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.

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

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

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.

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.

Reassessing Preterm Birth Prevention After the Withdrawal of 17-α Hydroxyprogesterone Caproate.

The U.S. Food and Drug Administration has recently withdrawn approval for 17-α hydroxyprogesterone caproate for prevention of recurrent preterm birth, and recent studies have called into question benefits of the pessary in the setting of a short cervix. Obstetric health care professionals are once again left with limited remaining options for preterm birth prevention. This narrative review summarizes the best current evidence on the use of vaginal progesterone, low-dose aspirin, and cerclage for the prevention of preterm birth; attempts to distill possible lessons learned from studies of progesterone and pessary, as well as their implementation into practice; and highlights areas where inroads into preterm birth prevention may be possible outside of the progesterone-aspirin-cerclage paradigm.

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.

Vaginal Progesterone Is Associated with Intrahepatic Cholestasis of Pregnancy.

OBJECTIVE: The frequency of intrahepatic cholestasis of pregnancy (ICP) peaks during the third trimester of pregnancy when plasma progesterone levels are the highest. Furthermore, twin pregnancies are characterized by higher progesterone levels than singletons and have a higher frequency of cholestasis. Therefore, we hypothesized that exogenous progestogens administered for reducing the risk of spontaneous preterm birth may increase the risk of cholestasis. Utilizing the large IBM MarketScan Commercial Claims and Encounters Database, we investigated the frequency of cholestasis in patients treated with vaginal progesterone or intramuscular 17α-hydroxyprogesterone caproate for the prevention of preterm birth. STUDY DESIGN: We identified 1,776,092 live-born singleton pregnancies between 2010 and 2014. We confirmed second and third trimester administration of progestogens by cross-referencing the dates of progesterone prescriptions with the dates of scheduled pregnancy events such as nuchal translucency scan, fetal anatomy scan, glucose challenge test, and Tdap vaccination. We excluded pregnancies with missing data regarding timing of scheduled pregnancy events or progesterone treatment prescribed only during the first trimester. Cholestasis of pregnancy was identified based on prescriptions for ursodeoxycholic acid. We used multivariable logistic regression to estimate adjusted (for maternal age) odds ratios for cholestasis in patients treated with vaginal progesterone, and in patients treated with 17α-hydroxyprogesterone caproate compared with those not treated with any type of progestogen (the reference group). RESULTS: The final cohort consisted of 870,599 pregnancies. Among patients treated with vaginal progesterone during the second and third trimester, the frequency of cholestasis was significantly higher than the reference group (0.75 vs. 0.23%, adjusted odds ratio [aOR]: 3.16, 95% confidence interval [CI]: 2.23-4.49). In contrast, there was no significant association between 17α-hydroxyprogesterone caproate and cholestasis (0.27%, aOR: 1.12, 95% CI: 0.58-2.16) CONCLUSION: Using a robust dataset, we observed that vaginal progesterone but not intramuscular 17α-hydroxyprogesterone caproate was associated with an increased risk for ICP. KEY POINTS: · Previous studies have been underpowered to detect potential association between progesterone and ICP.. · Vaginal progesterone was significantly associated with ICP.. · Intramuscular 17α-hydroxyprogesterone was not associated with ICP..

Effect of 17-Hydroxyprogesterone Caproate on Interleukin-6 and Tumor necrosis factor-alpha in expectantly managed early-onset preeclampsia.

The study aimed to evaluate the effect of 17 hydroxy progesterone (17-OHPC) on interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in expectantly managed early-onset preeclampsia (PE). A randomized open-label controlled study included women who were diagnosed as early-onset PE if they assigned to expectant management according to the American College of Obstetricians and Gynecologists (ACOG) 2013 criteria for diagnosis of severity of PE. Patients were randomized into Group A (40 patients) received 17-OHPC 250 mg intra-muscular at admission and every 7 days thereafter and Group B (40 patients) was given the usual conservative measures of early-onset PE as a control group. Blood samples were obtained from all participants for measurements of TNF-α and IL-6 levels at admission and repeated at termination of pregnancy. The primary outcome was the mean difference between TNF-α and IL-6 levels before and after treatment in both groups. TNF-α and IL-6 levels at admission were not different between the two groups. However, there was a significant difference concerning these inflammatory biomarkers within the same group at admission and at termination (p < 0.001), with significant decline of IL-6 and TNF-α level in the 17-OHPC treated group and significant rise of IL-6 and TNF-α in the control group. There was a strong positive correlation between systolic blood pressure (SBP) at admission and TNF-α level (r= 0.867, p=0.017), and moderately positive significant correlation between diastolic blood pressure (DBP) at admission and TNF-α (r=0.610, p < 0.001). There was a mild positive significant correlation between IL-6 levels and SBP (r= 0.231, p=0.039), and DBP (r= 0.203, p= 0.041) at admission. In conclusion, 17-OHPC has no effect in improving maternal or neonatal outcomes in conservatively managed early onset PE, although it alters the inflammatory markers levels (IL-6 and TNF-α) that could improve the pathogenesis of PE.

Obstetric Indications for Progestin Therapy.

Specifically, meta-analyses of randomized trials demonstrate that vaginal progesterone reduces the risk of preterm birth in selected high-risk singleton pregnancies. 17-OHPC may also reduce the risk of recurrent preterm birth in singletons. Finally, one trial suggests that vaginal progesterone may also be beneficial in improving live birth rates in singletons with prior miscarriages and early pregnancy bleeding.

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..

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..

Does the HCG trigger dose used for IVF impact luteal progesterone concentrations? a randomized controlled trial.

RESEARCH QUESTION: Is there an association between the ovulation trigger dose of human chorionic gonadotrophin (HCG) and endogenous progesterone production during the luteal phase? DESIGN: This randomized controlled four-arm study, at the Fertility Clinic, Odense University Hospital, Denmark, included women undergoing gonadotrophin-releasing hormone (GnRH) antagonist IVF treatment with ≤11 follicles ≥12 mm. Group 1-3 were triggered with 5000 IU, 6500 IU or 10,000 IU HCG, respectively, receiving 17α-hydroxyprogesterone caproate intramuscularly for luteal-phase support (LPS) to measure endogenous progesterone production. Group 4 received 6500 IU HCG trigger and vaginal progesterone. During the study, the 5000 IU and 10,000 IU HCG groups were switched from urinary to recombinant HCG, as urinary HCG was removed from market. Eight blood samples were drawn during the luteal phase. RESULTS: Ninety-four participants completed the study. There was a significant positive association between the HCG trigger dose and the progesterone at 8 days (P < 0.001), 10 days (P < 0.001) and 14 days (P < 0.001) post-oocyte retrieval. Comparing the groups individually revealed a significant difference in progesterone concentration between low and high trigger doses at 4 days (P = 0.037) and 8 days (P = 0.007) post-oocyte retrieval and between all intervention groups at oocyte retrieval + 6 days: group 1 and 2 (P = 0.011), group 2 and 3 (P = 0.042) and group 1 and 3 (P < 0.001). Higher HCG trigger dose increased the progesterone from the individual follicle. CONCLUSIONS: Increasing HCG trigger doses significantly increased endogenous progesterone concentration during the mid-late luteal phase.

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.

Should we stop prescribing IM progesterone to women with a history of preterm labor?

YES, we should stop the routine prescribing of IM progesterone to prevent preterm delivery. A 2003 randomized controlled trial (RCT) found that weekly intramuscular (IM) 17 hydroxyprogesterone (17-OHP) for women with a singleton pregnancy and a history of spontaneous preterm delivery decreased the preterm delivery rate by 34% (strength of recommendation [SOR]: B, single RCT). However, the follow-up 2020 PROLONG RCT did not find that 17-OHP prevents preterm birth or improves neonatal outcomes. This held true for subgroup analyses (SOR: B, single larger RCT). (Notably, though, the PROLONG study had very few Black participants when compared with the 2003 study.)The US Food and Drug Administration (FDA) has recommended withdrawing 17-OHP from the market. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have released statements supporting shared decision-making with women regarding the prescribing of 17-OHP for preterm delivery prevention (SOR: C, expert opinion).

¿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.

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.

In utero exposure to 17α-hydroxyprogesterone caproate and risk of cancer in offspring.

BACKGROUND: 17α-hydroxyprogesterone caproate is a synthetic progestogen initially approved in the 1950s to treat gynecologic and obstetrical conditions. Despite continued concerns about safety and short-term efficacy regarding the use of 17α-hydroxyprogesterone caproate for the prevention of preterm birth in pregnant women, little is known about the long-term effects of 17α-hydroxyprogesterone caproate on the health of the offsprings. OBJECTIVE: To examine the association between in utero exposure to 17α-hydroxyprogesterone caproate and the risk of cancer in the offspring. STUDY DESIGN: The Child Health and Development Studies was a population-based cohort of >18,000 mother-child dyads receiving prenatal care in the Kaiser Foundation Health Plan (Oakland, CA) between 1959 and 1966. Clinical information was abstracted from the mothers' medical records beginning 6 months before pregnancy through delivery. We identified the number and timing of 17α-hydroxyprogesterone caproate injections during pregnancy. Incident cancers diagnosed in the offspring were ascertained through 2019 by linkage to the California Cancer Registry. We used the Cox proportional hazard models to estimate the adjusted hazard ratios and their 95% confidence intervals, with the follow-up time accrued from the date of birth through the date of cancer diagnosis, death, or last contact. RESULTS: A total of 1008 offspring were diagnosed with cancer over 730,817 person-years of follow-up. Approximately 1.0% of the offspring (n=234) were exposed in utero to 17α-hydroxyprogesterone caproate. Exposure in the first trimester was associated with an increased risk of any cancer (adjusted hazard ratio, 2.57; 95% confidence interval, 1.59-4.15), and the risk increased with the number of injections (1-2 injections: adjusted hazard ratio, 1.80; 95% confidence interval, 1.12-2.90; ≥3 injections: adjusted hazard ratio, 3.07; 95% confidence interval, 1.34-7.05). Exposure in the second or third trimester conferred an additional risk for the male (adjusted hazard ratio, 2.59; 95% confidence interval, 1.07-6.28) but not for the female (adjusted hazard ratio, 0.30; 95% confidence interval, 0.04-1.11) offspring. The risk of colorectal (adjusted hazard ratio, 5.51; 95% confidence interval, 1.73-17.59), prostate (adjusted hazard ratio, 5.10; 95% confidence interval, 1.24-21.00), and pediatric brain (adjusted hazard ratio, 34.72; 95% confidence interval, 7.29-164.33) cancer was higher in the offspring first exposed to 17α-hydroxyprogesterone caproate in the first trimester than the offspring not exposed. CONCLUSION: Caution using 17α-hydroxyprogesterone caproate in early pregnancy is warranted, given the possible link with cancer in the offspring.

Comparison the efficacy of vaginal progesterone versus 17-alpha-hydroxyprogesterone caproate to prevent preterm birth in high-risk pregnant women undergo cerclage: a randomized clinical trial.

OBJECTIVE: The aim of this study was to compare the effect of vaginal progesterone with 17-alpha-hydroxyprogesterone caproate (17OHP-C) in prevention of preterm birth in high-risk pregnant women undergo cerclage. MATERIALS AND METHODS: This prospective randomized clinical trial registered in the Iranian Registry of Clinical Trials (IRCT20181107041585N4), was performed from May 2017 to August 2018 in Bandar Abbas, Iran. Fifty-eight eligible women who were scheduled for cervical cerclage due to a history of two or more previous preterm birth <28 weeks or a cervical length less than 25 mm with at least one previous preterm birth <34 weeks were randomly divided into two groups. The first group received 200 mg of vaginal progesterone suppository daily and the second one received 250 mg of 17OHP-C intramuscular weekly after cerclage procedure until the end of 36 weeks. Patients were followed up to the end of delivery and the newborn until the first 28 d after delivery. RESULTS: Gestational age at the time of birth in 17OHP-C group was significantly higher than vaginal progesterone group (p=.021). However, the incidence of preterm birth in both groups was not statistically significant (20.7% vs. 24.1%). Apgar scores, newborn birthweight, admission to neonatal intensive care unit (NICU), incidence of respiratory distress syndrome (RDS), sepsis, necrotizing enterocolitis (NEC), and, intraventricular hemorrhage (IVH), was similar in both groups. Adverse events were reported in 48.3% of patients in 17-OHP-C group, and 27.6% of patients in the vaginal progesterone group (p= .014). CONCLUSIONS: Vaginal progesterone and 17OHP-C had similar results in terms of prevention of preterm birth and neonatal outcome. However, the adverse events associated with 17-OHP-C were higher than vaginal progesterone.

Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth.

Inflammation contributes to nearly 4 million global premature births annually. Here, we used a mouse model of intrauterine inflammation to test clinically used formulations, as well as engineered nanoformulations, for the prevention of preterm birth (PTB). We observed that neither systemic 17a-hydroxyprogesterone caproate (Makena) nor vaginal progesterone gel (Crinone) was sufficient to prevent inflammation-induced PTB, consistent with recent clinical trial failures. However, we found that vaginal delivery of mucoinert nanosuspensions of histone deacetylase (HDAC) inhibitors, in some cases with the addition of progesterone, prevented PTB and resulted in delivery of live pups exhibiting neurotypical development. In human myometrial cells in vitro, the P4/HDAC inhibitor combination both inhibited cell contractility and promoted the anti-inflammatory action of P4 by increasing progesterone receptor B stability. Here, we demonstrate the use of vaginally delivered drugs to prevent intrauterine inflammation-induced PTB resulting in the birth of live offspring in a preclinical animal model.