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Objective: We aimed to compare the efficacy of commonly available progesterone preparations for preterm birth prevention. Methods: A retrospective cohort study of all women treated with progesterone to prevent preterm birth and delivered in a single university-affiliated tertiary medical-center. Four progesterone preparations were compared: vaginal Endometrin 100 mg twice daily, vaginal Crinone 8% gel 90 mg daily, vaginal Utrogestan 200 mg daily, and intramuscular 17α-hydroxyprogesterone caproate (17-OHPC) 250 mg weekly. All women were considered at risk for preterm birth according to: prior preterm birth or cervical length below 25 mm measured during the second trimester. Significant maternal morbidity, pregnancy achieved by artificial reproductive technique and cerclage placement were excluded. Primary outcome was the rate of preterm birth prior to 37 weeks of gestation. Results: Overall, 422 women were allocated to four study groups according to progesterone preparation: Endometrin 175 (41.5%), Crinone 73 (17.3%), Utrogestan 154 (36.5%), and 17-OHPC 20 (4.7%). Rates of preterm birth prior to 37 gestational weeks were lowest on the Endometrin treatment group (12.6 versus 20.5, 17.5, and 35% in the rest, p  = .05). Multivariate analysis revealed that the progesterone preparation was associated with preterm birth prior to 37 gestational weeks (LR = 8.3, p  = .004). The need for maternal red blood cells transfusion was significantly higher in the Endometrin subgroup (4% versus 0 in all others, p  = .018). This finding remained significant after adjustment to potential confounders (LR 16.44, p  < .001). Neonatal outcomes did not differ between groups. Conclusions: Different progesterone preparations prescribed to women at risk, may possess different efficacy in preventing preterm delivery prior to 37 weeks of gestation.

Objectives Strategies to prevent preterm birth are limited. 17 Alpha-Hydroxyprogesterone Caproate (17P) injections have been shown to be effective, but the intervention is under-used. This mixed methods study investigates barriers and facilitators to 17P administration among Medicaid and CHIP participants enrolled in Strong Start for Mothers and Newborns, a federal preterm birth prevention program. Methods Twenty-seven awardees with more than 200 sites in 30 states, the District of Columbia, and Puerto Rico enrolled approximately 46,000 women in Strong Start from 2013 to 2016. Participant data, including data on preterm birth and 17P, was collected for each woman. Intensive interviews (n = 211) conducted with Strong Start program staff and providers (n = 314) included questions about 17P provision. Results Of women whose data included a valid response regarding 17P initiation, 3919 had a prior preterm birth and current singleton pregnancy; 14.95% received 17P. Barriers to 17P administration include late entry to prenatal care, administrative burden of preauthorization, cost risks to providers, limits in scope of practice for non-physician providers, and social barriers among participants. Facilitators for provision include streamlined work flows and the option of home administration. Conclusions for Practice A universal insurance authorization process could mitigate many barriers to 17P use. Providers need continuing education regarding the effectiveness of 17P, and expanding scope of practice for non-physician prenatal care providers would increase access. Targeted program interventions can help to overcome social barriers Medicaid participants face in accessing care. Streamlined work processes and the option of home health services are two effective program-based facilitators for providing 17P to a Medicaid population.

For prevention of a recurrent preterm birth (PTB), intramuscular 17-α-hydroxy progesterone caproate (IM 17 OHPC) weekly is recommended. Vaginal progesterone is preferred for women at risk for PTB due to a short cervical length, but may be useful in women with a prior PTB. However, there is no consensus about the optimal vaginal formulation or its efficacy as compared to 17 OHPC to prevent recurrent PTB. We randomised 100 women with a singleton pregnancy between 16 and 24 weeks of gestation and ≥ one prior spontaneous PTB, of a singleton (>16 to <37 weeks of gestation) to receive the 200 mg vaginal progesterone effervescent tablet daily (Group A) or IM 17-OHPC, 250 mg weekly (Group B) till 37 weeks of gestation or delivery. The spontaneous PTB rate of <37 weeks was similar (20% in Group A and 20.8% in Group B, p =  .918). The PTB rate of <34 weeks or <28 weeks were also comparable. The mean birth weight and other neonatal outcomes were similar in the two groups. Two neonates in Group A and four neonates in Group B required NICU admission, one of whom (Group B) died due to prematurity. Twenty percent of women in Group A and 29.2% in Group B reported adverse effects from their respective study medications (p =  .408, NS). Thus, there did not appear to be a difference between vaginal progesterone and 17-OHPC when used for the prevention of a recurrent PTB. Impact statement What is already known on this subject? Progesterone administration is useful for prevention of a recurrent preterm birth (PTB) and these women are prescribed the intramuscular 17-α-hydroxy progesterone caproate (IM 17 OHPC), 250 mg, weekly. Some studies found that vaginal progesterone (once daily) is also beneficial in these women, but there is no consensus regarding its efficacy when compared to 17 OHPC, or its optimal formulation and dose. What do the results of this study add? In the present study, 100 women with a singleton pregnancy between 16 and 24 weeks of gestation and ≥ one prior spontaneous singleton PTB or mid-trimester abortion were randomised to receive 200 mg of vaginal progesterone effervescent tablet daily (Group A) or 250 mg IM 17-OHPC weekly (Group B) till 37 weeks of gestation or delivery. The spontaneous PTB rate <37 weeks was similar in the two groups (20% in Group A and 20.8% in Group B, p = .918). The PTB rate <34 weeks or <28 weeks were also comparable. The mean birth weight and other neonatal outcomes were similar. Twenty percent of women in Group A and 29.2% of women in Group B reported adverse effects from their respective study medications (p = .408, NS). Thus, there did not appear to be a difference between the vaginal progesterone effervescent tablet and 17-OHPC when used for the prevention of a recurrent PTB. What are the implications of these findings for clinical practice and/or further research? The vaginal progesterone effervescent tablet may be a suitable alternative to IM 17 OHPC to prevent recurrent PTB. Future studies should identify the most appropriate route (IM or vaginal) and vaginal progesterone formulation for PTB prevention in women at risk for a recurrent PTB and in women with a short cervical length.

Objective: To investigate the role of adjuvant 17-α-hydroxy-progesterone caproate (17OHP-C) in reducing the risk of preterm delivery <34 weeks and adverse perinatal outcomes in women with ≥3 second trimester pregnancy losses attributed to cervical insufficiency undergoing prophylactic cerclage., Material and Methods: Retrospective cohort study of women with prophylactic cerclage placed between 2006 and 2014 divided into a cohort of (i) those receiving adjuvant 17OHP-C (n=43), and (ii) controls with cerclage alone (n=59)., Results: Demographic characteristics were comparable in both groups. There was no significant difference in gestational age at delivery between the cerclage-17OHP-C group (33.4±5.6 weeks) and the cerclage-alone group (34.4±4.6 weeks); P=0.33. We noted a non-significant increase for deliveries <34 weeks in the cerclage-17OHP-C group (44.2%) compared to controls (28.8%) which remained non-significant after adjusting for confounders; P=0.46. There was no statistically significant difference in the rate of delivery <37, 32, 28 and 24 weeks. Adverse neonatal outcomes were comparable in both groups (cerclage-17OHP-C 48.8% vs. cerclage-alone 39%); P=0.43., Conclusion: Intramuscular 17OHP-C in combination with prophylactic cerclage in women with cervical insufficiency and ≥3 second trimester pregnancy losses had no synergistic effect in reducing the rate of recurrent preterm birth or improving perinatal outcomes.

Purpose: The purpose of this study was to evaluate the bioavailability of hydroxyprogesterone caproate (HPC) administered as a subcutaneous injection in the back of the upper arm using a prefilled autoinjector syringe with a 27-gauge needle compared with standard intramuscular injection in the gluteus maximus using a 21-gauge needle., Methods: Healthy postmenopausal women 50 to 75 years old were randomized in a parallel group design to receive a single SC injection of 1.1 mL (275-mg total dose) of preservative-free HPC administered using an autoinjector in the back of the upper arm or a single IM injection of 1 mL (250-mg total dose) of preservative-free HPC administered in the gluteus maximus. Blood samples were collected through 1008 hours (42 days) after injection. The primary measures were the C max , AUC 0-t , and AUC 0-∞ . Secondary measures were T max , k e , t ½ , and injection site reactions captured as a treatment-emergent adverse event., Findings: The pharmacokinetic population consisted of 90 individuals; 45 received subcutaneous administration and 45 received intramuscular administration. Geometric mean whole blood concentrations of HPC were comparable between administration regimens. Subcutaneous administration resulted in a higher geometric mean C max than intramuscular administration (7.88 vs 6.91 ng/mL), but median T max values were comparable (48.1 vs 49.7 hours). The least square geometric mean ratios for AUC 0-168) , AUC 0-t , and AUC 0-∞ were 102.89%, 110.25%, and 113.51%, respectively, with all 90% CIs within the 80.0% to 125.0% window that defined bioequivalence. The ratio for C max was 113.95% with a 90% CI of 91.94% to 141.23% but with substantial overlap of individual values between administration regimens. The geometric mean t ½ of HPC was 212 hours for the subcutaneous administration and 188 hours for the intramuscular administration. The most common treatment-emergent adverse event was injection site pain (subcutaneous, 37.3%; intramuscular, 8.2%), described as mild (85%) to moderate (15%)., Implications: Administration of HPC by SC injection of 1.1 mL (275 mg) via autoinjector is bioequivalent to IM injection of 1.0 mL (250 mg). ClinicalTrials.gov identifier: NCT02940522., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To analyze the effect of partial compliance on preterm birth (PTB) prevention among women with previous PTB and receiving 17 alpha-hydroxyprogesterone caproate (17-OHPC)., Study Design: This is a secondary analysis of a multicenter trial for the prevention of recurrent PTB. Women with prior PTB were randomly assigned between 15 0/7 and 20 3/7 weeks to weekly injections of either 17-OHPC or placebo. Full 100% compliance (group 1) was compared to 40-80% (group 2). Recurrent PTB rates and odds ratios were calculated. Student's t, Chi-square, Wilcoxon Rank-Sum, multivariate logistic regression and Breslow-Day tests were used., Results: Group 1 included 370 women versus 35 in group 2. In each group, the PTB rate was significantly reduced in pregnancies receiving 17-OHPC compared to placebo. The adjusted odds ratio for PTB rate in group 1 was 0.48 (95% CI 0.31-0.75) versus 0.18 (95% CI 0.04-0.92) in group 2. Comparing the homogeneity of both odds ratios, the rates of recurrent PTB prevention in both groups were not statistically different (Breslow-Day test; p= .15)., Conclusion: A compliance rate of 40-80% did not significantly reduce 17-OHPC's efficacy. If confirmed, our findings could lead to a dramatic decrease in costs related to prevention of recurrent PTB.

Background: Smoking during pregnancy is associated with adverse maternal and neonatal outcomes such as preterm delivery, intrauterine growth restriction, stillbirth, and low birth weight. Because smoking causes oxidative stress, some have suggested using antioxidants to counteract the effects of oxidative stress. Smokers have lower serum levels of omega-3 fatty acids, an important antioxidant, and thus, investigating whether omega-3 supplementation in smokers reduces adverse maternal and neonatal outcomes represents an important area of research., Objective: To investigate whether the antioxidant effect of omega-3 fatty acid supplementation on the incidence of adverse pregnancy outcomes differs between smokers and nonsmokers., Study Design: Secondary analysis of a multicenter randomized controlled trial of omega-3 supplementation for preterm delivery prevention in women with a singleton pregnancy and a history of a previous singleton spontaneous preterm delivery. Subjects were randomized to begin omega-3 or placebo before 22 weeks, which was continued until delivery. All women received 17 alpha-hydroxyprogesterone caproate intramuscularly weekly beginning between 16 and 20 weeks of gestation and continued until 36 weeks of gestation or delivery, whichever occurred first. The primary outcome was spontaneous preterm delivery. Secondary outcomes were indicated preterm delivery, any preterm delivery (spontaneous and indicated), pregnancy-associated hypertension (gestational hypertension and preeclampsia), a neonatal composite (retinopathy of prematurity, intraventricular hemorrhage grade III or IV, patent ductus arteriosus, necrotizing enterocolitis, sepsis, respiratory morbidity, or perinatal death), low birth weight (<2500 g), small for gestational age (less than the 10th percentile), and neonatal intensive care unit or intermediate nursery admission. The study population was stratified into smokers and nonsmokers, and the incidence of each outcome was compared by omega-3 supplementation versus placebo in each subgroup. Zelen tests were performed to test for homogeneity of effect in smokers and nonsmokers., Results: Of 851 subjects included in the analysis, 136 (16%) smoked. Baseline characteristics between omega-3 and placebo groups did not differ in smokers or nonsmokers. Omega-3 supplementation was associated with a lower risk of spontaneous preterm delivery in smokers (relative risk, 0.56, 95% confidence interval, 0.36-0.87) but not in nonsmokers (relative risk 1.04, 95% confidence interval 0.84-1.29); P value for interaction = 0.013. Low birth weight was also less frequent in smokers receiving omega-3 supplementation (relative risk 0.57, 95% confidence interval 0.36-0.90) compared with nonsmokers (relative risk 0.93, 95% confidence interval 0.71-1.24); P value for interaction = 0.047. The effect on other secondary outcomes did not differ significantly between smokers and nonsmokers., Conclusion: Omega-3 supplementation in smokers may have a protective effect against recurrent spontaneous preterm delivery and low birth weight., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Progesterone (hydroxyprogesterone caproate injection and vaginal progesterone) has been shown to reduce preterm birth (PTB) rates by a third among pregnant women at high risk. The purpose of this analysis is to report birth outcomes and medication adherence among Massachusetts Medicaid (MassHealth) members receiving progesterone, evaluate the association between member characteristics and birth outcomes and medication adherence, and compare cost of care with a prior preterm pregnancy., Methods: This retrospective cohort study used medical claims, pharmacy claims, and prior authorization (PA) request data for MassHealth members who had a PA submitted for progesterone between January 1, 2011, and March 31, 2015. Members were excluded due to breaks in coverage, progesterone was not indicated for prevention of PTB, and if current gestational week or date of delivery was unavailable., Main Results: A total of 418 members were screened for inclusion of whom 190 met criteria and 169 filled progesterone. Mean age was 29.2 years (SD = 5.23), and clinical comorbidities were identified in 90.5% of members. Consistent with clinical trials on progesterone effectiveness, 62.1% of members had a term delivery (37 wks of gestation). Among members with prior gestational age at delivery available, the average difference in gestational age between pregnancies was 8.25 weeks (SD = 6.11). In addition, 66.3% of members were adherent to progesterone based on proportion of days covered (PDC) of 0.8 or higher. The overall mean PDC was 0.79 (SD = 0.26)., Conclusion: Despite similar birth outcomes in clinical trials and national trends, medication adherence is low in this state Medicaid program. Therefore, members may benefit from adherence support., (© 2017 Pharmacotherapy Publications, Inc.)

Background: Infants born <37 weeks' gestation are of public health concern since complications associated with preterm birth are the leading cause of mortality in children <5 years of age and a major cause of morbidity and lifelong disability. The administration of 17-alpha hydroxyprogesterone caproate reduces preterm birth by 33% in women with history of spontaneous preterm birth. We demonstrated previously that plasma concentrations of 17-alpha hydroxyprogesterone caproate vary widely among pregnant women and that women with 17-alpha hydroxyprogesterone caproate plasma concentrations in the lowest quartile had spontaneous preterm birth rates of 40% vs rates of 25% in those women with higher concentrations. Thus, plasma concentrations are an important factor in determining drug efficacy but the reason 17-alpha hydroxyprogesterone caproate plasma concentrations vary so much is unclear. Predominantly, 17-alpha hydroxyprogesterone caproate is metabolized by CYP3A4 and CYP3A5 enzymes., 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 progesteronereceptor. 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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 <37 weeks' gestation. Secondary outcomes included recurrent preterm birth <34 and <28 weeks' gestation and composite major neonatal morbidity (diagnosis of grade III or IV intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, necrotizing enterocolitis stage II or III, or death). Gestational age at delivery was compared by quartile of 17-alpha hydroxyprogesterone caproate initiation using Kaplan-Meier survival curves and the log-rank test. Logistic regression models estimated odds ratios for the association between gestational age at 17-alpha hydroxyprogesterone caproate initiation and preterm birth <37 weeks' gestation, adjusting for demographics, prior pregnancy and antenatal characteristics., Results: A total of 132 women met inclusion criteria; 52 (39.6%) experienced recurrent preterm birth <37 weeks in the studied pregnancy. 17-Alpha hydroxyprogesterone caproate was initiated at a mean 17 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 <37 weeks compared with those with late-start 17-alpha hydroxyprogesterone caproate (41.3% vs 57.7%, P = .065). Delivery gestational age was inversely proportional to gestational age at 17-alpha hydroxyprogesterone caproate initiation (quartile 1, 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 < .001). In regression models, later initiation of 17-alpha hydroxyprogesterone caproate was significantly associated with increased odds of preterm birth <37 weeks. Women with early 17-alpha hydroxyprogesterone caproate initiation also had lower rates of major neonatal morbidity than those with later 17-alpha hydroxyprogesterone caproate initiation (1.5% vs 14.3%, P = .005)., 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Progestins, notably progesterone (P4) and 17 alpha hydroxyprogesterone caproate, are presently used to treat pregnant women at risk of preterm birth. The aim of this study was to assess the optimal treatment options for progesterone (P4) to delay delivery using a sensitive bioassay for progesterone., Study Design: Pregnant rats, known to be highly sensitive to progestins, were treated with P4, including Prochieve ® (also known as Crinone ® ), in various vehicles from day 13 of gestation and in late gestation, days 19 to 22, and delivery times noted. Various routes of administration of P4 and various treatment periods were studied., Results: Use of micronized P4 by rectal, subcutaneous injection (sc) and topical (transdermal) administration in various oils all significantly (P<0.05-<0.001) delay delivery, but vaginal Prochieve ® did not. Administration of P4 in late gestation also prevented (P<0.001) delivery even when given 8h before delivery., Conclusions: Prochieve ® possesses little biological activity to suppress delivery in a sensitive bioassay system and suggests that this preparation may be of little value in prevention and inhibition of preterm birth. Further, this study shows: 1) Inhibition of delivery is increased with P4 treatments when given subcutaneously or topically. 2) P4 in fish oil provides the best vehicle for topical treatment and may be an effective treatment of preterm birth. 3) P4 in fish oil also delays delivery even when treatment begins just prior to normal delivery. 4) To prevent preterm birth in pregnant women, randomized controlled studies are needed with a potent progestin using better formulations and routes of administration., (Copyright © 2017. Published by Elsevier B.V.)

Objective: To assess the efficacy of progestogens for maintenance tocolysis in women undelivered after their first preterm labor episode., Methods: Women with singleton pregnancies between 22 0/7 and 31 6/7 weeks of gestation with arrested preterm labor and a cervical length 25 mm or less at hospital discharge were eligible. Patients with a previous preterm birth were excluded. In a randomized controlled trial conducted in five university hospitals, women were randomized to receive vaginal progesterone (200 mg per day) or intramuscular 17α-hydroxyprogesterone caproate (341 mg per week) or to an observation groups (control group). The primary outcome was the proportion of women with preterm birth at less than 37 weeks of gestation. A sample size of 160 per group (n=480) was planned to compare vaginal progesterone and 17α-hydroxyprogesterone caproate groups with those in the control group. The sample size estimation was based on the hypothesis that the risk of experiencing preterm birth in the control group would be 30% and that 17α-hydroxyprogesterone caproate or progesterone would decrease this risk to 15%. A P value of <.025 was defined as statistically significant. At planned interim analysis (n=254), the trial was stopped for futility., Results: Between July 2010 and June 2015, 257 women were eligible and 254 were subsequently randomly assigned to vaginal progesterone (n=86), 17α-hydroxyprogesterone caproate (n=87), or observation (n=81). Nineteen (8%) were excluded from the analysis because they either dropped out or information was missing, leaving 235 women available for analysis. Demographic characteristics were similar across groups. The preterm birth rate did not differ significantly between groups: 23% in the 17α-hydroxyprogesterone caproate group, 39% in the vaginal progesterone group, and 22% in the women in the control group (P=.949 for 17α-hydroxyprogesterone caproate compared with the women in the control group and P=.027 for vaginal progesterone compared with women in the control group)., Conclusion: The use of progestogens for maintenance tocolysis in women with a short cervix did not reduce the rate of preterm birth., Clinical Trial Registration: ClinicalTrials.gov, NCT01178788.

Background: Vaginal progesterone and 17α-hydroxyprogesterone (17α-OHP) are both used to prevent preterm delivery in women who have experienced spontaneous preterm delivery (SPTD) previously. Randomized trial data of the comparative effectiveness of these interventions have been mixed., Objectives: To compare the efficacy of intramuscular 17α-OHP and vaginal progesterone in the prevention of recurrent SPTD., Search Strategy: Cochrane Central Register of Controlled Trials, African Journals Online, Embase, Google Scholar, ISI Web of Science, LILACS, CINAHL, PubMed, and registers of ongoing trials were searched using keywords related to 17α-OHP, vaginal progesterone, and preterm delivery., Selection Criteria: Randomized controlled trials published between January 1, 1966, and November 30, 2016, comparing 17α-OHP and vaginal progesterone for the prevention of recurrent SPTD during singleton pregnancies were included., Data Collection and Analysis: Study data were extracted and meta-analyses were performed when outcomes were comparable., Main Results: The meta-analyses included data from three randomized trials. Lower rates of SPTD before 34 weeks (relative risk 0.71, 95% confidence interval 0.53-0.95) and before 32 weeks (relative risk 0.62, 95% confidence interval 0.40-0.94) of pregnancy were observed among patients treated with vaginal progesterone., Conclusions: Vaginal progesterone and 17α-OHP were comparable for the prevention of recurrent SPTD in singleton pregnancies; vaginal progesterone could be superior., (© 2017 International Federation of Gynecology and Obstetrics.)

Background: 17-alpha Hydroxyprogesterone caproate for prevention of recurrent preterm birth is recommended for use in the United States., Objective: We sought to assess the clinical effectiveness of 17-alpha hydroxyprogesterone caproate to prevent recurrent preterm birth ≤35 weeks compared to similar births in our obstetric population prior to the implementation of 17-alpha hydroxyprogesterone caproate., Study Design: This was a prospective cohort study of 17-alpha hydroxyprogesterone caproate in our obstetric population. The primary outcome was the recurrence of birth ≤35 weeks for the entire study cohort compared to a historical referent rate of 16.8% of recurrent preterm birth in our population. There were 3 secondary outcomes. First, did 17-alpha hydroxyprogesterone caproate modify a woman's history of preterm birth when taking into account her prior number and sequence of preterm and term births? Second, was recurrence of preterm birth related to 17-alpha hydroxyprogesterone caproate plasma concentration? Third, was duration of pregnancy modified by 17-alpha hydroxyprogesterone caproate treatment compared to a prior preterm birth?, Results: From January 2012 through March 2016, 430 consecutive women with prior births ≤35 weeks were treated with 17-alpha hydroxyprogesterone caproate. Nearly two thirds of the women (N = 267) began injections ≤18 weeks and 394 (92%) received a scheduled weekly injection within 10 days of reaching 35 weeks or delivery. The overall rate of recurrent preterm birth was 25% (N = 106) for the entire cohort compared to the 16.8% expected rate (P = 1.0). The 3 secondary outcomes were also negative. First, 17-alpha hydroxyprogesterone caproate did not significantly reduce the rates of recurrence regardless of prior preterm birth number or sequence. Second, plasma concentrations of 17-alpha hydroxyprogesterone caproate were not different (P = .17 at 24 weeks; P = .38 at 32 weeks) between women delivered ≤35 weeks and those delivered later in pregnancy. Third, the mean (±SD) interval in weeks of recurrent preterm birth before 17-alpha hydroxyprogesterone caproate use was 0.4 ± 5.3 weeks and the interval of recurrent preterm birth after 17-alpha hydroxyprogesterone caproate treatment was 0.1 ± 4.7 weeks (P = .63). A side effect of weekly 17-alpha hydroxyprogesterone caproate injections was an increase in gestational diabetes. Specifically, the rate of gestational diabetes was 13.4% in 17-alpha hydroxyprogesterone caproate-treated women compared to 8% in case-matched controls (P = .001)., Conclusion: 17-alpha Hydroxyprogesterone caproate was ineffective for prevention of recurrent preterm birth and was associated with an increased rate of gestational diabetes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Randomized controlled trials (RCTs) have recently compared intramuscular 17α-hydroxyprogesterone caproate (17-OHPC) with vaginal progesterone for reducing the risk of spontaneous preterm birth (SPTB) in singleton gestations with prior SPTB. The aim of this systematic review and meta-analysis was to evaluate the efficacy of vaginal progesterone compared with 17-OHPC in prevention of SPTB in singleton gestations with prior SPTB., Methods: Searches of electronic databases were performed to identify all RCTs of asymptomatic singleton gestations with prior SPTB that were randomized to prophylactic treatment with either vaginal progesterone (intervention group) or intramuscular 17-OHPC (comparison group). No restrictions for language or geographic location were applied. The primary outcome was SPTB < 34 weeks. Secondary outcomes were SPTB < 37 weeks, < 32 weeks, < 28 weeks and < 24 weeks, maternal adverse drug reaction and neonatal outcomes. The summary measures were reported as relative risk (RR) with 95% CI. Risk of bias for each included study was assessed., Results: Three RCTs (680 women) were included. The mean gestational age at randomization was about 16 weeks. Women were given progesterone until 36 weeks or delivery. Regarding vaginal progesterone, one study used 90 mg gel daily, one used 100 mg suppository daily and one used 200 mg suppository daily. All included RCTs used 250 mg intramuscular 17-OHPC weekly in the comparison group. Women who received vaginal progesterone had significantly lower rates of SPTB < 34 weeks (17.5% vs 25.0%; RR, 0.71 (95% CI, 0.53-0.95); low quality of evidence) and < 32 weeks (8.9% vs 14.5%; RR, 0.62 (95% CI, 0.40-0.94); low quality of evidence) compared with women who received 17-OHPC. There were no significant differences in the rates of SPTB < 37 weeks, < 28 weeks and < 24 weeks. The rate of women who reported adverse drug reactions was significantly lower in the vaginal progesterone group compared with the 17-OHPC group (7.1% vs 13.2%; RR, 0.53 (95% CI, 0.31-0.91); very low quality of evidence). Regarding neonatal outcomes, vaginal progesterone was associated with a lower rate of neonatal intensive care unit admission compared with 17-OHPC (18.7% vs 23.5%; RR, 0.63 (95% CI, 0.47-0.83); low quality of evidence). For the comparison of 17-OHPC vs vaginal progesterone, the quality of evidence was downgraded for all outcomes by at least one degree due to imprecision (the optimal information size was not reached) and by at least one degree due to indirectness (different interventions)., Conclusions: Daily vaginal progesterone (either suppository or gel) started at about 16 weeks' gestation is a reasonable, if not better, alternative to weekly 17-OHPC injection for prevention of SPTB in women with singleton gestations and prior SPTB. However, the quality level of the summary estimates was low or very low as assessed by GRADE, indicating that the true effect may be, or is likely to be, substantially different from the estimate of the effect. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. COMPARACIÓN ENTRE LA PROGESTERONA VAGINAL Y EL 17Α-HIDROXIPROGESTERONA CAPROATO INTRAMUSCULAR PARA LA PREVENCIÓN DEL PARTO PRETÉRMINO ESPONTÁNEO RECURRENTE EN EMBARAZOS CON FETO ÚNICO: REVISIÓN SISTEMÁTICA Y METAANÁLISIS DE ENSAYOS CONTROLADOS ALEATORIOS: RESUMEN OBJETIVO: Recientemente se han realizado varios ensayos controlados aleatorios (ECA) que comparaban el caproato de 17α-hidroxiprogesterona (17-OHPC, por sus siglas en inglés) por vía intramuscular con la progesterona por vía vaginal para la reducción del riesgo de parto pretérmino espontáneo (PPTE) en embarazos con feto único de gestantes con historial de PPTE. El objetivo de esta revisión sistemática y metaanálisis fue evaluar la eficacia de la progesterona vaginal en comparación con la 17-OHPC en la prevención de embarazos con feto único de gestantes con historial de PPTE. MÉTODOS: Se realizaron búsquedas en bases de datos electrónicas para identificar todos los ECA con embarazos de feto único asintomáticos con historial de PPTE antes de ser asignados al azar a un tratamiento profiláctico, ya fuera con progesterona vaginal (grupo de intervención) o con 17-OHPC intramuscular (grupo de control). No se aplicaron restricciones respecto al idioma o la ubicación geográfica. El resultado primario fue PPTE < 34 semanas. Los resultados secundarios fueron PPTE <37 semanas, < 32 semanas, < 28 semanas y < 24 semanas, la reacción materna adversa al fármaco y los resultados neonatales. Las medidas del resumen se reportaron como riesgo relativo (RR) con IC del 95%. Para cada estudio incluido se evaluó el riesgo de sesgo., Resultados: Se incluyeron tres ECA (680 mujeres). La media de la edad gestacional en el momento de la aleatorización fue de 16 semanas. A las mujeres se les administró progesterona hasta la semana 36 o hasta el parto. Con respecto a la progesterona vaginal, un estudio utilizó gel de 90 mg diariamente, otro utilizó un supositorio diario de 100 mg y el otro utilizó un supositorio diario de 200 mg. Todos los ECA incluidos en el grupo de comparación utilizaron 250 mg semanales de 17-OHPC por vía intramuscular. Las mujeres que recibieron progesterona vaginal tuvieron tasas significativamente más bajas de PPTE < 34 semanas (17,5% vs. 25,0%; RR 0,71 (IC 95%, 0,53-0,95); calidad de la evidencia baja) y < 32 semanas (8,9% vs. 14,5%; RR 0,62 (IC 95%, 0,40-0,94); calidad de evidencia baja), en comparación con las mujeres que recibieron 17-OHPC. No hubo diferencias significativas en las tasas de PPTE < 37 semanas, < 28 semanas y < 24 semanas. La tasa de mujeres que reportaron reacciones adversas a los medicamentos fue significativamente menor en el grupo de progesterona vaginal en comparación con el grupo de 17-OHPC (7,1% vs. 13,2%; RR 0,53 (IC 95%, 0,31-0,91); calidad de la evidencia muy baja). En cuanto a los resultados neonatales, la progesterona vaginal se asoció a una menor tasa de admisiones en la unidad neonatal de cuidados intensivos en comparación con la 17-OHPC (18,7% vs. 23,5%; RR 0,63 (IC 95%, 0,47-0,83); calidad de evidencia baja). Para la comparación del 17-OHPC con la progesterona vaginal se rebajó la calidad de las pruebas para todos los resultados en al menos un grado debido a imprecisiones (no se alcanzó el tamaño óptimo de la información) y en al menos un grado debido al carácter indirecto de los estudios (diferentes intervenciones)., Conclusiones: La progesterona vaginal administrada diariamente (ya fuera como supositorio o como gel) desde la semana 16 de gestación es una alternativa razonable, si no mejor, a una inyección semanal de 17-OHPC para la prevención de PPTE en mujeres con embarazos de feto único e historial de PPTE. Sin embargo, el nivel de calidad de las estimaciones del resumen fue bajo o muy bajo según lo evaluado por GRADE, lo que indica que el verdadero efecto puede ser, o es probable que sea, sustancialmente diferente de la estimación del efecto. 17Α-:META: : (randomized controlled trials,RCTs)(spontaneous preterm birth,SPTB)17α-(intramuscular 17α-hydroxyprogesterone caproate,17-OHPC)SPTB。metaSPTB17-OHPCSPTB。 : ,SPTBRCTs,RCTs()17-OHPC()。。34SPTB。37、32、2824SPTB,。(relative risk,RR)95%CI。。 : 3RCTs(680)。16。,36。,90 mg,100 mg,200 mg。,RCTs250 mg 17-OHPC。17-OHPC,34 [17.5%25.0%;RR,0.71(95% CI,0.53 ~ 0.95);]32[8.9%14.5%;RR,0.62(95% CI,0.40 ~ 0.94);]SPTB。37、2824SPTB。17-OHPC,[7.1%13.2%;RR,0.53(95% CI,0.31 ~ 0.91);]。,17-OHPC,[18.7%23.5%;RR,0.63(95% CI,0.47 ~ 0.83);]。17-OHPC,(),()。 : SPTBSPTB,16()17-OHPC,。,GRADE,,。., (Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.)

Background: The safety of preventive progestogen therapy for preterm birth remains to be established. This meta-analysis aimed to evaluate the effects of preventive progestogen therapy on neonatal mortality., Methods: Randomized controlled trials (RCTs) on the preventive use of progestogen therapy, published between October 1971 and November 2015, were identified by searching MEDLINE/PubMed, EMBASE, Scopus, ClinicalTrials.gov, Cochrane Library databases, CINAHL, POPLINE, and LILACS using "progesterone" and "preterm birth" as key terms. We conducted separate analyses according to the type of progestogen administered and plurality of the pregnancy., Results: Twenty-two RCTs provided data on 11,188 neonates. Preventive progestogen treatment in women with a history of preterm birth or short cervical length was not associated with increased risk of neonatal death compared to placebo in all analyzed progestogen types and pregnancy conditions. The pooled relative risks (95% confidence interval) of neonatal mortality were 0.69 (0.31-1.54) for vaginal progestogen in singleton pregnancies, 0.6 (0.33-1.09) for intramuscular progestogen in singleton pregnancies, 0.96 (0.51-1.8) for vaginal progestogen in multiple pregnancies, and 0.96 (0.49-1.9) for intramuscular progestogen in multiple pregnancies., Conclusions: The results of this meta-analysis suggest that administration of preventive progestogen treatment to women at risk for preterm birth does not appear to negatively affect neonatal mortality in single or multiple pregnancies regardless of the route of administration.

Spontaneous preterm birth is a syndrome with many causes and thus unresponsive to a single intervention. It logically follows that patients with a prior spontaneous preterm birth are a heterogeneous group unlikely to respond equally to a single preventive intervention such as 17-α hydroxyprogesterone caproate. Further confounding this issue is our fundamental lack of knowledge about the mechanism(s) by which 17-α hydroxyprogesterone caproate reduces preterm birth. Recently, studies demonstrating that responders and nonresponders can be identified based on obstetric history, genotype, physical characteristics, and behavioral factors have begun to provide clues into both 17-α hydroxyprogesterone caproate's mechanism and the pathophysiology of recurrent preterm birth and may allow for more targeted therapy. These studies lend support to speculation that inflammation or nitric oxide metabolism may be common threads between 17-α hydroxyprogesterone caproate's mechanism and preterm birth prevention. It will remain critically important to avoid the temptation to regard prior spontaneous preterm birth as a single disease entity amenable to a single treatment.

Objective: To compare the efficacy of intramuscular hydroxyprogesterone caproate with that of vaginal progesterone for prevention of recurrent preterm birth., Methods: A prospective randomized controlled trial was conducted at a US tertiary care center between June 1, 2007, and April 30, 2010. Women with singleton pregnancies (16-20 weeks) and a history of spontaneous preterm birth were randomly allocated using a computer-generated randomization sequence to receive either a weekly intramuscular injection of hydroxyprogesterone caproate (250 mg) or a daily vaginal progesterone suppository (100 mg). Participants, investigators, and assessors were not masked to group assignment. The primary outcome was birth before 37 weeks of pregnancy. Per-protocol analyses were performed: participants who completed follow-up were included., Results: Analyses included 66 women given intramuscular progesterone and 79 given vaginal progesterone. Delivery before 37 weeks was recorded among 29 (43.9%) women in the intramuscular progesterone group and 30 (37.9%) in the vaginal progesterone group (P=0.50)., Conclusion: Weekly intramuscular administration of hydroxyprogesterone caproate and daily vaginal administration of a progesterone suppository exhibited similar efficacy in reducing the rate of recurrent preterm birth. ClinicalTrials.gov: NCT00579553., (Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

While the preterm neonate continues to benefit from improved perinatal care, the rate of preterm birth in the United States remains significant. An increasing body of scientific literature has demonstrated the benefits of maternal progesterone administration in reducing primary and recurrent preterm birth. Intramuscular hydroxyprogesterone caproate is indicated in singleton pregnancies in women with a prior spontaneous preterm birth, while vaginal progesterone demonstrates similar efficacy in prolonging pregnancy in women with asymptomatic cervical shortening in the midtrimester. Given these favorable benefits, the use of progesterone has been expanded to other clinical situations at risk for preterm birth with less rigorous scientific evidence. This review highlights the current evidence-based clinical applications of progesterone for prevention of preterm birth., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

1. Weekly intramuscular injections of (250 mg/week) of 17-hydroxyprogesterone caproate (17-OHPC) are the only treatment option for prevention of preterm birth in women with a prior history of preterm delivery. 2. The objective of the current study was to evaluate the use of an alternate formulation and the feasibility of an alternate route of administration of this agent. 17-OHPC was administered to adult female SD rats, as marketed oily formulation intramuscularly, or as a solution IV, IM, or PO. 3. Plasma concentrations of 17-OHPC were measured by LC-MS-MS and pharmacokinetic parameters were calculated by non-compartmental analysis, using WinNonLin (Certara, St. Louis, MO). 4. After IV or IM administration as a solution, the mean half-life of 17-OHPC was around 11 h. The bioavailability was nearly 100% after IM administration, but was very low (<3%) after PO administration of a solution dosage form. 5. Intramuscular injection of the oily formulation resulted in low levels of 17-OHPC that were sustained for a prolonged time period with a projected bioavailability close to 100%. 6. The pharmacokinetics of 17-OHPC is dependent on the formulation and the route of administration. 7. The low bioavailability after oral administration indicates that oral administration of 17-OHPC may not be feasible with simple formulations of this drug.

Objective: Progestogen (vaginal progesterone or 17-alpha-hydroxyprogesterone caproate [17OHP-C]) administration to patients at risk for preterm delivery is widely used for the prevention of preterm birth (PTB). The mechanisms by which these agents prevent PTB are poorly understood. Progestogens have immunomodulatory functions; therefore, we investigated the local effects of vaginal progesterone and 17OHP-C on adaptive and innate immune cells implicated in the process of parturition., Study Design: Pregnant C57BL/6 mice received vaginal progesterone (1 mg per 200 μL, n = 10) or Replens (control, 200 μL, n = 10) from 13 to 17 days postcoitum (dpc) or were subcutaneously injected with 17OHP-C (2 mg per 100 μL, n = 10) or castor oil (control, 100 μL, n = 10) on 13, 15, and 17 dpc. Decidual and myometrial leukocytes were isolated prior to term delivery (18.5 dpc) for immunophenotyping by flow cytometry. Cervical tissue samples were collected to determine matrix metalloproteinase (MMP)-9 activity by in situ zymography and visualization of collagen content by Masson's trichrome staining. Plasma concentrations of progesterone, estradiol, and cytokines (interferon [IFN]γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, keratinocyte-activated chemokine/growth-related oncogene, and tumor necrosis factor-α) were quantified by enzyme-linked immunosorbent assays. Pregnant mice pretreated with vaginal progesterone or Replens were injected with 10 μg of an endotoxin on 16.5 dpc (n = 10 each) and monitored via infrared camera until delivery to determine the effect of vaginal progesterone on the rate of PTB., Results: The following results were found: (1) vaginal progesterone, but not 17OHP-C, increased the proportion of decidual CD4+ regulatory T cells; (2) vaginal progesterone, but not 17OHP-C, decreased the proportion of decidual CD8+CD25+Foxp3+ T cells and macrophages; (3) vaginal progesterone did not result in M1→M2 macrophage polarization but reduced the proportion of myometrial IFNγ+ neutrophils and cervical active MMP-9-positive neutrophils and monocytes; (4) 17OHP-C did not reduce the proportion of myometrial IFNγ+ neutrophils; however, it increased the abundance of cervical active MMP-9-positive neutrophils and monocytes; (5) vaginal progesterone immune effects were associated with reduced systemic concentrations of IL-1β but not with alterations in progesterone or estradiol concentrations; and (6) vaginal progesterone pretreatment protected against endotoxin-induced PTB (effect size 50%, P = 0.011)., Conclusion: Vaginal progesterone, but not 17OHP-C, has local antiinflammatory effects at the maternal-fetal interface and the cervix and protects against endotoxin-induced PTB., (Published by Elsevier Inc.)

We sought to evaluate the efficacy of maintenance tocolysis with 17-alpha-hydroxyprogesterone caproate (17P) compared to control (either placebo or no treatment) in singleton gestations with arrested preterm labor (PTL), in a metaanalysis of randomized trials. Electronic databases (MEDLINE, OVID, Scopus, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials) were searched from 1966 through July 2014. Key words included "progesterone," "tocolysis," "preterm labor," and "17-alpha-hydroxyprogesterone caproate." We performed a metaanalysis of randomized trials of singleton gestations with arrested PTL and treated with maintenance tocolysis with either 17P or control. Primary outcome was preterm birth (PTB) <37 weeks. This metaanalysis was performed following the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) statement. The protocol was registered with PROSPERO (registration no: CRD42014013473). Five randomized trials met inclusion criteria, including 426 women. Women with a singleton gestation who received 17P maintenance tocolysis for arrested PTL had a similar rate of PTB <37 weeks (42% vs 51%; relative risk [RR], 0.78; 95% confidence intervals [CI], 0.50-1.22) and PTB <34 weeks (25% vs 34%; RR, 0.60; 95% CI, 0.28-1.12) compared to controls. Women who received 17P had significantly later gestational age at delivery (mean difference, 2.28 weeks; 95% CI, 1.46-13.51), longer latency (mean difference, 8.36 days; 95% CI, 3.20-13.51), and higher birthweight (mean difference, 224.30 g; 95% CI, 70.81-377.74) as compared to controls. Other secondary outcomes including incidences of recurrent PTL, neonatal death, admission to neonatal intensive care unit, neonatal respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal sepsis were similar in both groups. Maintenance tocolysis with 17P after arrested PTL is not associated with prevention of PTB compared to placebo or no treatment in a metaanalysis of the available randomized trials. As 17P for maintenance tocolysis is associated with a significant prolongation of pregnancy, and significantly higher birthweight, further research is suggested., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Preterm birth and its associated neonatal morbidities remain pertinent health care and economic issues in the United States. Progesterone supplementation in the form of 17α-hydroxyprogesterone caproate has been reported to reduce the risk for recurrent preterm birth in women with a prior spontaneous preterm delivery, but several barriers contribute to its underutilization. The Affordable Care Act has increased the number of women receiving insurance coverage for pre- and perinatal care. However, the increase in insurance coverage has not necessarily facilitated access to standard therapies such as progesterone for the prevention of preterm birth. Data from Louisiana illustrate this point, and the state has responded by developing educational programs and the nation's first pay-for-performance strategy targeting the initiation of progesterone therapy., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Complications resulting from the use of compounded medications have become a troubling trend nationwide. There is a significant potential for patients to suffer serious harm from the use of substandard medications prepared by compounding pharmacies, and the reality of this problem has been demonstrated in several well-publicized incidences of serious medical complications, including patient deaths, that directly resulted from the use of medications prepared at compounding pharmacies. Unlike US Food and Drug Administration (FDA)-approved drugs, compounded products are not required to meet evidentiary standards for establishing safety and efficacy. Moreover, these products are not held to Good Manufacturing Practices, which require regular inspections, quality control testing, and rejection of material not meeting specifications. Physicians, as well as other prescribers, need to be aware that when a patient suffers harm from using a compounded medication, those injured patients may bring negligence and malpractice claims, not only against the pharmacy and the pharmacist responsible for preparing the medication, but also against the prescribing physician and the physician’s practice. Consequently, the best way for physicians to manage professional risk and avoid both litigation and potential negative patient outcomes related to compounded pharmaceuticals is to not use these products if there is an FDA-approved product available. However, if the use of a compounded medication is medically necessary, then physicians should adhere to the FDA guidance concerning traditional compounding. Moreover, it would be prudent for any physician who intends to either resell or participate in the distribution of compounded products beyond the direct treatment of their patients to consider obtaining the appropriate insurance coverage for this activity.

Recognition of preterm birth as the major underlying cause of infant mortality in the United States has placed responsibility for prevention in the hands of obstetrician-gynecologists. The advent of effective methods to identify and treat women with increased risk is a major advance that will alter the focus of prenatal care. Adoption of research findings into clinical practice, never an easy task, will be particularly challenging for efforts to reduce the risk of preterm birth. Historical risk factors for preterm birth are numerous and variably defined. Measurement of the length of the cervix with ultrasonography requires unique personnel and facilities. Care algorithms exist but lack the detailed information that comes with experience. This review offers perspective and detail to aid health care practitioners in developing a prematurity prevention strategy appropriate to their practice population.

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 <34 weeks' gestation who received 17P were recruited prospectively and classified as a 17P responder or nonresponder by the difference in delivery gestational age between 17P-treated and -untreated pregnancies. Samples underwent whole exome sequencing. Coding variants were compared between responders and nonresponders with the use of the Variant Annotation, Analysis, and Search Tool (VAAST), which is a probabilistic search tool for the identification of disease-causing variants, and were compared with a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway candidate gene list. Genes with the highest VAAST scores were then classified by the online Protein ANalysis THrough Evolutionary Relationships (PANTHER) system into known gene ontology molecular functions and biologic processes. Gene distributions within these classifications were compared with an online reference population to identify over- and under- represented gene sets., Results: Fifty women (9 nonresponders) were included. Responders delivered 9.2 weeks longer with 17P vs 1.3 weeks' gestation for nonresponders (P < .001). A genome-wide search for genetic differences implicated the NOS1 gene to be the most likely associated gene from among genes on the KEGG candidate gene list (P < .00095). PANTHER analysis revealed several over-represented gene ontology categories that included cell adhesion, cell communication, signal transduction, nitric oxide signal transduction, and receptor activity (all with significant Bonferroni-corrected probability values)., 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., (Published by Mosby, Inc.)

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., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: Gestational diabetes (GDM) and obesity portend a high risk for subsequent type 2 diabetes. We examined maternal factors influencing the development of gestational diabetes (GDM) in obese women receiving 17-alpha-hydroxyprogesterone caproate (17OHPC) for preterm delivery prevention., Materials and Methods: Retrospectively identified were 899 singleton pregnancies with maternal prepregnancy body mass indices of ≥30 kg/m(2) enrolled for either 17OHPC weekly administration (study group) or daily uterine monitoring and nursing assessment (control group). Patients with history of diabetes type 1, 2, or GDM were excluded. Maternal characteristics were compared between groups and for women with and without development of GDM. A logistic regression model was performed on incidence of GDM, controlling for significant univariate factors., Results: The overall incidence of GDM in the 899 obese women studied was 11.9%. The incidence of GDM in the study group (n = 491) was 13.8% versus 9.6% in the control group (n = 408) (P = 0.048). Aside from earlier initiation of 17OHP and advanced maternal age, other factors including African American race, differing degrees of obesity, and use of tocolysis were not significant risks for the development of GDM., Conclusion: In obese women with age greater than 35 years, earlier initiation of 17OHPC may increase the risk for GDM.

Objective: To examine the influence of maternal pre-pregnancy body mass index (BMI) on the rates of recurrent spontaneous preterm birth (SPTB) in women receiving 17α-hydroxyprogesterone caproate (17P)., Methods: Retrospective analysis of a cohort of 6253 women with a singleton gestation and prior SPTB enrolled in 17P home administration program between 16.0 and 26.9 weeks. Data were grouped by pre-pregnancy BMI (lean <18.5 kg/m(2), normal 18.5-24.9 kg/m(2), overweight 25-29.9 kg/m(2) and obese ≥30.0 kg/m(2)). Delivery outcomes were compared using χ(2) and Kruskal-Wallis tests with statistical significance set at p < 0.05., Results: SPTB<28 weeks was significantly lower in normal weight women. Rates of recurrent SPTB<37 weeks were highest in the group with BMI<18.5 kg/m(2). Lean gravidas were younger, more likely to smoke, and less likely to be African-American than those with normal or increased BMI. In logistic regression, after controlling for race and prior preterm birth <28 weeks, the risk of SPTB<37 weeks decreased 2% for every additional 1 kg/m(2) increase in BMI., Conclusions: Recurrent spontaneous preterm delivery<37 weeks in patients on 17P is more common in lean women (BMI<18.5 kg/m(2)), and less common in obese women (BMI ≥30 kg/m(2)) suggesting that the current recommended dosing of 17 P is adequate for women with higher BMI.

Objective: Clinically, vaginal progesterone (VP) and 17 alpha-hydroxyprogesterone caproate (17P) have been shown to prevent preterm birth (PTB) in high-risk populations. We hypothesize that treatment with these agents may prevent PTB by altering molecular pathways involved in uterine contractility or cervical remodeling., Study Design: Using a mouse model, on embryonic day (E)14-E17 CD-1 pregnant mice were treated with: (1) 0.1 mL of 25 mg/mL of 17P subcutaneously; (2) 0.1 mL of castor oil subcutaneously; (3) 0.1 mL of 10 mg/mL of progesterone in a long-lasting Replens (Lil' Drug Store Products, Inc., Cedar Rapids, IA); or (4) 0.1 mL of the same Replens, with 4 dams per treatment group. Mice were sacrificed 6 hours after treatment on E17.5. Cervices and uteri were collected for molecular analysis., Results: Exposure to VP significantly increased the expression of defensin 1 compared to Replens (P < .01) on E17.5. Neither VP nor 17P altered the expression of uterine contraction-associated proteins, progesterone-mediated regulators of uterine quiescence, microRNA involved in uterine contractility, or pathways involved in cervical remodeling. In addition, neither agent had an effect on immune cell trafficking or collagen content in the cervix., Conclusion: Neither VP nor 17P had any effect on the studied pathways known to be involved in uterine contractility or quiescence. In the cervix, neither VP nor 17P altered pathways demonstrated to be involved in cervical remodeling. Administration of VP was noted to increase the expression of the antimicrobial protein defensin 1. Whether this molecular change from VP results in a functional effect and is a key mechanism by which VP prevents PTB requires further study., (Copyright © 2013 Mosby, Inc. All rights reserved.)

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 the prevention of recurrent PTB in women with short CL < 25 mm receiving 17P, but the sample size is insufficient for a definite conclusion given the 36% nonsignificant decrease in the odds of PTB < 35 weeks. Cerclage may further offer substantial benefit to women with very short CL < 15 mm and further study is needed.

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 < .001). Women receiving 17-OHPC demonstrated significantly higher (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 < .0001) positive relationship was observed between 17-OHPC concentration and progesterone and 17-hydroxyprogesterone concentrations at both epochs. Corticotropin-releasing hormone concentrations did not differ by treatment group., Conclusion: 17-OHPC may adversely impact gestational age at delivery in women with twin gestation., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objectives: Previous studies on singleton pregnancies have indicated that progestogens may reduce the rate of cervical shortening during pregnancy. The aim of this study was to investigate whether treatment with 17-alpha hydroxyprogesterone caproate (17-OHPC) has an effect on cervical shortening in twin pregnancies., Methods: This was a secondary analysis of patients who had participated in a multicenter randomized clinical trial on the effectiveness of 17-OHPC in preventing preterm birth in multiple pregnancies (the AMPHIA-trial). We included all trial participants with a twin gestation who had undergone repeat cervical length measurements during pregnancy. We performed a separate analysis of women with repeat measurements in centers where this was standard protocol for multiple pregnancies. The rate of cervical shortening for both the 17-OHPC group and the placebo group was analyzed using a linear mixed model., Results: Of the 671 patients who participated in the trial, 282 (42%) had a twin pregnancy and underwent two or more cervical length measurements. Of these women, 140 were monitored in centers where repeat measurements were standard protocol. We observed an overall reduction of cervical length from 44.3 mm at 14-18 weeks to 30.0 mm at 30-34 weeks' gestation. In the 17-OHPC group, cervical length decreased by 1.04 mm each gestational week, while this was 1.11 mm per week for the placebo group (P = 0.6). For the overall group, each 10% decrease in cervical length led to an increase in the risk of preterm birth (hazard ratio, 1.14; 95% CI, 1.08-1.21)., Conclusion: In women with a twin pregnancy, there is progressive shortening of the cervix during pregnancy, regardless of 17-OHPC use., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

The safety of supplemental progestin therapy during pregnancy reflects whether an agent exclusively promotes or potentially inhibits progestational cellular functions and whether treatment incites a metabolic derangement or other pathophysiology to initiate rare untoward events. No safety signal has been identified from intravaginal administration of natural progesterone from phase III clinical trials. The Food and Drug Administration has identified a legitimate safety signal regarding second-trimester miscarriage and stillbirth with exposure to 17-hydroxyprogesterone caproate (17-OHPC). Results from recent phase II and III trials in multiples also demonstrates concern with exposure to this synthetic for fetal loss and increased severe respiratory distress in neonates (one study each), as well as repeated significant associations for shorter duration of pregnancy and poorer fetal growth in others. The biological plausibility for 17-OHPC to be associated with adverse outcomes can be suggested from pharmacogenomic observations, ex vivo experimentation, and clinical observations. Further data are needed interrogating the potential for rare fetal or maternal adverse events/safety outcomes with exposure to progestins. Safety concerns should be incorporated into prescribing decisions., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To examine pregnancy outcomes of women receiving weekly compounded 17 α-hydroxyprogesterone caproate (17P) injections through a home nursing program compared with those reported in a multicenter trial by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Network., Methods: The study sample was comprised of patients receiving compounded 17P through a home nurse administration care management program. Included were women with current singleton gestation and prior spontaneous preterm birth (SPTB) initiating 17P between 16 and 20 weeks. Maternal characteristics and pregnancy outcomes were compared between study group and NICHD Network trial patients., Results: Women (n = 5493) received a mean of 16.9 ± 4.0 injections. Of the 92,700 injections, 98.4% were administered within the recommended 5- to 9-day interval. Recurrent SPTB occurred in 28.3%. The overall rate of SPTB at <37 weeks was similar for black and nonblack women (p = 0.592). Within black or nonblack groups, preterm birth rates at <37 weeks were similar regardless of gestational age at start of 17P (p = 0.894 and p = 0.374, respectively). These results were similar to those reported in the multicenter trial. Fetal and neonatal death occurred in 0.8% (46/5493). No significant difference was observed in rate of fetal or neonatal death by gestational age at initiation of 17P (p = 0.478)., Conclusion: Home nurse administration of compounded 17P is safe and effective., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Currently, the techniques for amniocentesis and chorionic villus sampling (CVS) tend to be described in local and national guidelines, but certain aspects, including the choice of instruments, is predominantly based upon the operator's personal preference. A survey of practice in the specialist UK centres revealed a wide variation of practice; therefore, standardising any element of technique could potentially influence the safety of the procedure., Objectives: The objective of this review was to compare the safety and effectiveness of all techniques of performing both amniocentesis and CVS for prenatal diagnosis., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 April 2012)., Selection Criteria: We included all randomised comparisons of different methods of performing amniocentesis after 15 weeks' gestation, or CVS (transabdominal or transvaginal) with each other or with no testing. We excluded quasi-randomised studies (e.g. alternate allocation)., Data Collection and Analysis: Both review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. Both review authors independently assessed trial quality. Both review authors extracted data. Data were checked for accuracy., Main Results: We included five randomised studies with total of 1049 women evaluating five different technique modifications during either amniocentesis (three studies) or CVS (two studies).For amniocentesis three interventions were evaluated - intramuscular progesterone, hexoprenaline and selecting high or low puncture sites for late 'blind' procedure - each intervention in a single small study. There was no conclusive evidence of benefit for any of them. The same applies for terbutaline tocolysis and use of continuous vacuum aspiration during CVS., Authors' Conclusions: Overall, the quality of evidence summarised in this review is not of sufficient quality to change current clinical practice. In the absence of clear evidence, the operators should continue to use methods and technique modifications with which they are most familiar with.Any randomised trials of technique modifications that are performed to high standard with adequate safety outcomes and power to detect important clinical differences would be clearly welcome.

Aim: Male-to-female (MTF) transsexuals are treated with estrogen with and without progestin through a variety of routes. The aim of this study is to evaluate the arterial stiffness in MTF transsexuals undergoing hormonal treatment., Methods: We evaluated the arterial stiffness in 156 MTF transsexuals (22 untreated and 129 treated with estrogen only or plus progestin) using a volume-plethysmographic apparatus equipped with a multi-element applanation tonometry sensor., Results: MTF transsexuals treated with parenteral estrogen were significantly older than untreated MTF transsexuals. Hematocrit, uric acid and activated partial thromboplastin time in treated MTF transsexuals were significantly lower than in untreated MTF transsexuals. The level of high-density lipoprotein cholesterol in MTF transsexuals treated with oral estrogen was significantly higher than in untreated MTF transsexuals or those treated with parenteral estrogen with and without progestin. The systolic blood pressure in MTF transsexuals treated with estrogen only is significantly lower than that in untreated MTF transsexuals. The brachial-ankle pulse wave velocity was significantly decreased in MTF transsexuals treated with estrogen compared to that in untreated MTF transsexuals or in those treated with estrogen plus progestin. The carotid augmentation index in MTF transsexuals treated with oral estrogen was significantly lower than that in MTF transsexuals treated with parenteral estrogen or oral estrogen plus progestin., Conclusions: Estrogen treatment is likely to have some beneficial effects on lipid metabolism and vascular function in MTF transsexuals; however, progestin administered with estrogen may have adverse effects on arterial stiffness., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

Growing evidence of neuroprotective and analgesic effects by progesterone (PROG) has been obtained in experimental animal models of neuropathy. In this paper, we report the results of the first experimental study to test the efficacy of PROG in a human neuropathy. The effects of a local administration of 17-alpha-hydroxyprogesterone caproate (17HPC) has been studied in patients with carpal tunnel syndrome (CTS) and compared with those of a local administration of corticosteroid (CS) in a analogous CTS group. Sixteen women affected by mild CTS were selected. Clinical, electrophysiological and ultrasonographic data of the median nerve were quantified at 0 (pre-injection), 1 and 6 months after CS or 17HPC injection. One month after injection, both 17HPC and CS groups exhibited similar reduction in pain scores, whereas only the 17HPC-treated group still manifested symptoms relief 6 months after. Only in CS-treated patients, improvement of the clinical data correlated with ultrasonographic and electrophysiological changes of the median nerve. The present study indicates that intra-carpal injection with a long-acting PROG derivative is effective for relief of symptoms in CTS. This effect is apparently mediated by a mechanism distinct from that of the CS.

Despite the introduction of 17-alpha-hydroxyprogesterone caproate (17P), the national preterm birth (PTB) rate remains unchanged. Our objectives were to determine whether the overall rate of PTB has decreased and whether there has been a shift in the trends of prematurity at our institution since the initiation of 17P use. We performed a cross sectional study of the PTB rate and gestational age distribution at delivery (GA-del) at our institution over two, 2-year time periods: TP1 (pre 17P, 1 Jan 2004-31 Dec 2005) and TP2 (post 17P, 1 Jan 2008-31 Dec 2009). Statistical analyses included χ(2) tests for categorical data, t-tests for continuous data, and multivariable logistic regression to control for confounders. Overall (n = 15,421), there was no difference in the rate of PTB from TP1 to TP2 (16.65 vs 16.95%, p = 0.62). Among those with a history of prior PTB (n = 2,141), the mean preterm GA-del was 10 days later in TP2 than in TP1 (33.13 vs 31.64 weeks, p < 0.01) and significantly more preterm infants in TP2 delivered between 34-36 6/7 weeks than in TP1 (65.00 vs 45.63%, p < 0.01). The odds of a preterm infant delivering in the late preterm period was 2.3-fold higher in TP2 than TP1 (95% CI 1.49-3.54) after controlling for confounders. The significant shift in GA-del towards the late preterm period in TP2 may be due to the introduction of 17P use at our institution. Additional studies are needed to determine whether these trends persist on a nationwide level.

Objective: To evaluate the effect of a single 250-mg dose of 17 alpha-hydroxyprogesterone caproate (17-OHPC) intramuscularly as adjunct to nifedipine tocolysis in preterm labor., Method: Women diagnosed with threatened preterm labor between 22 and 35 weeks' gestation scheduled to receive nifedipine tocolysis and prophylactic antenatal corticosteroid were randomized to a single intramuscular injection of 250 mg of 17-OHPC or placebo saline in a double-blind fashion. Nifedipine tocolysis and corticosteroids were administered to all participants. Further management was otherwise carried out according to providers' discretion. Main outcome measures are delivery within 48 h and 7 days., Results: Data were analyzed for the 56 participants randomized to 17-OHPC and 56 randomized to placebo. Delivery rates within 48 h were 11/54 (20.4%) versus 15/56 (26.8%) RR 0.76 (95% CI 0.38-1.51) and within 7 days were 13/52 (25.0%) versus 19/54 (35.2%) RR 0.71 (95% CI 0.39-1.29) for 17-OHPC and placebo groups, respectively, and were similar. Recruitment to delivery interval, gestation at delivery, delivery rate before 34 weeks' and 37 weeks' gestation, and neonatal outcomes were also similar., Conclusion: The results indicated that adjunctive single-dose 17-OHPC in combination with nifedipine tocolysis for threatened preterm labor did not delay delivery.

Use of 17-alpha-hydroxyprogesterone caproate for the prevention of spontaneous preterm birth in women at risk is reviewed. Early studies regarding this topic reached contradicting conclusions, however recent studies showed that weekly injections of 17-alpha-hydroxyprogesterone caproate beginning at 16-20 weeks' gestation resulted in a substantial reduction in the rate of spontaneous recurrent preterm birth. Long-term follow-up of children exposed in-utero to the drug has shown normal growth and development and normal scores for gender specific roles. In conclusion, 17-alpha-hydroxyprogesterone caproate is currently the only drug with sufficient evidence to support its use for prevention of spontaneous recurrent preterm birth., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Preterm birth is the leading cause of perinatal morbidity and mortality in otherwise healthy infants, and the rate of pregnancies complicated by a premature delivery continues to rise. Subsequently, attempts have been made to reduce this rate by using progesterone supplementation during pregnancy. 17alpha-Hydroxyprogesterone caproate (17P), a metabolite of progesterone, also has been used as supplementation during pregnancy to prevent preterm births. We report a case of iatrogenic autoimmune progesterone dermatitis (APD) in a pregnant woman who received 17P therapy. Due to the increased use of 17P, our case could represent an increasingly prevalent entity that dermatologists and obstetricians should recognize. In this article, we discuss our findings and provide a basic review of APD.

17 α-hydroxyprogesterone caproate is a synthetic progestin of which there is now a US FDA-approved formulation available for intramuscular administration (Makena™) to reduce the risk of preterm birth. Intramuscular 17 α-hydroxyprogesterone caproate (identical in formulation and manufacturing process to Makena™, thus hereafter referred to as Makena™) 250 mg once weekly, initiated at 16-20 weeks' gestation, was effective in reducing the risk of preterm birth in women with a singleton pregnancy at high risk of delivering preterm in a large, well designed, placebo-controlled trial (n = 463 randomized). Rates of delivery before 37 (primary endpoint), 35, or 32 weeks' gestation were significantly lower with Makena™ than with placebo, corresponding to relative risk reductions of 34%, 33%, and 42%, respectively. The benefit of the drug in reducing the risk of preterm birth was observed when deliveries were spontaneous (but not when indicated because of complications) and regardless of maternal race. In addition, there was a significantly lower rate of several adverse fetal/neonatal outcomes among infants of women who received Makena™ than among infants of placebo recipients, including necrotizing enterocolitis, need for supplemental oxygen, birth weight of <2500 g, and intraventricular hemorrhage. Makena™ was generally well tolerated in pregnant women in this trial. Moreover, fetal exposure to the drug appeared to be safe according to a 2- to 5-year follow-up of the study, with no evidence of a detrimental effect of the drug on child neurodevelopment and a low overall incidence (≈2%) of reproductive or genital abnormalities that was not significantly different from placebo.

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<37 weeks' gestation for rs471767 and rs578029, and for Hispanics/Caucasians delivering<37 weeks' gestation for rs500760 and <32 weeks' gestation for rs578029, rs503362, and rs666553., Conclusion: The clinical efficacy and safety of 17-OHPC for recurrent PTB prevention may be altered by PGR gene polymorphisms., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Purpose: Many nonrandomized studies have suggested better outcome for patients with breast cancer who undergo surgery during the luteal (progestogenic) phase of their menstrual cycle, but this is controversial. We investigated the effect of a single preoperative injection of hydroxyprogesterone in women with operable breast cancer (OBC) in a randomized controlled trial (ClinicalTrials.gov identifier, NCT00123669)., Patients and Methods: One thousand patients with OBC were randomly assigned to receive surgery or an intramuscular injection of depot hydroxyprogesterone 500 mg 5 to 14 days before surgery. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), respectively. An analysis by axillary lymph node status was preplanned., Results: At a median follow-up of 65 months among 976 eligible patients, 273 recurrences and 202 deaths were recorded. In the progesterone group versus control group, 5-year DFS and OS rates were 73.9% v 70.2% (hazard ratio [HR], 0.87; 95% CI, 0.68 to 1.09; P = .23) and 80.2% v 78.4% (HR, 0.92; 95% CI, 0.69 to 1.21; P = .53), respectively. In 471 node-positive patients, the 5-year DFS and OS rates in the progesterone group versus control group were 65.3% v 54.7% (HR, 0.72; 95% CI, 0.54 to 0.97; P = .02) and 75.7% v 66.8% (HR, 0.70; 95% CI, 0.49 to 0.99; P = .04), respectively. In multivariate analysis, DFS was significantly improved with progesterone in node-positive patients (adjusted HR, 0.71; 95% CI, 0.53 to 0.95; P = .02), whereas there was no significant effect in node-negative patients (P for interaction = .04)., Conclusion: A single injection of hydroxyprogesterone before surgery did not improve outcomes in all women with OBC. This intervention showed significant improvement in node-positive women that may be considered hypothesis generating. If replicated in other studies, this could be a simple and inexpensive intervention, especially in developing countries where the incidence of lymph node metastasis is high.

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., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Aim: To compare the success rates and gestational ages at delivery of nifedipine, proluton depot administration as a tocolytic agent and bed rest groups to pregnant women with threatened preterm labor., Material and Methods: A total of 150 pregnant women with threatened preterm labor between 28 and 35 weeks of gestation were enrolled in the study. All women underwent contraction inhibition randomly sorted into three groups. The first and second groups were inhibited with nifedipine and proluton depot, respectively. The third group was admitted for bed rest., Results: Nifedipine, proluton depot and bed rest can be used to inhibit contraction in threatened preterm labor. However, when time-to-event test was used, nifedipine took the shortest time for contraction inhibition with statistical significance., Conclusion: Nifedipine, proluton depot and bed rest can be used successfully to inhibit contraction in threatened preterm labor. However, nifedipine took the shortest time to inhibit uterine contraction in threatened preterm labor., (© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.)