Preterm Delivery
Conditions
Keywords
Preterm Labor, Preterm delivery
Brief summary
The hypothesis is that administration of two courses of antenatal corticosteroids, compared to one course, will show a 40% reduction in the incidence of composite neonatal morbidity in patients delivering prior to 34 weeks' gestation.
Detailed description
This is a randomized double-blinded placebo-controlled trial. The objective of this study is to evaluate the impact of one versus two courses of antenatal steroids on the incidence of major neonatal morbidity including respiratory distress syndrome in patients delivering prior to 34 weeks' gestation in a randomized prospective fashion. Preterm delivery occurs in approximately 10% of all deliveries in the United States. Preterm birth is the cause of 75% of neonatal mortality not mentioning the significantly increased morbidity from respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and sepsis. Numerous studies have evaluated the safety and efficacy of antenatal corticosteroid (ACS) administration in threatened preterm labor. National Institutes of Health (NIH) first consensus conference in 1994 evaluated the research in this field. Conclusions included the clear evidence that antenatal corticosteroids decrease the incidence of RDS in infants born at 29-34 weeks gestation, with a decrease in RDS severity for infants born at 24-28 weeks gestation and a decrease in the incidence of intraventricular hemorrhage in infants born at 24-28 weeks gestation without harm to mother or fetus. Their recommendation was to give a single course of corticosteroids to all pregnant women between 24 and 34 weeks gestation who are at risk of preterm delivery within 7 days. Since the studies on the duration of the effects of antenatal corticosteroids in the fetus are not conclusive, many obstetricians repeat corticosteroids weekly or bi-weekly to patients continuing to be at risk for preterm delivery. Lacking scientific evidence, many investigators have performed retrospective analyses regarding the effects of single-course versus multiple-course antenatal corticosteroids. The NIH consensus panel reconvened in 2000 and concluded that studies regarding repeated courses of corticosteroids are suggestive of possible benefits, especially in reduction of RDS, however, design flaws limit their validity. The more recent publication from Caughey and Parer examined the literature for evidence regarding a dose response of the benefits and detriments of antenatal corticosteroids. Based on their complex mathematical analysis they recommend all fetus' between 24 and 34 weeks' gestation at risk for preterm delivery should be given a first course of ANC. If the risk of preterm delivery persists the next course should be given 2 weeks later, for a maximum of two courses. Consistent with all previous articles, the call for a well designed randomized, controlled trial is made.
Interventions
DRUGBetamethasone or Dexamethasone (2nd course of ACS)
Course of Betamethasone or Dexamethasone
DRUGPlacebo
Course of Placebo (NS)
Sponsors
Obstetrix Medical Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* 25 to 32 6/7 weeks gestation * Singleton or twin gestation * Received 1st course of betamethasone prior to 30 weeks' gestation * Began 1st course of betamethasone at least 14 days prior to randomization * Risk of delivery in next 7 days due to either maternal or fetal complication (e.g. preterm labor, severe preeclampsia, IUGR, etc.) * Intact membranes
Exclusion criteria
* Known major fetal anomalies (eg: anencephaly, renal agenesis etc…) * High order multiple gestation (triplets or higher) * Cervical dilation \> 5 cm * Clinical chorioamnionitis prior to initiation of second course (two or more of the following; antepartum temperature \> 38ºC (100.4ºF), uterine tenderness, foul smelling vaginal discharge or amniotic fluid, maternal tachycardia (\>100beats/min), fetal tachycardia (\>160 beats/min), or white blood cell count \>20x109/L.define) * Ruptured membranes prior to initiation of second course of betamethasone * Already receiving corticosteroids for other conditions (e.g. Lupus, asthma) * Maternal condition contraindicating the use of steroids (e.g. HIV, active Tuberculosis) * Participation in conflicting study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Neonatal Morbidity < 34 Weeks Gestation at Time of Birth. | From birth to 28 days of life | This outcome measured the total number of neonates with Composite Neonatal morbidity who delivered at \< 34 weeks gestation. Composite Morbidity consisted of respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular hemorrhage, periventricular leukomalacia, proven sepsis, necrotizing enterocolitis, or perinatal death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gestational Age at (@) Delivery | gestational age at delivery in weeks of gestation | Reported the average/mean Neonatal gestational age (GA) (reported in weeks of pregnancy) at the time of birth for both groups (ACS vs. Placebo). |
| Neonatal Birth Weight Reported in Grams | At time of Birth | Measured mean Birth weights of Neonates in each arm as reported in grams on the birth record. |
| Neonatal Head Circumference Taken at Time of Birth. | Birth | Reported as the average of all neonatal head circumferences (HC) taken at time of birth in each group. |
| Interuterine Growth Restriction (IUGR) or Small for Gestational Age(SGA)in Babies Delivering at < 34 Weeks Gestation. | Measured at birth. | Noted as the total number of Neonates delivering at \< 34 weeks gestation for which their weights fell within the 10th percentile at time of birth. |
| Number of Neonates Who Required Surfactant Therapy After Birth. | Birth to 28 days of life | The Number of neonates who required surfactant therapy within the first 28 days after birth. |
| Number of Neonates With Pneumothorax | birth to 28 days of life | Total number of neonates with pneumothorax diagnosed postpartum. |
| Maternal Infectious Morbidity. | Up to 28 days after giving birth | Total number of Mothers having Maternal infectious morbidity (e.g. endometritis & maternal sepsis) noted from birth through 28 days after birth |
| Number of Babies Who Required Ventilatory Support Within the First 28 Days of Life. | birth to 28 days of life | The number of babies who required ventilatory support within the first 28 days of life. Equal to or great than 12 hours was considered one day. |
Countries
United States
Participant flow
Recruitment details
Pregnant women were recruited at 18 private (15) and university (3) medical centers from May 2003 through February 2008.
Pre-assignment details
no washout, run-in or transition events occurred between enrollment and group assignment.
Participants by arm
| Arm | Count |
|---|---|
| Rescue Course of Betamethasone or Dexamethasone Receive 2nd Rescue Course = Study drug (betamethasone or dexamethasone. If Dexamethasone, administered 6 mg IM q 12 hours x 4 doses total. If Betamethasone was used, 2 doses of 12 mg of betamethasone was given intramuscularly (IM) 24 hours apart. | 223 |
| Placebo (Normal Saline) Placebo consisted of quantity sufficient of Normal Saline with preservatives, Benzylalcohol and Benzylbenzoate.
The research subject received 2 doses of pharmacy prepared placebo (2ml normal saline)to conceal administration of dexamethasone or if to conceal betamethasone, 2 doses of Placebo (2ml normal saline) given IM 24 hours apart. | 214 |
| Total | 437 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Placebo (Normal Saline) | Rescue Course of Betamethasone or Dexamethasone | 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 | 214 Participants | 223 Participants | 437 Participants |
| Age, Continuous | 29 years STANDARD_DEVIATION 6 | 29 years STANDARD_DEVIATION 6 | 29 years STANDARD_DEVIATION 6 |
| Region of Enrollment United States | 214 participants | 223 participants | 437 participants |
| Sex: Female, Male Female | 214 Participants | 223 Participants | 437 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 | 0 / 512 | 0 / 502 |
| serious Total, serious adverse events | 40 / 512 | 41 / 502 |
Outcome results
Primary
Composite Neonatal Morbidity < 34 Weeks Gestation at Time of Birth.
This outcome measured the total number of neonates with Composite Neonatal morbidity who delivered at \< 34 weeks gestation. Composite Morbidity consisted of respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular hemorrhage, periventricular leukomalacia, proven sepsis, necrotizing enterocolitis, or perinatal death
Time frame: From birth to 28 days of life
Population: This was an intent to treat protocol. In patients delivering before 34 weeks we estimated that the sample size of at least 217 subjects in each arm would be needed to have 80% power to detect a 40% reduction in neonatal morbidity (to 16.8%).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rescue Course of Betamethasone or Dexamethasone | Composite Neonatal Morbidity < 34 Weeks Gestation at Time of Birth. | 71 participants |
| Placebo (Normal Saline) | Composite Neonatal Morbidity < 34 Weeks Gestation at Time of Birth. | 105 participants |
Comparison: Our Hypothesis was that administration of a rescue ACS would show a 40% reduction in incidence of composite neonatal morbity in patients delivering \< 34 weeks. Sample size estimates based on composite morbidity of 28%. Each arm required 217 subjects to have 80% power to detect a 40% reduction to 16.8%(2-tailed,alpha =0.05)using comparison for proportions/groups(Fisher exact test) OR,95% CI \& P values were determined using a repeated measure model where each twin is considered a repeat measure.p-value: 0.00295% CI: [0.27, 0.75]Fisher Exact
Secondary
Gestational Age at (@) Delivery
Reported the average/mean Neonatal gestational age (GA) (reported in weeks of pregnancy) at the time of birth for both groups (ACS vs. Placebo).
Time frame: gestational age at delivery in weeks of gestation
Population: Modified intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rescue Course of Betamethasone or Dexamethasone | Gestational Age at (@) Delivery | 33.1 Weeks | Standard Deviation 3.1 |
| Placebo (Normal Saline) | Gestational Age at (@) Delivery | 33.0 Weeks | Standard Deviation 3.1 |
Secondary
Interuterine Growth Restriction (IUGR) or Small for Gestational Age(SGA)in Babies Delivering at < 34 Weeks Gestation.
Noted as the total number of Neonates delivering at \< 34 weeks gestation for which their weights fell within the 10th percentile at time of birth.
Time frame: Measured at birth.
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rescue Course of Betamethasone or Dexamethasone | Interuterine Growth Restriction (IUGR) or Small for Gestational Age(SGA)in Babies Delivering at < 34 Weeks Gestation. | 25 paticipants |
| Placebo (Normal Saline) | Interuterine Growth Restriction (IUGR) or Small for Gestational Age(SGA)in Babies Delivering at < 34 Weeks Gestation. | 20 paticipants |
Secondary
Maternal Infectious Morbidity.
Total number of Mothers having Maternal infectious morbidity (e.g. endometritis & maternal sepsis) noted from birth through 28 days after birth
Time frame: Up to 28 days after giving birth
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rescue Course of Betamethasone or Dexamethasone | Maternal Infectious Morbidity. | 8 participants |
| Placebo (Normal Saline) | Maternal Infectious Morbidity. | 10 participants |
Secondary
Neonatal Birth Weight Reported in Grams
Measured mean Birth weights of Neonates in each arm as reported in grams on the birth record.
Time frame: At time of Birth
Population: Intent to treat protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rescue Course of Betamethasone or Dexamethasone | Neonatal Birth Weight Reported in Grams | 1905 grams | Standard Deviation 738 |
| Placebo (Normal Saline) | Neonatal Birth Weight Reported in Grams | 1920 grams | Standard Deviation 667 |
Secondary
Neonatal Head Circumference Taken at Time of Birth.
Reported as the average of all neonatal head circumferences (HC) taken at time of birth in each group.
Time frame: Birth
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rescue Course of Betamethasone or Dexamethasone | Neonatal Head Circumference Taken at Time of Birth. | 30.2 centemeters (cm) | Standard Deviation 3 |
| Placebo (Normal Saline) | Neonatal Head Circumference Taken at Time of Birth. | 30.0 centemeters (cm) | Standard Deviation 2.9 |
Secondary
Number of Babies Who Required Ventilatory Support Within the First 28 Days of Life.
The number of babies who required ventilatory support within the first 28 days of life. Equal to or great than 12 hours was considered one day.
Time frame: birth to 28 days of life
Population: Intent to treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rescue Course of Betamethasone or Dexamethasone | Number of Babies Who Required Ventilatory Support Within the First 28 Days of Life. | 70 participants |
| Placebo (Normal Saline) | Number of Babies Who Required Ventilatory Support Within the First 28 Days of Life. | 95 participants |
Secondary
Number of Neonates Who Required Surfactant Therapy After Birth.
The Number of neonates who required surfactant therapy within the first 28 days after birth.
Time frame: Birth to 28 days of life
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rescue Course of Betamethasone or Dexamethasone | Number of Neonates Who Required Surfactant Therapy After Birth. | 70 participant |
| Placebo (Normal Saline) | Number of Neonates Who Required Surfactant Therapy After Birth. | 99 participant |
Secondary
Number of Neonates With Pneumothorax
Total number of neonates with pneumothorax diagnosed postpartum.
Time frame: birth to 28 days of life
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rescue Course of Betamethasone or Dexamethasone | Number of Neonates With Pneumothorax | 4 participants |
| Placebo (Normal Saline) | Number of Neonates With Pneumothorax | 4 participants |