A Randomized Trial Comparing the Impact of One Versus Two Courses of Antenatal Steroids (ACS) on Neonatal Outcome

Study Overview
=================
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.

Official Title
-----------------
A Randomized Double-Blinded Study Comparing the Impact of One Versus Two Courses of Antenatal Steroids on Neonatal Outcome

Conditions
-----------------
Preterm Delivery

Intervention / Treatment
-----------------
* Drug: Betamethasone or Dexamethasone (2nd course of ACS)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 Test group<br>Receive 2nd Course = Study drug (betamethasone or dexamethasone) | Drug: Betamethasone or Dexamethasone (2nd course of ACS)<br>* Course of Betamethasone or Dexamethasone<br>* Other names: Dex;|
| Placebo Comparator: 2 - Control<br>Placebo group = received placebo course | Drug: Placebo<br>* Course of Placebo (NS)<br>* Other names: Placebo, Normal Saline.;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | From birth to 28 days of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | gestational age at delivery in weeks of gestation | 
| Neonatal Birth Weight Reported in Grams | Measured mean Birth weights of Neonates in each arm as reported in grams on the birth record. | At time of Birth | 
| 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. | Measured at birth. | 
| 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. | Birth | 
| 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. | birth to 28 days of life | 
| Number of Neonates Who Required Surfactant Therapy After Birth. | The Number of neonates who required surfactant therapy within the first 28 days after birth. | Birth to 28 days of life | 
| Number of Neonates With Pneumothorax | Total number of neonates with pneumothorax diagnosed postpartum. | birth to 28 days of life | 
| Maternal Infectious Morbidity. | Total number of Mothers having Maternal infectious morbidity (e.g. endometritis & maternal sepsis) noted from birth through 28 days after birth | Up to 28 days after giving birth | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Preterm Labor, Preterm delivery