Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | 100980 |
| Journal | American Journal of Obstetrics and Gynecology MFM |
| Volume | 5 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2023 |
Funding
The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (gran numbers: U54HD047905 , U54HD047891 , and U54HD085601 ). AMAG Pharmaceuticals provided the 17-OHPC for this study. AMAG Pharmaceuticals had no role in the study design, data analysis, collection or interpretation, journal selection, or writing of any aspect of the manuscript. S.N.C. and R.V. received funding from AMAG Pharmaceuticals to compare pharmacokinetics of intramuscular and subcutaneous administrations of 17-hydroxyprogesterone caproate (17-OHPC). J.W.K. reports receiving payment from CVS Health. The other authors report no conflict of interest. The authors thank Dawn Fischer, RN, University of Pittsburgh, for coordinating all clinical aspects of this trial, including recruitment, fulfilling regulatory requirements, and training coordinators from each site; Donna DeAngelis, University of Pittsburgh, for assisting in recruitment and data collection from each site; Holly West, DHEd, MPAS, PA-C, University of Texas Medical Branch, for coordinating all interactions with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and each member site of the Obstetric-Fetal Pharmacology Research Centers; Katherine Wisner, MD, MS, Northwestern University Feinberg School of Medicine, for her assistance in protocol development and site preparation for recruitment; Leo Brancazio, MD, medical safety officer at West Virginia University, who was responsible for the evaluation of all adverse events; and the Data Monitoring Committee for their suggestions relating to study recruitment and patient safety. All individuals received some support from the NICHD (grant numbers: U54HD047905, U54HD047891, and U54HD085601).
Keywords
- 17-hydroxyprogesterone caproate
- Delalutin
- Food and Drug Administration
- Makena
- cerclage
- gestational length
- pharmacodynamics
- pharmacokinetics
- pregnancy prolongation
- short cervix
- spontaneous preterm birth
ASJC Scopus subject areas
- Obstetrics and Gynecology