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

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

Challenges in Using Progestin to Prevent Singleton Preterm Births: Current Knowledge and Clinical Advice.

Preterm birth is the leading cause of infant morbidity and mortality in children younger than 5 years old and accounts for approximately 35% of newborn deaths worldwide. The use of progestogen therapy for prevention of preterm birth has been one of the most controversial topics in modern obstetrics. Progestogens can be classified as natural or synthetic. Progesterone is a natural progestogen while progestins such as 17-alpha-hydroxyprogesterone caproate (17OHP-C) are synthetic steroid hormones. Evidence supporting the use of progestogens varies by formulation and populations studied. After more than a decade, the US Food and Drug Administration has withdrawn accelerated approval of 17OHP-C for the prevention of recurrent preterm birth in pregnant individuals with a singleton gestation. With this decision, there is no current FDA-approved treatment for prevention of spontaneous preterm birth. In this review, we provide a historical context behind the rise and fall of 17OHP-C clinical application, highlight the challenges behind the data supporting progestogen use, and offer suggestions on how to make an impact on preterm birth moving forward.

What now? A critical evaluation of over 20 years of clinical and research experience with 17-alpha hydroxyprogesterone caproate for recurrent preterm birth prevention.

Spontaneous preterm birth is multifactorial, and underlying etiologies remain incompletely understood. Supplementation with progestogens, including 17-alpha hydroxyprogesterone caproate has been a mainstay of prematurity prevention strategies in the United States in the last 2 decades. Following a recent negative confirmatory trial, 17-alpha hydroxyprogesterone caproate was withdrawn from the US market and is currently available only through clinical research studies. This expert review summarized clinical and research data regarding the use of 17-alpha hydroxyprogesterone caproate in the United States from 2003 to 2023 for recurrent prematurity prevention. In 17-alpha hydroxyprogesterone caproate. The history of the use, mechanisms of action, clinical trial results, and efficacy by clinical and biologic criteria of 17-alpha hydroxyprogesterone caproate are presented. We report that disparate findings and conclusions between similarly designed rigorous studies may reflect differences in a priori risk and population incidence and extreme care should be taken in interpreting the studies and making decisions regarding efficacy of 17-alpha hydroxyprogesterone caproate for the prevention of preterm birth. The likelihood of improved obstetrical outcomes after receiving 17-alpha hydroxyprogesterone caproate may vary by clinical factors (eg, body mass index), plasma drug concentrations, and genetic factors, although the identification of individuals most likely to benefit remains imperfect. It is crucial for the medical community to recognize the importance of preserving the decades-long efforts invested in preventing recurrent preterm birth in the United States. Moreover, it is important that we thoroughly and thoughtfully evaluate 17-alpha hydroxyprogesterone caproate as a promising contender for future well-executed prematurity studies.

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.

Racial and ethnic representation in 17-hydroxyprogesterone caproate preterm birth prevention studies: a systematic review.

OBJECTIVES: The US preterm birth rate varies dramatically by race and ethnicity yet the racial and ethnic representation within studies evaluating 17-hydroxprogesterone caproate (17-P) for preterm birth prevention is unknown. The objectives of our study were to 1) examine the racial and ethnic representation of participants in 17-P preterm birth prevention studies, 2) evaluate adherence to the NIH race and ethnicity reporting guidelines and 3) compare racial and ethnic representation in research studies to national preterm birth incidence. METHODS: We systematically reviewed US studies published between January 2000 and December 2019. Study participant's race and ethnicity were reported using descriptive statistics then compared to US 2017//2018 preterm birth data using Pearson's chi-square. RESULTS: Eighteen studies met the inclusion criteria, 17 studies reported race, 11 studies reported ethnicity, and yet none of the studies followed the NIH criteria. Compared to 2017/2018 US preterm births, the proportion of black/African American study participants was significantly higher whereas the proportions of all other race categories were lower. CONCLUSIONS: More detailed reporting of race and ethnicity is needed in 17-P literature. Black women appear to be well represented while other racial and ethnic groups may be understudied.

Vaginal progesterone compared with intramuscular 17-alpha-hydroxyprogesterone caproate for prevention of recurrent preterm birth in singleton gestations: a systematic review and meta-analysis.

OBJECTIVE: Randomized trials have found benefits of both vaginal progesterone and 17-alpha-hydroxyprogesterone caproate in the prevention of recurrent preterm birth. A previous meta-analysis directly comparing the two was limited by low-quality evidence, and national and international society guidelines remain conflicting regarding progestin formulation recommended for prevention of recurrent preterm birth. The aim of this updated systematic review with meta-analysis was to evaluate the efficacy of vaginal progesterone compared with 17-alpha-hydroxyprogesterone caproate in the prevention of spontaneous preterm birth in patients with singleton gestations and previous spontaneous preterm birth. DATA SOURCES: Searches were performed in MEDLINE, Ovid, Scopus, ClinicalTrials.gov, the International Prospective Register of Systematic Reviews (PROSPERO), SciELO, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) with the use of a combination of keywords and text words related to "preterm birth," "preterm delivery," "singleton," "cervical length," "progesterone," "progestogens," "vaginal," "17-alpha-hydroxy-progesterone caproate," and "intramuscular" from inception of each database to September 2021. No restrictions for language or geographic location were applied. STUDY ELIGIBILITY CRITERIA: We included all randomized controlled trials of asymptomatic singleton gestations with previous spontaneous preterm birth that were randomized to prophylactic treatment with either vaginal progesterone (ie, intervention group) or intramuscular 17-alpha-hydroxyprogesterone caproate (ie, comparison group). Post hoc sensitivity analysis was performed for studies with low risk of bias and studies with protocol registration. METHODS: The primary outcome was preterm birth <34 weeks' gestation. The summary measures were reported as relative risks with 95% confidence intervals. RESULTS: Seven randomized controlled trials including 1910 patients were included in the meta-analysis. Patients who received vaginal progesterone had a significantly lower rate of preterm birth at <34 weeks (14.7% vs 19.9%; relative risk, 0.74; 95% confidence interval, 0.57-0.96), preterm birth at <37 weeks (36.0% vs 46.6%; relative risk, 0.76; 95% confidence interval, 0.69-0.85), and preterm birth at <32 weeks of gestation (7.9% vs 13.6%; relative risk, 0.58; 95% confidence interval, 0.39-0.86), compared with women who received intramuscular 17-alpha-hydroxyprogesterone caproate. There were no significant differences in the rate of preterm birth at <28 weeks' gestation. Adverse drug reactions were significantly lower in the vaginal progesterone group than in the 17-alpha-hydroxyprogesterone caproate group (15.6% vs 22.2%; relative risk, 0.71; 95% confidence interval, 0.54-0.92). Perinatal mortality was lower in the vaginal progesterone group than in the 17-alpha-hydroxyprogesterone caproate group (2.2% vs 4.4%; relative risk, 0.51; 95% confidence interval, 0.25-1.01). In sensitivity analysis including trials rated with at least 4 Cochrane tools as of "low risk of bias," 4 trials were included (N=575), and there was no longer a significant difference in preterm birth at <34 weeks' gestation between vaginal progesterone and 17-alpha-hydroxyprogesterone caproate (12.2% vs 13.9%; relative risk, 0.87; 95% confidence interval, 0.57-1.32). CONCLUSION: Overall, vaginal progesterone was superior to 17-alpha-hydroxyprogesterone caproate in the prevention of preterm birth at <34 weeks' gestation in singleton pregnancies with previous spontaneous preterm birth. Although sensitivity analysis of high-fidelity studies showed the same trend, findings were no longer statistically significant.

¿La progesterona natural micronizada previene el trabajo de parto pretérmino?: Revisión sistemática de literatura / Does Natural Micronized Progesterone Prevent Preterm Labor?: Systematic Literature Review / A progesterona natural micronizada previne o trabalho de parto prematuro?: Revisão sistemática da literatura

Introducción. La progesterona es una hormona que favorece el mantenimiento del embarazo, es la protagonista de la fisiopatología del trabajo de parto pretérmino. De esta manera, se propone realizar una revisión sistemática que permita demostrar la utilidad de la progesterona natural micronizada en la mitigación de los efectos deletéreos del trabajo de parto pretérmino. Metodología. Revisión sistemática en la que se utilizaron los términos "MeSH" y "No ­ MeSH". Se empleó el programa "Publish or Perish" y bases de datos como: Medline, PubMed, Embase, Clinical Key, Cochrane Library, Scopus y Google Scholar. Se incluyeron artículos de revisión, meta-análisis, artículos originales (publicaciones preliminares o completas), resúmenes de congresos, seminarios publicados, libros de texto, protocolos hospitalarios regionales y consensos nacionales, en donde cada autor evaluó individualmente cada artículo y aplicó la herramienta CASPE. Resultados. En la literatura no es posible encontrar pautas concisas internacionales sobre el uso de la progesterona micronizada frente a la amenaza de trabajo de parto pretérmino (TPP). En general, para la mitigación del trabajo de parto, según lo analizado por los autores, se recomienda usar progesterona natural micronizada en cápsulas de 100 a 400 mg/día vía oral o 100 a 200 mg cada 12 a 24 horas vía vaginal. Desde la semana 16 hasta la semana 36 de gestación por vía oral y desde la semana 24 a 34 de gestación por vía vaginal. Discusión. El uso de la progesterona micronizada ha demostrado mitigar complicaciones posteriores al trabajo de parto pretérmino, sin embargo, no hay consenso sobre la dosificación y las vías de administración. Sumado a lo anterior, los estudios analizados pueden contener sesgos, por lo que se deja a elección del clínico el uso este medicamento. Conclusiones. La progesterona natural micronizada podría ser empleada para mitigar el trabajo de parto pretérmino según los artículos analizados por los autores a lo largo de la revisión. Sin embargo, se necesitan más estudios para legitimar dicha hipótesis.

Introduction. Progesterone is a hormone that favors maintaining pregnancy. It is the protagonist of the physiopathology of preterm labor. In this sense, a systematic review is proposed to demonstrate the usefulness of natural micronized progesterone in mitigating the harmful effects of preterm labor. Methodology. A systematic review in which the terms "MeSH" and "No ­ MeSH" were used. The "Publish or Perish" program was used, as well as databases, such as: Medline, PubMed, Embase, Clinical Key, Cochrane Library, Scopus, and Google Scholar. Review and meta-analysis articles, original articles (preliminary or complete publications), congress summaries, published seminars, textbooks, regional hospital protocols and national consensuses were included, in which each author individually assessed each article and applied the CASPE tool. Results. It was not possible to find concise international guidelines on using micronized progesterone for the threat of preterm labor (PTL) in literature. According to what the authors analyzed, for the mitigation of labor it is generally recommended the use of natural micronized progesterone in 100 to 400 mg/day capsules orally or 100 to 200 mg every 12 to 24 hours through the vagina. From week 16 to week 36 of pregnancy orally and from week 24 to 34 through the vagina. Discussion. Using micronized progesterone has demonstrated mitigating complications subsequent to preterm labor. However, there is no consensus on dosage and routes of administration. Added to the above, the analyzed studies may contain biases, reason why using this medication is left to the physician's discretion. Conclusions. Natural micronized progesterone can be used to mitigate preterm labor according to the articles the authors analyzed throughout the review. However, more studies are needed to validate this hypothesis.

Introdução. A progesterona é um hormônio que favorece a manutenção da gravidez, é a protagonista da fisiopatologia do parto prematuro. Dessa forma, propõe-se a realização de uma revisão sistemática que permita demonstrar a utilidade da progesterona natural micronizada na mitigação dos efeitos deletérios do trabalho de parto prematuro. Metodologia. Revisão sistemática em que foram utilizados os termos "MeSH" e "Não­MeSH". Foram utilizados o programa "Publish or Perish" e bases de dados como: Medline, PubMed, Embase, Clinical Key, Cochrane Library, Scopus e Google Scholar. Foram incluídos artigos de revisão, meta-análises, artigos originais (publicações preliminares ou completas), resumos de congressos, seminários publicados, livros didáticos, protocolos hospitalares regionais e consensos nacionais, onde cada autor avaliou individualmente cada artigo e aplicou a ferramenta CASPE. Resultados. Não é possível encontrar na literatura diretrizes internacionais concisas sobre o uso de progesterona micronizada diante da ameaça de trabalho de parto prematuro (TPP). Em geral, para a mitigação do trabalho de parto, conforme analisado pelos autores, recomenda-se o uso de progesterona natural micronizada em cápsulas de 100 a 400mg/dia por via oral ou 100 a 200mg a cada 12 a 24 horas por via vaginal. Da 16ª à 36ª semana de gestação por via oral e da 24ª à 34ª semana de gestação por via vaginal. Discussão. O uso de progesterona micronizada demonstrou mitigar as complicações após o trabalho de parto prematuro, no entanto, não há consenso sobre a dosagem e as vias de administração. Além do exposto, os estudos analisados podem conter vieses, pelo que cabe ao médico escolher o uso deste medicamento. Conclusões. A progesterona natural micronizada poderia ser utilizada para mitigar o trabalho de parto prematuro de acordo com os artigos analisados pelos autores ao longo da revisão. No entanto, mais estudos são necessários para legitimar essa hipótese.

17-alpha hydroxyprogesterone caproate and risk for venous thromboembolism during pregnancy.

INTRODUCTION: 17-alpha hydroxyprogesterone caproate (17 P) is a progestin commonly used during pregnancy to reduce risk of recurrent preterm birth. History of thromboembolism is a contraindication to 17 P and the package insert for 17 P recommends discontinuation in the setting of an acute VTE event. The objective of this study was to determine whether 17 P is associated with increased risk of VTE. STUDY DESIGN: The MarketScan claims database was used to perform a retrospective cohort of women who underwent delivery from 4/2008 to 1/2015. We identified women who received 17 P during pregnancy based on pharmacy benefits. Risk for VTE including deep vein thrombosis, pulmonary embolism, or both was stratified based on the presence or absence of 17 P pharmacy receipt. Both antenatal and delivery hospitalization VTE events were asceratined and these periods were analyzed individually. Relative risk (RR) was determined based on 17 P receipt. RESULTS: Among 4,775,667 delivery hospitalizations, 18,745 women received 17 P. Among women who did not receive 17 P, 0.52% of women (n = 24,529) had a VTE diagnosis compared to 0.61% (n = 114) receiving 17 P (RR 1.18, 95% CI 0.98-1.42). Comparing VTE events (i) during the antenatal period and (ii) during delivery hospitalizations, risks did not differ significantly for patients receiving 17 P. When risk was restricted to the cohort of patients without a diagnosis of a prior VTE event, 0.30% of women (n = 56) receiving 17 P were diagnosed with an event versus 0.28% of women (n = 13,427) not receiving 17 P (RR 1.07, 95% 0.82-1.39). DISCUSSION: No significant increased risk for VTE was noted with 17 P receipt. While new research has led to reconsideration of clinical use of 17 P for preterm birth prevention based on efficacy, findings from this analysis do not support major risk for thrombosis.

17-Alpha-Hydroxyprogesterone vs. Placebo for Preventing of Recurrent Preterm Birth: A Systematic Review and Meta-Analysis of Randomized Trials.

Background: Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality. Objective: To estimate the effect of 17-alpha-hydroxyprogesterone caproate (17-OHPC) compared to placebo in singleton gestations for reducing the risk of recurrent PTB and neonatal morbidity and mortality. Work Design: Systematic review and meta-analysis. Search Strategy: Searching MEDLINE, Embase, Web of Science, SCOPUS, Cochrane Library, and clinical trial registries. Selection Criteria: Randomized controlled trials of singleton gestations with a history of PTB and treated with a weekly intramuscular injection of 17-OHPC or placebo. Data Collection and Analysis: A random meta-analysis model was performed for the PTB outcomes (<32, <35, and <37 weeks) and neonatal outcomes (neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and sepsis). Effect estimates were measured by relative risk ratio (RR) with a 95% confidence interval (CI). Main Results: Six works were included. There were no statistically significant reductions in the PTB risk following the use of 17-OHPC at <32 weeks (RR = 0.61, 95% CI: 0.13-2.77, and I 2 = 39%), <35weeks (RR = 0.60, 95% CI: 0.10-3.67, and I 2 = 51%), and <37 weeks (RR = 0.68, 95% CI: 0.46-1, and I 2 = 75%). Furthermore, all the neonatal outcomes were statistically similar between the two groups. Conclusion: Treatment with 17-OHPC is not associated with reducing the risk of PTB or neonatal outcomes compared to placebo.

17-alpha hydroxyprogesterone caproate for the prevention of recurrent preterm birth among singleton pregnant women with a prior history of preterm birth: a systematic review and meta-analysis of six randomized controlled trials.

To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) that investigated the clinical benefits of 17-alpha hydroxyprogesterone caproate (17OHPC) in the prevention of recurrent preterm birth (PTB) among singleton pregnant women with a previous history of PTB. We searched four major databases up till April 2021 and assessed the risk of bias in the included studies. We meta-analyzed various maternal-neonatal endpoints (n=18) and pooled them as mean difference or risk ratio (RR) with 95% confidence interval (CI) using the random-effects model. Six RCTs met the inclusion criteria, comprising 2,573 patients (17OHPC=1,617, control=956). RCTs revealed an overall low risk of bias. The rates of PTB <35 weeks (n=5 RCTs; RR, 0.77; 95% CI, 0.63-0.93; P=0.008), PTB <32 weeks (n=3 RCTs; RR, 0.68; 95% CI, 0.51-0.91; P=0.009), neonates with low birth weight (<2.5 kg) at delivery (n=3 RCTs; RR, 0.63; 95% CI, 0.5-0.79; P<0.001), and neonatal death (n=4 RCTs; RR, 0.41; 95% CI, 0.20-0.84; P=0.02) were significantly reduced in the 17OHPC group compared with the control group. Moreover, 17OHPC treatment correlated with a significantly decreased rate of retinopathy (n=2 RCTs; RR, 0.42; 95% CI, 0.18-0.97; P=0.004). However, there were no significant differences in the rates of neonatal intensive care unit admission, cesarean delivery, and other pretermrelated complications between both the groups. Among singleton pregnant women with a prior history of PTB, 17OHPC may favorably decrease the risks of recurrent PTB and reduce the rate of neonatal death.

Preventing recurrent preterm birth with 125 mg of 17-alpha-hydroxyprogesterone caproate.

AIM: There is strong evidence that weekly intramuscular (IM) injections of 250 mg of 17-alpha-hydroxyprogesterone caproate (17-OHPC) reduce the risk of recurrent preterm birth (PTB); however, whether a lower dose of 17-OHPC could reduce the risk of recurrent PTB remains unclear. This study aimed to assess whether 125 mg of 17-OHPC reduces recurrent PTB among women with a prior singleton spontaneous PTB and cervical length >25 mm. METHODS: This retrospective cohort study at a tertiary-care medical center in Japan included women with a prior singleton spontaneous PTB between 20 and 36 weeks' gestation and cervical length >25 mm, between 2008 and 2018. Primary outcomes were PTB <37 and <34 weeks' gestation. We calculated the adjusted odds ratio (aOR) and 95% confidence interval (CI) using a multiple logistic regression model. Gestational age at delivery was compared using the Kaplan-Meier survival curve and log-rank test. RESULTS: Overall, 173 women met the inclusion criteria. Eighty-four women received weekly injections of 125 mg of 17-OHPC, and 89 did not. Treatment with 125 mg of 17-OHPC significantly reduced the risk of recurrent spontaneous PTB <37 (aOR: 0.156 [95% CI: 0.049-0.497]) and <34 weeks' gestation (aOR: 0.156 [95% CI: 0.049-0.497]). The mean delivery gestational age was also significantly longer in the 17-OHPC group (log-rank p = 0.005). CONCLUSIONS: In this study population, weekly IM injections of 125 mg of 17-OHPC reduced the risk of recurrent PTB <37 and <34 weeks' gestation.

Patient and Provider Perspectives on Acceptability, Access, and Adherence to 17-Alpha-Hydroxyprogesterone Caproate for Preterm Birth Prevention.

Background: Preterm birth (PTB) is a pressing maternal and child health issue with long-standing racial inequities in outcomes and care provision. 17-Alpha-hydroxyprogesterone caproate (17OHPC) has been one of few clinical interventions for recurrent PTB prevention. Little is known about the factors influencing successful administration and receipt of 17OHPC among mothers in the Medicaid program. Materials and Methods: We conducted individual semistructured interviews with 17OHPC-eligible pregnant women and obstetric providers from two academic medical centers in Philadelphia, PA. Patient participants were publicly insured, eligible for 17OHPC treatment, and purposively sampled as either (1) actively receiving treatment or (2) declining/discontinuing treatment. Providers had experience providing care to Medicaid-enrolled patients. Interview transcripts were coded and analyzed to identify themes related to treatment acceptability, access, and adherence. Results: Of the 17 patient participants, the mean age was 30 years. Ten providers (MDs, nurse practitioners, and registered nurses) were also interviewed. Factors facilitating 17OHPC uptake and adherence among patients included severity of prior PTB, provider counseling, and coordination among the clinic, pharmacy, and insurance. Pain was cited as the most significant barrier to 17OHPC for patients, while providers perceived social adversity and beliefs about patients' commitment to treatment to be primary patient barriers. For providers, clinical experience and practice guidelines contributed to their use of 17OHPC. Administrative complexity and coordination of services were the primary provider barrier to 17OHPC administration. Conclusions: Patient-provider communication is a primary driver of 17OHPC acceptability and adherence. Comprehensive patient-centered consultation may improve uptake of clinical therapies among pregnant women at high risk for PTB.

Utilization, adherence, and outcomes of 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention.

OBJECTIVE: To describe the use of and adherence to 17-alpha hydroxyprogesterone caproate (17-OHPC), explore factors associated with its utilization and adherence, and to investigate the outcomes of 17-OHPC in a real-world setting. METHODS: The Decision Resources Group (DRG) database (1 January 2012-31 December 2017) was used to identify women with diagnosis of "history of preterm labor", aged 16-50 years old, had a singleton gestation, were continuously enrolled for at least 6 months and 9 months before and after the index date, respectively, and had a delivery outcome recorded. Adequate adherence was defined and compared using two approaches: (1) patients receiving at least 10 injections of 17-OHPC; (2) number of received injections/eligible number of injections ≥0.7. The outcome of 17-OHPC was evaluated by the incidence rate of preterm birth (PTB). Bivariate tests compared patients' characteristics with their use of and adherence to 17-OHPC, and examined the associations between 17-OHPC utilization and incidence of diabetes or hypertension. Stepwise logistic regression was conducted to assess the effect of adherence on the delivery outcome. RESULTS: Of 28,339 patients meeting study criteria, 2585 (9.1%) had ≥1 claim for 17-OHPC. An increasing trend of utilization was observed from 2012 to 2017 (7.6-13.1%). The utilization rate was highest in the Southwest US (13.8%) (p < .001). Commercial insurance patients (9.6%) were more likely to use 17-OHPC than Medicaid patients (7.9%) (p < .001). Patients with higher Charlson Comorbidity Index (CCI) scores were less likely to use 17-OHPC. Of women prescribed 17-OHPC, 792 (30.6%) and 424 (16.4%) were adherent using two definitions, respectively. No difference in PTB rate was observed between adherers and non-adherers (definition 1: aOR = 0.97, 95% CI = 0.81-1.16; definition 2: aOR = 1.18, 95% CI = 0.95-1.48). No association was found between 17-OHPC and incidence of diabetes (p = .96); however, use of 17-OHPC was associated with a lower incidence rate of hypertension (p = .002). CONCLUSIONS: 17-OHPC utilization and adherence rates remain low. Insurance type and geographic region were associated with both utilization and adherence. There was no association between 17-OHPC adherence and effectiveness. More evidence is needed to determine if the use of 17-OHPC is advantageous in a sub-group of patients.

Understanding barriers to uptake of 17 alpha-hydroxyprogesterone caproate (17-OHP) in women with history of preterm birth.

Background: Premature birth is responsible for approximately 38% of infant deaths as well as a host of complications, including abnormal lung development, infection, and long-term disabilities. For women with a history of spontaneous preterm birth in a singleton pregnancy, use of 17 alpha-hydroxyprogesterone caproate (17-OHP) can reduce the risk of a recurrent preterm birth by up to 42%. However, less than half of eligible women currently receive 17-OHP.Objectives: The purpose of this study was to understand the barriers to access and acceptability of 17-OHP use from the patient perspective.Study design: A qualitative study was conducted of women with a history of a prior spontaneous, singleton preterm birth who were eligible for 17-OHP during a subsequent singleton pregnancy. Researchers recruited 118 eligible women during the Spring and Summer of 2018 from a safety-net hospital in Denver, CO, USA, a hospital that provides healthcare for individuals regardless of their insurance status or ability to pay. Responses from 35 participants were analyzed, looking at themes surrounding knowledge of and counseling received regarding 17-OHP, hesitations, and barriers toward receiving the treatment.Results: Among respondents (34.0% response rate), the mean age was 31.5 years and mean gestational age at delivery was 32.1 weeks. Major themes from interviews included reasons that encouraged women to use 17-OHP, such as the desire to do anything for the health of their baby and reasons that women felt discouraged from using 17-OHP, including unknown complications and lack of information. Other barriers to this treatment method included the time commitment, specifically the length of clinic appointments and concerns about the safety of the 17-OHP injection.Conclusions: One of the strongest reasons for women choosing to use 17-OHP was a desire to do anything possible to support their babies. Somewhat surprisingly, there was not a significant relationship with the participants between gestational age of prior preterm deliveries and subsequent use of 17-OHP. There were two important reasons women cited most frequently for choosing not to use 17-OHP. One was feeling that they lacked information or knowledge about 17-OHP to make an informed decision, which is crucial because the study also showed that all eligible women are not being appropriately counseled on the option of 17-OHP. In terms of time commitment, it was the length of individual appointments, rather than frequency that was a barrier to receiving weekly injections.

A chronicle of the 17-alpha hydroxyprogesterone caproate story to prevent recurrent preterm birth.

Preterm birth is a substantial public health concern. In 2019, the US preterm birth rate was 10.23%, which is the fifth straight year of increase in this rate. Moreover, preterm birth accounts for approximately 1 in 6 infant deaths, and surviving children often suffer developmental delay or long-term neurologic impairment. Although the burden of preterm birth is clear, identifying strategies to reduce preterm birth has been challenging. On October 29, 2019, a US Food and Drug Administration advisory committee voted 9 vs 7 to withdraw interim accelerated approval of 17-alpha hydroxyprogesterone caproate for preventing recurrent preterm birth because the called for a confirmatory trial, known as the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial, was not confirmatory. The Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial included subjects enrolled in the United States and Canada to ensure that at least 10% of patients would be from North America; however, this trial took 9 years to complete and did not demonstrate significant treatment effects in the 2 primary outcomes of interest. Delivery before 35 weeks' gestation occurred in 122 of 1130 women (11%) given 17-alpha hydroxyprogesterone caproate compared with 66 of 578 women (11.5%) given placebo (relative risk, 0.95; 95% confidence interval, 0.71-1.26; P=.72). Similarly, the coprimary outcome neonatal composite index occurred in 61 of 1093 women (5.6%) given 17-alpha hydroxyprogesterone caproate compared with 28 of 559 women (5.0%) given placebo (relative risk, 1.12; 95% confidence interval, 0.68-1.61; P=.73). There was also a lack of efficacy for 17-alpha hydroxyprogesterone caproate treatment in the analysis of a variety of secondary outcomes. Like the Maternal-Fetal Medicine Units Network trial, the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery trial was also flawed. Importantly, the Maternal-Fetal Medicine Unit Network trial was the sole justification for treating women in the United States with 17-alpha hydroxyprogesterone caproate for nearly 2 decades. Currently, despite more than half a century, 17-alpha hydroxyprogesterone caproate still has not been found to be clearly effective. In this context, how does the advising physician dependent on scientific evidence advise a patient that 17-alpha hydroxyprogesterone caproate is effective when the evidence to support this advice has repeatedly been found to be inadequate? This clinical opinion is a critical appraisal of the 2 randomized trials examining the efficacy of 17-alpha hydroxyprogesterone caproate to prevent recurrent preterm birth and a chronicle of events in the regulatory process of drug approval to help answer this question. With this examination, these events illustrate the complexity of pharmaceutical regulations in the era of accelerated Food and Drug Administration approval and characterize the financial impact and influence in medicine. In this report, we also emphasize the value of observational studies in contemporary practice and identify other examples in medicine where accelerated Food and Drug Administration approval has been withdrawn. Importantly, the themes of the 17-alpha hydroxyprogesterone caproate story are not limited to obstetrics. It can also serve as a microcosm of issues within the US healthcare system, which ultimately contributes to the high cost of healthcare. In our opinion, the answer to the question is clear-the facts speak for themselves-and we believe 17-alpha hydroxyprogesterone caproate should not be endorsed for use to prevent recurrent preterm birth in the United States.

Successful treatment of severe intra-amniotic inflammation and cervical insufficiency with continuous transabdominal amnioinfusion and cerclage: A case report.

Severe intra-amniotic inflammation, even with a negative bacterial culture, can lead to premature labor. We report a 43-year-old multiparous woman with severe intra-amniotic inflammation and cervical insufficiency at 23 weeks and 5 days of gestation. Continuous transabdominal amnioinfusion was started 2 days after the diagnosis. The amniotic fluid interleukin-6 level normalized after 2 days of treatment. She underwent Shirodkar cervical cerclage on day 7. Despite termination of amnioinfusion and catheter removal on day 16, the pregnancy was maintained without any subsequent treatment. At 33 weeks and 5 days of gestation, an intrauterine Ureaplasma parvum infection and the onset of contractions led to repeat cesarean delivery. The birth weight was 2292 g, and the Apgar scores were 8/8. Both mother and infant had good outcomes. Continuous transabdominal amnioinfusion may have eliminated factors causing intra-amniotic inflammation, thereby prolonging the pregnancy and improving the infant's prognosis.

FDA approved vs. Pharmacy compounded 17-OHPC-current issues for obstetricians to consider in reducing recurrent preterm birth.

17α-hydroxyprogesterone caproate (17-OHPC; MAKENA and generic equivalents) is the only FDA-approved medicine available to reduce the risk of preterm birth (PTB) in pregnant women with a singleton pregnancy who have a history of singleton spontaneous PTB. The FDA held an Advisory Committee meeting in October 2019 to review conflicting data between one positive U.S.-based study and one international study that failed to confirm the benefit. At this meeting, the key vote as to whether the FDA should pursue withdrawal of Makena resulted in a split; 9 members voted that the FDA pursue withdrawal and 7 members voted to leave Makena on the market and require that additional effectiveness data be generated. Removal of FDA-approved formulations of 17-OHPC-both brand name Makena and the generic equivalents-would foreseeably result in clinicians administering compounded 17-OHPC to prevent PTB in their patients. Unlike FDA-approved products, compounded drugs are not approved by the FDA and, thus, have not undergone any FDA scrutiny with regard to safety, effectiveness, or quality (as designated by good manufacturing practices; GMP) before they are marketed. Compounded drugs may be associated with significant safety risks, as poor compounding practices have resulted in serious problems with drug quality (lack of sterility or stability) and potency. Given the markedly higher rates of PTB in the U.S. compared with other industrialized nations, it is imperative that FDA-approved, GMP-produced 17-OHPC (FDA-approved brand and generic formulations) is available while additional research on its optimal use is conducted, without providers and patients resorting to pharmacist-compounded formulations for their high-risk pregnant patients.

Current Approaches to Risk Assessment and Prevention of Preterm Birth-A Continuing Public Health Crisis.

Background: Preterm birth remains a major cause of neonatal morbidity and mortality. Several potential pathways and pathophysiologic processes can lead to preterm birth, complicating efforts to screen for the risk of preterm birth and making implementation of prevention strategies difficult. Methods: Based on a review of the literature, this article addresses screening strategies for preterm birth risk stratification and interventions for preterm birth prevention. Results: In women with a history of a prior spontaneous preterm birth, cervical cerclage placement in the setting of short cervix reduces the rate of recurrent spontaneous preterm birth. Weekly injections of 17-hydroxyprogesterone caproate (17-P) have been used as standard treatment for the prevention of recurrent preterm birth since 2011. However, results of a replication study of 17-P published in 2020 have raised questions regarding the effectiveness of this drug, and it is under review by the US Food and Drug Administration. Among women with no history of preterm birth, cervical length appears to be the best predictor of risk for preterm birth in asymptomatic women. In women with a cervical length <25 mm, vaginal progesterone has been demonstrated to reduce the risk of preterm birth. Conclusion: Strategies including cervical length screening, vaginal progesterone administration, cervical cerclage placement, and, potentially, 17-P administration may help reduce rates of preterm birth when used in the appropriate patient populations. Development of protocols for patient evaluation and risk stratification will help identify patients at highest risk for preterm birth and allow use of the best available therapeutic interventions.

A systematic review and meta-analysis of randomized controlled trials comparing 17-alpha-hydroxyprogesterone caproate versus placebo for the prevention of recurrent preterm birth.

BACKGROUND: Preterm birth causes an increased risk for perinatal morbidity and mortality. OBJECTIVE: To determine whether mid-trimester 17-alpha-hydroxyprogesterone caproate (17-OHPC) reduces the risk of recurrent preterm birth and adverse perinatal outcomes. SEARCH STRATEGY: Systematic search to identify relevant studies published in different languages, registered after 2000, using appropriate MeSH terms. SELECTION CRITERIA: Inclusion criteria were women between 16 and 26+6  weeks of pregnancy with history of preterm delivery in any pregnancy randomized to either 17-OHPC or placebo/no treatment. DATA COLLECTION AND ANALYSIS: The number of preterm births and adverse outcomes in the 17-OHPC and placebo arms over the total number of patients in each randomized group were used to calculate the risk ratio (RR) by random-effects models using the Mantel-Haenszel method. Between-study heterogeneity was assessed using tau2 , χ2 (Cochrane Q), and I2 statistics. MAIN RESULTS: Four studies were included. There was a 29% (RR 0.71; 95% CI, 0.53-0.96; P=0.001), 26% (RR 0.74; 95% CI, 0.58-0.96; P=0.021), and 40% (RR 0.60; 95% CI, 0.42-0.85; P=0.004) reduction in recurrent preterm birth at <37, <35, and <32 weeks, respectively, in the 17-OHPC group compared with placebo. The reduction in neonatal death was 68% (RR 0.32; 95% CI, 0.15-0.66; P=0.002). CONCLUSIONS: 17-OHPC could reduce the risk of recurrent preterm birth at <37, <35, and <28 weeks and neonatal death. PROSPERO: CDR42017082190.

Vaginal progesterone is associated with decreased group B streptococcus colonisation at term: a retrospective cohort study.

OBJECTIVE: To investigate whether women using intravaginal progesterone suppositories for preterm birth prevention during pregnancy will have lower rates of group B streptococcus (GBS) colonisation at term, compared with women receiving intramuscular 17-alpha-hydroxyprogesterone caproate. DESIGN: This was a retrospective observational cohort study of women who were prescribed a progestogen during their pregnancy for preterm birth prevention, and who delivered at term. SETTING: A tertiary referral hospital in central Ohio. POPULATION: Patients who were prescribed a progestogen during their pregnancy for preterm birth prevention between 2004 and 2017 were included in the study. Patients who delivered at <37 weeks of pregnancy, switched progestogen type during the pregnancy, or had a pessary or cerclage placed were excluded. METHODS: Baseline characteristics were compared using Mann-Whitney U-test or Chi-square test as appropriate. The association between type of progestogen and GBS colonisation was assessed using bivariate and multivariable analyses. MAIN OUTCOME MEASURES: The primary outcome was GBS colonisation. RESULTS: In all, 565 patients were included in the study, of whom 173 received intravaginal progesterone, and 392 17-alpha-hydroxyprogesterone caproate. Patients receiving intravaginal progesterone were less likely to be colonised with GBS (19.7 versus 28.1%). After adjustments for potential confounders were made in a multivariable logistic regression analysis, receiving intravaginal progesterone suppositories (adjusted odds ratio [OR] 0.61, 95% CI 0.39-0.95) was associated with reduced GBS colonisation. CONCLUSIONS: Intravaginal progesterone is associated with a decreased prevalence of rectovaginal GBS colonisation at term. TWEETABLE ABSTRACT: Vaginal progesterone is associated with a lower incidence of rectovaginal GBS colonisation, compared with 17α-hydroxyprogesterone caproate.