Relationship between plasma concentration of 17-hydroxyprogesterone caproate and gestational age at preterm delivery.

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.

Vaginal Progesterone Is Associated with Intrahepatic Cholestasis of Pregnancy.

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..

The association of different progesterone preparations with preterm birth prevention.

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.

17-alpha Hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort study.

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.

Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety.

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.

Association of 17α-Hydroxyprogesterone Caproate and Risk of Infection.

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.

Maternal characteristics influencing the development of gestational diabetes in obese women receiving 17-alpha-hydroxyprogesterone caproate.

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.

The rebirth of progesterone in the prevention of preterm labor.

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.

17 α-hydroxyprogesterone caproate (Makena®): a guide to its use in the prevention of preterm birth.

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.

Relationship between 17-hydroxyprogesterone caproate concentrations and gestational age at delivery in twin gestation.

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.

The safety of progesterone and 17-hydroxyprogesterone caproate administration for the prevention of preterm birth: an evidence-based assessment.

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.

Altered arterial stiffness in male-to-female transsexuals undergoing hormonal treatment.

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.

Single dose 17 alpha-hydroxyprogesterone caproate in preterm labor: a randomized trial.

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.

17α Hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth.

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.