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

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.

• Betamethasone or Dexamethasone (2nd course of ACS) (Drug), also known as Beta, Dex: Course of Betamethasone or Dexamethasone
• Placebo (Drug), also known as Placebo, Normal Saline.: Course of Placebo (NS)

Primary outcomes

• 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 outcomes

• 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.
• 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.
• 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.
• 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.
• 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

Sex: Female, ages: 18 Years to 60 Years

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

Participant flow

Outcome results

• Composite Neonatal Morbidity < 34 Weeks Gestation at Time of Birth. (Primary), Number, participants: "Rescue" Course of Betamethasone or Dexamethasone 71; Placebo (Normal Saline) 105 (p 0.002)
• Gestational Age at (@) Delivery (Secondary), Mean, Weeks: "Rescue" Course of Betamethasone or Dexamethasone 33.1 +/- 3.1; Placebo (Normal Saline) 33.0 +/- 3.1
• Neonatal Birth Weight Reported in Grams (Secondary), Mean, grams: "Rescue" Course of Betamethasone or Dexamethasone 1905 +/- 738; Placebo (Normal Saline) 1920 +/- 667
• Interuterine Growth Restriction (IUGR) or Small for Gestational Age(SGA)in Babies Delivering at < 34 Weeks Gestation. (Secondary), Number, paticipants: "Rescue" Course of Betamethasone or Dexamethasone 25; Placebo (Normal Saline) 20
• Neonatal Head Circumference Taken at Time of Birth. (Secondary), Mean, centemeters (cm): "Rescue" Course of Betamethasone or Dexamethasone 30.2 +/- 3.0; Placebo (Normal Saline) 30.0 +/- 2.9
• Number of Babies Who Required Ventilatory Support Within the First 28 Days of Life. (Secondary), Number, participants: "Rescue" Course of Betamethasone or Dexamethasone 70; Placebo (Normal Saline) 95
• Number of Neonates Who Required Surfactant Therapy After Birth. (Secondary), Number, participant: "Rescue" Course of Betamethasone or Dexamethasone 70; Placebo (Normal Saline) 99
• Number of Neonates With Pneumothorax (Secondary), Number, participants: "Rescue" Course of Betamethasone or Dexamethasone 4; Placebo (Normal Saline) 4
• Maternal Infectious Morbidity. (Secondary), Number, participants: "Rescue" Course of Betamethasone or Dexamethasone 8; Placebo (Normal Saline) 10

Adverse events

Time frame: 4 years and (&) 9 months

Serious adverse events by term

• Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consens Statement. 1994 Feb 28-Mar 2;12(2):1-24. PMID 7728157
• Vermillion ST, Soper DE, Newman RB. Is betamethasone effective longer than 7 days after treatment? Obstet Gynecol. 2001 Apr;97(4):491-3. doi: 10.1016/s0029-7844(00)01178-9. PMID 11275015
• Antenatal corticosteroids revisited: repeat courses. NIH Consens Statement. 2000 Aug 17-18;17(2):1-18. PMID 11725806
• Guinn DA, Atkinson MW, Sullivan L, Lee M, MacGregor S, Parilla BV, Davies J, Hanlon-Lundberg K, Simpson L, Stone J, Wing D, Ogasawara K, Muraskas J. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: A randomized controlled trial. JAMA. 2001 Oct 3;286(13):1581-7. doi: 10.1001/jama.286.13.1581. PMID 11585480
• Caughey AB, Parer JT. Recommendations for repeat courses of antenatal corticosteroids: a decision analysis. Am J Obstet Gynecol. 2002 Jun;186(6):1221-6; discussion 1226-9. doi: 10.1067/mob.2002.123742. PMID 12066102

• Kimberly Maurel, RN, MSN, CNS, Study director, Obstetrix Medical Group, Inc.