Serum Progesterone May Not Define Pharmacokinetics of Vaginal Progesterone for Preterm Birth Prevention

Introduction

Dosing of vaginal progesterone for preterm birth prevention has been empirical and based on pharmacokinetic studies in nonpregnant subjects. However, due to the elevated endogenous progesterone levels in pregnancy, changes in vaginal and uterine blood flow, altered hepatic metabolism and renal clearance, studies outside of pregnancy may not be applicable.

Aim

This study assessed whether serum progesterone levels could be used to define the basic pharmacokinetic parameters of vaginal progesterone in pregnancy for preterm birth prevention.

Method

Study Design

• Prospective study

Inclusion Criteria

• Pregnant, low-risk singletons >18 years old
• Gestational age 18 0/7 to 23 6/7 weeks
• Body mass index 20-40
• No prior preterm birth

Exclusion Criteria

• Contraindication to progesterone therapy
• Adverse reaction to progesterone
• Medical comorbidity requiring daily medication, including hypertension, diabetes, opioid use disorder, and thyroid disease
• Major fetal anomaly or known chromosomal anomaly
• Symptoms of vaginal bleeding
• Preterm labor or rupture of membranes
• Any prior progesterone use in the pregnancy
• Active vaginitis
• Illicit substance use
• Known or suspected malignancy of breast or genital organs
• Abnormal Pap smear including positive result for human papillomavirus
• Cervical length < 25 mm

Treatment Strategy

• Cohort received a single dose of 200 mg micronized vaginal progesterone
• Serum progesterone levels were measured every 2 hours from 0 to 12 hours and then 24 hours post dose.

End Point

• Concentration/time profile of serum progesterone.

Results

• Median maternal age was 27 years, median body mass index was 26.5 kg/m², and median gestational age was 22.9 weeks
• Median (range) baseline serum progesterone was 47 (40-52) ng/mL, median peak concentration was 54 (48-68) ng/mL, and median time to peak was 12 (4-15) hours
• A rise in serum progesterone levels over baseline was observed with a median change in peak concentration of 11 ng/mL (interquartile range of 2-22 ng/mL)
• Median percent change from baseline was an increase by 24%
• However, there was no clear elimination phase and the median area under the curve was 112 ng*h/mL  

Conclusion

• Administration of vaginal progesterone in pregnant women only minimally impacts systemic exposure, unlike in nonpregnant women
• Serum progesterone is not likely to be a good biomarker for determining pharmacokinetics or dosing of vaginal progesterone in pregnancy for preterm birth prevention.

Am J Obstet Gynecol. 2019 Sep;221(3):263.e1-263.e7. Doi:10.1016/j.ajog.2019.06.019.