Placental histology for targeted risk assessment of recurrent spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth significantly increases the risk for a recurrent preterm birth. Only a few identifiable clinical risk factors can be referenced in counseling for recurrent preterm birth. Furthermore, treatment using progesterone supplementation has not consistently prevented preterm birth among high-risk patients, but it may be effective in a subset of those patients. Placental pathology from a previous pregnancy may be used to predict which patients will experience a recurrent preterm birth or to identify a subset of patients more likely to respond to treatment with antenatal progesterone. OBJECTIVE: This study aimed to determine if histologic patterns are associated with recurrent preterm birth among patients with an index spontaneous preterm birth. A secondary objective was to determine if placental histologic types and/or progesterone receptor density in the decidua are associated with the response to progesterone supplementation with intramuscular 17-hydroxyprogesterone caproate. STUDY DESIGN: This was a retrospective cohort study at a single institution of women with singleton pregnancies with an index spontaneous preterm birth and a subsequent birth within the same hospital system between 2009 and 2019. Patients were included if placental pathology was available for the index spontaneous preterm birth. A logistic regression was used to determine if there were independent associations between 4 histologic types (acute inflammation, maternal vascular malperfusion, fetal vascular malperfusion, chronic inflammation) and recurrent preterm birth. For the secondary endpoint, 17-hydroxyprogesterone caproate response was defined as prolonging gestation by >3 weeks beyond the gestational age at delivery in the index pregnancy. Patients who delivered <3 weeks beyond the gestational age in the index pregnancy but at ≥39 weeks' gestation were excluded. A logistic regression was used to assess the independent association between placental histology and 17-hydroxyprogesterone caproate response. Sensitivity analyses were completed using only patients with an index birth <36 weeks' gestation, and then excluding those with medically indicated preterm birth in a subsequent pregnancy. A nested case-control immunohistochemical study was done among 20 patients with a subsequent term birth and 20 patients with a subsequent spontaneous preterm birth. The percentage of cells in the maternal decidua positive for progesterone receptors was correlated with the subsequent pregnancy outcome. RESULTS: A total of 352 patients were included. Acute inflammation was the most common histologic type seen among patients with spontaneous preterm birth (44.1%), followed by chronic inflammation (40.9%) and maternal vascular malperfusion (31.3%). No histologic type was independently associated with recurrent preterm birth. A total of 155 patients received 17-hydroxyprogesterone caproate in a second pregnancy. Low-grade acute inflammation was significantly associated with a decreased likelihood of 17-hydroxyprogesterone caproate response. Low-grade maternal vascular malperfusion among those with an index pregnancy delivered at <36 weeks' gestation was significantly associated with a more than 4 times increased likelihood of 17-hydroxyprogesterone caproate response when excluding those with a subsequent iatrogenic preterm birth. Progesterone receptor staining was not associated with recurrent preterm birth. CONCLUSION: Although acute inflammation was prevalent among spontaneous preterm births, more than half of the spontaneous preterm births were not associated with acute inflammation. Low-grade acute inflammation was associated with a significantly decreased response to 17-hydroxyprogesterone caproate supplementation. Low-grade maternal vascular malperfusion was associated with a 4-fold increased likelihood of 17-hydroxyprogesterone caproate response among those with index deliveries <36 weeks' gestation. Further work is needed to determine if placental pathologic examination can be used to target treatment in subsequent pregnancies to prevent recurrent preterm birth.

Deciphering the mechanisms of action of progesterone in breast cancer.

A practice-changing, randomized, controlled clinical study established that preoperative hydroxyprogesterone administration improves disease-free and overall survival in patients with node-positive breast cancer. This research perspective summarizes evidences from our studies that preoperative hydroxyprogesterone administration may improve disease-free and overall survival in patients with node-positive breast cancer by modulating cellular stress response and negative regulation of inflammation. Non-coding RNAs, particularly DSCAM-AS1, play a regulatory role in this process, along with the upregulation of the kinase gene SGK1 and activation of the SGK1/AP-1/NDRG1 axis. Progesterone-induced modification of the progesterone receptor and estrogen receptor genomic binding pattern is also involved in orchestrating estrogen signaling in breast cancer, preventing cell migration and invasion, and improving patient outcomes. We also highlight the role of progesterone in endocrine therapy resistance, which could lead to novel treatment options for patients with hormone receptor-positive breast cancer and for those who develop resistance to traditional endocrine therapies.

Addressing a broken drug pipeline for preterm birth: why early preterm birth is an orphan disease.

Preterm birth remains one of the most urgent unresolved medical problems in obstetrics, yet only 2 therapeutics for preventing preterm birth have ever been approved by the United States Food and Drug Administration, and neither remains on the market. The recent withdrawal of 17-hydroxyprogesterone caproate (17-OHPC, Makena) marks a new but familiar era for obstetrics with no Food and Drug Administration-approved pharmaceuticals to address preterm birth. The lack of pharmaceuticals reflects a broad and ineffective pipeline hindered by extensive regulatory hurdles, soaring costs of performing drug research, and concerns regarding adverse effects among a particularly vulnerable population. The pharmaceutical industry has historically limited investments in research for diseases with similarly small markets, such as cystic fibrosis, given their rarity and diminished projected financial return. The Orphan Drug Act, however, incentivizes drug development for "orphan diseases", defined as affecting <200,000 people in the United States annually. Although the total number of preterm births in the United States exceeds this threshold annually, the early subset of preterm birth (<34 weeks' gestation) would qualify, which is predominantly caused by inflammation and infection. The scientific rationale for classifying preterm birth into early and late subsets is strong given that their etiologies differ, and therapeutics that may be efficacious for one subset may not work for the other. For example, antiinflammatory therapeutics would be expected to be highly effective for early but not late preterm birth. A robust therapeutic pipeline of antiinflammatory drugs already exists, which could be used to target spontaneous early preterm birth, in combination with antibiotics shown to sterilize the amniotic cavity. New applications for therapeutics targeting spontaneous early preterm birth could categorize as orphan disease drugs, which could revitalize the preterm birth therapeutic pipeline. Herein, we describe why drugs targeting early preterm birth should qualify for orphan status, which may increase pharmaceutical interest for this vitally important obstetrical condition.

Society for Maternal-Fetal Medicine Statement: Response to the Food and Drug Administration's withdrawal of 17-alpha hydroxyprogesterone caproate.

On April 5, 2023, the US Food and Drug Administration withdrew the approval of 17-alpha hydroxyprogesterone caproate, effective immediately, because of the lack of evidence that it reduces the risk of recurrent spontaneous preterm birth. This decision withdraws approval for all formulations of 17-alpha hydroxyprogesterone caproate (both intramuscular and subcutaneous) and applies to both brand name (Makena) and generic versions of the medication. We agree with the Food and Drug Administration determination and discourage continued prescribing of 17-alpha hydroxyprogesterone caproate, including through compounding pharmacies. We do not recommend changing indications for cerclage, indications for vaginal progesterone in patients with a short cervix, or recommendations against activity restriction based on the Food and Drug Administration withdrawal of 17-alpha hydroxyprogesterone caproate from the market. We recommend that discussion of the use of vaginal progesterone for primary prevention of recurrent preterm birth without input of cervical length or in those with a cervical length of ≥25 mm includes a shared decision-making process, especially if a progesterone formulation for preterm birth prevention was received in a previous pregnancy. The Food and Drug Administration determined that it would be inappropriate to delay the effective date of the withdrawal to allow patients currently receiving 17-alpha hydroxyprogesterone caproate to finish treatment. We agree with the Food and Drug Administration that there is no evidence of benefit with continued treatment. Patients currently receiving 17-alpha hydroxyprogesterone caproate can be counseled that the Food and Drug Administration's Center for Drug Evaluation and Research has not identified evidence of harm from discontinuation before 37 weeks of gestation.

A Possible Mechanism of Action of 17α-Hydroxyprogesterone Caproate: Enhanced IL-10 Production.

OBJECTIVE: The rate of recurrent spontaneous preterm birth (PTB) was reduced by 33% in the Maternal-Fetal Medicine Unit (MFMU) Network trial of 17α-hydroxyprogesterone caproate (17-OHPC), but the mechanism of action, 17 years later, remains elusive. The robustness of the interleukin-10 (IL-10) response to lipopolysaccharide (LPS) stimulation of leukocytes in pregnant women with a prior PTB correlates with gestational age at delivery. This study sought to determine if there is a relationship between the concentration of 17-OHPC and response to LPS stimulation. STUDY DESIGN: We performed a secondary analysis of data from the Omega-3 MFMU trial which evaluated the effectiveness of omega-3 fatty acid supplementation in reducing recurrent PTB. We utilized previously characterized data from a subanalyses of the Omega-3 trial of IL-10 and tumor necrosis factor alpha (TNF-α) levels from peripheral blood mononuclear cells stimulated with LPS. Blood was obtained from enrolled women at 16 to 22 weeks' gestation (baseline) and 25 to 28 weeks' gestation (posttreatment). All women received 17-OHPC and plasma 17-OHPC concentrations were measured at 25 to 28 weeks' gestation. We analyzed these data to determine if there was a relationship between 17-OHPC concentration and cytokine production. We then performed an in vitro study to determine if 17-OHPC could directly alter cytokine production by THP-1-derived macrophages. RESULTS: In the clinical samples, we found that 17-OHPC plasma concentrations were correlated with the quantity of the LPS-stimulated production of IL-10. TNF-α production after LPS stimulation was unrelated to 17-OHPC concentration. In the in vitro study, we demonstrate a 17-OHPC concentration dependent increase in IL-10 production. CONCLUSION: In women receiving 17-OHPC for PTB prevention, we demonstrate a relationship between plasma 17-OHPC and LPS-stimulated IL-10 production by circulating leukocytes. We also demonstrate that, in vitro, 17-OHPC treatment affects IL-10 production by LPS-stimulated macrophages. Collectively, these findings support an immunomodulatory mechanism of action of 17-OHPC in the prevention of recurrent PTB. KEY POINTS: · 17-OHPC plasma concentrations and LPS-stimulated IL-10 levels correlate in clinical samples in women at risk for recurrent preterm birth.. · 17-OHPC can modulate the response of LPS-stimulated macrophages to increase IL-10 production.. · There was no relationship between TNF-α and plasma concentration of 17-OHPC in clinical samples or in vitro..

Eligibility, Utilization, and Effectiveness of 17-Alpha Hydroxyprogesterone Caproate in a Statewide Population-Based Cohort of Medicaid Enrollees.

OBJECTIVE: The primary objective was to estimate the initiation and adherence rates of 17 α-hydroxyprogesterone caproate (17OHPC) among eligible mothers in a statewide population-based cohort of Medicaid enrollees. The secondary objectives were to (1) determine the association of maternal sociodemographic and clinical characteristics with 17OHPC utilization and (2) assess the real-world effectiveness of 17OHPC on recurrent preterm birth prevention and admission to neonatal intensive care unit (NICU). STUDY DESIGN: This is a retrospective cohort study using a linked, longitudinal administrative dataset of birth certificates and medical assistance claims. Medicaid-enrolled mothers in Pennsylvania were included in this study if they had at least one singleton live birth from 2014 to 2016 following at least one spontaneous preterm birth. Maternal Medicaid claims were used to ascertain the use of 17OHPC from various manufacturers, including compounded formulations. Propensity score matching was used to create a covariate balance between 17OHPC treatment and comparison groups. RESULTS: We identified 4,781 Medicaid-covered 17OHPC-eligible pregnancies from 2014 to 2016 in Pennsylvania, 3.4% of all Medicaid-covered singleton live births. The population-based initiation rate was 28.5% among eligible pregnancies. Among initiators, 50% received ≥16 doses as recommended, while 10% received a single dose only. The severity of previous spontaneous preterm birth was the strongest predictor for the initiation and adherence of 17OHPC. In the matched treatment (n = 1,210) and comparison groups (n = 1,210), we found no evidence of 17OHPC effectiveness. The risks of recurrent preterm birth (relative risk [RR] 1.10, 95% confidence interval [CI] 0.97-1.24) and births admitted to NICU (RR 1.00, 95% CI 0.84-1.18) were similar in treated and comparison mothers. CONCLUSION: The 17OHPC-eligible population represented 3.4% of singleton live births. Less than one-third of eligible mothers initiated treatment. Among initiators, 50% were treatment adherent. We found no difference in the risk of recurrent preterm birth or admission to NICU between treatment and comparison groups. KEY POINTS: · About 3.4% of singleton live births were eligible for 17OHPC.. · About 30% of eligible mothers initiated treatment.. · We found no association of 17OHPC with recurrent preterm birth..

A Comparison of Vaginal and Intramuscular Progesterone for the Prevention of Recurrent Preterm Birth.

OBJECTIVE: This study aimed to examine whether vaginal progesterone is noninferior to 17-α hydroxyprogesterone caproate (17OHP-C) in the prevention of recurrent preterm birth (PTB). STUDY DESIGN: This retrospective cohort study included singleton pregnancies among women with a history of spontaneous PTB who received prenatal care at a single tertiary center from 2011 to 2016. Pregnancies were excluded if progesterone was not initiated prior to 24 weeks or the fetus had a major congenital anomaly. The primary outcome was PTB <37 weeks. A priori, noninferiority was to be established if the upper bound of the adjusted two-sided 90% confidence interval (CI) for the difference in PTB fell below 9%. Inverse probability of treatment weighting (IPTW) was used to carefully control for confounding associated with choice of treatment and PTB. Adjusted differences in PTB proportions were estimated via IPTW regression, with standard errors adjustment for multiple pregnancies per woman. Secondary outcomes included PTB <34 and <28 weeks, spontaneous PTB, neonatal intensive care unit admission, and gestational age at delivery. RESULTS: Among 858 pregnancies, 41% (n = 353) received vaginal progesterone and 59% (n = 505) were given 17OHP-C. Vaginal progesterone use was more common later in the study period, and among women who established prenatal care later, had prior PTBs at later gestational ages, and whose race/ethnicity was neither non-Hispanic white nor non-Hispanic Black. Vaginal progesterone did not meet noninferiority criteria compared with 17-OHPC in examining PTB <37 weeks, with an IPTW adjusted difference of 3.4% (90% CI: -3.5, 10.3). For secondary outcomes, IPTW adjusted differences between treatment groups were generally small and CIs were wide. CONCLUSION: We could not conclude noninferiority of vaginal progesterone to 17OHP-C; however, women and providers may be willing to accept a larger difference (>9%) when considering the cost and availability of vaginal progesterone versus 17OHP-C. A well-designed randomized trial is needed. KEY POINTS: · Vaginal progesterone is not noninferior to 17OHP-C.. · PTB risk may be 10% higher with vaginal progesterone.. · Associations did not differ based on obesity status..

Regional differences in utilization of 17α-hydroxyprogesterone caproate (17-OHP).

OBJECTIVES: To describe regional differences in utilization of 17α-hydroxyprogesterone caproate (17-OHP). METHODS: Retrospective cohort study of a large, US commercial managed care plan claims database with pharmacy coverage from 2008 to 2018. Singleton pregnancies with at least one prior spontaneous preterm birth (sPTB) were included. Regional and state-based differences in 17-OHP use were compared. Data were analyzed using t-tests and Fisher's exact tests. RESULTS: Of the 4,514 individuals with an indication for 17-OHP, 580 (12.8%) were prescribed 17-OHP. Regional and state-based differences in 17-OHP utilization were identified; Northeast 15.7%, Midwest 13.7%, South 12.0%, and West 10.4% (p=0.003). CONCLUSIONS: While significant regional differences in 17-OHP utilization were demonstrated, 17-OHP utilization remained low despite this cohort having insurance through a US commercial managed care plan. Suboptimal utilization demonstrates a disconnect between research and uptake in clinical practice. This underscores a need for implementation science in obstetrics to translate updated recommendations more effectively and efficiently into clinical practice.

Vaginal progesterone vs intramuscular 17-hydroxyprogesterone caproate for prevention of recurrent preterm birth: a randomized controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality, and previous preterm birth is one of the strongest risk factors for preterm birth. National and international obstetrical societies have different recommendations regarding progesterone formulation for the prevention of recurrent preterm birth. OBJECTIVE: This study aimed to determine whether vaginal progesterone is superior to 17-hydroxyprogesterone caproate in the prevention of recurrent preterm birth in patients with singleton pregnancies who had a previous spontaneous preterm birth. STUDY DESIGN: This was an open-label multicenter pragmatic randomized controlled trial at 5 US centers of patients with singleton pregnancies at <24 weeks of gestation who had a previous spontaneous preterm birth randomized 1:1 to either 200 mg vaginal progesterone suppository nightly or 250 mg intramuscular 17-hydroxyprogesterone caproate weekly from 16 to 36 weeks of gestation. Based on the estimated recurrent preterm birth rate of 36% with 17-hydroxyprogesterone caproate, 95 participants were needed in each arm to detect a 50% reduction in preterm birth rate with vaginal progesterone, with 80% power and 2-sided alpha of 0.05. The primary outcome was preterm birth at <37 weeks of gestation. Prespecified secondary outcomes included preterm birth at <34 and <28 weeks of gestation, mean gestational age at delivery, neonatal morbidity and mortality, and measures of adherence. Analysis was by intention to treat. The chi-square test and Student t test were used as appropriate. P<.05 was considered significant. RESULTS: Overall, 205 participants were randomized; 94 participants in the vaginal progesterone group and 94 participants in 17-hydroxyprogesterone caproate group were included. Although gestational age at enrollment was similar, those assigned to vaginal progesterone initiated therapy earlier (16.9±1.4 vs 17.8±2.5 weeks; P=.001). Overall continuation of assigned formulation until delivery was similar (73% vs 69%; P=.61). There was no significant difference in preterm birth at <37 (31% vs 38%; P=.28; relative risk, 0.81 [95% confidence interval, 0.54-1.20]), <34 (9.6% vs 14.9%; P=.26; relative risk, 0.64 [95% confidence interval, 0.29-1.41]), or <28 (1.1% vs 4.3%; P=.37; relative risk, 0.25 [95% confidence interval, 0.03-2.20]) weeks of gestation. Participants in the vaginal progesterone group had a later mean gestational age at delivery than participants in the 17-hydroxyprogesterone caproate group (37.36±2.72 vs 36.34±4.10 weeks; mean difference, 1.02 [95% confidence interval, 0.01-2.01]; P=.047). CONCLUSION: Vaginal progesterone did not reduce the risk of recurrent preterm birth by 50% compared with 17-OHPC; however, vaginal progesterone may lead to increased latency to delivery. This trial was underpowered to detect a smaller, but still clinically significant, difference in the efficacy of preterm birth prevention. Patient factors that impact adherence and ability to obtain medication in a timely fashion should be included in counseling on progesterone selection.

Utilization of hydroxyprogesterone caproate among pregnancies with live birth deliveries in the sentinel distributed database.

BACKGROUND: The U.S. Food and Drug Administration (FDA) approved Makena® (hydroxyprogesterone caproate [HPC] injection) in February 2011 for reducing the risk of preterm birth (PTB) in women with a singleton pregnancy who had a history of singleton spontaneous PTB (sPTB). Makena was approved under accelerated approval and required a postmarketing study to verify its clinical benefits. However, the postmarketing trial (PROLONG) failed to verify Makena's clinical benefit to neonates and substantiate its effect on reducing the risk of recurrent PTB. This study examined the utilization of HPC, along with another progestogen (vaginal progesterone) used to reduce the risk of sPTB during pregnancy, to inform the landscape of HPC use in the United States. METHODS: We included pregnant women aged 10-54 years with a live birth delivery from 1 January, 2008 to 31 December, 2018 in the Sentinel Distributed Database (SDD). We examined the prevalence of injectable HPC (Makena and its generics), compounded HPC, and vaginal progesterone use during the second and third trimesters during the study period. We also assessed the proportion of these HPC-exposed pregnancies with obstetrical conditions of interest as potential reasons for use: (1) history of preterm delivery; (2) cervical shortening in the current pregnancy; and (3) preterm labor in the current pregnancy. RESULTS: We identified a total of 3,445,739 live-birth pregnancies (among 2.9 million women) between 2008 and 2018 in the SDD. Of these pregnancies, 6.5 per 1,000 pregnancies used injectable HPC, 2.3 per 1,000 pregnancies used compounded HPC, and 1.5 per 1,000 pregnancies used vaginal progesterone during the second and/or third trimesters. The yearly uptakeof pregnancies with injectable HPC use increased during the study period from 2.1 per 1,000 pregnancies in 2012 to 12.6 per 1,000 pregnancies in 2018; use of compounded HPC decreased from 3.3 per 1,000 pregnancies to 0.25 per 1,000 pregnancies over the same period. Of 16,524 pregnancies with injectable HPC use, 12,054 (73%) had at least one related obstetrical condition, including 6,439 (39%) with a recorded history of preterm delivery. In addition, 4,665 (28%) had a PTB recorded as the outcome for the current pregnancy. CONCLUSIONS: We found modest use of HPC during the second and/or third trimesters among all live-birth pregnancies in SDD. The majority of pregnancies with injectable HPC use had at least one of three obstetrical indications of interest recorded before or during the pregnancy.

17 Alpha-hydroxyprogesterone caproate use in a rural state.

BACKGROUND: 17 alpha-hydroxyprogesterone caproate (17OHP) is used to reduce the recurrent risk of preterm delivery in women with a history of preterm delivery. Meis et al. conducted a double-blind placebo controlled trial to evaluate the effectiveness of 17OHP and observed a significant reduction in the risk of recurrent preterm delivery. The FDA granted 17OHP a conditional approval on 2011. A second study observed that 17OHP did not decrease the risk of a recurrent preterm delivery. Criticism of the second study derived from a dissimilarity of the study population. OBJECTIVE: Our investigation examined the effectiveness of 17OHP in women with a prior preterm delivery in a rural US state with a patient population similar to the original Meis trial. STUDY DESIGN: 17OHP became largely unavailable (due to cost and local pharmacies no longer compounding 17 OHP) and the University of Arkansas for Medical Sciences, Department of Health, and Arkansas Medicaid co-operated to make 17OHP available to women with a prior PTB in our state. This study was a retrospective review of the 17OHP that was offered to women with a prior preterm delivery. For our retrospective review, logistic regression was used on cases of prior preterm delivery between January 2014 and December of 2018 to examine the relationship between 17OHP injections and preterm delivery. RESULTS: A total of 268 women were analyzed for this review. They were divided into three groups: 0 injections, 1-10 injections, and > 10 injections. We found no relationship between 17OHP injections with preterm delivery. CONCLUSION: Although our patient population was similar to that of the original Meis trial, our results were more similar to the second study by Blackwell.

Delivering equity: preterm birth by socioeconomic class before and after coverage of 17-hydroxyprogesterone caproate.

OBJECTIVE: We compare the preterm birth rate across socioeconomic strata in Michigan before and after the decision by Michigan Medicaid to provide coverage for 17-hydroxyprogesterone caproate (17-OHP), a costly medication for recurrent preterm birth prevention. STUDY DESIGN: We retrospectively analyzed births recorded in the Michigan Department of Health & Human Services database from 2008-2016, comparing the rate of preterm birth stratified by standardized US Census Bureau socioeconomic levels (affluent, higher-middle class, lower-middle class, and poverty) across three time periods: pre-Federal Drug Administration approval of 17-OHP (2008-2011), pre-Medicaid coverage (2012-2014), and post-Medicaid coverage (2015-2016). RESULTS: Of 1,034,901 total live births, 10% (N = 103,869) were premature. An ANOVA with post-hoc testing showed the preterm birth rate was highest for those living in poverty, lower for the lower-middle class, and lowest for the collective higher-middle and affluent classes. The preterm birth rate dropped for all classes after Michigan Medicaid began paying for 17-OHP, but inter-class gaps remained. CONCLUSION: Extended financial coverage for 17-OHP may have contributed to modest decreases in preterm birth rates, but this policy did not equalize outcomes between those with disparate resources.

Progestogens for preventing miscarriage: a network meta-analysis.

BACKGROUND: Miscarriage, defined as the spontaneous loss of a pregnancy before 24 weeks' gestation, is common with approximately 25% of women experiencing a miscarriage in their lifetime, and 15% to 20% of pregnancies ending in a miscarriage. Progesterone has an important role in maintaining a pregnancy, and supplementation with different progestogens in early pregnancy has been attempted to rescue a pregnancy in women with early pregnancy bleeding (threatened miscarriage), and to prevent miscarriages in asymptomatic women who have a history of three or more previous miscarriages (recurrent miscarriage). OBJECTIVES: To estimate the relative effectiveness and safety profiles for the different progestogen treatments for threatened and recurrent miscarriage, and provide rankings of the available treatments according to their effectiveness, safety, and side-effect profile. SEARCH METHODS: We searched the following databases up to 15 December 2020: Cochrane Central Register of Controlled Trials, Ovid MEDLINE(R), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials assessing the effectiveness or safety of progestogen treatment for the prevention of miscarriage. Cluster-randomised trials were eligible for inclusion. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. We excluded quasi- and non-randomised trials. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the trials for inclusion and risk of bias, extracted data and checked them for accuracy. We performed pairwise meta-analyses and indirect comparisons, where possible, to determine the relative effects of all available treatments, but due to the limited number of included studies only direct or indirect comparisons were possible. We estimated the relative effects for the primary outcome of live birth and the secondary outcomes including miscarriage (< 24 weeks of gestation), preterm birth (< 37 weeks of gestation), stillbirth, ectopic pregnancy, congenital abnormalities, and adverse drug events. Relative effects for all outcomes are reported separately by the type of miscarriage (threatened and recurrent miscarriage). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Our meta-analysis included seven randomised trials involving 5,682 women, and all provided data for meta-analysis. All trials were conducted in hospital settings. Across seven trials (14 treatment arms), the following treatments were used: three arms (21%) used vaginal micronized progesterone; three arms (21%) used dydrogesterone; one arm (7%) used oral micronized progesterone; one arm (7%) used 17-α-hydroxyprogesterone, and six arms (43%) used placebo. Women with threatened miscarriage Based on the relative effects from the pairwise meta-analysis, vaginal micronized progesterone (two trials, 4090 women, risk ratio (RR) 1.03, 95% confidence interval (CI) 1.00 to 1.07, high-certainty evidence), and dydrogesterone (one trial, 406 women, RR 0.98, 95% CI 0.89 to 1.07, moderate-certainty evidence) probably make little or no difference to the live birth rate when compared with placebo for women with threatened miscarriage. No data are available to assess the effectiveness of 17-α-hydroxyprogesterone or oral micronized progesterone for the outcome of live birth in women with threatened miscarriage. The pre-specified subgroup analysis by number of previous miscarriages is only possible for vaginal micronized progesterone in women with threatened miscarriage. In women with no previous miscarriages and early pregnancy bleeding, there is probably little or no improvement in the live birth rate (RR 0.99, 95% CI 0.95 to 1.04, high-certainty evidence) when treated with vaginal micronized progesterone compared to placebo. However, for women with one or more previous miscarriages and early pregnancy bleeding, vaginal micronized progesterone increases the live birth rate compared to placebo (RR 1.08, 95% CI 1.02 to 1.15, high-certainty evidence). Women with recurrent miscarriage Based on the results from one trial (826 women) vaginal micronized progesterone (RR 1.04, 95% CI 0.95 to 1.15, high-certainty evidence) probably makes little or no difference to the live birth rate when compared with placebo for women with recurrent miscarriage. The evidence for dydrogesterone compared with placebo for women with recurrent miscarriage is of very low-certainty evidence, therefore the effects remain unclear. No data are available to assess the effectiveness of 17-α-hydroxyprogesterone or oral micronized progesterone for the outcome of live birth in women with recurrent miscarriage. Additional outcomes All progestogen treatments have a wide range of effects on the other pre-specified outcomes (miscarriage (< 24 weeks of gestation), preterm birth (< 37 weeks of gestation), stillbirth, ectopic pregnancy) in comparison to placebo for both threatened and recurrent miscarriage. Moderate- and low-certainty evidence with a wide range of effects suggests that there is probably no difference in congenital abnormalities and adverse drug events with vaginal micronized progesterone for threatened (congenital abnormalities RR 1.00, 95% CI 0.68 to 1.46, moderate-certainty evidence; adverse drug events RR 1.07 95% CI 0.81 to 1.39, moderate-certainty evidence) or recurrent miscarriage (congenital abnormalities 0.75, 95% CI 0.31 to 1.85, low-certainty evidence; adverse drug events RR 1.46, 95% CI 0.93 to 2.29, moderate-certainty evidence) compared with placebo. There are limited data and very low-certainty evidence on congenital abnormalities and adverse drug events for the other progestogens. AUTHORS' CONCLUSIONS: The overall available evidence suggests that progestogens probably make little or no difference to live birth rate for women with threatened or recurrent miscarriage. However, vaginal micronized progesterone may increase the live birth rate for women with a history of one or more previous miscarriages and early pregnancy bleeding, with likely no difference in adverse events. There is still uncertainty over the effectiveness and safety of alternative progestogen treatments for threatened and recurrent miscarriage.

The effects of progesterone therapy in pregnancy: vaginal and intramuscular administration.

AIM: This study was performed to evaluate the effects of vaginal versus intramuscular progesterone supplementations on the mood, quality of life, and metabolic changes in pregnant women with the history of previous preterm birth. METHODS: This study was conducted as a prospective, randomized, open label, clinical trial evaluated 100 pregnant women who referred for prenatal visit, with 16-17 weeks of gestation from September 2014 through October 2015. The mothers were then randomly allocated into two groups: the vaginal progesterone group to receive 400 mg cyclogest vaginal suppositories (Actavis, UK limited, England) once daily, and the intramuscular progesterone group to receive weekly intramuscular injections of 250 mg of 17-hydroxyprogesterone caproate (17-HPC) (Bayer Schering Pharma, Germany), starting from the 16th to the 35th weeks of pregnancy. Demographics, medical and obstetrical history, sleeping disturbances, alteration in sexual desire, nausea/vomiting, serum levels of fasting blood sugar (FBS), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were evaluated, first and 8 weeks later. RESULTS: About 11 (11.2%) screened positive for psychosocial disorders; 25 (25.5%) had sleep disturbance, 11 (11.2%) had alteration in sexual desire, and 29 (29.6%) had nausea/vomiting upon enrollment. After 2 months of receiving daily vaginal progesterone, there was a significant increase in the GHQ-28 score (p < .001), and rates of positive screening for psychosocial disorders (p = .001) in this group. No statistically significant differences were observed in the HDL levels (p = .06), LDL levels (p = .15), rates of impaired FBS (p = .08), nausea/vomiting (p = .2), sexual desire alteration (p = .56), and sleep disturbance (p = 1) in the participants who were randomized to this group. CONCLUSION: Our results indicated that psychosocial disorders increased significantly at 24th week gestational age after 2 months of progesterone consumption in both groups which could show psychological impact of progesterone regardless of the route of consumption. This calls for higher psychological attention in these women.

Adherence rates and outcomes for 17-hydroxyprogesterone caproate use in women with a previous history of preterm birth.

BACKGROUND: Progesterone has been used for preventing preterm birth with mixed results. The American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine recommended the use of 17-hydroxyprogesterone caproate for risk reduction of recurrent spontaneous preterm birth based on the results of a multicenter, randomized trial in the United States. However, recent literature lacks consensus for efficacy in the American population. In addition, partial adherence and outcomes thereof are underreported. Hence, the relationship between practical adherence to 17-hydroxyprogesterone caproate and outcomes were evaluated. OBJECTIVE: The objective of this study was to evaluate the adherence to 17-hydroxyprogesterone caproate, defined as receipt of greater than 80% of intended injections, at an outpatient maternal-fetal medicine center and its effect on maternal and neonatal outcomes. STUDY DESIGN: This retrospective cohort study included women older than 18 years with a singleton gestation, history of spontaneous preterm birth who initiated 17-hydroxyprogesterone caproate weekly injections between 16 and 20 weeks' gestational age and delivered between the years 2014 and 2017. Women receiving 17-hydroxyprogesterone caproate injections outside of the clinic were excluded. The primary outcome of adherence and secondary outcomes of gestational age at delivery, birthweight, and neonatal outcomes were analyzed using descriptive data, independent t-test, Mann-Whitney U test, chi-square test, and Fisher exact test, where appropriate, with a P value <.05 being considered significant. RESULTS: Adherence to 17-hydroxyprogesterone caproate occurred in 38 of 92 (41.3%) women included in the study. At baseline, there was a difference in age between groups of adherent and nonadherent women (adherent: 30.8 years; nonadherent: 27.4 years; P=.002). The rate of spontaneous preterm birth less than 37, 35, and 32 weeks were not significantly different in those who were adherent vs nonadherent to 17-hydroxyprogesterone caproate. There were no differences in gestational age at delivery (adherent: 36.8±2.6 weeks; nonadherent: 36.5±3.8 weeks; P=.66), birthweight (adherent: 2776 g; nonadherent: 2709 g; P=.68), or composite neonatal morbidity (adherent: 18.4%; nonadherent: 20.4%; P=.86) between the adherent and nonadherent groups. Neonatal intensive care unit length of stay was 15.5 days in the adherent group compared with 15 days in the nonadherent group (P=.72). CONCLUSION: Real-world adherence to 17-hydroxyprogesterone caproate is suboptimal with less than half of women adherent to in-clinic administration. Adherence to 17-hydroxyprogesterone caproate was not associated with a difference in gestational age at delivery or birthweight compared with nonadherence. Further studies are needed to assess the outpatient administration and benefit of 17-hydroxyprogesterone caproate therapy.

Pregnancy duration with use of 17-α-hydroxyprogesterone caproate in a retrospective cohort at high risk of recurrent preterm birth.

BACKGROUND: The use of 17-α-hydroxyprogesterone caproate for the prevention of recurrent spontaneous preterm birth has become widespread, yet there are conflicting data regarding its efficacy. OBJECTIVE: We sought to determine whether administration of 17-α-hydroxyprogesterone caproate was associated with pregnancy prolongation in women at a high risk of recurrent spontaneous preterm birth. STUDY DESIGN: This is a retrospective cohort study of women with singleton pregnancies and a history of spontaneous preterm birth at <37 weeks' gestation who received care at our academic tertiary care center between 2009 and 2019. We included women with gestations that progressed beyond 16 weeks. We excluded those who underwent history-indicated cerclage placement. We first examined the characteristics of women who received 17-α-hydroxyprogesterone caproate and those who did not. Covariates with a P value of ≤.2 on this univariate analysis were considered for incorporation into a Cox proportional hazards model to assess the association between 17-α-hydroxyprogesterone caproate use and pregnancy prolongation up to 35 weeks. RESULTS: Of 861 women included in the study, 570 (66.2%) reported non-Hispanic black racial identity, 237 (27.5%) lived in zip codes with a high infant mortality rate (≥12.1/1000 infants), 287 (33.3%) had more than 1 previous spontaneous preterm birth, 372 (43.2%) had previous spontaneous preterm birth at ≤32 weeks' gestation, and 242 (28.1%) were smokers. Here, 152 pregnancies (17.6%) were complicated by spontaneous preterm birth at <35 weeks' gestation. Factors independently associated with pregnancy duration up to 35 weeks included weight gain of <0.2 kg (0.5 lb) per week, first recorded weight of <98 kg (215 lb), obstetrical history, non-Hispanic white racial identity, lack of prenatal care, and vaginal bleeding. Gestational age at delivery was also independently associated with interventions typically employed for midtrimester cervical shortening and/or dilation, including ultrasound- and examination-indicated cerclage, pessary placement, and vaginal progesterone administration. The use of 17-α-hydroxyprogesterone caproate was not associated with pregnancy prolongation (adjusted hazard ratio, 0.83; 95% confidence interval, 0.60-1.15). CONCLUSION: The risk profile of our cohort is similar to that of women enrolled in the landmark trial that led to the Food and Drug Administration's approval of 17-α-hydroxyprogesterone caproate. Despite the high-risk nature of the pregnancies examined, we found no association between use of the medication in daily clinical practice and pregnancy prolongation up to 35 weeks. This finding adds to the mounting evidence that calls into question the drug's efficacy in reducing the risk of recurrent spontaneous preterm birth.

The association between 17-hydroxyprogesterone caproate use and postpartum hemorrhage.

OBJECTIVE: To evaluate whether receipt of 17α-hydroxyprogesterone caproate within seven days of delivery is associated with increased risk of postpartum hemorrhage. STUDY DESIGN: This was a retrospective cohort study of women who were receiving 17α-hydroxyprogesterone caproate for preterm birth prevention and delivered between 2010 and 2014. Women were dichotomized by whether a dose of 17α-hydroxyprogesterone caproate was administered within seven days of delivery. Demographic and clinical characteristics were examined, including obstetric history and details of 17α-hydroxyprogesterone caproate receipt. Bivariable analyses were used to compare the frequency of postpartum hemorrhage in women stratified by 17α-hydroxyprogesterone caproate receipt within seven days of delivery. Multivariable analysis was used to adjust for potential confounders. RESULTS: Of 221 women who met inclusion criteria, 93 (42%) received 17α-hydroxyprogesterone caproate within seven days of delivery and 18 (7.8%) experienced a postpartum hemorrhage. No differences were observed in the frequency of postpartum hemorrhage between women who did and did not deliver within seven days of 17α-hydroxyprogesterone caproate injection (9.7% vs 7.0%, p=0.478). These findings persisted after adjusting for potential confounders (aOR for PPH 2.9, 95% CI, 0.5-15.8). CONCLUSION: Recent receipt of 17α-hydroxyprogesterone caproate for prevention of recurrent preterm birth is not associated with risk of postpartum hemorrhage.