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Tracy A Manuck - One of the best experts on this subject based on the ideXlab platform.
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17 alpha Hydroxyprogesterone caproate for preterm birth prevention where have we been how did we get here and where are we going
Seminars in Perinatology, 2017Co-Authors: Tracy A ManuckAbstract:Abstract Prematurity is a major public health problem in the United States and worldwide. Women with a history of a previous preterm birth are at high risk for recurrence. Progesterone is a key hormone involved in pregnancy maintenance. In general, progesterone is thought to maintain pregnancy through several closely linked mechanisms: (1) promotion of uterine quiescence, (2) inhibition of pro-inflammatory cells, and (3) immunosuppressive action. 17-Alpha Hydroxyprogesterone caproate is currently the only medication approved to prevent recurrent preterm birth. The purpose of this review is to discuss the history of 17-alpha Hydroxyprogesterone caproate use for recurrent preterm birth prevention, the rationale behind 17-alpha Hydroxyprogesterone caproate administration, and current evidence-based indications for 17-alpha Hydroxyprogesterone caproate use.
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gestational age at initiation of 17 alpha Hydroxyprogesterone caproate and recurrent preterm birth
American Journal of Obstetrics and Gynecology, 2017Co-Authors: Angela Ning, Catherine J Vladutiu, Sarah K Dotterskatz, William Goodnight, Tracy A ManuckAbstract:Background 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. Objective 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. Study Design 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, 14 0/7 to 16 1/7 ; quartile 2, 16 2/7 to 17 0/7 ; quartile 3, 17 1/7 to 18 6/7 ; and quartile 4, 19 0/7 to 27 5/7 ). 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 Results A total of 132 women met inclusion criteria; 52 (39.6%) experienced recurrent preterm birth 6/7 ± 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 P = .065). Delivery gestational age was inversely proportional to gestational age at 17-alpha Hydroxyprogesterone caproate initiation (quartile 1, 37 4/7 weeks vs quartile 2, 36 5/7 vs quartile 3, 36 1/7 weeks vs quartile 4, 34 0/7 , 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 P = .005). Conclusion 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.
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the association among cytochrome p450 3a progesterone receptor polymorphisms plasma 17 alpha Hydroxyprogesterone caproate concentrations and spontaneous preterm birth
American Journal of Obstetrics and Gynecology, 2017Co-Authors: Martha L Bustos, Steve Caritis, Tracy A Manuck, Yoram Sorokin, Michael W Varner, Ronald J Wapner, Jay D Iams, Kathleen A Jablonski, Uma M Reddy, Marshall W CarpenterAbstract:Background Infants born Objective We sought to: (1) determine the relation between 17-alpha Hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha Hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms. Study Design In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha Hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha Hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesterone receptor . We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17-alpha Hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17-alpha Hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth. Results The association between CYP single nucleotide polymorphisms *22, *1G, *1B, and *3 and trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate was not statistically significant ( P = .68, .44, .08, and .44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth ( P = .29, .10, .76, .09, and .43, respectively). Low trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61–0.99; P = .04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed ( P = .13, .08, .10, .08, and .13, respectively). Conclusion The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17-alpha Hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17-alpha Hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17-alpha Hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self-reported by the patients.
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nonresponse to 17 alpha Hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention clinical prediction and generation of a risk scoring system
American Journal of Obstetrics and Gynecology, 2016Co-Authors: Tracy A Manuck, Michael W Varner, Sean M Esplin, Gregory J StoddardAbstract:Background 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. Objective 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. Study Design Secondary analysis of a prospective, multicenter, randomized controlled trial enrolling women with ≥1 previous singleton spontaneous preterm birth Results 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 P P 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. Conclusions 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.
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17 Hydroxyprogesterone caproate 17ohp c coverage among eligible women delivering at 2 north carolina hospitals in 2012 and 2013 a retrospective cohort study
American Journal of Obstetrics and Gynecology, 2016Co-Authors: Elizabeth M Stringer, Catherine J Vladutiu, Jeffrey S A Stringer, Tracy A Manuck, Sarah Verbiest, Arthur Ollendorff, Kathryn M MenardAbstract:Background Although a weekly injection of 17-hydroxyprogestone caproate is recommended for preventing recurrent preterm birth, clinical experience in North Carolina suggested that many eligible patients were not receiving the intervention. Objective Our study sought to assess how well practices delivering at 2 major hospitals were doing in providing access to 17-Hydroxyprogesterone caproate treatment for eligible patients. Study Design This retrospective cohort analysis studied all deliveries occurring between January 1, 2012, and December 31, 2013, at 2 large hospitals in North Carolina. Women were included if they had a singleton pregnancy and history of a prior spontaneous preterm birth. We extracted demographic, payer, and medical information on each pregnancy, including whether women had been offered, accepted, and received 17-Hydroxyprogesterone caproate. Our outcome of 17-Hydroxyprogesterone caproate coverage was defined as documentation of ≥1 injection of the drug. Results Over the 2-year study period, 1216 women with history of a prior preterm birth delivered at the 2 study hospitals, of which 627 were eligible for 17-Hydroxyprogesterone caproate eligible after medical record review. Only 296 of the 627 eligible women (47%; 95% confidence interval, 43–51%) received ≥1 dose of the drug. In multivariable analysis, hospital of delivery, later presentation for prenatal care, fewer prenatal visits, later gestation of prior preterm birth, and having had a term delivery immediately before the index pregnancy were all associated with failed coverage. Among those women who were “covered,” the median number of 17-Hydroxyprogesterone caproate injections was 9 (interquartile range, 4–15), with 84 of 296 charts (28%) not having complete information on the number of doses. Conclusion Even under our liberal definition of coverage, less than half of eligible women received 17-Hydroxyprogesterone caproate in this sample. Low overall use suggests that there is opportunity for improvement. Quality improvement strategies, including population-based measurement of 17-Hydroxyprogesterone caproate coverage, are needed to fully implement this evidence-based intervention to decrease preterm birth.
Michael W Varner - One of the best experts on this subject based on the ideXlab platform.
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the association among cytochrome p450 3a progesterone receptor polymorphisms plasma 17 alpha Hydroxyprogesterone caproate concentrations and spontaneous preterm birth
American Journal of Obstetrics and Gynecology, 2017Co-Authors: Martha L Bustos, Steve Caritis, Tracy A Manuck, Yoram Sorokin, Michael W Varner, Ronald J Wapner, Jay D Iams, Kathleen A Jablonski, Uma M Reddy, Marshall W CarpenterAbstract:Background Infants born Objective We sought to: (1) determine the relation between 17-alpha Hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha Hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms. Study Design In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha Hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha Hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesterone receptor . We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17-alpha Hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17-alpha Hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth. Results The association between CYP single nucleotide polymorphisms *22, *1G, *1B, and *3 and trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate was not statistically significant ( P = .68, .44, .08, and .44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth ( P = .29, .10, .76, .09, and .43, respectively). Low trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61–0.99; P = .04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed ( P = .13, .08, .10, .08, and .13, respectively). Conclusion The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17-alpha Hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17-alpha Hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17-alpha Hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self-reported by the patients.
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nonresponse to 17 alpha Hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention clinical prediction and generation of a risk scoring system
American Journal of Obstetrics and Gynecology, 2016Co-Authors: Tracy A Manuck, Michael W Varner, Sean M Esplin, Gregory J StoddardAbstract:Background 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. Objective 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. Study Design Secondary analysis of a prospective, multicenter, randomized controlled trial enrolling women with ≥1 previous singleton spontaneous preterm birth Results 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 P P 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. Conclusions 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.
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predictors of response to 17 alpha Hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth
American Journal of Obstetrics and Gynecology, 2015Co-Authors: Tracy A Manuck, Sean M Esplin, Joseph R Biggio, Radek Bukowski, Samuel Parry, Heping Zhang, Hao Huang, Michael W VarnerAbstract:Background 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. Objective 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." Study Design This was a planned secondary analysis of a prospective, multicenter, longitudinal study of women with ≥1 previous documented singleton spontaneous preterm birth at 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. Results 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 P 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. Conclusion 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.
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relationship between 17 alpha Hydroxyprogesterone caproate concentration and spontaneous preterm birth
American Journal of Obstetrics and Gynecology, 2014Co-Authors: Steve Caritis, Raman Venkataramanan, Elizabeth Thom, Margaret Harper, Mark A Klebanoff, Yoram Sorokin, John M Thorp, Michael W Varner, Ronald J Wapner, Jay D IamsAbstract:Objective 17-alpha Hydroxyprogesterone caproate 250 mg weekly reduces recurrent spontaneous preterm birth in women with a prior spontaneous preterm birth by 33%. The dose is not based on pharmacologic considerations. A therapeutic concentration has not been determined hampering any attempt to optimize treatment. This study evaluated the relationship between 17-alpha Hydroxyprogesterone caproate plasma concentrations and the rate of spontaneous preterm birth in women with singleton gestation. Study Design A single blood sample was obtained between 25 and 28 weeks' gestation from 315 women with a spontaneous preterm birth who participated in a placebo-controlled, prospective, randomized clinical trial evaluating the benefit of omega-3 supplementation in reducing preterm birth. All women in the parent study received 17-alpha Hydroxyprogesterone caproate and 434 received omega-3 supplementation and 418 received a placebo. Plasma from 315 consenting women was analyzed for 17-alpha Hydroxyprogesterone caproate concentration. Results There were no differences between placebo and omega-3 supplemented groups in demographic variables, outcomes or in mean 17-alpha Hydroxyprogesterone caproate concentration. Plasma concentrations of 17-alpha Hydroxyprogesterone caproate ranged from 3.7-56 ng/mL. Women with plasma concentrations of 17-alpha Hydroxyprogesterone caproate in the lowest quartile had a significantly higher risk of spontaneous preterm birth ( P = .03) and delivered at significantly earlier gestational ages ( P = .002) than did women in the second to fourth quartiles. The lowest preterm birth rates were seen when median 17-alpha Hydroxyprogesterone caproate concentrations exceeded 6.4 ng/mL. Conclusion Low plasma 17-alpha Hydroxyprogesterone caproate concentration is associated with an increased risk of spontaneous preterm birth. This finding validates efficacy of this treatment but suggests that additional studies are needed to determine the optimal dosage.
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prevention of preterm birth in triplets using 17 alpha Hydroxyprogesterone caproate a randomized controlled trial
Obstetrics & Gynecology, 2009Co-Authors: Steve Caritis, Valerija Momirova, Dwight J Rouse, Alan M Peaceman, Anthony Sciscione, Catherine Y Spong, Michael W Varner, Ronald J Wapner, Jay D Iams, Marshall W CarpenterAbstract:OBJECTIVE: To assess whether 17 alpha-Hydroxyprogesterone caproate reduces the rate of preterm birth in women carrying triplets. METHODS: 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. RESULTS: 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. CONCLUSION: Treatment with 17 alpha-Hydroxyprogesterone caproate did not reduce the rate of preterm birth in women with triplet gestations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00099164 LEVEL OF EVIDENCE: I.
Steve Caritis - One of the best experts on this subject based on the ideXlab platform.
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the association among cytochrome p450 3a progesterone receptor polymorphisms plasma 17 alpha Hydroxyprogesterone caproate concentrations and spontaneous preterm birth
American Journal of Obstetrics and Gynecology, 2017Co-Authors: Martha L Bustos, Steve Caritis, Tracy A Manuck, Yoram Sorokin, Michael W Varner, Ronald J Wapner, Jay D Iams, Kathleen A Jablonski, Uma M Reddy, Marshall W CarpenterAbstract:Background Infants born Objective We sought to: (1) determine the relation between 17-alpha Hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha Hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms. Study Design In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha Hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha Hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesterone receptor . We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17-alpha Hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17-alpha Hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth. Results The association between CYP single nucleotide polymorphisms *22, *1G, *1B, and *3 and trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate was not statistically significant ( P = .68, .44, .08, and .44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth ( P = .29, .10, .76, .09, and .43, respectively). Low trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61–0.99; P = .04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed ( P = .13, .08, .10, .08, and .13, respectively). Conclusion The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17-alpha Hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17-alpha Hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17-alpha Hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self-reported by the patients.
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Stability of Hydroxyprogesterone caproate alone and in a compounded pharmaceutical product
American Journal of Health-system Pharmacy, 2014Co-Authors: Yang Zhao, Steve Caritis, Joseph Bettinger, Raman VenkataramananAbstract:Purpose The chemical stability of Hydroxyprogesterone caproate in powder form and in a pharmaceutical formulation under different experimental conditions was evaluated. Methods Pure Hydroxyprogesterone caproate was subjected to hydrolysis, photolysis, and thermal degradation. The content of Hydroxyprogesterone caproate in pharmaceutical products was evaluated after using two different sterilization methods and after exposure to light. Hydroxyprogesterone caproate and its degradation products were analyzed using a validated reverse-phase high-performance liquid chromatographic method. Variables examined included specificity, accuracy, precision, linearity, theoretical plate numbers, signal:noise ratio, resolution between any two peaks, and relative standard deviation of the peak response. Statistical analysis was performed with Stata software, version 11 (StataCorp, College Station, TX). Mean values and standard deviations were calculated. The level of significance was set at p < 0.05. Results Components of Hydroxyprogesterone caproate and organic impurities in pharmaceutical products were scanned with wide ultraviolet wavelength from 200 to 400 nm. In powder form, Hydroxyprogesterone caproate was stable when exposed to high temperatures and light. Considerable degradation of Hydroxyprogesterone caproate was observed in alkaline solution, with the major degradation product being Hydroxyprogesterone. Much less degradation of Hydroxyprogesterone caproate was observed in acidic conditions over 72 hours. The content of Hydroxyprogesterone caproate in pharmaceutical products was not altered by the sterilization methods (filtration or heat sterilization) used and after exposure to light. Conclusion Hydroxyprogesterone caproate in powder form and in a pharmaceutical formulation under different experimental conditions appeared to be fairly stable in the presence of strong acid, high temperatures, and light.
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relationship between 17 alpha Hydroxyprogesterone caproate concentration and spontaneous preterm birth
American Journal of Obstetrics and Gynecology, 2014Co-Authors: Steve Caritis, Raman Venkataramanan, Elizabeth Thom, Margaret Harper, Mark A Klebanoff, Yoram Sorokin, John M Thorp, Michael W Varner, Ronald J Wapner, Jay D IamsAbstract:Objective 17-alpha Hydroxyprogesterone caproate 250 mg weekly reduces recurrent spontaneous preterm birth in women with a prior spontaneous preterm birth by 33%. The dose is not based on pharmacologic considerations. A therapeutic concentration has not been determined hampering any attempt to optimize treatment. This study evaluated the relationship between 17-alpha Hydroxyprogesterone caproate plasma concentrations and the rate of spontaneous preterm birth in women with singleton gestation. Study Design A single blood sample was obtained between 25 and 28 weeks' gestation from 315 women with a spontaneous preterm birth who participated in a placebo-controlled, prospective, randomized clinical trial evaluating the benefit of omega-3 supplementation in reducing preterm birth. All women in the parent study received 17-alpha Hydroxyprogesterone caproate and 434 received omega-3 supplementation and 418 received a placebo. Plasma from 315 consenting women was analyzed for 17-alpha Hydroxyprogesterone caproate concentration. Results There were no differences between placebo and omega-3 supplemented groups in demographic variables, outcomes or in mean 17-alpha Hydroxyprogesterone caproate concentration. Plasma concentrations of 17-alpha Hydroxyprogesterone caproate ranged from 3.7-56 ng/mL. Women with plasma concentrations of 17-alpha Hydroxyprogesterone caproate in the lowest quartile had a significantly higher risk of spontaneous preterm birth ( P = .03) and delivered at significantly earlier gestational ages ( P = .002) than did women in the second to fourth quartiles. The lowest preterm birth rates were seen when median 17-alpha Hydroxyprogesterone caproate concentrations exceeded 6.4 ng/mL. Conclusion Low plasma 17-alpha Hydroxyprogesterone caproate concentration is associated with an increased risk of spontaneous preterm birth. This finding validates efficacy of this treatment but suggests that additional studies are needed to determine the optimal dosage.
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Stability of Hydroxyprogesterone caproate alone and in a compounded pharmaceutical product
American Journal of Health-System Pharmacy, 2014Co-Authors: Yang Zhao, Steve Caritis, Joseph Bettinger, Raman VenkataramananAbstract:PURPOSE: The chemical stability of Hydroxyprogesterone caproate in powder form and in a pharmaceutical formulation under different experimental conditions was evaluated. METHODS: Pure Hydroxyprogesterone caproate was subjected to hydrolysis, photolysis, and thermal degradation. The content of Hydroxyprogesterone caproate in pharmaceutical products was evaluated after using two different sterilization methods and after exposure to light. Hydroxyprogesterone caproate and its degradation products were analyzed using a validated reverse-phase high-performance liquid chromatographic method. Variables examined included specificity, accuracy, precision, linearity, theoretical plate numbers, signal:noise ratio, resolution between any two peaks, and relative standard deviation of the peak response. Statistical analysis was performed with Stata software, version 11 (StataCorp, College Station, TX). Mean values and standard deviations were calculated. The level of significance was set at p < 0.05. RESULTS: Components of Hydroxyprogesterone caproate and organic impurities in pharmaceutical products were scanned with wide ultraviolet wavelength from 200 to 400 nm. In powder form, Hydroxyprogesterone caproate was stable when exposed to high temperatures and light. Considerable degradation of Hydroxyprogesterone caproate was observed in alkaline solution, with the major degradation product being Hydroxyprogesterone. Much less degradation of Hydroxyprogesterone caproate was observed in acidic conditions over 72 hours. The content of Hydroxyprogesterone caproate in pharmaceutical products was not altered by the sterilization methods (filtration or heat sterilization) used and after exposure to light. CONCLUSION: Hydroxyprogesterone caproate in powder form and in a pharmaceutical formulation under different experimental conditions appeared to be fairly stable in the presence of strong acid, high temperatures, and light.
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the effect of 17 alpha Hydroxyprogesterone caproate on the risk of gestational diabetes in singleton or twin pregnancies
American Journal of Obstetrics and Gynecology, 2009Co-Authors: Cynthia Gyamfi, Steve Caritis, Amanda L Horton, Valerija Momirova, Dwight J Rouse, Alan M Peaceman, Anthony Sciscione, Paul J Meis, Catherine Y Spong, Mitchell P DombrowskiAbstract:Objective To compare the rates of gestational diabetes among women who received serial doses of 17-alpha Hydroxyprogesterone caproate vs placebo. Study Design Secondary analysis of 2 double-blind randomized placebo-controlled trials of 17-alpha Hydroxyprogesterone caproate given to women at risk for preterm delivery. The incidence of gestational diabetes was compared between women who received 17-alpha Hydroxyprogesterone caproate or placebo. Results We included 1094 women; 441 had singleton and 653 had twin gestations. Combining the 2 studies, 616 received 17-alpha Hydroxyprogesterone caproate and 478 received placebo. Among singleton and twin pregnancies, rates of gestational diabetes were similar in women receiving 17-alpha Hydroxyprogesterone caproate vs placebo (5.8% vs 4.7%; P = .64 and 7.4% vs 7.6%; P = .94, respectively). In the multivariable model, progesterone was not associated with gestational diabetes (adjusted odds ratio, 1.04; 95% confidence interval, 0.62–1.73). Conclusion Weekly administration of 17-alpha Hydroxyprogesterone caproate is not associated with higher rates of gestational diabetes in either singleton or twin pregnancies.
Jay D Iams - One of the best experts on this subject based on the ideXlab platform.
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the association among cytochrome p450 3a progesterone receptor polymorphisms plasma 17 alpha Hydroxyprogesterone caproate concentrations and spontaneous preterm birth
American Journal of Obstetrics and Gynecology, 2017Co-Authors: Martha L Bustos, Steve Caritis, Tracy A Manuck, Yoram Sorokin, Michael W Varner, Ronald J Wapner, Jay D Iams, Kathleen A Jablonski, Uma M Reddy, Marshall W CarpenterAbstract:Background Infants born Objective We sought to: (1) determine the relation between 17-alpha Hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha Hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms. Study Design In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha Hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha Hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesterone receptor . We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17-alpha Hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17-alpha Hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth. Results The association between CYP single nucleotide polymorphisms *22, *1G, *1B, and *3 and trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate was not statistically significant ( P = .68, .44, .08, and .44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth ( P = .29, .10, .76, .09, and .43, respectively). Low trough plasma concentrations of 17-alpha Hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61–0.99; P = .04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed ( P = .13, .08, .10, .08, and .13, respectively). Conclusion The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17-alpha Hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17-alpha Hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17-alpha Hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self-reported by the patients.
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relationship between 17 alpha Hydroxyprogesterone caproate concentration and spontaneous preterm birth
American Journal of Obstetrics and Gynecology, 2014Co-Authors: Steve Caritis, Raman Venkataramanan, Elizabeth Thom, Margaret Harper, Mark A Klebanoff, Yoram Sorokin, John M Thorp, Michael W Varner, Ronald J Wapner, Jay D IamsAbstract:Objective 17-alpha Hydroxyprogesterone caproate 250 mg weekly reduces recurrent spontaneous preterm birth in women with a prior spontaneous preterm birth by 33%. The dose is not based on pharmacologic considerations. A therapeutic concentration has not been determined hampering any attempt to optimize treatment. This study evaluated the relationship between 17-alpha Hydroxyprogesterone caproate plasma concentrations and the rate of spontaneous preterm birth in women with singleton gestation. Study Design A single blood sample was obtained between 25 and 28 weeks' gestation from 315 women with a spontaneous preterm birth who participated in a placebo-controlled, prospective, randomized clinical trial evaluating the benefit of omega-3 supplementation in reducing preterm birth. All women in the parent study received 17-alpha Hydroxyprogesterone caproate and 434 received omega-3 supplementation and 418 received a placebo. Plasma from 315 consenting women was analyzed for 17-alpha Hydroxyprogesterone caproate concentration. Results There were no differences between placebo and omega-3 supplemented groups in demographic variables, outcomes or in mean 17-alpha Hydroxyprogesterone caproate concentration. Plasma concentrations of 17-alpha Hydroxyprogesterone caproate ranged from 3.7-56 ng/mL. Women with plasma concentrations of 17-alpha Hydroxyprogesterone caproate in the lowest quartile had a significantly higher risk of spontaneous preterm birth ( P = .03) and delivered at significantly earlier gestational ages ( P = .002) than did women in the second to fourth quartiles. The lowest preterm birth rates were seen when median 17-alpha Hydroxyprogesterone caproate concentrations exceeded 6.4 ng/mL. Conclusion Low plasma 17-alpha Hydroxyprogesterone caproate concentration is associated with an increased risk of spontaneous preterm birth. This finding validates efficacy of this treatment but suggests that additional studies are needed to determine the optimal dosage.
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prevention of preterm birth in triplets using 17 alpha Hydroxyprogesterone caproate a randomized controlled trial
Obstetrics & Gynecology, 2009Co-Authors: Steve Caritis, Valerija Momirova, Dwight J Rouse, Alan M Peaceman, Anthony Sciscione, Catherine Y Spong, Michael W Varner, Ronald J Wapner, Jay D Iams, Marshall W CarpenterAbstract:OBJECTIVE: To assess whether 17 alpha-Hydroxyprogesterone caproate reduces the rate of preterm birth in women carrying triplets. METHODS: 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. RESULTS: 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. CONCLUSION: Treatment with 17 alpha-Hydroxyprogesterone caproate did not reduce the rate of preterm birth in women with triplet gestations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00099164 LEVEL OF EVIDENCE: I.
Mark Edward Votruba - One of the best experts on this subject based on the ideXlab platform.
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Medical cost savings associated with 17 alpha-Hydroxyprogesterone caproate.
American journal of obstetrics and gynecology, 2020Co-Authors: Jennifer L Bailit, Mark Edward VotrubaAbstract:This study was undertaken to assess the impact of 17 alpha Hydroxyprogesterone caproate treatment on future medical costs for expectant mothers with a prior spontaneous preterm birth. Data on the costs of preterm birth were combined with published data on the effectiveness of 17 alpha Hydroxyprogesterone caproate to produce estimates of the effect of treatment on expected future direct medical costs. These estimates were compared with an estimate of the cost of a typical 17 alpha Hydroxyprogesterone caproate treatment regimen to estimate the net savings per treated woman. Treatment is estimated to reduce initial neonatal hospitalization costs by 3800 dollars per woman treated with 17 alpha Hydroxyprogesterone caproate. Expected lifetime medical costs (discounted) of treated infants are estimated to decline 15,900 dollars. Treating expectant mothers with a prior spontaneous preterm birth with 17 alpha Hydroxyprogesterone caproate generates future medical cost savings that substantially exceed the cost of treatment. If this population were universally treated with 17 alpha Hydroxyprogesterone caproate, discounted lifetime medical costs of their offspring could be reduced by more than 2.0 billion dollars annually.
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medical cost savings associated with 17 alpha Hydroxyprogesterone caproate
American Journal of Obstetrics and Gynecology, 2007Co-Authors: Jennifer L Bailit, Mark Edward VotrubaAbstract:Objective This study was undertaken to assess the impact of 17 alpha Hydroxyprogesterone caproate treatment on future medical costs for expectant mothers with a prior spontaneous preterm birth. Study design Data on the costs of preterm birth were combined with published data on the effectiveness of 17 alpha Hydroxyprogesterone caproate to produce estimates of the effect of treatment on expected future direct medical costs. These estimates were compared with an estimate of the cost of a typical 17 alpha Hydroxyprogesterone caproate treatment regimen to estimate the net savings per treated woman. Results Treatment is estimated to reduce initial neonatal hospitalization costs by $3800 per woman treated with 17 alpha Hydroxyprogesterone caproate. Expected lifetime medical costs (discounted) of treated infants are estimated to decline $15,900. Conclusions Treating expectant mothers with a prior spontaneous preterm birth with 17 alpha Hydroxyprogesterone caproate generates future medical cost savings that substantially exceed the cost of treatment. If this population were universally treated with 17 alpha Hydroxyprogesterone caproate, discounted lifetime medical costs of their offspring could be reduced by more than $2.0 billion annually.
