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

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

Massa K ，Childress K ，Vricella LK ，Boerrigter A ，Franklin BHK ，Sauer M ，Armbruster R ，Tomlinson T ... -  《-》

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 ... -  《-》

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 ... -  《-》

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

Suresh S ，Freedman A ，Adams M ，Hirsch E ，Ernst LM ... -  《-》

Gestational age at initiation of 17-alpha hydroxyprogesterone caproate and recurrent preterm birth.

Preterm birth is the leading cause of neonatal morbidity and mortality in nonanomalous neonates in the United States. Women with a previous early spontaneous preterm birth are at highest risk for recurrence. Weekly intramuscular 17-alpha hydroxyprogesterone caproate reduces the risk of recurrent prematurity. Although current guidelines recommend 17-alpha hydroxyprogesterone caproate initiation between 16 and 20 weeks, in clinical practice, 17-alpha hydroxyprogesterone caproate is started across a spectrum of gestational ages. The objective of the study was to examine the relationship between the gestational age at 17-alpha hydroxyprogesterone caproate initiation and recurrent preterm birth among women with a prior spontaneous preterm birth 16-28 weeks' gestation. This was a retrospective cohort study of women from a single tertiary care center, 2005-2016. All women with ≥1 singleton preterm births because of a spontaneous onset of contractions, preterm prelabor rupture of membranes, or painless cervical dilation between 16 and 28 weeks followed by a subsequent singleton pregnancy treated with 17-alpha hydroxyprogesterone caproate were included. Women were grouped based on quartiles of gestational age of 17-alpha hydroxyprogesterone caproate initiation (quartile 1, 140/7 to 161/7; quartile 2, 162/7 to 170/7; quartile 3, 171/7 to 186/7; and quartile 4, 190/7 to 275/7). Women with a gestational age of 17-alpha hydroxyprogesterone caproate initiation in quartiles 1 and 2 were considered to have early-start 17-alpha hydroxyprogesterone caproate; those in quartiles 3 and 4 were considered to have late-start 17-alpha hydroxyprogesterone caproate. The primary outcome was recurrent preterm birth <37 weeks' gestation. Secondary outcomes included recurrent preterm birth <34 and <28 weeks' gestation and composite major neonatal morbidity (diagnosis of grade III or IV intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, necrotizing enterocolitis stage II or III, or death). Gestational age at delivery was compared by quartile of 17-alpha hydroxyprogesterone caproate initiation using Kaplan-Meier survival curves and the log-rank test. Logistic regression models estimated odds ratios for the association between gestational age at 17-alpha hydroxyprogesterone caproate initiation and preterm birth <37 weeks' gestation, adjusting for demographics, prior pregnancy and antenatal characteristics. A total of 132 women met inclusion criteria; 52 (39.6%) experienced recurrent preterm birth <37 weeks in the studied pregnancy. 17-Alpha hydroxyprogesterone caproate was initiated at a mean 176/7 ± 2.5 weeks. Demographic and baseline characteristics were similar between women with early-start 17-alpha hydroxyprogesterone caproate (quartiles 1 and 2) compared with those with late-start 17-alpha hydroxyprogesterone caproate (quartiles 3 and 4). Women with early-start 17-alpha hydroxyprogesterone caproate trended toward lower rates of recurrent preterm birth <37 weeks compared with those with late-start 17-alpha hydroxyprogesterone caproate (41.3% vs 57.7%, P = .065). Delivery gestational age was inversely proportional to gestational age at 17-alpha hydroxyprogesterone caproate initiation (quartile 1, 374/7 weeks vs quartile 2, 365/7 vs quartile 3, 361/7 weeks vs quartile 4, 340/7, P = .007). In Kaplan-Meier survival analyses, these differences in delivery gestational age by 17-alpha hydroxyprogesterone caproate initiation quartile persisted across pregnancy (log-rank P < .001). In regression models, later initiation of 17-alpha hydroxyprogesterone caproate was significantly associated with increased odds of preterm birth <37 weeks. Women with early 17-alpha hydroxyprogesterone caproate initiation also had lower rates of major neonatal morbidity than those with later 17-alpha hydroxyprogesterone caproate initiation (1.5% vs 14.3%, P = .005). Rates of recurrent preterm birth among women with a prior spontaneous preterm birth 16-28 weeks are high. Women beginning 17-alpha hydroxyprogesterone caproate early deliver later and have improved neonatal outcomes. Clinicians should make every effort to facilitate 17-alpha hydroxyprogesterone caproate initiation at 16 weeks.

Ning A ，Vladutiu CJ ，Dotters-Katz SK ，Goodnight WH ，Manuck TA ... -  《-》