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Safety review of hydroxyprogesterone caproate in women with a history of spontaneous preterm birth.

ABSTRACT: 17-alpha-hydroxyprogesterone caproate (17P) has been in use for prevention of recurrent preterm birth since 2003 when the Meis trial was published. A requirement for Food and Drug Administration approval of 17P was a confirmatory trial, called "PROLONG", which was recently completed, but did not replicate the efficacy demonstrated in the Meis trial. This review analyzes the safety data from each trial, as well as integrated data from the two trials. The relative risks (95% CI) with 17P versus placebo in the integrated dataset were 0.66 (0.25-1.78) for miscarriage, 1.83 (0.68-4.91) for stillbirth, and 0.86 (0.53-1.41) for all fetal and neonatal death. The rate of gestational diabetes in the integrated dataset was 3.6% for 17P vs. 3.8% for placebo. Similar findings with low and comparable rates between 17P and placebo were also found for other adverse events. The integrated safety data demonstrate a favorable safety profile that was comparable to placebo.

SUBMITTER: Sibai B

PROVIDER: S-EPMC8049867 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Safety review of hydroxyprogesterone caproate in women with a history of spontaneous preterm birth.

Sibai Baha B Saade George R GR Das Anita F AF Gudeman Jennifer J

Journal of perinatology : official journal of the California Perinatal Association 20201014 4

17-alpha-hydroxyprogesterone caproate (17P) has been in use for prevention of recurrent preterm birth since 2003 when the Meis trial was published. A requirement for Food and Drug Administration approval of 17P was a confirmatory trial, called "PROLONG", which was recently completed, but did not replicate the efficacy demonstrated in the Meis trial. This review analyzes the safety data from each trial, as well as integrated data from the two trials. The relative risks (95% CI) with 17P versus pl ...[more]

PMID: 33057132

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Project description:BackgroundWomen with HIV face an increased risk of preterm birth. 17 alpha-hydroxyprogesterone caproate (17P) has been shown in some trials to reduce early delivery among women with a history of spontaneous preterm birth. We investigated whether 17P would reduce this risk among women with HIV.MethodsWe did a randomised, double-blind, placebo-controlled trial in pregnant women with HIV at the University Teaching Hospital and Kamwala District Health Centre in Lusaka, Zambia. Eligible patients were women aged 18 years or older with confirmed HIV-1 infection, viable intrauterine singleton pregnancy at less than 24 weeks of gestation, and were receiving or intending to commence antiretroviral therapy during pregnancy. Exclusion criteria were major uterine or fetal anomaly; planned or in situ cervical cerclage; evidence of threatened miscarriage, preterm labour, or ruptured membranes at screening; medical contraindication to 17P; previous participation in the trial; or history of spontaneous preterm birth. Eligible participants provided written informed consent and were randomly assigned (1:1) to receive 250 mg intramuscular 17P or placebo once per week, starting between 16 and 24 weeks of gestation until delivery, stillbirth, or reaching term (37 weeks). Participants and study staff were masked to assignment, except for pharmacy staff who did random assignment and prepared injections but did not interact with participants. The primary outcome was a composite of delivery before 37 weeks or stillbirth at any gestational age. Patients attended weekly visits for study drug injections and antenatal care. We estimated the absolute and relative difference in risk of the primary outcome and safety events between treatment groups by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03297216, and is complete.FindingsBetween Feb 7, 2018 and Jan 13, 2020, we assessed 1042 women for inclusion into the study. 242 women were excluded after additional assessments, and 800 eligible patients were enrolled and randomly assigned to receive intramuscular 17P (n=399) or placebo (n=401). Baseline characteristics were similar between groups. Adherence to study drug injections was 98% in both groups, no patients were lost to follow-up, and the final post-partum visit was on Aug 6, 2020. 36 (9%) of 399 participants assigned to 17P had preterm birth or stillbirth, compared with 36 (9%) of 401 patients assigned to placebo (risk difference 0·1, 95% CI -3·9 to 4·0; relative risk 1·0, 95% CI 0·6 to 1·6; p=0·98). Intervention-related adverse events were reported by 140 (18%) of 800 participants and occurred in similar proportions in both randomisation groups. No serious adverse events were reported.InterpretationAlthough 17P seems to be safe and acceptable to participants, available data do not support the use of the drug to prevent preterm birth among women whose risk derives solely from HIV infection. The low risk of preterm birth in both randomisation groups warrants further investigation.FundingUS National Institutes of Health and the Bill and Melinda Gates Foundation.

Project description:BackgroundA history of spontaneous preterm birth (sPTB) is a significant risk factor for recurrence. Intra-muscular-7α-hydroxyprogesterone caproate (17P) has been the preventive treatment of choice until the recent "Prolong study" that reported no benefit.ObjectiveTo determine the benefit of (17P) treatment in preventing reoccurrence of sPTB, by evaluating two presenting symptoms of the first sPTB: premature contractions (PMC) and preterm premature rupture of membranes (pPROM).Study designThis retrospective study included 342 women with a previous singleton sPTB followed by a subsequent pregnancy. sPTB were either due to PMC (n = 145) or pPROM (n = 197). During the subsequent pregnancy, 90 (26.3%) patients received 250 mg 17P IM. Each presenting symptom-PMC or pPROM-was evaluated within itself comparing treated vs. untreated groups. Data were analyzed using t-test, Chi-square and Fisher's exact test. Logistic regression analysis was also performed.ResultsPatients treated with 17P in the subsequent pregnancy had delivered earlier in the previous pregnancy (33.4w vs. 35.3w in the PMC group, and 34.1w vs. 35.7w in the pPROM group, p<0.001). In the following pregnancy, they had higher admission rates due to suspected preterm labor (31.7% vs. 10.9% in the treated vs. untreated PMC group (p = 0.003) and 26.1% vs. 5.4% in the treated vs. untreated pPROM group (p<0.001). In both groups, but more prominently in the previous PMC group, treatment compared to non-treatment in the subsequent pregnancy significantly prolonged it (4.3w vs. 2.6w in the PMC group (p = 0.007), and 3.7w vs. 2.7w in the pPROM group (p = 0.018)). The presenting symptom of sPTB in the following pregnancy tended to recur in cases of another sPTB, with a significantly greater likelihood of repeating the sPTB mechanism in cases with PMC, regardless of receiving 17P (69% in the PMC cohort and 60% in the pPROM cohort, p<0.001).Conclusions17P might delay preterm delivery in patients with a previous sPTB on an individual level (prolongation of the pregnancy for each patient compared to her previous delivery). Therefore, our results imply that 17P can decrease potential premature delivery complications for patients with a previous sPTB due to PMC or pPROM.

Dataset Information

Safety review of hydroxyprogesterone caproate in women with a history of spontaneous preterm birth.

Publications

Safety review of hydroxyprogesterone caproate in women with a history of spontaneous preterm birth.

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