Obstetric Labor, Premature
Conditions
Brief summary
Indomethacin and Nifedipine are commonly used medications for treatment of pre term labor. This study will compare the efficacy and adverse outcomes of oral nifedipine versus oral indomethacin for preterm labor tocolysis in an effort to identify which drug is most effective. Patients diagnosed with preterm labor who grant consent will be randomized by the pharmacy to receive oral nifedipine or oral indomethacin. Both the patient and primary medical provider will be blinded to the identity of the study drug. An abdominal ultrasound will be performed in the labor and delivery unit prior to the administration of the tocolytic in order to assess fetal position and fluid level, and to document fetal cardiac activity and movement, and will be repeated at 48 hours post-randomization. Following randomization, the patient will be given either 50 mg oral indomethacin with two pills of placebo, or 3 pills each containing 10 mg oral nifedipine for a total of 30 mg. The patients will then receive either 25 mg of oral indomethacin every 6 hours for 48 hours, or 20 mg of oral nifedipine every 6 hours for 48 hours. Tocolysis beyond 48 hours will not be used.
Detailed description
Patients presenting between 24-34 weeks gestation diagnosed with preterm labor who grant consent will be randomized by the pharmacy to receive oral nifedipine or oral indomethacin. Both the patient and primary medical provider will be blinded to the identity of the study drug. An abdominal ultrasound will be performed in the labor and delivery unit prior to the administration of the tocolytic in order to assess fetal position and fluid level, and to document fetal cardiac activity and movement, and will be repeated at 48 hours post-randomization. Following randomization, the patient will be given either 50 mg oral indomethacin with two pills of placebo, or 3 pills each containing 10 mg oral nifedipine for a total of 30 mg. The patients will then receive either 25 mg of oral indomethacin every 6 hours for 48 hours, or 20 mg of oral nifedipine every 6 hours for 48 hours. Tocolysis beyond 48 hours will not be used. Antibiotics and steroids for fetal lung maturity will be administered as per standard of care for preterm labor. Maternal side effects and delivery outcomes will be assessed from questionnaires administered by the study team following treatment, and/or from review of the patient's medical records.
Interventions
DRUGIndomethacin
One 50 mg tablet of Indomethacin plus 2 pills of placebo followed by one 25 mg tablet of oral indomethacin every 6 hrs for 48 hrs.
DRUGNifedipine
Three 10 mg tablets of Nifedipine followed by one 20 mg tablet every 6 hrs for 48 hrs.
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Singleton and twin gestations * Intact amniotic membranes * No contra-indications to tocolysis * 24-34 weeks gestation by last menstrual period and/or ultrasound * Documented cervical change, and regular painful uterine contractions at least every 5 minutes, or at least 2 cm cervical dilation and 80% effacement
Exclusion criteria
* Ruptured amniotic membranes * Signs/symptoms of chorioamnionitis (maternal temperature greater than 100.4 F/38.0 C, fetal tachycardia, uterine tenderness) * Non-reassuring fetal heart rate tracings * Contra-indications to indomethacin or nifedipine * Contra-indications to tocolysis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Count of Patients With Recurrent Preterm Labor Within Two Weeks of Randomization | Two weeks after enrolled and randomized, up to 37 weeks of pregnancy | Preterm labor was defined as documented cervical change and regular uterine contractions at least every 5 minutes, or at least 2 cm cervical dilation and 80% cervical effacement. Preterm labor is defined as uterine contractions occurring up to 37 weeks of pregnancy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gestational Age at Delivery | Up to 42 weeks of pregnancy | — |
| Days From First Medication Initiation to Delivery as a Measure of Delay in Delivery | Up to 42 weeks of pregnancy | — |
| Neonatal Birthweight | Until discharge of mother and neonate from delivery hospital, up to 30 days after delivery | Birthweight is presented in grams |
| Count of Participants With Side-effect Due to the Medication | Up to 42 weeks of pregnancy | Monitored side-effects for this outcome included abdominal pain, blood pressure change, GI-symptoms and skin rash. |
| Time to Uterine Quiescence | Up to 42 weeks of pregnancy | Uterine quiescence was defined as six or fewer uterine contractions per hour. Outcome was described as days. |
| Count of Participants With Neonatal Morbidity | Up to 42 weeks of pregnancy | Neonatal morbidity included admission to neonatal intensive care unit, respiratory distress or sepsis. |
Countries
United States
Participant flow
Recruitment details
A total of 29 patients were initially consented and enrolled. Patients were enrolled through December 2012 but protocol remained open until 2018. Due to patient privacy regulations, the data were accessible for only 10 patients.
Participants by arm
| Arm | Count |
|---|---|
| Indomethacin 50 mg. oral Indomethacin initially, followed by 25 mg every 6 hrs for 48 hrs.
Indomethacin: One 50 mg tablet of Indomethacin plus 2 pills of placebo followed by one 25 mg tablet of oral indomethacin every 6 hrs for 48 hrs. | 5 |
| Nifedipine 30 mg Nifedipine initially followed by 10 mg every 6 hrs for 48 hrs.
Nifedipine: Three 10 mg tablets of Nifedipine followed by one 20 mg tablet every 6 hrs for 48 hrs. | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Nifedipine | Indomethacin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Continuous | 30 years | 26.0 years | 26.5 years |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 5 | 3 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Count of Patients With Recurrent Preterm Labor Within Two Weeks of Randomization
Preterm labor was defined as documented cervical change and regular uterine contractions at least every 5 minutes, or at least 2 cm cervical dilation and 80% cervical effacement. Preterm labor is defined as uterine contractions occurring up to 37 weeks of pregnancy.
Time frame: Two weeks after enrolled and randomized, up to 37 weeks of pregnancy
Population: Participants with accessible data are included in the analysis. Not all data were accessible due to patient data privacy regulations.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Indomethacin | Count of Patients With Recurrent Preterm Labor Within Two Weeks of Randomization | 2 Participants |
| Nifedipine | Count of Patients With Recurrent Preterm Labor Within Two Weeks of Randomization | 1 Participants |
p-value: 0.004Fisher Exact
Secondary
Count of Participants With Neonatal Morbidity
Neonatal morbidity included admission to neonatal intensive care unit, respiratory distress or sepsis.
Time frame: Up to 42 weeks of pregnancy
Population: Participants with accessible data are included in the analysis. Not all data were accessible due to patient data privacy regulations.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Indomethacin | Count of Participants With Neonatal Morbidity | 2 Participants |
| Nifedipine | Count of Participants With Neonatal Morbidity | 3 Participants |
Secondary
Count of Participants With Side-effect Due to the Medication
Monitored side-effects for this outcome included abdominal pain, blood pressure change, GI-symptoms and skin rash.
Time frame: Up to 42 weeks of pregnancy
Population: Participants with accessible data are included in the analysis. Not all data were accessible due to patient data privacy regulations.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Indomethacin | Count of Participants With Side-effect Due to the Medication | 2 Participants |
| Nifedipine | Count of Participants With Side-effect Due to the Medication | 3 Participants |
Secondary
Days From First Medication Initiation to Delivery as a Measure of Delay in Delivery
Time frame: Up to 42 weeks of pregnancy
Population: Participants with accessible data are included in the analysis. Not all data were accessible due to patient data privacy regulations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Indomethacin | Days From First Medication Initiation to Delivery as a Measure of Delay in Delivery | 34.0 days |
| Nifedipine | Days From First Medication Initiation to Delivery as a Measure of Delay in Delivery | 36.0 days |
Secondary
Gestational Age at Delivery
Time frame: Up to 42 weeks of pregnancy
Population: Participants with accessible data are included in the analysis. Not all data were accessible due to patient data privacy regulations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Indomethacin | Gestational Age at Delivery | 37.0 weeks |
| Nifedipine | Gestational Age at Delivery | 34.0 weeks |
Secondary
Neonatal Birthweight
Birthweight is presented in grams
Time frame: Until discharge of mother and neonate from delivery hospital, up to 30 days after delivery
Population: Participants with accessible data are included in the analysis. Not all data were accessible due to patient data privacy regulations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Indomethacin | Neonatal Birthweight | 2830 grams |
| Nifedipine | Neonatal Birthweight | 2240 grams |
Secondary
Time to Uterine Quiescence
Uterine quiescence was defined as six or fewer uterine contractions per hour. Outcome was described as days.
Time frame: Up to 42 weeks of pregnancy
Population: Participants with accessible data are included in the analysis. Not all data were accessible due to patient data privacy regulations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Indomethacin | Time to Uterine Quiescence | 2.0 days |
| Nifedipine | Time to Uterine Quiescence | 2.0 days |