Search

Objective: The frequency of intrahepatic cholestasis of pregnancy (ICP) peaks during the third trimester of pregnancy when plasma progesterone levels are the highest. Furthermore, twin pregnancies are characterized by higher progesterone levels than singletons and have a higher frequency of cholestasis. Therefore, we hypothesized that exogenous progestogens administered for reducing the risk of spontaneous preterm birth may increase the risk of cholestasis. Utilizing the large IBM MarketScan Commercial Claims and Encounters Database, we investigated the frequency of cholestasis in patients treated with vaginal progesterone or intramuscular 17α-hydroxyprogesterone caproate for the prevention of preterm birth., Study Design: We identified 1,776,092 live-born singleton pregnancies between 2010 and 2014. We confirmed second and third trimester administration of progestogens by cross-referencing the dates of progesterone prescriptions with the dates of scheduled pregnancy events such as nuchal translucency scan, fetal anatomy scan, glucose challenge test, and Tdap vaccination. We excluded pregnancies with missing data regarding timing of scheduled pregnancy events or progesterone treatment prescribed only during the first trimester. Cholestasis of pregnancy was identified based on prescriptions for ursodeoxycholic acid. We used multivariable logistic regression to estimate adjusted (for maternal age) odds ratios for cholestasis in patients treated with vaginal progesterone, and in patients treated with 17α-hydroxyprogesterone caproate compared with those not treated with any type of progestogen (the reference group)., Results: The final cohort consisted of 870,599 pregnancies. Among patients treated with vaginal progesterone during the second and third trimester, the frequency of cholestasis was significantly higher than the reference group (0.75 vs. 0.23%, adjusted odds ratio [aOR]: 3.16, 95% confidence interval [CI]: 2.23-4.49). In contrast, there was no significant association between 17α-hydroxyprogesterone caproate and cholestasis (0.27%, aOR: 1.12, 95% CI: 0.58-2.16) CONCLUSION:  Using a robust dataset, we observed that vaginal progesterone but not intramuscular 17α-hydroxyprogesterone caproate was associated with an increased risk for ICP., Key Points: · Previous studies have been underpowered to detect potential association between progesterone and ICP.. · Vaginal progesterone was significantly associated with ICP.. · Intramuscular 17α-hydroxyprogesterone was not associated with ICP.., Competing Interests: A.T. is the primary medical inventor of a mechanical device for the prevention of preterm birth and holds minority shares in PregnanTech, a company commercializing the invention under the name “The Lioness.” In addition, A.T. serves as medical advisor of Pollie Inc., developing a digital intervention for women with polycystic ovary syndrome., (Thieme. All rights reserved.)

Background: The effectiveness of 17-hydroxyprogesterone caproate is unclear as trials have provided conflicting results. With the absence of fundamental pharmacologic studies addressing dosing or the relationship between drug concentration and gestational age at delivery, the effectiveness of the medication cannot be evaluated., Objective: This study aimed to evaluate the relationship between plasma concentrations of 17-hydroxyprogesterone caproate and preterm birth rates and gestational age at preterm delivery and to assess the safety of the 500-mg dose., Study Design: This study recruited 2 cohorts with previous spontaneous preterm birth; 1 cohort (n=143) was randomly assigned to either 250-mg or 500-mg 17-hydroxyprogesterone caproate, and the other cohort (n=16) was receiving the 250-mg dose for routine care. Steady-state trough plasma concentrations of 17-hydroxyprogesterone caproate obtained at 26 to 30 weeks of gestation were correlated to dose, spontaneous preterm birth rates, and measures of gestational length. Furthermore, maternal and neonatal safety outcomes were evaluated according to dose., Results: There was a dose proportional increase in trough plasma concentrations with the 250-mg (median, 8.6 ng/m; n=66) and 500-mg (median, 16.2 ng/mL; n=55) doses. In 116 compliant participants with blood samples, drug concentration was not related to the spontaneous preterm birth rate (odds ratio, 1.00; 95% confidence interval, 0.93-1.08). However, there was a significant relationship between drug concentration and both the interval from the first administration to delivery (interval A: coefficient, 1.11; 95% confidence interval, 0.00-2.23; P=.05) and the interval from the 26- to 30-week blood draw to delivery (interval B: coefficient, 1.56; 95% confidence interval, 0.25-2.87; P=.02). The spontaneous preterm birth rate or measures of gestational length were not related to dose. Postenrollment cerclage adversely affected all pharmacodynamic assessments because it was a powerful predictor of spontaneous preterm birth (odds ratio, 4.03; 95% confidence interval, 1.24-13.19; P=.021) and both measures of gestational length (interval A [coefficient, -14.9; 95% confidence interval, -26.3 to -3.4; P=.011] and interval B [coefficient, -15.9; 95% confidence interval, -25.8 to -5.9; P=.002]). Initial cervical length was significantly related to the risk of postenrollment cerclage (odds ratio, 0.80; 95% confidence interval, 0.70-0.92; P=.001). Maternal and neonatal safety outcomes were similar in both dosing groups., Conclusion: In this pharmacodynamic study, trough plasma 17-hydroxyprogesterone caproate concentrations were significantly associated with gestational age at preterm birth but not with the preterm birth rate. Postenrollment cerclage was a powerful predictor of spontaneous preterm birth rate and gestational length. Initial cervical length predicted the risk of postenrollment cerclage. Adverse events were similar with the 500-mg and 250-mg doses of 17-hydroxyprogesterone caproate., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.

Competing Interests: Conflict of Interest: None.

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.)

Progestogens are the first drugs to demonstrate reproducibly a reduction in the rate of early preterm birth. The efficacy and safety of progestogens are related to individual pharmacologic properties of each drug within this class of medication and characteristics of the population that is treated. The synthetic 17-hydroxyprogesterone caproate and natural progesterone have been studied with the use of a prophylactic strategy in women with a history of preterm birth and in women with a multiple gestation. Evidence from a single large comparative efficacy trial suggests that vaginal natural progesterone is superior to 17-hydroxyprogesterone caproate as a prophylactic treatment in women with a history of mid-trimester preterm birth. Progestogen therapy is indicated for women with this highest risk profile based on evidence from 2 trials. A therapeutic approach based on the identification of a sonographic short cervix has been studied in several phase III trials. Independent phase III trials and an individual patient metaanalysis suggest that vaginal progesterone is efficacious and safe in women with a singleton and a short cervix. Two trials that tested 17-hydroxyprogesterone caproate in women with a short cervix showed no benefit. No consistent benefit for the prophylactic or therapeutic use of progestogens has been demonstrated in larger trials of women whose pregnancies were complicated by a multiple gestation (twins or triplets), preterm labor, or preterm rupture of membranes. Unfortunately, several large randomized trials in multiple gestations have identified harm related to 17-hydroxyprogesterone caproate exposure, and the synthetic drug is contraindicated in this population. The current body of evidence is evaluated by the Grading of Recommendations Assessment, Development, and Evaluation guidelines to derive the strength of recommendation in each of these populations. A large confirmatory trial that is testing 17-hydroxyprogesterone caproate exposure in women with a singleton pregnancy and a history of preterm birth is near completion. Additional study of the efficacy and safety of progestogens is suggested in well-selected populations based on the presence of biomarkers., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To evaluate whether exposure to 17α-hydroxyprogesterone caproate is associated with the rate of peripartum infection in women who deliver preterm and their neonates., Methods: This is a retrospective cohort study of patients who delivered before 37 weeks of gestation at a tertiary care hospital between July 1, 2005, and December 31, 2012. Women in the case group (women exposed to 17α-hydroxyprogesterone caproate) were matched to women in a control group (unexposed patients) by gestational age and delivery date. The primary outcome was a composite infection rate comprising histologic or clinical chorioamnionitis, endometritis, or early-onset neonatal sepsis. To detect a 15% difference in composite infection rate between women exposed to 17α-hydroxyprogesterone caproate and those unexposed (two-tailed α=0.05 and power=80%), 183 patients per group were required. Logistic regression was performed to control for a history of prior spontaneous preterm birth and exposure to betamethasone., Results: The primary outcome frequency for women exposed to 17α-hydroxyprogesterone caproate was 34.6% (64 patients) compared with 33% (61 patients) in those unexposed (P=.74). There was no significant difference between women exposed to 17α-hydroxyprogesterone caproate and those unexposed in frequency of clinical chorioamnionitis (1.9% compared with 1.1%, P=.66), histologic chorioamnionitis (39.4% compared with 40%, P=.92), or early-onset neonatal sepsis (2.7% compared with 1.1%, P=.28). A total of 7.1% of women exposed to 17α-hydroxyprogesterone caproate developed endometritis compared with 2.7% of those unexposed (P=.05). The adjusted odds ratio for the primary outcome in women exposed to 17α-hydroxyprogesterone caproate was 0.65 (95% confidence interval 0.31-1.38)., Conclusion: Exposure to 17α-hydroxyprogesterone caproate does not increase the risk of peripartum infection among women who deliver preterm or their neonates., Level of Evidence: II.

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 evaluate data since 2003 on the efficacy and safety of progesterone supplementation in the prevention of preterm labor., Data Sources: A MEDLINE and Ovid database search (January 2003-September 2012) was performed using the search terms preterm, progesterone, and 17α-hydroxyprogesterone caproate. All relevant abstracts were reviewed., Study Selection: For efficacy and safety data, the search was limited to randomized, double-blind, placebo-controlled trials with the primary outcome of preterm delivery, fetal loss, or neonatal morbidity or mortality. Quality of the studies was assessed using the CONSORT (Consolidated Standards of Reporting Trials) guidelines for reporting parallel-group randomized trials. Eleven articles were selected for review., Data Synthesis: Preterm birth, prior to 37 weeks' gestation, remains the leading cause of neonatal morbidity and mortality in the US due to lack of treatment options. Recently, the use of progesterone to prevent preterm labor, deemed decades ago to be ineffective, has been reexamined. Progesterone formulations and dosage regimens varied greatly between studies. In patients with prior preterm birth or shortened cervix shown on transvaginal ultrasound, progesterone appears efficacious in reducing the rate of preterm birth. However, this benefit was not demonstrated in multiple-gestation pregnancies. Overall, progesterone was well tolerated and appeared safe for mother and fetus. More studies are needed to confirm the dosage regimen and population that will benefit most from progesterone., Conclusions: Progesterone appears to be safe and efficacious in reducing the risk of preterm birth in a select group of high-risk women with prior spontaneous preterm births and those with an ultrasound-confirmed short cervix. Women with multiple gestations do not benefit from progesterone supplementation.

Intramuscular 17 α-hydroxyprogesterone caproate (Makena(®)), a synthetic progestin, is indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of a singleton spontaneous preterm birth. Makena(®) reduces the risk of preterm birth in this patient population, and is associated with improvements in certain fetal/neonatal outcomes. The use of this US FDA-approved formulation of 17 α-hydroxyprogesterone caproate reduces the inherent risks associated with the use of pharmacy-compounded formulations of the drug.

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.)

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.)

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.)

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.)

We compared the rates of abnormal 1-hour glucose challenge tests (GCT) and gestational diabetes (GDM) between women receiving 17α-hydroxyprogesterone caproate (17-P) and women who did not receive 17-P to determine if the effect varies based on the number of doses received or in a group of high-risk obese women. We performed a secondary analysis of a prospective cohort study where women with a history of a previous preterm delivery in the antecedent pregnancy followed at a high-risk clinic were offered 17-P. GCT was performed after the initiation of 17-P, and doses given prior to testing were recorded. Rates of abnormal GCT and GDM were compared between those receiving 17-P ( N = 67) and controls ( N = 140). Mean glucose values (112.4 versus 111.3, P = 0.8), rate of abnormal GCT (23.9% versus 20%, adjusted odds ratio 1.45, 95% confidence interval 0.7 to 3.0), and rate of GDM (6% versus 8.6%, adjusted odds ratio 1.21, 95% confidence interval 0.3 to 4.5) were similar between groups. In this prospective study, 17-P administration to women at risk of recurrent preterm delivery did not significantly affect glucose tolerance., (© Thieme Medical Publishers.)

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.

Preterm birth has increased over the last decade. In 2006, 12.5% of all births in the United States occurred at fewer than 37 weeks gestation. This is associated with significant health care costs as well as related neonatal morbidity and mortality. In 2003, costs related to care for infants with preterm-birth or low-birth weight exceeded 11 billion dollars. This article reviews the literature on 17 alpha-hydroxyprogesterone caproate (17-P) and natural progesterone and concludes that 17-P is indicated for prevention of preterm birth in women with a documented history of a preterm birth before 37 weeks., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To estimate whether 17alpha-hydroxyprogesterone caproate treatment in pregnancy increases the frequency of abnormal glucose screening and gestational diabetes mellitus (GDM)., Methods: This is a retrospective cohort study of women treated with weekly 17alpha-hydroxyprogesterone caproate. Women with pregestational diabetes and multiple gestations were excluded. 17alpha-hydroxyprogesterone caproate-exposed women were randomly matched with three unexposed controls by maternal age and prepregnancy body mass index (BMI). The main outcomes were an abnormal 1-hour 50-g glucose screen (at least 135 mg/dL) and GDM (a 1-hour 50-g glucose screen of at least 200 mg/dL or two or more abnormal values on a 3-hour 100-g oral glucose tolerance test)., Results: A total of 110 17alpha-hydroxyprogesterone caproate-exposed women were matched with 330 controls. Maternal race between exposed women and controls was similar (46% compared with 39% African American, 17% compared with 18% Hispanic, 36% compared with 40% white, P=.57). Abnormal 1-hour glucose screens were more frequent in the 17alpha-hydroxyprogesterone group (23.6% compared with 11.2%, P<.001), as was the diagnosis of GDM (10.9% compared with 3.6%, P=.003). 17alpha-hydroxyprogesterone caproate remained independently associated with the diagnosis of GDM (odds ratio 3.3, 95% confidence interval 1.3-8.1) in a conditional multiple logistic regression analysis controlling for maternal race, age, BMI, and parity., Conclusion: Women receiving weekly intramuscular 17alpha-hydroxyprogesterone caproate have more frequent abnormal glucose testing and gestational diabetes compared with unexposed controls. These results are consistent with published data regarding the effect of progesterone on insulin resistance., Level of Evidence: II.

Objective: To assess whether there are evident adverse effects of 17 alpha-hydroxyprogesterone caproate after in utero exposure., Methods: This study evaluated surviving children of mothers who participated in a multicenter placebo-controlled trial of weekly intramuscular 17 alpha-hydroxyprogesterone caproate, with a 2:1 allocation to 17 alpha-hydroxyprogesterone caproate and placebo, respectively. The guardian was interviewed about the child's general health. Children underwent a physical examination and developmental screen with the Ages and Stages Questionnaire. Gender-specific roles were assessed with the Preschool Activities Inventory., Results: Of 348 eligible surviving children, 278 (80%) were available for evaluation (194 in the 17 alpha-hydroxyprogesterone caproate group and 84 in the placebo group). The mean age at follow-up was 48 months. No significant differences were seen in health status or physical examination, including genital anomalies, between 17 alpha-hydroxyprogesterone caproate and placebo children. Scores for gender-specific roles (Preschool Activities Inventory) were within the normal range and similar between 17 alpha-hydroxyprogesterone caproate and placebo groups., Conclusion: 17 alpha-hydroxyprogesterone caproate seems to be safe for the fetus when administered in the second and third trimesters.

Background: In singleton gestations, 17 alpha-hydroxyprogesterone caproate (17P) has been shown to reduce the rate of recurrent preterm birth. This study was undertaken to evaluate whether 17P would reduce the rate of preterm birth in twin gestations., Methods: We performed a randomized, double-blind, placebo-controlled trial in 14 centers. Healthy women with twin gestations were assigned to weekly intramuscular injections of 250 mg of 17P or matching placebo, starting at 16 to 20 weeks of gestation and ending at 35 weeks. The primary study outcome was delivery or fetal death before 35 weeks of gestation., Results: Six hundred sixty-one women were randomly assigned to treatment. Baseline demographic data were similar in the two study groups. Six women were lost to follow-up; data from 655 were analyzed (325 in the 17P group and 330 in the placebo group). Delivery or fetal death before 35 weeks occurred in 41.5% of pregnancies in the 17P group and 37.3% of those in the placebo group (relative risk, 1.1; 95% confidence interval [CI], 0.9 to 1.3). The rate of the prespecified composite outcome of serious adverse fetal or neonatal events was 20.2% in the 17P group and 18.0% in the placebo group (relative risk, 1.1; 95% CI, 0.9 to 1.5). Side effects of the injections were frequent in both groups, occurring in 65.9% and 64.4% of subjects, respectively (P=0.69), but were generally mild and limited to the injection site., Conclusions: Treatment with 17 alpha-hydroxyprogesterone caproate did not reduce the rate of preterm birth in women with twin gestations. (ClinicalTrials.gov number, NCT00099164 [ClinicalTrials.gov].)., (Copyright 2007 Massachusetts Medical Society.)

Among the cellular molecules, lipids containing unsaturated fatty acids with more than one double bond are particularly susceptible to action of free radicals. The resulting reaction, known as lipid peroxidation, has deleterious effect on biological membranes, leading sometimes even to disrupting them, or influencing their structure and function. Different toxic products are formed during this process. In this context, the present study was made to explore the suppressive actions of some conventional antioxidant compounds e.g., ascorbic acid, alpha-tocopherol and probucol on lipid peroxidation induced by hydroxyprogesterone caproate (HP), a progestogenic compound. The study has been performed using goat liver homogenate. It was found that HP increased thiobarbituric acid reactive substance i.e., malondialdehyde (MDA) and also other major toxic end product of lipid peroxidantion - 4-hydroxynonenal (4-HNE). HP decreased significantly the levels of reduced glutathione (GSH) and nitric oxide (NO) in the liver homogenates. This suggests that HP caused lipid peroxidation to a significant extent, which may be related to the toxic potential of the drug. It was further found that all of the above mentioned antioxidants could suppress HP-induced lipid peroxidation to the significant extent.

Hydroxyprogesterone, a synthetic progestin, was used for the treatment of pregnant women with threatened abortion and preterm delivery. Previous studies showed some association between hydroxyprogesterone use during early pregnancy and some specific congenital abnormalities. The population-based large Hungarian data set seemed to be appropriate to check this possible association. The Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996 includes 22 843 cases with congenital abnormalities and 38 151 controls without any defect. 318 (1.4%) cases, while 433 (1.1%) controls had mothers with hydroxyprogesterone treatment during pregnancy (adjusted POR with 95% CI: 1.3, 1.1-1.5). However, there was no association between risk for any congenital abnormality group and a higher use of maternal hydroxyprogesterone treatment during the second and third month of gestation. On the other hand hydroxyprogesterone is not effective in the prevention of preterm delivery. In conclusion, there was no detectable risk for congenital abnormalities in the offspring of mothers with hydroxyprogesterone treatment during early pregnancy, however, there is no reasonable indication of this treatment during pregnancy.

The aim of the present study was to evaluate the efficacy (in terms of induction of uterine bleeding) and safety (in terms of absence of endometrial hyperplasia) of 17alpha-hydroxyprogesterone caproate (17alpha-HPC) in a therapeutic regimen for hormonal replacement after menopause. Fifty postmenopausal patients received hormone replacement therapy (HRT) for 24 weeks. The treatment regimen consisted of standard estrogen replacement therapy at commonly prescribed doses for the prevention of climacteric symptoms and 341 mg of 17alpha-HPC every 30 days. Enrolled women were told to expect withdrawal bleeding 7-10 days after the administration of 17alpha-HPC. Forty-eight patients completed the trial. In 91.7% of cases, patients experienced the expected pattern, i.e., strict withdrawal bleeding exclusive of any other form of bleeding. Breakthrough bleeding and/or other forms of abnormal bleeding affected only four women. At the 6th month none of the endometrial samplings motivated by endometrial thickness >10 mm and evidence of heterogeneous echogenicity (two cases) was positive for carcinoma. No biopsies had to be performed at the end of the 12th month of treatment. No serious adverse effect where recorded during the study period. In conclusion, our data show the efficacy and safety of 17alpha-HPC in HRT.

We report on the development of transient parkinsonism after progesterone injection in a pregnant patient with a risk of abortion. Etiological possibilities are discussed, including pregnancy itself, possible toxic effects of the dead fetus, and progesterone injection. Progesterone-induced parkinsonism seems the most likely diagnosis in this case.

Preterm birth affects 12% of all births in the United States. Recent studies support the hypothesis that progesterone supplementation reduces preterm birth in a select group of women (ie, those with a prior spontaneous birth at <37 weeks of gestation). Despite the apparent benefits of progesterone in this high-risk population, the ideal progesterone formulation is unknown. The American College of Obstetricians and Gynecologists Committee on Obstetric Practice believes that further studies are needed to evaluate the use of progesterone in patients with other high-risk obstetric factors, such as multiple gestations, short cervical length, or positive test results for cervicovaginal fetal fibronectin. When progesterone is used, it is important to restrict its use to only women with a documented history of a previous spontaneous birth at less than 37 weeks of gestation because unresolved issues remain, such as optimal route of drug delivery and long-term safety of the drug.

Background: Women who have had a spontaneous preterm delivery are at greatly increased risk for preterm delivery in subsequent pregnancies. The results of several small trials have suggested that 17 alpha-hydroxyprogesterone caproate (17P) may reduce the risk of preterm delivery., Methods: We conducted a double-blind, placebo-controlled trial involving pregnant women with a documented history of spontaneous preterm delivery. Women were enrolled at 19 clinical centers at 16 to 20 weeks of gestation and randomly assigned by a central data center, in a 2:1 ratio, to receive either weekly injections of 250 mg of 17P or weekly injections of an inert oil placebo; injections were continued until delivery or to 36 weeks of gestation. The primary outcome was preterm delivery before 37 weeks of gestation. Analysis was performed according to the intention-to-treat principle., Results: Base-line characteristics of the 310 women in the progesterone group and the 153 women in the placebo group were similar. Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks of gestation (incidence, 36.3 percent in the progesterone group vs. 54.9 percent in the placebo group; relative risk, 0.66 [95 percent confidence interval, 0.54 to 0.81]), delivery at less than 35 weeks of gestation (incidence, 20.6 percent vs. 30.7 percent; relative risk, 0.67 [95 percent confidence interval, 0.48 to 0.93]), and delivery at less than 32 weeks of gestation (11.4 percent vs. 19.6 percent; relative risk, 0.58 [95 percent confidence interval, 0.37 to 0.91]). Infants of women treated with 17P had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen., Conclusions: Weekly injections of 17P resulted in a substantial reduction in the rate of recurrent preterm delivery among women who were at particularly high risk for preterm delivery and reduced the likelihood of several complications in their infants., (Copyright 2003 Massachusetts Medical Society)

Purpose: To describe a case of a retinal arteriolar occlusion associated with progestogen treatment of threatened abortion., Methods: Case report., Results: A 30-year-old woman who had received a 2-week course of high dose intramuscular progestogen for a threatened abortion presented with a paracentral scotoma in her right eye and occlusion of a small arteriole adjacent to the macula. There were no major subsequent variations in haemostasis and pre-existing systemic diseases were excluded., Conclusions: Retinal arteriolar occlusion may be associated with high dose progestogen-only therapy in pregnant women.

History and Clinical Findings: A 29-year-old female was admitted with the diagnosis of multiple deep vein thrombosis of the upper limbs and neck and pneumonia secondary to pulmonary embolism on the right side. Medical history revealed that in vitro fertilization with hormone stimulation had been carried out 5 weeks before. For ten days the patient had noticed a growing, painful swelling on the right side of her neck accompanied by difficulties in swallowing. Since this time she had experienced episodes of shortness of breath without chest pain. Clinical findings showed a soft and slightly painful swelling of the right side of the neck without dyspnoea or cyanosis at rest. Breath sounds were decreased over the right lower lung on auscultation., Investigations: Magnetic resonance imaging (MRI) confirmed complete obstruction of the subclavian and brachiocephalic vein on the right side and clots in the superior vena cava, left subclavian vein, bilateral internal jugular veins and the right axillar vein. Chest x-ray showed pleural effusion on the right side., Treatment and Course: As the seven-week pregnancy was found not to be viable anymore, fibinolysis with streptokinase was started under protection of a temporary cava filter. During the following hours the patient developed serious bleeding as a complication of this therapy and fibrinolysis had to be discontinued after 16 hours. In subsequent examinations the obstruction of the left internal jugular vein was unchanged but collaterals around the obstruction were noticed. The other veins affected were open, some with reduced flow. Several risk factors were found in the history of the patient such as smoking, immobilization, a positive family history, protein S deficiency and APC resistance. After 3 weeks of hospital therapy the patient was discharged under oral anticoagulation with coumarin., Conclusion: In vitro fertilization with hormonal stimulation may cause serious complications in patients with unknown coagulation disorders or with an ovarian hyperstimulation syndrome. Risk factors for thromboembolism need to be ruled out carefully before starting the procedure.

A phase III clinical study was carried out among 5680 fertile Chinese women to evaluate efficacy and side effects of three monthly injectable contraceptives: Mesigyna, Cyclofem and Chinese Injectable No. 1. When used in a once-a-month treatment schedule (part 1 of study), the effectiveness of Chinese Injectable No. 1 was unacceptably low; 36 pregnancies occurred during the first 1743 women-months of use, 16 before the second injection. The study was restarted with a revised injection schedule for Injectable No. 1: two injections separated by 9 +/- 1 days during the first month and subsequent injections given 10-12 days after the onset of bleeding, or if no bleeding occurred, 28 days after previous injection. In part 2 of the study, 988, 990 and 992 subjects were provided Mesigyna, Cyclofem and Injectable No. 1, respectively. Life-table pregnancy rates at one year were 0.41%, 0% and 0.77% (p < 0.05), respectively; the overall discontinuation rates at one year were 13.9%, 19.1% and 20.4% (p < 0.001). Discontinuation rates for bleeding problems were significantly different between the groups: discontinuation rates for amenorrhea were 0.58%, 3.71% and 0.68% (p < 0.001) for Mesigyna, Cyclofem and Injectable No. 1; for other bleeding problems, the rates were 4.88%, 8.38% and 12.64% (p < 0.001). There were no significant differences between the groups regarding discontinuation for other medical or non-medical reasons. Mean weight changes after one year of use were small: 0.73, 0.86 and 0.17 kg for the three groups, respectively. Both Mesigyna and Cyclofem were very effective for contraception, but Mesigyna appeared to be tolerated slightly better with regard to cycle control; the modified dose regimen for Injectable No. 1 also gave a low pregnancy rate but was associated with higher rates of discontinuation.

Between 1988 and 1992, a randomized phase III clinical trial was conducted in China to compare three monthly injectable contraceptives: Mesigyna, Cyclofem and Injectable No. 1. This paper presents a detailed analysis of the menstrual diaries provided by 5098 (89%) of the subjects. In total, 902, 903 and 913 diaries were analyzed to compare bleeding patterns induced by Mesigyna, Cyclofem and Injectable No. 1. The first withdrawal bleeding usually occurs 14-20 days after the first injection for all three of these preparations. Thereafter, 50% of Mesigyna users had precisely 3 bleeding/spotting episodes every 90 days, 50% of Cyclofem users had 2-3 and 50% of Injectable No. 1 users had 3-4 episodes every 90 days. Relative to users of Mesigyna or Cyclofem, Injectable No. 1 users had 2-3 more bleeding/spotting days, and a shorter length of bleeding/spotting-free intervals in each period. 63.7%, 41.4% and 60.6% of subjects using Mesigyna, Cyclofem and Injectable No. 1, respectively, had bleeding patterns similar to their untreated patterns in the first 90-day period. The percentages increased to 82.2% 67.8% and 75.0% in the fourth 90-day period. A total of 1815 diaries for Mesigyna and 1802 for Cyclofem were analyzed for more in depth comparison of these two methods. The number of bleeding/spotting days over four periods showed little difference between the two group, but there were more spotting days and there was greater individual variability among Cyclofem users.(ABSTRACT TRUNCATED AT 250 WORDS)

This prospective pilot study has been carried out to assess the effect of high parenteral doses of estrogens and progestogens on lumbar spine bone density in osteopenic women. Thirteen osteopenic women received 40 mg estradiol valerate and 250 mg hydroxyprogesterone caproate by intramuscular injections once a week for 6 months (so called "pseudopregnancy"). One g oral calcium was added. Six out of the 13 patients (49.5 +/- 4.8 y were peri- and postmenopausal = group A. Seven patients (21.5 +/- 2.2 y) suffered from primary and secondary amenorrhea, in 4 out of them due to gonadal dysgenesis = group B. Estradiol was measured by commercial radioimmunoassay. Bone density was determined by dual-energy X-ray absorptiometry (DEXA) of the upper 4 lumbar vertebrae. Lumbar spine bone density as well as estradiol serum levels were measured before and 3 and 6 months after therapy, respectively. Estradiol increased from 34.8 +/- 7.5 pg/ml to 3226 +/- 393 pg/ml after 3 months and to 2552 +/- 254 pg/ml after 6 months, respectively, in group A. Bone density increased by 15.3 +/- 3.6% within the first 3 months to a total of 18.8 +/- 3.9% after 6 months, respectively. Two patients we have controlled for two years, maintained this increase. In group B estradiol increased from 27.8 +/- 6.5 pg/ml to 3028 +/- 728 after 3 and to 2491 +/- 684 pg/ml after 6 months. Bone density in this group increased by 11.8 +/- 1.9% within 3 and to a total of 18.2 +/- 2.8% after 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoimmune progesterone dermatitis is a rare condition, characterized by recurrent premenstrual exacerbations of a dermatosis, in which sensitivity to progesterone can be demonstrated. The sensitizing mechanism is unknown. The aim of this study was to test the hypothesis that cross-sensitivity between steroid groups could induce allergy to endogenous progesterone in these patients. 5 patients with autoimmune progesterone dermatitis and 1 with oestrogen-sensitive dermatitis have been patch tested with a corticosteroid series, conjugated oestrogen 1% in petrolatum (pet.), and 17-alpha-OH-progesterone 2% pet. There were no immediate or delayed reactions at 2 and 4 days to any steroid group. We have therefore been unable to demonstrate steroid cross-sensitivity, or a use for 17-alpha-OH-progesterone in the investigation of oestrogen - and progesterone-sensitive dermatoses.

The results of metabolic studies on once-a-month combined injectable contraceptives are summarized, focusing on four preparations: dihydroxyprogesterone acetophenide 150 mg/estradiol enanthate 10 mg; depot-medroxyprogesterone acetate 25 mg/estradiol cypionate 5 mg; norethisterone enanthate 50 mg/estradiol valerate 5 mg; and 17 beta-hydroxyprogesterone caproate 250 mg/estradiol valerate 5 mg. Their effects on carbohydrate metabolism, lipid metabolism, hemostasis, serum prolactin, cortisol, binding globulins and liver functions are reviewed. Areas requiring further research are identified.

The pharmacology and clinical assessment of existing first generation once-a-month combined injectable contraceptives, mainly Deladroxate and Chinese Injectable No. 1, are reviewed. Although these two types of monthly injectables have been used in some million women in China and Latin America, Deladroxate needs indepth re-evaluation of its long-term toxicity and possible accumulation. For injectable No. 1, its disadvantage of being administered on an erratic schedule will cause significant confusion in family planning practice. When used in a strict once-a-month schedule, it is not sufficiently effective for contraception. In order to attain predictable menstrual cycle control as well as high efficacy with a 30-day injection schedule, two improved once-a-month injectable formulations, Cyclofem and Mesigyna, were developed. Pharmacokinetic/pharmacodynamic study on estrogenic components suggested that estradiol valerate and cypionate were suitable estrogen esters to give elevated plasma estrogen levels for 7 to 11 days. After a single injection of Cyclofem and Mesigyna, both formulations showed equal contraceptive effect with inhibition of follicle maturation for some 30 days and ovulation, corpus luteum formation for some 60 days. Multicentre studies on the optimization of dosages of progestogens and estrogens in once-a-month injectables confirmed that the full doses of Cyclofem (DMPA 25 mg/estradiol cypionate 5 mg) and Mesigyna (NET-EN 50 mg/estradiol valerate 5 mg) are suitable for large scale clinical trials. Pharmacodynamics and progestogen/estrogen ratio study indicated the importance of not only the absolute amounts of the progestogen and estrogen but also of their ratio. Reduction of estrogen dose resulted in breakthrough ovulation with both Cyclofem and Mesigyna. Also, it is important to note that the second part of the injection cycle is dominated by the progestogen component of both monthly formulations. A longitudinal study indicated that there is no accumulation of norethisterone after 12 months of treatment with NET-EN 50 mg and estradiol valerate 5 mg.

Reports of the phase III clinical trials on four combined progestogen-estrogen once-a-month injectable contraceptives, Deladroxate, Cyclofem, Mesigyna and Chinese Injectable No. 1, are reviewed focussing on efficacy and reasons for discontinuation. Deladroxate, currently used in many Latin American countries has proved to be highly effective and well accepted. However, this combination was withdrawn by the original manufacturer because the progestogen component of this drug induced a high number of breast cancers in dogs and very curious pituitary hyperplasia in rats. Cyclofem and Mesigyna were found to be highly effective and highly acceptable drugs. Side-effects were minimal and were of minor importance. The Chinese Injectable No. 1 had unacceptably high failure rates with a monthly injection schedule. After doubling the dose in the first month of use, the efficacy was satisfactory. It was found that all monthly injectable contraceptives provided better cycle control than the every 3 months depot-medroxyprogesterone acetate, although abnormal bleeding was still the main drug-related complaint and reason for discontinuation. Missed appointment is another reason for discontinuation which might reflect the problem of frequent injection schedule, thus indicating the need for proper selection of the users and good counselling.