Does a Rescue Course of Betamethasone in Pregnant Women With PPROM Decrease Neonatal Morbidity?

Overview

The purpose of this study is to determine if a repeat course of betamethasone given to pregnant women with preterm premature rupture of membranes (PPROM) will decrease the infant's length of stay in the neonatal intensive care unit (NICU) and the overall neonatal morbidity associated with this condition.

Full Title of Study: “Does a Repeat Course of Antenatal Corticosteroids in Pregnant Women With Preterm Premature Rupture of Membranes Decrease Neonatal Morbidity?”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: November 2022

Detailed Description

While the fetal benefits of a repeat course of antenatal corticosteroids have been demonstrated in several randomized controlled studies, to the investigators' knowledge they have not been adequately demonstrated in women with PPROM. Given the potential benefit of a repeat course of antenatal corticosteroids in women with PPROM on decreasing neonatal morbidity and the reassuring data from various cohorts on its safety, the investigators sought to propose a randomized controlled trial (RCT) with the hypothesis that a repeat course of antenatal corticosteroids in women with PPROM decreases neonatal morbidity.

Objectives

1. To evaluate the impact of maternal treatment with a second course of betamethasone on infant length of stay in the NICU.

2. To evaluate the impact of maternal treatment with a second course of betamethasone on the duration of neonatal need for oxygen supplementation.

3. To evaluate the impact of maternal treatment with a second course of betamethasone on neonatal morbidity overall.

Hypotheses The investigators hypothesize that treatment of women with PPROM between 24 and 34 weeks of gestation with a repeat course of antenatal corticosteroids decreases infant length of stay in the NICU and neonatal morbidity.

Aim To describe and compare the neonatal outcomes of PPROM infants exposed to a repeat course of antenatal corticosteroids compared to infants in the same antenatal conditions who are exposed to only one betamethasone course.

Subject Safety and Data Monitoring This study does not place subjects at risk of their safety. This medication is well studied and known to be safe in pregnancy.

Data monitoring will be performed and viewed by study personnel only. The data will be de-identified and a study number will be assigned to each patient. The patient's identity will be secured on a UTMB encrypted laptop device and a hard copy stored in the locked file cabinet in the locked office of the principal investigator.

Procedures to Maintain Confidentiality:

Data will be viewed by study personnel only. The data will then be de-identified and a study number will be assigned to each patient. The patient's identity will then be secured on a UTMB encrypted laptop device and a hard copy stored in the locked file cabinet in the locked office of the principal investigator.

Potential Benefits The potential benefits to subjects participating in the study include possible decreased neonatal morbidity and length of stay in the NICU.

Biostatistics Using data from the University of Texas Medical Branch (UTMB) on women with PPROM between 24 and 34 weeks, who fit the inclusion criteria, and who received the standard one course of betamethasone, the average length of stay in the NICU was 59.3 ± 36.3 days. The gestational age at delivery in this cohort was 26.5 ± 3.2 weeks.

Assuming that a second course of betamethasone reduces the length of stay needed in the NICU by 35%, and for a power of 80% and alpha 0.05, it is anticipated that enrollment of 49 women in each group will be needed, or 98 women total.

At UTMB, there are approximately 400 women per year hospitalized with PPROM. Assuming 50% of eligible women consent, the investigators estimate to finish recruitment for this study in 1-2 years.

Sample Size and Assumptions

1. Frequency of primary outcome in control group (single course of betamethasone): is 59.3 days. The investigators assume a 35% reduction in length of NICU stay using two courses of betamethasone.

2. α = 0.05, two sided

3. β = 0.2

4. Effect size: 35% reduction in primary outcome

Interventions

  • Drug: Betamethasone
    • Betamethasone 12mg IM given every 24 hours for two doses
  • Drug: Placebo
    • Sterile 0.9% normal saline solution given IM every 24 hours for two doses

Arms, Groups and Cohorts

  • Experimental: Betamethasone
    • Women admitted with PPROM who will receive a second course of two betamethasone 12mg intramuscular (IM) injections given 24 hours apart.
  • Placebo Comparator: Saline Placebo
    • Women admitted with PPROM who will receive intramuscular saline placebo, given as two injections 24 hours apart.

Clinical Trial Outcome Measures

Primary Measures

  • Length of stay in the neonatal intensive care unit (NICU)
    • Time Frame: daily from birth of infant up to one year
    • expressed in days

Secondary Measures

  • Composite neonatal morbidity
    • Time Frame: assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
    • defined as ≥ 1 of the following: RDS (oxygen requirement, clinical diagnosis, and consistent chest radiograph), bronchopulmonary dysplasia (requirement for oxygen support at 30 days of life), severe IVH (grades III or IV), periventricular leukomalacia, blood culture-proven sepsis, necrotizing enterocolitis, or perinatal death (stillbirth or death before neonatal hospital discharge)
  • Duration of oxygen and ventilatory support
    • Time Frame: assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
    • Amount of time in days from birth that the infant requires supplemental oxygen of any form, including nasal cannula, positive airway pressure, or ventilatory support
  • Development of Respiratory Distress Syndrome (RDS)
    • Time Frame: assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
    • Will be quantified as either present or absent. RDS defined as: compatible symptoms with radiographic evidence of hyaline membrane disease or respiratory insufficiency of prematurity requiring ventilatory support for ≥ 24 hrs
  • Grade III or IV intraventricular hemorrhage (IVH)
    • Time Frame: assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
    • Will be quantified as either present or absent. Grade III IVH defined as ventricles enlarged by accumulating blood. Grade IV IVH defined as bleeding extending into brain matter around the ventricles.
  • Neonatal Sepsis
    • Time Frame: daily up to 72 hours of life
    • confirmed by culture in the first 72 hours of life
  • Necrotizing enterocolitis (NEC) stage 2 or 3
    • Time Frame: assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
    • Will be quantified as either present or absent. Stage 2 NEC will be defined as mild to moderate systemic illness, absent bowel sounds, abdominal tenderness, pneumatosis intestinalis or portal venous gas, metabolic acidosis, decreased platelets. Stage 3 NEC will be defined as severely ill, marked distention, signs of peritonitis, hypotension, metabolic & respiratory acidosis, disseminated intravascular coagulopathy, pneumoperitoneum if bowel perforation present.
  • Perinatal death
    • Time Frame: assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
    • defined as stillbirth or death before neonatal discharge

Participating in This Clinical Trial

Inclusion Criteria

  • Maternal age ≥ 18 years
  • Preterm premature rupture of membranes, demonstrated clinically by speculum exam
  • Cervical dilation visually ≤ 5cm on sterile speculum exam
  • Planned delivery at John Sealy Hospital (JSH)
  • Gestational age of membrane rupture and initiation of first course of antenatal corticosteroids between 23 5/7 – 32 5/7 weeks
  • Planned pregnancy continuation with no indication for delivery for at least 7 days

Exclusion Criteria

  • Maternal age > 50 years
  • Gestational age < 23 5/7 weeks or > 32 5/7 weeks
  • Known major congenital abnormalities, aneuploidy, or genetic syndrome
  • Intrauterine fetal demise
  • Any indication for expedited delivery
  • Maternal chorioamnionitis
  • Known allergy or adverse reaction to corticosteroids

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: 50 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • The University of Texas Medical Branch, Galveston
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Maged M Costantine, MD, Principal Investigator, University of Texas Medical Branch in Galveston
  • Overall Contact(s)
    • Mauricio La Rosa De Los Rios, MD, 409-772-1571, malarosa@UTMB.EDU

References

Atarod Z, Taghipour M, Roohanizadeh H, Fadavi S, Taghavipour M. Effects of single course and multicourse betamethasone prior to birth in the prognosis of the preterm neonates: A randomized, double-blind placebo-control clinical trial study. J Res Med Sci. 2014 Aug;19(8):715-9.

Brookfield KF, El-Sayed YY, Chao L, Berger V, Naqvi M, Butwick AJ. Antenatal corticosteroids for preterm premature rupture of membranes: single or repeat course? Am J Perinatol. 2015 May;32(6):537-44. doi: 10.1055/s-0034-1396690. Epub 2014 Dec 29.

Elimian A, Verma U, Canterino J, Shah J, Visintainer P, Tejani N. Effectiveness of antenatal steroids in obstetric subgroups. Obstet Gynecol. 1999 Feb;93(2):174-9.

Elimian A, Verma U, Visintainer P, Tejani N. Effectiveness of multidose antenatal steroids. Obstet Gynecol. 2000 Jan;95(1):34-6.

Gyamfi-Bannerman C, Son M. Preterm premature rupture of membranes and the rate of neonatal sepsis after two courses of antenatal corticosteroids. Obstet Gynecol. 2014 Nov;124(5):999-1003. doi: 10.1097/AOG.0000000000000460.

Mazumder P, Dutta S, Kaur J, Narang A. Single versus multiple courses of antenatal betamethasone and neonatal outcome: a randomized controlled trial. Indian Pediatr. 2008 Aug;45(8):661-7.

National Institutes of Health Consensus Development Panel. Antenatal corticosteroids revisited: repeat courses – National Institutes of Health Consensus Development Conference Statement, August 17-18, 2000. Obstet Gynecol. 2001 Jul;98(1):144-50. Review.

Practice bulletins No. 139: premature rupture of membranes. Obstet Gynecol. 2013 Oct;122(4):918-30. doi: 10.1097/01.AOG.0000435415.21944.8f.

Wijnberger LD, Mostert JM, van Dam KI, Mol BW, Brouwers H, Visser GH. Comparison of single and repeated antenatal corticosteroid therapy to prevent neonatal death and morbidity in the preterm infant. Early Hum Dev. 2002 Apr;67(1-2):29-36.

Yang SH, Choi SJ, Roh CR, Kim JH. Multiple courses of antenatal corticosteroid therapy in patients with preterm premature rupture of membranes. J Perinat Med. 2004;32(1):42-8.

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