Pregnancy, Premature Birth, Premature Labor
Conditions
Keywords
Pharmacokinetics, Pharmacodynamics, Preterm labor, Preterm birth, Estradiol, Indomethacin, Pregnancy, Short Cervix, CYP2C9 Genotype
Brief summary
This study will follow pregnant women who are taking indomethacin as Standard of Care (SOC) for the indications of preterm labor (PTL), short cervix, or other indications, to evaluate the pharmacokinetics (PK), what the body does to the drug, and pharmacodynamics (PD), effectiveness of the drug in treating the specific intended disease process of this medication. This will help us develop more information for medication dosing specific to pregnant women experiencing preterm labor. Indomethacin is often prescribed to pregnant women presenting with preterm labor or shortened cervix, which places them at risk for preterm labor and delivery. Indomethacin has been used since the 1970s to prolong pregnancy by decreasing uterine contractions. However, despite the widespread use of indomethacin in pregnancy, there is limited information available to help physicians determine how much indomethacin to prescribe and how often to prescribe it.
Detailed description
Opportunistic study of indomethacin prescribed to patients per standard of care. Determine the pharmacokinetics, pharmacodynamics and pharmacogenomics of Indomethacin in pregnant patients with the hypothesis that that estradiol levels during pregnancy (12-32 weeks of gestation) and CYP2C9 polymorphisms affect the PK of indomethacin, and subsequently, the response to indomethacin therapy in patients at risk of Preterm birth (PTB). This hypothesis will be tested with the following specific aims: (1) Determine the PK of indomethacin in pregnant women at risk of PTB and its PD effects on reducing the rate of PTB before 34 weeks of gestation, as well as any associations between the PK and secondary maternal/neonatal clinical outcomes; (2) Determine the effects of maternal levels of estradiol in mid-pregnancy and CYP2C9 polymorphisms on indomethacin biotransformation to O-desmethylindomethacin in pregnant patients; (3) Construct a population PK/PD model of indomethacin in patients at risk of PTB (12-32 weeks of gestation) in order to optimize the dose and the dosing frequency for indomethacin prescribed to each individual based on covariates such as race/ethnicity, CYP2C9 genotype, gestational age, estradiol levels, smoking status, and body mass index (BMI). The investigators will enroll 300 subjects with spontaneous preterm labor (sPTL) or shortened cervix in a prospective opportunistic PK study designed to correlate the PK of indomethacin, patient genotype, and clinical outcomes. The investigators will merge dosing, sampling, demographic, and clinical information with the drug concentration data and use population PK methodologies to analyze the data using nonlinear mixed effect modeling. Quantification of the differences within and between individuals allows for identification of covariates (e.g., CYP2C9 genotype, estradiol levels, BMI, etc.) that can explain variability and affect drug exposure. These covariates, if significant, can then be used in the future to optimize dosing in individual patients at risk for PTB. Achieving this goal of individualized indomethacin therapy could have a significant impact on clinical practice and improve maternal and neonatal outcomes.
Interventions
OTHERSerial blood collection
Serial blood collection from IV for pharmacokinetic and pharmacodynamic analysis. No drug, device, or biologic intervention. Opportunistic.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The University of Texas Medical Branch, Galveston
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
To be enrolled in the study, patients must meet all of the following criteria: 1. Age at least 18 years 2. Singleton gestation 3. 12 0/7 to 32 0/7 weeks gestation (see Gestational Age Determination section 3.2.1.1) 4. Patient receiving indomethacin for any of the following diagnoses: 1. Preterm labor: regular uterine contractions with documented cervical change or dilatation ≥ 2 cm and 80% effacement 2. Cervical shortening (\< 2.5 cm documented on transvaginal ultrasound) with or without funneling membranes 3. Planned cervical cerclage or emergent cerclage 4. Other condition whereby Indomethacin is indicated 5. Maternal and fetal condition allows anticipated delay of delivery for more than 24 hours -
Exclusion criteria
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gestational age at delivery | Enrollment until delivery of the participant | Gestational age at delivery calculated from the first day of last menstrual period unless unsure and then it will be calculated from ultrasound measurements |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maternal outcomes | Enrollment until delivery and maternal discharge | Diagnosed maternal outcomes including oligohydramnios, chorioamnionitis, preterm premature rupture of membranes, venous thromboembolism, pulmonary edema, postpartum hemorrhage, and maternal death |
| Neonatal outcomes | The earlier of neonatal discharge or up to 120 days postnatal | Diagnosed neonatal outcomes including birth weight, APGAR scores, neonatal sepsis, respiratory distress syndrome, patent ductus arteriosis, necrotizing enterocolitis, broncopulmonary dysplasia, paraventricular leukomalacia, intraventricular hemorrhage, fetal, or neonatal death |
| Neonatal admission to Neonatal intensive care unit (NICU) | The earlier of neonatal discharge or up to 120 days postnatal | Documentation of NICU admission \[yes/no\] |
| Length of stay in the Neonatal intensive care unit (NICU) | The earlier of neonatal discharge or up to 120 days postnatal | If admitted to the NICU, number of days in the NICU |
Countries
United States
Outcome results
None listed