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

Does a Repeat Course of Antenatal Corticosteroids in Pregnant Women With Preterm Premature Rupture of Membranes Decrease Neonatal Morbidity?

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.

Study Overview

• Status: Terminated
• Conditions: PPROM; Respiratory Distress Syndrome in Premature Infants
• Intervention / Treatment: Drug: Betamethasone; Drug: Placebo

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

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Texas
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch in Galveston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Betamethasone; Women admitted with PPROM who will receive a second course of two betamethasone 12mg intramuscular (IM) injections given 24 hours apart.	Drug: Betamethasone; Betamethasone 12mg IM given every 24 hours for two doses; Other Names: Celestone
Placebo Comparator: Saline Placebo; Women admitted with PPROM who will receive intramuscular saline placebo, given as two injections 24 hours apart.	Drug: Placebo; Sterile 0.9% normal saline solution given IM every 24 hours for two doses; Other Names: Saline placebo

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite neonatal morbidity	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)	assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
Duration of oxygen and ventilatory support	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	assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
Development of Respiratory Distress Syndrome (RDS)	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	assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
Grade III or IV intraventricular hemorrhage (IVH)	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.	assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
Neonatal Sepsis	confirmed by culture in the first 72 hours of life	daily up to 72 hours of life
Necrotizing enterocolitis (NEC) stage 2 or 3	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.	assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first
Perinatal death	defined as stillbirth or death before neonatal discharge	assessed daily up to 120 days after birth or discharge from hospital, whichever occurs first

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Labor latency	time from diagnosis of PPROM from admission until delivery of neonate or until completion of the study	time from admission to delivery up to one year, or through study completion
Infectious morbidities	Chorioamnionitis will be defined as at least one temperature elevation above 38°C combined with at least two of the following signs: maternal or fetal tachycardia, uterine tenderness, foul smelling vaginal discharge, white blood count > 18,000. Postpartum endometritis will be defined as postpartum temperature elevation above 38°C without other localizing sources of infection and with either uterine tenderness or foul-smelling lochia.	time from admission until maternal discharge from the hospital and up until 6 weeks postpartum, or through study completion

Collaborators and Investigators

• Sponsor: The University of Texas Medical Branch, Galveston
• Investigators: Principal Investigator: Benjamin Bush, MD, University of Texas Medical Branch in Galveston

Publications and helpful links

General Publications

• Practice bulletins No. 139: premature rupture of membranes. Obstet Gynecol. 2013 Oct;122(4):918-930. doi: 10.1097/01.AOG.0000435415.21944.8f.
• 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. doi: 10.1016/s0029-7844(98)00400-1.
• Elimian A, Verma U, Visintainer P, Tejani N. Effectiveness of multidose antenatal steroids. Obstet Gynecol. 2000 Jan;95(1):34-6. doi: 10.1016/s0029-7844(99)00471-8.
• 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. doi: 10.1016/s0029-7844(01)01410-7.
• 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. doi: 10.1016/s0378-3782(01)00248-1.
• 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. doi: 10.1515/JPM.2004.007.

Study record dates

Study Major Dates

• Study Start: November 1, 2016
• Primary Completion (Actual): December 20, 2023
• Study Completion (Actual): December 20, 2023

Study Registration Dates

• First Submitted: September 23, 2016
• First Submitted That Met QC Criteria: October 17, 2016
• First Posted (Estimated): October 20, 2016

Study Record Updates

• Last Update Posted (Actual): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: respiratory distress syndrome; neonatal morbidity; betamethasone; antenatal corticosteroids; preterm premature rupture of membranes; complications of prematurity
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Infant, Premature, Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Physiological Effects of Drugs; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Asthmatic Agents; Respiratory System Agents; Betamethasone
• Other Study ID Numbers: 15-0280

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No