood samples were collected just before the intake of MVP,at 8:00h and 20:00h. Main results and the role of chance Mean age of the study population was 33.95 ± 3.98 years and BMI 23.10 ± 1.95 kg/m2. Basal FSH was 7.84 ± 2.31 IU/L and estradiol concentration at 8:00h on the day of FET was 206.04 ± 93.32 ng/L. Mean P values at 08:00h, 12:00h, 16:00h and 20:00h were 11.72 ± 4.99 µg/L, 13.59 ± 6.33 µg/L, 10.23 ± 3.81 µg/L and 9.28 ± 3.09 µg/L,respectively. Statistically significant differences in P values were observed between measurements performed at 08:00h and 20:00h (p = 0,007), 8:00h and 12:00h(p &amp;lt; 0,001), 12:00h and 16:00h (p &amp;lt; 0,001), and 16:00h and 20:00h (p = 0,004). The proportion of patients encountering low P values, defined as P &amp;lt; 8.8 ng/ml, was 27,3% at 8:00h, 13,6% at 12:00h, 40,9% at 16:00h, and 36,4% at 20:00h. Moreover, the difference in patients with normal P values (&amp;gt; 8.8 ng/ml) was statistically significant between samples performed at 8:00h and 12:00h and 12:00h and 16:00h (p = 0.009 and p = 0.01 respectively). No difference was observed in normal P values between 16:00h and 20:00h(p = 0.3) and 8:00h and 20:00h(p = 0,07). Additionally, no association was found either between age and BMI and the first progesterone evaluation of the day, neither between these parameters and the difference in P levels between 8:00h and 20:00h. Limitations, reasons for caution The strict inclusion criteria applied in this study could potentially imply a bias when extrapolating the results to a wider infertile population undergoing AC-FET cycles. A confirmation of the findings in larger prospective studies including a more heterogeneous patient population is recommended. Wider implications of the findings The results of this study highlight the importance of a standardized procedure for the timing of progesterone measurements, partly taken into account the last MVP intake. This is especially important when clinical actions, such as additional P supplementation, are considered when low or high P values are encountered. Trial registration number not applicable

Patient attitudes towards and satisfaction with subcutaneous injection of progesterone versus vaginal administration in assisted reproductive technology treatment

The hormones used in fertility treatment come in various forms. Progesterone used for luteal phase support is often administered vaginally as either suppositories, tablets or gel. However, in Denmark the administration of progesterone as a subcutaneous injection has newly been introduced. The aim of the study was to explore patient attitudes towards and satisfaction with subcutaneous injection of progesterone versus vaginal administration of progesterone in Assisted Reproductive Technology (ART) treatments. Methods and analysisA qualitative study with online and face to face interviews with a total of 19 women undergoing an ART treatment. Only women with at least one previous blastocyst transfer using vaginal progesterone or subcutaneous progesterone could be recruited. All participants were included from either the Fertility Clinic at Copenhagen University Hospital – Herlev and Gentofte or from the Fertility Unit at Aalborg University Hospital. ResultsThe analysis resulted in four themes: (1) medication, (2) everyday life, (3) bodily experiences and (4) infertility or hope. Most informants highlighted the administration of subcutaneous progesterone only once a day and avoidance of the vaginal discharge as clear advantages. Reasons for preferring the vaginal administration were inconvenience of bringing the subcutaneous medication along and resistance to inject oneself. ConclusionThe findings of this study suggest that the satisfaction with the subcutaneous progesterone is generally positive. However, valuable thoughts have given insights into possible areas, which could be improved. Further, that some women prefer vaginal progesterone. The results show that the women are interested in being included in the decision-making when choosing the administration form of progesterone.

Serum Progesterone Concentration and Ongoing Pregnancy Rate in Frozen-Thawed Embryo Transfers with Intramuscular Plus Vaginal Progesterone Administration for Endometrial Preparation

Background: Insufficient serum progesterone level in the implantation phase may reduce the rate of pregnancy during freeze embryo transfer (FET) cycles. The present study aimed to evaluate the impact of FET day serum progesterone level on pregnancy outcomes in patients receiving intramuscular plus vaginal progesterone administration for endometrial preparation. Methods: Based on serum progesterone level on FET day, patients were divided into four quartiles: first (&lt;25%), second (26–50%), third (51%–75%), and fourth (&gt;75%). There was no significant difference among groups in basal characteristics. Results: No statistically significant difference was seen among groups concerning the mean number of retrieved and mature oocytes, embryos transferred, and endometrial thickness (EnT). The rate of implantation (P=0.5), biochemical (P=0.75), clinical (P=0.54), and ongoing pregnancy (P=0.5) were not associated with serum progesterone level on embryo transfer day. Conclusion: We found that there is no association between serum progesterone level on ET day and pregnancy outcome during FET cycles. It seems that combination therapy using intramuscular and vaginal progesterone, keeps the serum progesterone on ET day high enough that eliminates the need for serum progesterone measurement.

VAGINAL PROGESTERONE IN RISK REDUCTION OF PRETERM BIRTH IN WOMEN WITH SHORT CERVIX IN MID TRIMESTER OF PREGNANCY

Background: Preterm labour is a major health challenge in obstetrics. Many risk factors being identified, the most common one is short cervical length, can be diagnosed by transvaginal ultrasound scan after 13 weeks of pregnancy. Vaginal progesterone is the most bioavailable form of progesterone that have effect on uterine and cervix. Progesterone is found to inhibit the production of proinflammatory cytokines and prostaglandins within the uterus and to inhibit myometrial contractility Aim:To evaluate the efficacy of vaginal progesterone administration for preventing preterm birth and decrease perinatal morbidity and mortality in asymptomatic women with a singleton gestation and a mid-trimester sonographic cervical length (CL) ≤ 25 mm. Materials And Methods:This is a prospective study of asymptomatic women with a singleton pregnancy and a sonographic short cervix (&lt;25mm) at 19 + 0 to 23 + 6 weeks of gestation. Women were allocated randomly to receive vaginal progesterone or placebo daily starting from 19 + 0 to 23 + 6 weeks until 36 + 6 weeks, rupture of membranes or delivery, whichever occurred first. Randomization sequence was stratified by centre and history of a previous preterm birth. The primary endpoint was preterm birth before 33 weeks of gestation. Analysis was by intention to treat. Results:Out of 100 patients for whom study was done, 20 lost to followup and remaining divided into two groups: 40 Singleton pregnant women with CL&lt;25mm between 19 + 0 to 23 + 6 weeks of gestation with no sign and symptoms were given daily vaginal progesterone for up to 36 + 6 weeks, rupture of membranes or delivery, whichever occurred first. The dose is 200 mg once daily and a group of 40 women with cervical length of &lt;25 mm between 19 + 0 to 23 + 6 weeks of pregnancy were given no treatment, Maximum distribution belongs to age of 19-24 years followed by 30-34 years. Most of women in this study have no history of preterm labour. In those who received vaginal progesterone 5 women had history of previous preterm labour and five women in no treatment group. It was found that there was statistically significant reduction in preterm labour in women with short cervix &lt;2.5cm with 200mg vaginal progesterone. Conclusions:This updated systematic review and meta-analysis reaffirms that vaginal progesterone reduces the risk of preterm birth and neonatal morbidity and mortality in women with a singleton gestation and a mid-trimester CL ≤ 25 mm, without any deleterious effects on neurodevelopmental outcome. Clinicians should continue to perform universal transvaginal CL screening at 19 + 0 to 23 + 6 weeks of gestation in women with a singleton gestation and to offer vaginal progesterone to those with a CL ≤ 25 mm.

The role of vaginal progesterone for preterm birth prevention in women with threatened labor and shortened cervix diagnosed after 24 weeks of pregnancy.

To determine whether vaginal progesterone treatment for women with a short cervix, diagnosed after 24 weeks of pregnancy, reduces preterm birth rates. A retrospective cohort study that included women with a singleton pregnancy, threatened preterm labor, and a short cervix measured between 24+0 and 33+6 weeks. Women who received vaginal progesterone were compared with women who did not receive progesterone. The primary outcome was spontaneous preterm birth before 37 weeks of pregnancy. Patients who received vaginal progesterone had a lower rate of preterm delivery at less than 37 weeks of pregnancy (18.2% [22/121] versus 28.9% [73/253]; adjusted hazard ratio 0.50; 95% confidence interval 0.28-0.73, P= 0.001). The diagnosis-to-delivery interval was significantly greater in patients who received progesterone than in those who did not-median time to delivery in weeks: 8.2 (interquartile range [IQR] 6.2-9.8) versus 6.6 (4.8-8.8), (P< 0.001). The frequency of neonatal intensive care unit admission was significantly lower in patients who received progesterone than in those who did not (8.3% [10/121] versus 16.2% [41/253], P= 0.04). The administration of vaginal progesterone to patients with an episode of threatened premature labor and a short cervix presenting after 24 weeks of pregnancy was associated with lower rates of premature births.

Development of Vaginal Carriers Based on Chitosan-Grafted-PNIPAAm for Progesterone Administration.

Chitosan-based hydrogels possess numerous advantages, such as biocompatibility and non-toxicity, and it is considered a proper material to be used in biomedical and pharmaceutical applications. Vaginal administration of progesterone represents a viable alternative for maintaining pregnancy and reducing the risk of miscarriage and in supporting the corpus luteum during fertilization cycles. This study aimed to develop new formulations for vaginal administration of progesterone (PGT). A previously synthesized responsive chitosan-grafted-poly (N-isopropylacrylamide) (CS-g-PNIPAAm) was formulated in various compositions with polyvinyl alcohol (PVA) as external crosslinking agent to obtain pH- and temperature-dependent hydrogels; the hydrogels had the capacity to withstand shear forces encountered in the vagina due to its mechanism of swelling once in contact with vaginal fluids. Three different hydrogels based on grafted chitosan were analyzed via Fourier-transform infrared spectroscopy (FTIR), swelling tests, in vitro drug release, and bioadhesion properties by TA.XTplus texture analysis. A higher amount of PVA decreased the swelling and the bioadhesion capacities of the hydrogel. All hydrogels showed sensitivity to temperature and pH in terms of swelling and in vitro delivery characteristics. By loading progesterone, the studied hydrogels seemed to possess even higher sensitivity than drug–free matrices. The release profile of the active substance and the bioadhesion characteristics recommended the CS-g-PNIPAAm/PVA 80/20 +PGT (P1) hydrogel as a proper constituent for the vaginal formulation for progesterone administration.

Association between progesterone treatment and neonatal outcome in preterm births: a retrospective analysis

This retrospective study was conducted to determine if infants born prematurely despite prophylactic maternal progesterone treatment during pregnancy may still benefit from its adjunct properties and have decreased neonatal complications. 248 women treated with vaginal/intramuscular progesterone during pregnancy and 2519 controls who gave birth to a preterm newborn (24 + 0–36 + 6 gestational weeks) at a tertiary medical centre in 2012–2019. The primary outcome measure was neonatal infectious composite outcome. Secondary outcome measures were other maternal and neonatal complications. Compared to controls, the study group was characterised by lower gestational age at birth (35.0 ± 2.66 vs. 36.0 ± 2.23 weeks, p < .001), lower birth weight (2294 vs. 2485 g, p < .001), higher rates of neonatal infectious composite outcome (27.82 vs. 21.36%, p = 0.024), NICU admission, periventricular leukomalacia, and mechanical ventilation. The higher neonatal infectious composite outcome is likely associated with the lower gestational age at birth in this high-risk group and not the progesterone treatment per se. IMPACT STATEMENT What is already known on this subject? Several randomised controlled trials have shown that progesterone administration in pregnancy significantly reduced the rate and complications of preterm birth. A recent study reported that vaginal administration of progesterone during pregnancy was more effective than intramuscular administration in decreasing vaginal group B Streptococcus (GBS) colonisation. This finding raises the question of whether progesterone treatment may have additional benefits besides preventing preterm birth and may reduce neonatal complication rate in preterm infants. What do the results of this study add? This is the first study examining the impact of gestational progesterone exposure on outcomes of preterm infants. The primary objective was a composite measure of infectious neonatal outcomes. Newborns who had progesterone exposure on average had lower gestational age, lower birth weight and higher neonatal infectious composite outcome. The significant difference is explained by lower gestational age. What are the implications of these findings for clinical practice and/or further research? Progesterone is widely used to prevent preterm birth, and may have important additive effects even when prematurity is not avoided. Although the findings did not support our initial hypothesis, they warrant further examination with larger cohorts.

Luteal Phase Support in Intrauterine Insemination Cycles: A Randomized Clinical Trial of Vaginal Versus Intramuscular Progesterone Administration.

Background:Different progesterone doses and routes are used for luteal phase support in stimulated intrauterine insemination (IUI) cycles, but the optimal supplementation scheme has not yet been determined. Therefore, our aim was to compare the administration of two different doses of vaginal progesterone with two doses of intramuscular (IM) progesterone for luteal phase support in patients undergoing IUI cycles.Methods:In this randomized clinical trial, 312 women with unexplained or malefactor infertility intending to start IUI cycles between April 2015 and January 2018 were included. They were randomized into four groups (n=78/each) including group 1 who received IM progesterone in oil (25 mg daily), group 2 who received IM progesterone in oil (50 mg daily), group 3 who received progesterone suppository (400 mg daily), and group 4 who received progesterone suppository (800 mg daily; 400 mg twice daily). The primary outcome was the clinical pregnancy rate. The ongoing pregnancy rate, abortion rate, and patients’ satisfaction, and convenience the secondary outcomes.Results:In our study, the overall clinical and ongoing pregnancy rates per cycle with COS and IUI were 16.02% and 12.8%, respectively. There were no significant differences in clinical pregnancy, ongoing pregnancy, and abortion rates among groups (p=0.84). The overall patients’ satisfaction and convenience was significantly higher in the vaginal progesterone suppository groups than the IM progesterone groups (p=0.001).Conclusion:The results of this study showed that vaginal progesterone administration provides a more easy-to-use and convenient method than IM progesterone administration for luteal phase support in IUI cycles with comparable pregnancy rates.

The role of vaginal progesterone in established pre-term labor: A randomized controlled trial.

Pre-term birth (PTB) is the leading cause of mortality and morbidity in newborn and infants. One of the proposed theories is the withdrawal of progesterone, either actual or functional, to be an antecedent to the onset of labor. The aim of the study is to evaluate the role of vaginal progesterone in delaying delivery following an episode of arrested pre-term labor. This is a pragmatic open-label randomized controlled trial that was conducted in the Department of Obstetrics and Gynecology at All India Institute of Medical Sciences, Jodhpur. Hundred patients with singleton pregnancies presenting with pre-term labor between 24 and 34 weeks of gestation and treated successfully with acute tocolysis for 48 hours and steroids covered were randomized to receive either progesterone 400 mg vaginal suppository or no treatment. The primary outcome was the duration of randomization to delivery interval, which was significantly higher in the study than in the control group (28 days versus 10 days). The secondary outcomes such as gestational age at delivery was also higher in the study group compared to the control group (82% versus 60% delivered after 37 weeks in the study group and control group, respectively). The neo-natal outcomes such as birth weight (2802 grams versus 2324 grams), incidence of respiratory distress syndrome (RDS) (13% versus 26%), and newborn intensive care unit (NICU) admission (17% versus 31%) were lower in the study group, which signifies decreased neo-natal morbidities and mortalities in pre-term labor treated with maintenance tocolysis in the form of vaginal progesterone. Administration of vaginal progesterone (400 mg, daily) following an episode of arrested pre-term labor significantly increased the duration to delivery interval; that is, it reduced the rate of PTB before 37, 32, and 28 weeks of gestation among women. It further reduced the neo-natal morbidities such as RDS and NICU admission and increased the birth weight among infants of women assigned to progesterone treatment.

Stress-protective effects of micronized progesterone in treatment of anxiety disorders in pregnant women after in vitro fertilisation

Aim. To study a stress-protective efficacy of micronized progesterone (MP) in pregnant women with anxiety disorders after in vitro fertilisation (IVF).&#x0D; Materials and methods. We conducted a prospective, comparative open-label randomized trial in two IVF-clinics. A total of 98 pregnant women after IVF with anxiety disorders were recruited at the 9th week of pregnancy. Progesterone supplementation after IVF for luteal phase support was administered out until 9 weeks gestation. Then, after randomization, group 1 (n=35) received 400 mg per day of MP vaginally, group 2 (n=33) received 400 mg of MP orally, group 3 (n=30) was comparative for the other groups. The duration of progesterone treatment was 12 weeks. The Spielberger State Trait Anxiety Inventory (STAI), the Montgomerysberg depression rating scale (MADRS), Hospital Anxiety and Depression Scale (HADS), and the Epworth Sleepiness Questionnaires (ESQ) were used to compare maternal mood at 9 weeks (day of randomization) after delivery and at 283, 565, 847 days after randomization.&#x0D; Results. The mean STAI sumscore in MP-groups was significantly lower than in group 3 starting from day 565 and continued until the end of the study. There were no significant differences between vaginal and oral administration of progesterone. There were no significant differences between the mean sumscores when questioning on the HADS, MADRS and ESQ.&#x0D; Conclusion. Prolonged use of MP in pregnant women with anxiety disorders led to the prevention of manifestations of an increase in anxiety and depression. The stress-protective and neuromodulating properties of MP can determine additional indications for its prolonged administration in women with anxiety disorders and/or premorbid history.

Hydroxyprogesterone caproate for preterm birth: A situational analysis from the Indian perspective

BackgroundPreterm birth can cause morbidity and mortality in addition to trauma or loss to the mother, and present a major financial burden to the family. This risk may be minimized by timely intervention. ObjectiveTo understand the safety and efficacy of hydroxyprogesterone in decreasing the incidence of preterm birth, neonatal complications, and maternal mortality, based on evidence obtained from the Indian scientific literature. MethodsRelevant articles were searched for and retrieved from the databases PubMed, medrXiv, Embase, Cochrane, biorXiv, and arXiv. ResultsA total of 62 relevant articles were assessed, and of these, 59 articles did not meet the eligibility criteria. In total, 3 articles which satisfied the criteria and 2 articles sourced from cross references were included in the study. Across these 5 articles, a total of 536 patients received hydroxyprogesterone caproate or placebo for preterm birth. ConclusionIn all five articles, recurrence rate of preterm birth was reduced in the treated group compared to control group. The safety profile of progesterone tends to be better than that of the placebo. The findings of our analysis of individual patient data (IPD) summarizes various clinical trial data, which can assure clinicians that vaginal progesterone administration is effective and well tolerated.

Vaginal progesterone for preterm birth prevention in women with arrested preterm labor

Objective We tested the hypothesis that administration of vaginal progesterone in women with arrested preterm labor would result in lower rates of preterm birth <37 weeks compared to placebo. Study design We performed a randomized, placebo-controlled trial comparing vaginal progesterone to placebo in women with arrested preterm labor. Our trial included women with a singleton or twin gestation at 240 /7–336/7 weeks’ gestation who presented with preterm labor with cervical dilation ≥1 centimeter but remained undelivered. Participants were randomized to receive vaginal progesterone 200 mg daily or an identical placebo. The primary outcome was preterm birth <37 weeks. We performed an updated systematic review and meta-analysis of clinical trials, including our results. We searched MEDLINE, EMBASE, CINHAL, Scopus, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov using the key terms to identify relevant trials. The risk of bias was appraised using the Cochrane risk-of-bias tool. Data were synthesized using random-effects models. Heterogeneity was assessed using Higgins I 2. Results The randomized trial was prematurely terminated due to slow recruitment. There were 18 women randomized to receive vaginal progesterone who had complete follow-up data and 18 women in the placebo group. The risk of preterm birth <37 weeks was not significantly different in the groups (RR 1.10, 95% CI 0.63–1.19). Secondary outcomes were also similar. Thirteen trials with 1658 women (835 in the vaginal progesterone and 823 in the control groups) were included in the meta-analysis. Risk of preterm birth <37 weeks was similar in women who received progesterone and those in the control group (pooled RR 1.06, 95% CI 0.83–1.35). Latency was significantly longer among women with arrested preterm labor who received vaginal progesterone (weighted mean difference: 9.2 d, 95% CI 3.2–15.1), but further analysis showed that prolonged latency was only observed in the subgroup of studies that were not placebo-controlled. Conclusions This randomized controlled trial and meta-analysis do not support the use of vaginal progesterone for the prevention of preterm birth in women who present in preterm labor.

P–605 Low serum progesterone on the day of frozen embryo transfer after artificial endometrial preparation: exploring the clinical impact of “rescue” strategies

Abstract Study question Can we rescue treatments with low progesterone (PG) levels the day of frozen embryo transfer (FET) by adding subcutaneous progesterone? Summary answer After receiving additional supplementation with subcutaneous progesterone, women with low serum progesterone on cryotransfer day, have similar ongoing pregnancy rates as women with normal levels. What is known already Micronized vaginal progesterone fails to achieve optimal serum levels in up to 30% of patients receiving frozen embryos under artificial cycles (AC) despite the administration of 400 mg twice daily. Cancelling the thawing process and restarting a new treatment is a very disappointing option for patients and doctors. An alternative strategy is to administrate additional progesterone subcutaneously. The efficacy of the additional administration of subcutaneous progesterone as a “rescue” strategy in terms of clinical outcomes remains to be validated. Study design, size, duration We included 356 FET performed at Instituto Bernabeu between January 2019 - August 2020 in a retrospective case-control study. Groups were established according to PG levels on the day of the embryo transfer. The Control Group included: patients with optimal progesterone levels (≥8.8 ng ml); while the Rescue Group included those with suboptimal progesterone levels (&amp;lt;8.8 ng ml). Participants/materials, setting, methods All patients performed frozen embryo transfer after artificial endometrial preparation. All embryo transfers were performed at blastocyst stage after 5 days of progesterone administration. Progesterone levels were assessed the day of the embryo transfer by an electrochemiluminescence immunoassay. Samples were obtained 2–5 hours after the last vaginal progesterone administration. Primary outcome was Ongoing Pregnancy Rates (OPR). Secondary outcomes were pregnancy rates (PR), miscarriage rates (MR) and biochemical miscarriage (BM). Main results and the role of chance 301 patients were included in the Control Group and 55 in the Rescue Group. No significant differences were found between both groups. OPR rate was 34.7% for patients in the control group versus 26.4% in the rescue group (p = 0.240) PR was 52.5% for patients with optimal PG levels vs 54.5% when PG levels were below 8.8 ng/mL. Both BM and MR tend to be higher in women who had low serum PG: BM (21.4% vs 15.5%) and MR (28.6% vs 18.1%), without reaching significant statistical difference. In addition, we analyzed data from a sub-group of patients who received extra subcutaneous progesterone (based on cliniciańs decision), despite having normal serum PG levels. No differences in clinical outcomes between these groups were observed either. OPR was 29%, vs 35.4% (p = 0.241), PR was 51.8% vs 53.7%; BM was 16.7% vs 16.3% and MR was 26.9% vs 17.1% between women who received an extra subcutaneous PG dose versus women who did not, respectively. Weight and BMI distribution were homogeneous across groups. A discreet difference was observed in age distribution (control group mean age 41.6 years vs. 39.7 years in the rescue group). Limitations, reasons for caution The retrospective collection of data and a limited sample size constitutes the main limitations of the study. Significant statistical differences were not found between groups but still differences might be clinically relevant. Larger studies are needed to reach robust conclusions on the strategy. Wider implications of the findings: In AC cycles, when supplemented with additional subcutaneous progesterone, women showing low serum progesterone on cryotransfer day may expect similar clinical outcomes as women with normal levels. Pending on confirmatory studies, this strategy could consider as an alternative to cycle cancellation. Trial registration number Not applicable