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Michael W. Varner - One of the best experts on this subject based on the ideXlab platform.
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epigenetic regulation of the nitric oxide pathway 17 α Hydroxyprogesterone Caproate and recurrent preterm birth
American Journal of Perinatology, 2017Co-Authors: Tracy A. Manuck, Michael W. Varner, Lisa Smeester, Elizabeth M Martin, Martha Scott Tomlinson, Christina SmithAbstract:Objective We sought to evaluate nitric oxide pathway placental gene expression and the epigenome (CpG methylation) among women receiving 17-α Hydroxyprogesterone Caproate (17-OHPC) with and without recurrent preterm birth (PTB). Study Design This was a case–control study. We prospectively recruited women with ≥ 1 prior singleton spontaneous PTB p -values. Results In this study, 17 women met inclusion criteria; 7 preterm cases (delivered at 22.6 ± 2.9 weeks) and 10 term controls (delivered at 38.5 ± 0.8 weeks). Groups had similar PTB history, race/ethnicity, and socioeconomic risk factors for PTB. Twenty-seven nitric oxide genes displayed differential expression ( p q p -value Conclusion CpG methylation and gene expression patterns in nitric oxide pathway genes differ among placentas from recurrent PTB compared with term birth following 17-OHPC exposure.
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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, Kathleen A Jablonski, Ronald J. Wapner, Yoram Sorokin, Uma M Reddy, Michael W. Varner, Tracy A. Manuck, Jay D Iams, 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: Gregory J Stoddard, Sean M Esplin, Michael W. Varner, Tracy A. ManuckAbstract: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: Radek Bukowski, Sean M Esplin, Tracy A. Manuck, Samuel Parry, Joseph R. Biggio, 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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pharmacogenomics of 17 alpha Hydroxyprogesterone Caproate for recurrent preterm birth prevention
American Journal of Obstetrics and Gynecology, 2014Co-Authors: Sean M Esplin, Michael W. Varner, Tracy A. Manuck, Scott W Watkins, Barry Moore, Marc G JacksonAbstract:Objective We hypothesized that genetic variation affects responsiveness to 17-alpha Hydroxyprogesterone Caproate (17P) for recurrent preterm birth prevention. Study Design Women of European ancestry with ≥1 spontaneous singleton preterm birth at Results Fifty women (9 nonresponders) were included. Responders delivered 9.2 weeks longer with 17P vs 1.3 weeks' gestation for nonresponders (P Conclusion 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.
Steve Caritis - One of the best experts on this subject based on the ideXlab platform.
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impact of obesity on the rate of recurrent spontaneous preterm birth in women treated with 17 alpha Hydroxyprogesterone Caproate
American Journal of Perinatology, 2018Co-Authors: Alisse Hauspurg, Raman Venkataramanan, Shringi Sharma, Lara S Lemon, Allison Serra, Steve CaritisAbstract:Objective We sought to determine if the rate of recurrent spontaneous preterm birth (PTB) in women treated with 17-α Hydroxyprogesterone Caproate (17-OHPC) is modified by maternal body mass index (BMI). Study Design We performed a secondary analysis of the Maternal-Fetal Medicine Units Network omega-3 fatty acid supplementation to prevent recurrent PTB randomized controlled trial. All women received 17-OHPC. Results A total of 708 women were included. Rates of spontaneous PTB did not vary significantly by BMI category. With stratification by obesity class and gestational age at delivery, the unadjusted risk for PTB using earlier gestational cutoffs ( Conclusion We demonstrated that the risk of PTB in women receiving 250 mg 17-OHPC is not dependent on maternal BMI after adjustment for confounding variables. Pharmacokinetic studies have demonstrated a wide variation in plasma concentration of 17-OHPC across the population with likely considerable overlap in plasma concentrations among the obese and nonobese population. Further studies are needed to evaluate the impact of BMI on efficacy of 17-OHPC prior to any dose adjustment in this population.
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impact of pregnancy history and 17 Hydroxyprogesterone Caproate on cervical cytokines and matrix metalloproteinases
American Journal of Perinatology, 2017Co-Authors: Steve Caritis, Mahmoud S. Ahmed, Hyagriv N Simhan, Gary D V Hankins, Justine Chang, Mary F Hebert, David M Haas, Laura A Haneline, John A Harris, Alyssa Stephenson FamyAbstract:Objective The objective of this study was to evaluate the impact of pregnancy history and 17-Hydroxyprogesterone Caproate (17-OHPC) treatment on cervical fluid cytokines and matrix metalloproteinases (MMPs). Study Design Cervical fluid was obtained between 16 0/7 and 24 6/7 weeks from women with only prior term births (controls, n = 26), women with one or more prior spontaneous preterm births (SPTBs) choosing to receive 17-OHPC (17-OHPC, n = 24), or to not receive 17-OHPC (refusers, n = 12). Cervical fluid collections were repeated 2, 4, and 8 weeks after the first sample and concentrations of MMPs and cytokines were measured by multiplex immune assay. Results Among women whose earliest prior delivery occurred between 16 and 23 weeks, cervical fluid concentration of interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α at baseline were significantly elevated when compared with cervical cytokines of women whose earliest delivery occurred between 32 and 36 weeks (relative risk ratio was 3.37 for IL-6 [95% confidence interval, CI, 1.08–10.53, p p p Conclusion The cervical fluid of women with a history of an early prior SPTB is characterized by inflammation that is unaffected by 17-OHPC.
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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, Kathleen A Jablonski, Ronald J. Wapner, Yoram Sorokin, Uma M Reddy, Michael W. Varner, Tracy A. Manuck, Jay D Iams, 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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population pharmacokinetics of 17α Hydroxyprogesterone Caproate in singleton gestation
British Journal of Clinical Pharmacology, 2016Co-Authors: Shringi Sharma, Steve Caritis, Donald R. Mattison, Gary D V Hankins, Menachem Miodovnik, Mary F Hebert, Raman VenkataramananAbstract:AIMS: 17α-Hydroxyprogesterone Caproate (17-OHPC) reduces the rate of preterm birth in women with a prior preterm birth. Limited data exist on the pharmacokinetics (PK) of 17-OHPC or the plasma concentrations achieved during therapy. In this study, we evaluated the population PK of 17-OHPC in pregnant subjects with singleton gestation and also evaluated intrinsic and extrinsic factors that may potentially affect 17-OHPC PK in this patient population. METHODS: Sixty-one women with singleton pregnancies participated in this trial. Subjects received weekly intramuscular injections of 250 mg 17-OHPC in 1 ml castor oil from the time of enrolment (16 0/7 weeks - 20 6/7 weeks) up to 35 weeks gestation or until delivery. Blood samples were obtained between 24 and 28 weeks, between 32 and 35 weeks and over a 28-day period beyond the last injection. Maternal and/or cord blood were obtained at delivery. Data analysis was performed by nonlinear mixed effects modelling (NONMEM(®) ). RESULTS: The 17-OHPC PK were best described by a model with one maternal compartment and one fetal compartment, with first-order absorption and elimination from the maternal compartment. Maternal body weight was a significant covariate for both clearance (CL/F) and volume of distribution (Vmaternal /F). The final population mean estimates were: CL/F 1797 l/d, Vmaternal /F 32 610 l and mother to cord rate constant 0.005 day(-1) . This report describes for the first time the population PK of 17-OHPC in singleton pregnancy. CONCLUSIONS: The population PK study reported here represents the initial steps in understanding and optimizing 17-OHPC therapy for preventing preterm birth.
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what we have learned about the role of 17 alpha Hydroxyprogesterone Caproate in the prevention of preterm birth
Seminars in Perinatology, 2016Co-Authors: Steve Caritis, Maisa Feghali, William A Grobman, Dwight J. RouseAbstract:Despite major advances in neonatal care, the burden of preterm birth remains high. This is not unexpected since strategies to identify and treat risk factors in early pregnancy have not been very effective in reducing the preterm birth rate. Initial studies suggested a potential benefit for 17-alpha-Hydroxyprogesterone Caproate (17-OHPC) in decreasing the risk of recurrent preterm birth women with a singleton gestation. However, the use of 17-OHPC has not conferred benefit for other categories of women at high risk for preterm delivery (twins, triplets, and short cervical length). The increasing body of evidence suggests that preterm birth is a complex condition with variable mechanisms of disease and significant individual heterogeneity. This review will examine the plausibility of 17-OHPC in preventing preterm birth and the investigation of its clinical efficacy. We will also highlight factors to explain variations in clinical trial outcomes and outline the trajectory needed for future investigations.
Tracy A. Manuck - One of the best experts on this subject based on the ideXlab platform.
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prolong clinical study protocol Hydroxyprogesterone Caproate to reduce recurrent preterm birth
American Journal of Perinatology, 2018Co-Authors: Sean C Blackwell, Tracy A. Manuck, Joseph R. Biggio, Cynthia Gyamfibannerman, Suneet P Chauhan, Brenna L Hughes, Judette Louis, Hugh Miller, Robert Birch, Michael J JozwiakowskiAbstract:The objective of this commentary is to describe the background, rationale, and methods of the PROLONG (Progestin's Role in Optimizing Neonatal Gestation) trial, which is a multicenter, multinational, placebo-controlled, randomized clinical trial (RCT) designed to assess the safety and efficacy of Makena (Hydroxyprogesterone Caproate injection, 250 mg/mL) in reducing the risk of preterm birth (PTB) and neonatal morbidity/mortality in women pregnant with a singleton gestation who had a previous singleton spontaneous PTB. The total sample size of the RCT will include 1,707 women. The trial has two coprimary outcomes: PTB less than 35 weeks and a composite neonatal morbidity and mortality index. This study sample size will provide 90% power to assess for a 35% reduction in neonatal morbidity and mortality. Secondary outcomes will include 2-year follow-up of infants. The trial is ongoing and targeted to complete recruitment in 2018.
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pharmacogenomics of 17 alpha Hydroxyprogesterone Caproate for recurrent preterm birth a case control study
British Journal of Obstetrics and Gynaecology, 2018Co-Authors: Radek Bukowski, Tracy A. Manuck, Joseph R. Biggio, Hao Huang, W S Watkins, Sam Parry, H Zhan, William W AndrewsAbstract:Objective To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha Hydroxyprogesterone Caproate (17-P) administration for the prevention of recurrent preterm birth (PTB). Design Case–control. Setting Three tertiary-care centres across the USA. Population Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P. Methods Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P). Main outcome measures To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction). Conclusion A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P. Tweetable abstract Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.
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epigenetic regulation of the nitric oxide pathway 17 α Hydroxyprogesterone Caproate and recurrent preterm birth
American Journal of Perinatology, 2017Co-Authors: Tracy A. Manuck, Michael W. Varner, Lisa Smeester, Elizabeth M Martin, Martha Scott Tomlinson, Christina SmithAbstract:Objective We sought to evaluate nitric oxide pathway placental gene expression and the epigenome (CpG methylation) among women receiving 17-α Hydroxyprogesterone Caproate (17-OHPC) with and without recurrent preterm birth (PTB). Study Design This was a case–control study. We prospectively recruited women with ≥ 1 prior singleton spontaneous PTB p -values. Results In this study, 17 women met inclusion criteria; 7 preterm cases (delivered at 22.6 ± 2.9 weeks) and 10 term controls (delivered at 38.5 ± 0.8 weeks). Groups had similar PTB history, race/ethnicity, and socioeconomic risk factors for PTB. Twenty-seven nitric oxide genes displayed differential expression ( p q p -value Conclusion CpG methylation and gene expression patterns in nitric oxide pathway genes differ among placentas from recurrent PTB compared with term birth following 17-OHPC exposure.
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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, Sarah K Dotterskatz, William Goodnight, Catherine J Vladutiu, 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.
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, Kathleen A Jablonski, Ronald J. Wapner, Yoram Sorokin, Uma M Reddy, Michael W. Varner, Tracy A. Manuck, Jay D Iams, 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, Margaret Harper, Mark A. Klebanoff, Ronald J. Wapner, Yoram Sorokin, Elizabeth Thom, John M. Thorp, Michael W. Varner, Raman Venkataramanan, 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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relationship between 17 Hydroxyprogesterone Caproate concentrations and gestational age at delivery in twin gestation
American Journal of Obstetrics and Gynecology, 2012Co-Authors: Steve Caritis, Fergal D. Malone, Alan M. Peaceman, Hyagriv N Simhan, Dwight J. Rouse, Catherine Y. Spong, Michael W. Varner, Anthony Sciscione, Yuan Zhao, Jay D IamsAbstract:Objective We sought to evaluate in women with twin gestation the relationship between 17-Hydroxyprogesterone Caproate (17-OHPC) concentration and gestational age at delivery and select biomarkers of potential pathways of drug action. Study Design Blood was obtained between 24-28 weeks (epoch 1) and 32-35 weeks (epoch 2) in 217 women with twin gestation receiving 17-OHPC or placebo. Gestational age at delivery and concentrations of 17-OHPC, 17-Hydroxyprogesterone, progesterone, C-reactive protein (CRP), and corticotrophin-releasing hormone were assessed. Results Women with higher concentrations of 17-OHPC delivered at earlier gestational ages than women with lower concentrations ( P P = .005) concentrations of CRP in epoch 1 than women receiving placebo but CRP values were similar in epoch 2 in both groups. A highly significant ( P Conclusion 17-OHPC may adversely impact gestational age at delivery in women with twin gestation.
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cerclage for the prevention of preterm birth in high risk women receiving intramuscular 17 α Hydroxyprogesterone Caproate
Journal of Maternal-fetal & Neonatal Medicine, 2012Co-Authors: Jeff M Szychowski, Gary D V Hankins, Vincenzo Berghella, Jay D Iams, John Owen, Jeanne S Sheffield, Annette Perezdelboy, Deborah A Wing, Edwin GuzmanAbstract:Objective: To assess cerclage benefit in women with short cervix also receiving 17-α-Hydroxyprogesterone Caproate (17P) to prevent recurrent preterm birth (PTB). Methods: 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. Results: 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). Conclusions: Cerclage was shown not to offer additional benefit for t...
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pharmacokinetics of 17 Hydroxyprogesterone Caproate in multifetal gestation
American Journal of Obstetrics and Gynecology, 2011Co-Authors: Steve Caritis, Fergal D. Malone, Alan M. Peaceman, Dwight J. Rouse, Catherine Y. Spong, Michael W. Varner, Anthony Sciscione, Raman Venkataramanan, Shringi Sharma, Jay D IamsAbstract:Objective The purpose of this study was to define the pharmacokinetic parameters of 17-Hydroxyprogesterone Caproate (17-OHPC) in multifetal gestation. Study Design Blood was obtained at 24-28 weeks' gestation and at 32–35 weeks gestation in 97 women with twin and 26 women with triplet gestation who were receiving 17-OHPC. Six of the women with twins had daily blood sampling for 7 days between 24 and 28 weeks' gestation, and pharmacokinetic parameters were estimated with the use of noncompartmental analysis. Modeling was applied to estimate the population parameters and to simulate various treatment scenarios. Results The apparent half-life of 17-OHPC was 10 days. Body mass index significantly impacted 17-OHPC concentrations, but fetal number and parity did not. Apparent clearance was significantly greater in African American than in white women (P = .025). Conclusion This is the first pharmacokinetic analysis of 17-OHPC in pregnant women. Determination of half-life, covariates that affect plasma 17-OHPC concentrations, and the modeling of drug behavior provide insights into this drug's pharmacologic properties during multifetal pregnancy.
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what we have learned about the role of 17 alpha Hydroxyprogesterone Caproate in the prevention of preterm birth
Seminars in Perinatology, 2016Co-Authors: Steve Caritis, Maisa Feghali, William A Grobman, Dwight J. RouseAbstract:Despite major advances in neonatal care, the burden of preterm birth remains high. This is not unexpected since strategies to identify and treat risk factors in early pregnancy have not been very effective in reducing the preterm birth rate. Initial studies suggested a potential benefit for 17-alpha-Hydroxyprogesterone Caproate (17-OHPC) in decreasing the risk of recurrent preterm birth women with a singleton gestation. However, the use of 17-OHPC has not conferred benefit for other categories of women at high risk for preterm delivery (twins, triplets, and short cervical length). The increasing body of evidence suggests that preterm birth is a complex condition with variable mechanisms of disease and significant individual heterogeneity. This review will examine the plausibility of 17-OHPC in preventing preterm birth and the investigation of its clinical efficacy. We will also highlight factors to explain variations in clinical trial outcomes and outline the trajectory needed for future investigations.
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17 Hydroxyprogesterone Caproate in triplet pregnancy an individual patient data meta analysis
British Journal of Obstetrics and Gynaecology, 2016Co-Authors: C A Combs, Steve Caritis, Dwight J. Rouse, Elizabeth Thom, Ewoud Schuit, Thomas J Garite, Kimberly Maurel, Alan T N TitaAbstract:BACKGROUND: Preterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective. OBJECTIVE: To determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-Hydroxyprogesterone Caproate (17OHPc). SEARCH STRATEGY: We searched literature databases, trial registries and references in published articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) of progestogens versus control that included women with triplet pregnancies. DATA COLLECTION AND ANALYSIS: Investigators from identified RCTs collaborated on the protocol and contributed their IPD. The primary outcome was a composite measure of adverse perinatal outcome. The secondary outcome was the rate of birth before 32 weeks of gestation. Other pre-specified outcomes included randomisation-to-delivery interval and rates of birth at <24, <28 and <34 weeks of gestation. MAIN RESULTS: Three RCTs of 17OHPc versus placebo included 232 mothers with triplet pregnancies and their 696 offspring. Risk-of-bias scores and between-study heterogeneity were low. Baseline characteristics were comparable between 17OHPc and placebo groups. The rate of the composite adverse perinatal outcome was similar among those treated with 17OHPc and those treated with placebo (34 and 35%, respectively; risk ratio [RR] 0.98, 95% confidence interval [95% CI] 0.79-1.2). The rate of birth at <32 weeks was also similar in the two groups (35 and 38%, respectively; RR 0.92, 95% CI 0.55-1.56). There were no significant between-group differences in perinatal mortality rate, randomisation-to-delivery interval, or other specified outcomes. CONCLUSION: Prophylactic 17OHPc given to mothers with triplet pregnancies had no significant impact on perinatal outcome or pregnancy duration. TWEETABLE ABSTRACT: 17-Hydroxyprogesterone Caproate had no significant impact on the outcome or duration of triplet pregnancy.
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17-Hydroxyprogesterone Caproate in triplet pregnancy: an individual patient data meta-analysis.
BJOG : an international journal of obstetrics and gynaecology, 2015Co-Authors: C A Combs, Steve Caritis, Dwight J. Rouse, Elizabeth Thom, Ewoud Schuit, Thomas J Garite, Kimberly Maurel, Alan T N Tita, Arianne C. Lim, B. W. J. MolAbstract:BACKGROUND: Preterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective. OBJECTIVE: To determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-Hydroxyprogesterone Caproate (17OHPc). SEARCH STRATEGY: We searched literature databases, trial registries and references in published articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) of progestogens versus control that included women with triplet pregnancies. DATA COLLECTION AND ANALYSIS: Investigators from identified RCTs collaborated on the protocol and contributed their IPD. The primary outcome was a composite measure of adverse perinatal outcome. The secondary outcome was the rate of birth before 32 weeks of gestation. Other pre-specified outcomes included randomisation-to-delivery interval and rates of birth at
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relationship between 17 Hydroxyprogesterone Caproate concentrations and gestational age at delivery in twin gestation
American Journal of Obstetrics and Gynecology, 2012Co-Authors: Steve Caritis, Fergal D. Malone, Alan M. Peaceman, Hyagriv N Simhan, Dwight J. Rouse, Catherine Y. Spong, Michael W. Varner, Anthony Sciscione, Yuan Zhao, Jay D IamsAbstract:Objective We sought to evaluate in women with twin gestation the relationship between 17-Hydroxyprogesterone Caproate (17-OHPC) concentration and gestational age at delivery and select biomarkers of potential pathways of drug action. Study Design Blood was obtained between 24-28 weeks (epoch 1) and 32-35 weeks (epoch 2) in 217 women with twin gestation receiving 17-OHPC or placebo. Gestational age at delivery and concentrations of 17-OHPC, 17-Hydroxyprogesterone, progesterone, C-reactive protein (CRP), and corticotrophin-releasing hormone were assessed. Results Women with higher concentrations of 17-OHPC delivered at earlier gestational ages than women with lower concentrations ( P P = .005) concentrations of CRP in epoch 1 than women receiving placebo but CRP values were similar in epoch 2 in both groups. A highly significant ( P Conclusion 17-OHPC may adversely impact gestational age at delivery in women with twin gestation.
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progesterone receptor polymorphisms and clinical response to 17 alpha Hydroxyprogesterone Caproate
American Journal of Obstetrics and Gynecology, 2011Co-Authors: Mitchell P. Dombrowski, Catherine Y. Spong, Tracy A. Manuck, Paul J Meis, Bahaeddine M Sibai, Dwight J. RouseAbstract:Objective Seventeen-alpha-Hydroxyprogesterone Caproate (17-OHPC) reduces recurrent preterm birth (PTB). We hypothesized that single nucleotide polymorphisms in the human progesterone receptor (PGR) affect response to 17-OHPC in the prevention of recurrent PTB. Study Design We conducted secondary analysis of a study of 17-OHPC vs placebo for recurrent PTB prevention. Twenty PGR gene single nucleotide polymorphisms were studied. Multivariable logistic regression assessed for an interaction between PGR genotype and treatment status in modulating the risk of recurrent PTB. Results A total of 380 women were included; 253 (66.6%) received 17-OHPC and 127 (33.4%) received placebo. In all, 61.1% of women were African American. Multivariable logistic regression demonstrated significant treatment-genotype interactions (either a beneficial or harmful treatment response) for African Americans delivering Conclusion The clinical efficacy and safety of 17-OHPC for recurrent PTB prevention may be altered by PGR gene polymorphisms.
