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

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. 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. 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. 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). 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.

Boelig RC ，Schoen CN ，Frey H ，Gimovsky AC ，Springel E ，Backley S ，Berghella V ... -  《-》

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

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. 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. 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. The primary outcome was preterm birth <34 weeks' gestation. The summary measures were reported as relative risks with 95% confidence intervals. 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). 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.

Boelig RC ，Locci M ，Saccone G ，Gragnano E ，Berghella V ... -  《-》

Vaginal progesterone vs intramuscular 17α-hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: systematic review and meta-analysis of randomized controlled trials.

Randomized controlled trials (RCTs) have recently compared intramuscular 17α-hydroxyprogesterone caproate (17-OHPC) with vaginal progesterone for reducing the risk of spontaneous preterm birth (SPTB) in singleton gestations with prior SPTB. The aim of this systematic review and meta-analysis was to evaluate the efficacy of vaginal progesterone compared with 17-OHPC in prevention of SPTB in singleton gestations with prior SPTB. Searches of electronic databases were performed to identify all RCTs of asymptomatic singleton gestations with prior SPTB that were randomized to prophylactic treatment with either vaginal progesterone (intervention group) or intramuscular 17-OHPC (comparison group). No restrictions for language or geographic location were applied. The primary outcome was SPTB < 34 weeks. Secondary outcomes were SPTB < 37 weeks, < 32 weeks, < 28 weeks and < 24 weeks, maternal adverse drug reaction and neonatal outcomes. The summary measures were reported as relative risk (RR) with 95% CI. Risk of bias for each included study was assessed. Three RCTs (680 women) were included. The mean gestational age at randomization was about 16 weeks. Women were given progesterone until 36 weeks or delivery. Regarding vaginal progesterone, one study used 90 mg gel daily, one used 100 mg suppository daily and one used 200 mg suppository daily. All included RCTs used 250 mg intramuscular 17-OHPC weekly in the comparison group. Women who received vaginal progesterone had significantly lower rates of SPTB < 34 weeks (17.5% vs 25.0%; RR, 0.71 (95% CI, 0.53-0.95); low quality of evidence) and < 32 weeks (8.9% vs 14.5%; RR, 0.62 (95% CI, 0.40-0.94); low quality of evidence) compared with women who received 17-OHPC. There were no significant differences in the rates of SPTB < 37 weeks, < 28 weeks and < 24 weeks. The rate of women who reported adverse drug reactions was significantly lower in the vaginal progesterone group compared with the 17-OHPC group (7.1% vs 13.2%; RR, 0.53 (95% CI, 0.31-0.91); very low quality of evidence). Regarding neonatal outcomes, vaginal progesterone was associated with a lower rate of neonatal intensive care unit admission compared with 17-OHPC (18.7% vs 23.5%; RR, 0.63 (95% CI, 0.47-0.83); low quality of evidence). For the comparison of 17-OHPC vs vaginal progesterone, the quality of evidence was downgraded for all outcomes by at least one degree due to imprecision (the optimal information size was not reached) and by at least one degree due to indirectness (different interventions). Daily vaginal progesterone (either suppository or gel) started at about 16 weeks' gestation is a reasonable, if not better, alternative to weekly 17-OHPC injection for prevention of SPTB in women with singleton gestations and prior SPTB. However, the quality level of the summary estimates was low or very low as assessed by GRADE, indicating that the true effect may be, or is likely to be, substantially different from the estimate of the effect. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. COMPARACIÓN ENTRE LA PROGESTERONA VAGINAL Y EL 17Α-HIDROXIPROGESTERONA CAPROATO INTRAMUSCULAR PARA LA PREVENCIÓN DEL PARTO PRETÉRMINO ESPONTÁNEO RECURRENTE EN EMBARAZOS CON FETO ÚNICO: REVISIÓN SISTEMÁTICA Y METAANÁLISIS DE ENSAYOS CONTROLADOS ALEATORIOS: RESUMEN OBJETIVO: Recientemente se han realizado varios ensayos controlados aleatorios (ECA) que comparaban el caproato de 17α-hidroxiprogesterona (17-OHPC, por sus siglas en inglés) por vía intramuscular con la progesterona por vía vaginal para la reducción del riesgo de parto pretérmino espontáneo (PPTE) en embarazos con feto único de gestantes con historial de PPTE. El objetivo de esta revisión sistemática y metaanálisis fue evaluar la eficacia de la progesterona vaginal en comparación con la 17-OHPC en la prevención de embarazos con feto único de gestantes con historial de PPTE. MÉTODOS: Se realizaron búsquedas en bases de datos electrónicas para identificar todos los ECA con embarazos de feto único asintomáticos con historial de PPTE antes de ser asignados al azar a un tratamiento profiláctico, ya fuera con progesterona vaginal (grupo de intervención) o con 17-OHPC intramuscular (grupo de control). No se aplicaron restricciones respecto al idioma o la ubicación geográfica. El resultado primario fue PPTE < 34 semanas. Los resultados secundarios fueron PPTE <37 semanas, < 32 semanas, < 28 semanas y < 24 semanas, la reacción materna adversa al fármaco y los resultados neonatales. Las medidas del resumen se reportaron como riesgo relativo (RR) con IC del 95%. Para cada estudio incluido se evaluó el riesgo de sesgo. Se incluyeron tres ECA (680 mujeres). La media de la edad gestacional en el momento de la aleatorización fue de 16 semanas. A las mujeres se les administró progesterona hasta la semana 36 o hasta el parto. Con respecto a la progesterona vaginal, un estudio utilizó gel de 90 mg diariamente, otro utilizó un supositorio diario de 100 mg y el otro utilizó un supositorio diario de 200 mg. Todos los ECA incluidos en el grupo de comparación utilizaron 250 mg semanales de 17-OHPC por vía intramuscular. Las mujeres que recibieron progesterona vaginal tuvieron tasas significativamente más bajas de PPTE < 34 semanas (17,5% vs. 25,0%; RR 0,71 (IC 95%, 0,53-0,95); calidad de la evidencia baja) y < 32 semanas (8,9% vs. 14,5%; RR 0,62 (IC 95%, 0,40-0,94); calidad de evidencia baja), en comparación con las mujeres que recibieron 17-OHPC. No hubo diferencias significativas en las tasas de PPTE < 37 semanas, < 28 semanas y < 24 semanas. La tasa de mujeres que reportaron reacciones adversas a los medicamentos fue significativamente menor en el grupo de progesterona vaginal en comparación con el grupo de 17-OHPC (7,1% vs. 13,2%; RR 0,53 (IC 95%, 0,31-0,91); calidad de la evidencia muy baja). En cuanto a los resultados neonatales, la progesterona vaginal se asoció a una menor tasa de admisiones en la unidad neonatal de cuidados intensivos en comparación con la 17-OHPC (18,7% vs. 23,5%; RR 0,63 (IC 95%, 0,47-0,83); calidad de evidencia baja). Para la comparación del 17-OHPC con la progesterona vaginal se rebajó la calidad de las pruebas para todos los resultados en al menos un grado debido a imprecisiones (no se alcanzó el tamaño óptimo de la información) y en al menos un grado debido al carácter indirecto de los estudios (diferentes intervenciones). La progesterona vaginal administrada diariamente (ya fuera como supositorio o como gel) desde la semana 16 de gestación es una alternativa razonable, si no mejor, a una inyección semanal de 17-OHPC para la prevención de PPTE en mujeres con embarazos de feto único e historial de PPTE. Sin embargo, el nivel de calidad de las estimaciones del resumen fue bajo o muy bajo según lo evaluado por GRADE, lo que indica que el verdadero efecto puede ser, o es probable que sea, sustancialmente diferente de la estimación del efecto. 17Α-:META: : (randomized controlled trials,RCTs)(spontaneous preterm birth,SPTB)17α-(intramuscular 17α-hydroxyprogesterone caproate,17-OHPC)SPTB。metaSPTB17-OHPCSPTB。 : ,SPTBRCTs,RCTs()17-OHPC()。。34SPTB。37、32、2824SPTB,。(relative risk,RR)95%CI。。 : 3RCTs(680)。16。,36。,90 mg,100 mg,200 mg。,RCTs250 mg 17-OHPC。17-OHPC,34 [17.5%25.0%;RR,0.71(95% CI,0.53 ~ 0.95);]32[8.9%14.5%;RR,0.62(95% CI,0.40 ~ 0.94);]SPTB。37、2824SPTB。17-OHPC,[7.1%13.2%;RR,0.53(95% CI,0.31 ~ 0.91);]。,17-OHPC,[18.7%23.5%;RR,0.63(95% CI,0.47 ~ 0.83);]。17-OHPC,(),()。 : SPTBSPTB,16()17-OHPC,。,GRADE,,。.

Saccone G ，Khalifeh A ，Elimian A ，Bahrami E ，Chaman-Ara K ，Bahrami MA ，Berghella V ... -  《-》

Nonresponse to 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention: clinical prediction and generation of a risk scoring system.

Spontaneous preterm birth remains a leading cause of neonatal morbidity and mortality among nonanomalous neonates in the United States. Spontaneous preterm birth tends to recur at similar gestational ages. Intramuscular 17-alpha hydroxyprogesterone caproate reduces the risk of recurrent spontaneous preterm birth. Unfortunately, one-third of high-risk women will have a recurrent spontaneous preterm birth despite 17-alpha hydroxyprogesterone caproate therapy; the reasons for this variability in response are unknown. We hypothesized that clinical factors among women treated with 17-alpha hydroxyprogesterone caproate who suffer recurrent spontaneous preterm birth at a similar gestational age differ from women who deliver later, and that these associations could be used to generate a clinical scoring system to predict 17-alpha hydroxyprogesterone caproate response. Secondary analysis of a prospective, multicenter, randomized controlled trial enrolling women with ≥1 previous singleton spontaneous preterm birth <37 weeks' gestation. Participants received daily omega-3 supplementation or placebo for the prevention of recurrent preterm birth; all were provided 17-alpha hydroxyprogesterone caproate. Women were classified as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproate-treated pregnancy and her earliest previous spontaneous preterm birth. Responders were women with pregnancy extending ≥3 weeks later compared with the delivery gestational age of their earliest previous preterm birth; nonresponders delivered earlier or within 3 weeks of the gestational age of their earliest previous preterm birth. A risk score for nonresponse to 17-alpha hydroxyprogesterone caproate was generated from regression models via the use of clinical predictors and was validated in an independent population. Data were analyzed with multivariable logistic regression. A total of 754 women met inclusion criteria; 159 (21%) were nonresponders. Responders delivered later on average (37.7±2.5 weeks) than nonresponders (31.5±5.3 weeks), P<.001. Among responders, 27% had a recurrent spontaneous preterm birth (vs 100% of nonresponders). Demographic characteristics were similar between responders and nonresponders. In a multivariable logistic regression model, independent risk factors for nonresponse to 17-alpha hydroxyprogesterone caproate were each additional week of gestation of the earliest previous preterm birth (odds ratio, 1.23; 95% confidence interval, 1.17-1.30, P<.001), placental abruption or significant vaginal bleeding (odds ratio, 5.60; 95% confidence interval, 2.46-12.71, P<.001), gonorrhea and/or chlamydia in the current pregnancy (odds ratio, 3.59; 95% confidence interval, 1.36-9.48, P=.010), carriage of a male fetus (odds ratio, 1.51; 95% confidence interval, 1.02-2.24, P=.040), and a penultimate preterm birth (odds ratio, 2.10; 95% confidence interval, 1.03-4.25, P=.041). These clinical factors were used to generate a risk score for nonresponse to 17-alpha hydroxyprogesterone caproate as follows: black +1, male fetus +1, penultimate preterm birth +2, gonorrhea/chlamydia +4, placental abruption +5, earliest previous preterm birth was 32-36 weeks +5. A total risk score >6 was 78% sensitive and 60% specific for predicting nonresponse to 17-alpha hydroxyprogesterone caproate (area under the curve=0.69). This scoring system was validated in an independent population of 287 women; in the validation set, a total risk score >6 performed similarly with a 65% sensitivity, 67% specificity and area under the curve of 0.66. Several clinical characteristics define women at risk for recurrent preterm birth at a similar gestational age despite 17-alpha hydroxyprogesterone caproate therapy and can be used to generate a clinical risk predictor score. These data should be refined and confirmed in other cohorts, and women at high risk for nonresponse should be targets for novel therapeutic intervention studies.

Manuck TA ，Stoddard GJ ，Fry RC ，Esplin MS ，Varner MW ... -  《-》

Predictors of response to 17-alpha hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth.

Prematurity is the leading cause of neonatal morbidity and death among nonanomalous neonates in the United States. Intramuscular 17-alpha hydroxyprogesterone caproate injections reduce the risk of recurrent prematurity by approximately one third. Unfortunately, prophylactic 17-alpha hydroxyprogesterone caproate is not always effective, and one-third of high-risk women will have a recurrent preterm birth, despite 17-alpha hydroxyprogesterone caproate therapy. The reasons for this variability in response are unknown. Previous investigators have examined the influence of a variety of factors on 17-alpha hydroxyprogesterone caproate response but have analyzed data that used a fixed outcome of term delivery to define progesterone response. We hypothesized that the demographics, history, and pregnancy course among women who deliver at a similar gestational age with 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention differs when compared with those women who deliver later with 17-alpha hydroxyprogesterone caproate and that these associations could be refined by the use of a contemporary definition of 17-alpha hydroxyprogesterone caproate "responder." This was a planned secondary analysis of a prospective, multicenter, longitudinal study of women with ≥1 previous documented singleton spontaneous preterm birth at <37 weeks gestation. Data were collected at 3 prespecified gestational age epochs during pregnancy. All women who were included in this analysis received 17-alpha hydroxyprogesterone caproate during the studied pregnancy. We classified women as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproate-treated pregnancy and her earliest spontaneous preterm birth. Responders were defined as those with pregnancy that extended ≥3 weeks later with 17-alpha hydroxyprogesterone caproate, compared with the delivery gestational age of their earliest previous spontaneous preterm birth. Data were analyzed with the use of chi-square test, t-test, and logistic regression. One hundred fifty-five women met the inclusion criteria. The 118 responders delivered later on average (37.7 weeks gestation) than the 37 nonresponders (33.5 weeks gestation; P < .001). Among responders, 32% (38/118 women) had a recurrent spontaneous preterm birth. Demographics (age, race/ethnicity, education, and parity) were similar between groups. In the regression model, the gestational age of the previous spontaneous preterm birth (odds ratio, 0.68; 95% confidence interval, 0.56-0.82; P < .001), vaginal bleeding/abruption in the current pregnancy (odds ratio, 0.24; 95% confidence interval, 0.06-0.88; P = .031), and first-degree family history of spontaneous preterm birth (odds ratio, 0.37; 95% confidence interval, 0.15-0.88; P = .024) were associated with response to 17-alpha hydroxyprogesterone caproate. Because women with a penultimate preterm pregnancy were more likely to be 17-alpha hydroxyprogesterone caproate nonresponders, we performed an additional limited analysis examining only the 130 women whose penultimate pregnancy was preterm. In regression models, the results were similar to those in the main cohort. Several historic and current pregnancy characteristics define women who are at risk for recurrent preterm birth at a similar gestational age, despite 17-alpha hydroxyprogesterone caproate therapy. These data should be studied prospectively in larger cohorts and combined with genetic and environmental data to identify women who are most likely to benefit from this intervention.

Manuck TA ，Esplin MS ，Biggio J ，Bukowski R ，Parry S ，Zhang H ，Huang H ，Varner MW ，Andrews W ，Saade G ，Sadovsky Y ，Reddy UM ，Ilekis J ，Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR) ... -  《-》