Safety review of hydroxyprogesterone caproate in women with a history of spontaneous preterm birth.
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ABSTRACT:
SUBMITTER: Sibai B
PROVIDER: S-EPMC8049867 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We hypothesized that genetic variation affects responsiveness to 17-alpha hydroxyprogesterone caproate (17P) for recurrent preterm birth prevention.Women of European ancestry with ?1 spontaneous singleton preterm birth at <34 weeks' gestation who received 17P were recruited prospectively and classified as a 17P responder or nonresponder by the difference in delivery gestational age between 17P-treated and -untreated pregnancies. Samples underwent whole exome sequencing. Coding variants were compared between responders and nonresponders with the use of the Variant Annotation, Analysis, and Search Tool (VAAST), which is a probabilistic search tool for the identification of disease-causing variants, and were compared with a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway candidate gene list. Genes with the highest VAAST scores were then classified by the online Protein ANalysis THrough Evolutionary Relationships (PANTHER) system into known gene ontology molecular functions and biologic processes. Gene distributions within these classifications were compared with an online reference population to identify over- and under- represented gene sets.Fifty women (9 nonresponders) were included. Responders delivered 9.2 weeks longer with 17P vs 1.3 weeks' gestation for nonresponders (P < .001). A genome-wide search for genetic differences implicated the NOS1 gene to be the most likely associated gene from among genes on the KEGG candidate gene list (P < .00095). PANTHER analysis revealed several over-represented gene ontology categories that included cell adhesion, cell communication, signal transduction, nitric oxide signal transduction, and receptor activity (all with significant Bonferroni-corrected probability values).We identified sets of over-represented genes in key processes among responders to 17P, which is the first step in the application of pharmacogenomics to preterm birth prevention.
| S-EPMC4266558 | biostudies-literature
Project description:To assess cerclage benefit in women with short cervix also receiving 17-?-hydroxyprogesterone caproate (17P) to prevent recurrent preterm birth (PTB).Secondary analysis of a multicenter trial of ultrasound-indicated cerclage for shortened cervical length (CL). Women with prior spontaneous PTB at 16-33 6/7 weeks, singleton gestation and CL < 25?mm between 16 and 22 6/7 weeks were counseled on use of 17P and randomized to cerclage or no cerclage. Outcomes of women who received 17P were analyzed by randomization group. Primary outcome was PTB < 35 weeks.99 women received 17P: 47 cerclage; 52 no cerclage. Rates of PTB < 35 weeks were similar, 30% for cerclage and 38% for no cerclage (aOR 0.64 (0.27-1.52)). In women with CL < 15?mm, PTB < 35 weeks was reduced for the cerclage group (17% vs. 75%, p = 0.02). However, this difference was nullified after controlling for total progesterone doses received (p = 0.40).Cerclage was shown not to offer additional benefit for the prevention of recurrent PTB in women with short CL < 25?mm receiving 17P, but the sample size is insufficient for a definite conclusion given the 36% nonsignificant decrease in the odds of PTB < 35 weeks. Cerclage may further offer substantial benefit to women with very short CL < 15?mm and further study is needed.
| S-EPMC3991237 | biostudies-literature
Project description:To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) that investigated the clinical benefits of 17-alpha hydroxyprogesterone caproate (17OHPC) in the prevention of recurrent preterm birth (PTB) among singleton pregnant women with a previous history of PTB. We searched four major databases up till April 2021 and assessed the risk of bias in the included studies. We meta-analyzed various maternal-neonatal endpoints (n=18) and pooled them as mean difference or risk ratio (RR) with 95% confidence interval (CI) using the random-effects model. Six RCTs met the inclusion criteria, comprising 2,573 patients (17OHPC=1,617, control=956). RCTs revealed an overall low risk of bias. The rates of PTB <35 weeks (n=5 RCTs; RR, 0.77; 95% CI, 0.63-0.93; P=0.008), PTB <32 weeks (n=3 RCTs; RR, 0.68; 95% CI, 0.51-0.91; P=0.009), neonates with low birth weight (<2.5 kg) at delivery (n=3 RCTs; RR, 0.63; 95% CI, 0.5-0.79; P<0.001), and neonatal death (n=4 RCTs; RR, 0.41; 95% CI, 0.20-0.84; P=0.02) were significantly reduced in the 17OHPC group compared with the control group. Moreover, 17OHPC treatment correlated with a significantly decreased rate of retinopathy (n=2 RCTs; RR, 0.42; 95% CI, 0.18-0.97; P=0.004). However, there were no significant differences in the rates of neonatal intensive care unit admission, cesarean delivery, and other pretermrelated complications between both the groups. Among singleton pregnant women with a prior history of PTB, 17OHPC may favorably decrease the risks of recurrent PTB and reduce the rate of neonatal death.
| S-EPMC8595047 | biostudies-literature
Project description:To assess whether 17 alpha-hydroxyprogesterone caproate reduces the rate of preterm birth in women carrying triplets.We performed this randomized, double-blinded, placebo-controlled trial in 14 centers. Healthy women with triplets were randomly assigned to weekly intramuscular injections of either 250 mg of 17 alpha-hydroxyprogesterone caproate or matching placebo, starting at 16-20 weeks and ending at delivery or 35 weeks of gestation. The primary study outcome was delivery or fetal loss before 35 weeks.One hundred thirty-four women were assigned, 71 to 17 alpha-hydroxyprogesterone caproate and 63 to placebo; none were lost to follow-up. Baseline demographic data were similar in the two groups. The proportion of women experiencing the primary outcome (a composite of delivery or fetal loss before 35 0/7 weeks) was similar in the two treatment groups: 83% of pregnancies in the 17 alpha-hydroxyprogesterone caproate group and 84% in the placebo group, relative risk 1.0, 95% confidence interval 0.9-1.1. The lack of benefit of 17 alpha-hydroxyprogesterone caproate was evident regardless of the conception method or whether a gestational age cutoff for delivery was set at 32 or 28 weeks.Treatment with 17 alpha-hydroxyprogesterone caproate did not reduce the rate of preterm birth in women with triplet gestations.ClinicalTrials.gov, www.clinicaltrials.gov, NCT00099164I.
| S-EPMC2790283 | biostudies-literature
Project description:BACKGROUND:Each year, an estimated 15 million babies are born preterm, a global burden borne disproportionately by families in lower-income countries. Maternal HIV infection increases a woman's risk of delivering prematurely, and antiretroviral therapy (ART) may compound this risk. While prenatal progesterone prophylaxis prevents preterm birth among some high-risk women, it is unknown whether HIV-infected women could benefit from this therapy. We are studying the efficacy of progesterone supplementation to reduce the risk of preterm birth among pregnant women with HIV in Lusaka, Zambia. METHODS:The Improving Pregnancy Outcomes with Progesterone (IPOP) study is a Phase III double-masked, placebo-controlled, randomized trial of intramuscular 17-alpha hydroxprogesterone caproate (17P) to prevent preterm birth in HIV-infected women. A total of 800 women will be recruited prior to 24?weeks of gestation and randomly allocated to 17P or placebo administered by weekly intramuscular injection. The primary outcome will be a composite of live birth prior to 37 completed gestational weeks or stillbirth at any gestational age. Secondary outcomes will include very preterm birth (<?34?weeks), extreme preterm birth (<?28?weeks), small for gestational age (<10th centile), low birth weight (<?2500?g), and neonatal outcomes. In secondary analysis, we will assess whether specific HIV-related covariates, including the timing of maternal ART initiation relative to conception, is associated with progesterone's prophylactic efficacy, if any. DISCUSSION:We hypothesize that weekly prenatal 17P will reduce the risk of HIV-related preterm birth. An inexpensive intervention to prevent preterm birth among pregnant women with HIV could have substantial global public health impact. TRIAL REGISTRATION:NCT03297216 ; September 29, 2017.
| S-EPMC6391830 | biostudies-literature
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.
| S-EPMC8476342 | biostudies-literature
Project description:ObjectiveDetermine whether gestational age of 17-hydroxyprogesterone caproate (17-OHPC) initiation is associated with preterm birth (PTB) risk.Study designWe performed a retrospective cohort study using MarketScan® data. The primary outcome was PTB < 37 weeks. Rates of PTB were compared between medication initiation at 16-21 weeks versus 21-29 weeks. The association between compliance with weekly 17-OHPC injections and preterm birth rate was tested after adjusting for potential confounding variables.ResultIn all 3374 pregnancies met inclusion criteria. Women with an early 17-OHPC start were less likely to deliver preterm than those with a late start (aRR 0.88; 95%CI 0.79-0.97; p = 0.02). Less compliant patients receiving <25% of recommended doses had a higher PTB rate than those receiving >85% of recommended doses (aRR 1.5; 95%CI 1.2-1.7; p < 0.01).ConclusionThere is an association between both early 17-OHPC initiation and compliance with reduced rates of PTB.
| S-EPMC6890226 | biostudies-literature
Project description:Background17-alpha Hydroxyprogesterone caproate for prevention of recurrent preterm birth is recommended for use in the United States.ObjectiveWe sought to assess the clinical effectiveness of 17-alpha hydroxyprogesterone caproate to prevent recurrent preterm birth ≤35 weeks compared to similar births in our obstetric population prior to the implementation of 17-alpha hydroxyprogesterone caproate.Study designThis was a prospective cohort study of 17-alpha hydroxyprogesterone caproate in our obstetric population. The primary outcome was the recurrence of birth ≤35 weeks for the entire study cohort compared to a historical referent rate of 16.8% of recurrent preterm birth in our population. There were 3 secondary outcomes. First, did 17-alpha hydroxyprogesterone caproate modify a woman's history of preterm birth when taking into account her prior number and sequence of preterm and term births? Second, was recurrence of preterm birth related to 17-alpha hydroxyprogesterone caproate plasma concentration? Third, was duration of pregnancy modified by 17-alpha hydroxyprogesterone caproate treatment compared to a prior preterm birth?ResultsFrom January 2012 through March 2016, 430 consecutive women with prior births ≤35 weeks were treated with 17-alpha hydroxyprogesterone caproate. Nearly two thirds of the women (N = 267) began injections ≤18 weeks and 394 (92%) received a scheduled weekly injection within 10 days of reaching 35 weeks or delivery. The overall rate of recurrent preterm birth was 25% (N = 106) for the entire cohort compared to the 16.8% expected rate (P = 1.0). The 3 secondary outcomes were also negative. First, 17-alpha hydroxyprogesterone caproate did not significantly reduce the rates of recurrence regardless of prior preterm birth number or sequence. Second, plasma concentrations of 17-alpha hydroxyprogesterone caproate were not different (P = .17 at 24 weeks; P = .38 at 32 weeks) between women delivered ≤35 weeks and those delivered later in pregnancy. Third, the mean (±SD) interval in weeks of recurrent preterm birth before 17-alpha hydroxyprogesterone caproate use was 0.4 ± 5.3 weeks and the interval of recurrent preterm birth after 17-alpha hydroxyprogesterone caproate treatment was 0.1 ± 4.7 weeks (P = .63). A side effect of weekly 17-alpha hydroxyprogesterone caproate injections was an increase in gestational diabetes. Specifically, the rate of gestational diabetes was 13.4% in 17-alpha hydroxyprogesterone caproate-treated women compared to 8% in case-matched controls (P = .001).Conclusion17-alpha Hydroxyprogesterone caproate was ineffective for prevention of recurrent preterm birth and was associated with an increased rate of gestational diabetes.
| S-EPMC5449222 | biostudies-literature
Project description:Background: Preterm birth (PTB) is a pressing maternal and child health issue with long-standing racial inequities in outcomes and care provision. 17-Alpha-hydroxyprogesterone caproate (17OHPC) has been one of few clinical interventions for recurrent PTB prevention. Little is known about the factors influencing successful administration and receipt of 17OHPC among mothers in the Medicaid program. Materials and Methods: We conducted individual semistructured interviews with 17OHPC-eligible pregnant women and obstetric providers from two academic medical centers in Philadelphia, PA. Patient participants were publicly insured, eligible for 17OHPC treatment, and purposively sampled as either (1) actively receiving treatment or (2) declining/discontinuing treatment. Providers had experience providing care to Medicaid-enrolled patients. Interview transcripts were coded and analyzed to identify themes related to treatment acceptability, access, and adherence. Results: Of the 17 patient participants, the mean age was 30 years. Ten providers (MDs, nurse practitioners, and registered nurses) were also interviewed. Factors facilitating 17OHPC uptake and adherence among patients included severity of prior PTB, provider counseling, and coordination among the clinic, pharmacy, and insurance. Pain was cited as the most significant barrier to 17OHPC for patients, while providers perceived social adversity and beliefs about patients' commitment to treatment to be primary patient barriers. For providers, clinical experience and practice guidelines contributed to their use of 17OHPC. Administrative complexity and coordination of services were the primary provider barrier to 17OHPC administration. Conclusions: Patient-provider communication is a primary driver of 17OHPC acceptability and adherence. Comprehensive patient-centered consultation may improve uptake of clinical therapies among pregnant women at high risk for PTB.
| S-EPMC8317597 | biostudies-literature
Project description:BACKGROUND:Specialised preterm birth clinics care for women at high risk of spontaneous preterm birth. This systematic review assesses current practice within preterm birth clinics globally. METHODS:A comprehensive search strategy was used to identify all studies on preterm birth clinics on the MEDLINE, Embase, PsycINFO, CENTRAL and CINAHL databases. There were no restrictions to study design. Studies were limited to the English language and publications from 1998 onwards. Two reviewers assessed studies for inclusion, performed data extraction and reviewed methodological quality. Primary outcomes were referral criteria, investigations and interventions offered in preterm birth clinics. Secondary outcomes were the timing of planned first and last appointments and frequency of review. RESULTS:Thirty-two records fulfilled eligibility criteria and 20 studies were included in the main analysis following grouping of records describing the same study or clinic. Studies were of mixed study design and methodological quality. A total of 39 clinics were described; outcome data was not available for all clinics. Referral criteria included previous spontaneous preterm birth (38/38, 100%), previous mid-trimester loss (34/38, 89%) and previous cervical surgery (33/38, 87%). All clinics offered transvaginal cervical length scans. Additional investigations varied, including urogenital swabs (16/28, 57%) and fetal fibronectin (8/28, 29%). The primary treatment of choice for a sonographic short cervix was cervical cerclage in 10/33 (30%) clinics and vaginal progesterone in 6/33 (18%), with 10/33 (30%) using multiple first-line options and 6/33 (18%) using a combination of treatments. The majority of clinics planned timing of first review for 12-16?weeks (30/35, 86%) and the frequency of review was usually determined by clinical findings (18/24, 75%). There was a wide variation in gestational age at clinic discharge between 24 and 37?weeks. CONCLUSIONS:There is variation in the referral criteria, investigations and interventions offered in preterm birth clinics and in the timing and frequency of review. Consistency in practice may improve with the introduction of consensus guidelines and national preterm birth prevention programmes. TRIAL REGISTRATION:Systematic review registration number: CRD42019131470.
| S-EPMC6990596 | biostudies-literature