Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial

Pregnancy Clinical Trial

— ALPS  

Official title:

Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01222247
• Other study ID #: HL98354-HD36801-ALPS
• Secondary ID: U10HD021410U10HD
• Status: Completed
• Phase: Phase 3
• Start date: October 2010
• Est. completion date: August 31, 2022

Study information

• Verified date: March 2023
• Source: The George Washington University Biostatistics Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized placebo controlled trial to evaluate whether antenatal corticosteroids can decrease the rate of neonatal respiratory support, thus decreasing the rate of NICU admissions and improving short-term outcomes in the late preterm infant. The use of antenatal corticosteroids has been shown to be beneficial in women at risk for preterm delivery prior to 34 weeks but has not been evaluated in those likely to deliver in the late preterm period

Description:

The rate of preterm birth has steadily increased in the United States over the past 10 years. This increase is driven in part by the rising rate of late preterm birth, defined as those births occurring between 34 and 36 weeks. Late preterm infants experience a higher rate of readmission than their term counterparts, and these infants are more likely to suffer complications such as respiratory distress, kernicterus, feeding difficulties, and hypoglycemia. Late preterm infants also have a higher mortality for all causes when compared to term infants. The use of antenatal corticosteroids has been shown to be beneficial in women at risk for preterm delivery prior to 34 weeks but has not been evaluated in those likely to deliver in the late preterm period. If shown to reduce the need for respiratory support and thus to decrease the rate of special care nursery admissions and improve short-term outcomes, the public health and economic impact will be considerate.This protocol describes a randomized placebo controlled trial to evaluate whether antenatal corticosteroids can decrease the rate of neonatal respiratory support, thus decreasing the rate of neonatal intensive care unit (NICU) admissions and improving short-term outcomes in the late preterm infant.

Two follow-up studies will be conducted concurrently. The first follow-up study will examine if the positive effects of betamethasone on lung function will persist in children at 6 years of age of mothers randomized to betamethasone with an expected late preterm delivery. Neonatal respiratory morbidity is associated with an increased risk of adverse childhood respiratory disease. Thus it is quite plausible that the effect of betamethasone, in reducing neonatal morbidity, particularly TTN, will translate into improved respiratory morbidity in early childhood.The primary outcome is childhood respiratory disease defined by a composite outcome of abnormal pulmonary function test (PFT) measured by spirometry, physician diagnosis of asthma, or other respiratory illnesses with medication.

The second follow-up study will examine whether late preterm antenatal betamethasone treatment is associated with long-term neurocognitive functioning, and whether there are any long-term consequences of what is believed to be transient neonatal hypoglycemia. Cognitive function will be measured by the Differential Ability Scales 2nd Edition (DAS-II) core components of the general conceptual ability (GCA) that includes verbal ability, non-verbal reasoning ability and spatial ability. The primary outcome is defined as a GCA score of <85 (1 standard deviation below the mean) at 6 years of age or greater.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2831
• Est. completion date: August 31, 2022
• Est. primary completion date: March 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: N/A and older

Eligibility

Inclusion Criteria:

Singleton Pregnancy. A twin pregnancy reduced to singleton (either spontaneously or therapeutically) before 14,0 weeks by project gestational age is acceptable

Gestational age at randomization between 34,0 weeks and 36,5 weeks confirmed by study criteria

High probability of delivery in the late preterm period (any one of the following):

• Membrane rupture as defined by the occurrence of any two of the following: pooling of fluid in the vaginal vault, positive Nitrazine test, ferning of vaginal fluid, positive AmniSure test; or any one of the following: indigo carmine pooling in the vagina after amnioinfustion, visible leakage of amniotic fluid from the cervix

or

• Preterm labor with intact membranes. Preterm labor is defined as at least 6 regular uterine contractions in an observation period of no more than 60 minutes and at least one of the following: cervix greater than or equal to 3cm dilated or at least 75% effaced

or

• Planned delivery by induction of labor or cesarean section in no less than 24 hours and no more than 7 days, as deemed necessary by the provider. An induction must be scheduled to start by 36,5 weeks at the latest, whereas a cesarean delivery must be scheduled by 36,6 weeks at the latest. Therefore the latest gestational age for randomization is 36,4 weeks for a planned induction. The planned delivery may be for any indication, such as the following: prior myomectomy, prior classical cesarean, intrauterine growth restriction (IUGR), oligohydramnios, preeclampsia, nonreassuring fetal heart rate tracing warranting delivery, abruption, placenta previa

Exclusion Criteria:

1. Any prior antenatal corticosteroid course during the pregnancy because of potential contamination of the placebo group

2. Candidate for stress dose corticosteroids because of chronic steroid therapy to prevent suppression of adrenal gland, because of potential contamination of the placebo group

3. Twin gestation reduced to a singleton gestation at or after 14 weeks 0 days by project gestational age either spontaneously or therapeutically

4. Fetal demise, or known major fetal anomaly, including cardiac anomaly and hydrops

5. Maternal contraindication to betamethasone: hypersensitivity reaction to any components of the medication, idiopathic thromboycytopenic purpura, systemal fungal infection in case of exacerbation by betamethasone, use of amphotericin B due to the possibility of heart failure with concomitant betamethasone

6. Pre-gestational diabetes - exclude if the patient was on medication (insulin, glyburide) prior to pregnancy

7. Delivery expected within 12 hours of randomization, because of insufficient time of corticosteroids to confer benefit, including any of the following:

A. Rupture of Membranes (ROM) does not satisfy protocol criteria - exclude if the patient being evaluated for Preterm Premature Rupture of Membranes (pPROM), does not have preterm labor or planned delivery and does not satisfy the spontaneous membrane rupture criteria (any 2 of: positive Nitrazine test, pooling of fluid in the vaginal vault test or ferning of vaginal fluid; or indigo carmine pooling in the vagina after amnioinfusion; or visible leakage of amniotic fluid from the cervix) B. Rupture of the membranes in the presence of more than 6 contractions per hour or cervical dilation of 3 cm or more, unless oxytocin was withheld for at least 12 hours (other induction agents allowed) C. Chorioamnionitis - exclude if patient is diagnosed with chorioamnionitis D. Cervical dilation = 8 cm E. Evidence of non-reassuring fetal status requiring immediate delivery

8. Participation in another interventional study that influences neonatal morbidity and mortality

9. Participation in this trial in a previous pregnancy

10. Delivery at a non-network hospital

11. At 36, 0 weeks to 36, 5 weeks and quota for 36 weeks already met. To ensure there is an adequate proportion of women presenting at 34 to 35 weeks of gestation, enrollment will be restricted so that no more than 50% of the women in the trial present at 36 weeks.

Related Conditions & MeSH terms

• Pregnancy
• Pregnancy Outcomes
• Premature Birth
• Preterm Birth
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn

Intervention

Drug:
• Betamethasone
The active study drug, betamethasone. 3 mg per ml betamethasone sodium phosphate 3 mg per milliliter betamethasone acetate The first dose of study drug medication will be administered at randomization as 2 ml injection; the next dose of 2 ml will be administered 24 hours later.
• Placebo
Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.

Locations

Country	Name	City	State
United States	University of Alabama - Birmingham	Birmingham	Alabama
United States	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Case Western Reserve University	Cleveland	Ohio
United States	Ohio State University	Columbus	Ohio
United States	University of Texas - Southwest	Dallas	Texas
United States	University of Colorado	Denver	Colorado
United States	Wayne State University	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	University of Texas - Galveston	Galveston	Texas
United States	University of Texas - Houston	Houston	Texas
United States	Columbia University	New York	New York
United States	University of Pittsburgh Magee Womens Hospital	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Brown University	Providence	Rhode Island
United States	University of Utah Medical Center	Salt Lake City	Utah
United States	Stanford University	Stanford	California

Sponsors (3)

Lead Sponsor	Collaborator
The George Washington University Biostatistics Center	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (24)

Bhutani VK, Johnson L. Kernicterus in late preterm infants cared for as term healthy infants. Semin Perinatol. 2006 Apr;30(2):89-97. doi: 10.1053/j.semperi.2006.04.001. — View Citation

Buus-Frank ME. The great imposter. Adv Neonatal Care. 2005 Oct;5(5):233-6. doi: 10.1016/j.adnc.2005.08.012. No abstract available. — View Citation

Clark RH. The epidemiology of respiratory failure in neonates born at an estimated gestational age of 34 weeks or more. J Perinatol. 2005 Apr;25(4):251-7. doi: 10.1038/sj.jp.7211242. — View Citation

Davidoff MJ, Dias T, Damus K, Russell R, Bettegowda VR, Dolan S, Schwarz RH, Green NS, Petrini J. Changes in the gestational age distribution among U.S. singleton births: impact on rates of late preterm birth, 1992 to 2002. Semin Perinatol. 2006 Feb;30(1):8-15. doi: 10.1053/j.semperi.2006.01.009. Erratum In: Semin Perinatol. 2006 Oct;30(5):313. — View Citation

Dudell GG, Jain L. Hypoxic respiratory failure in the late preterm infant. Clin Perinatol. 2006 Dec;33(4):803-30; abstract viii-ix. doi: 10.1016/j.clp.2006.09.006. — View Citation

Escobar GJ, Clark RH, Greene JD. Short-term outcomes of infants born at 35 and 36 weeks gestation: we need to ask more questions. Semin Perinatol. 2006 Feb;30(1):28-33. doi: 10.1053/j.semperi.2006.01.005. — View Citation

Gray RF, Indurkhya A, McCormick MC. Prevalence, stability, and predictors of clinically significant behavior problems in low birth weight children at 3, 5, and 8 years of age. Pediatrics. 2004 Sep;114(3):736-43. doi: 10.1542/peds.2003-1150-L. — View Citation

Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, Saade GR, Rouse DJ, McKenna DS, Clark EA, Thorp JM Jr, Chien EK, Peaceman AM, Gibbs RS, Swamy GK, Norton ME, Casey BM, Caritis SN, Tolosa JE, Sorokin Y, VanDorsten JP, Jain L; NICHD Maternal-Fe — View Citation

Hamilton BE, Ventura SJ, Martin JA, and Sutton PD. Preliminary births for 2004. Health E-stats. Hyattsville, MD: National Center for Health Statistics. Released October 28, 2005.

Hoyert DL, Mathews TJ, Menacker F, Strobino DM, Guyer B. Annual summary of vital statistics: 2004. Pediatrics. 2006 Jan;117(1):168-83. doi: 10.1542/peds.2005-2587. Erratum In: Pediatrics. 2006 Jun;117(6):2338. — View Citation

Kramer MS, Demissie K, Yang H, Platt RW, Sauve R, Liston R. The contribution of mild and moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System. JAMA. 2000 Aug 16;284(7):843-9. doi: 10.1001/jama.284.7.843. — View Citation

Laptook A, Jackson GL. Cold stress and hypoglycemia in the late preterm ("near-term") infant: impact on nursery of admission. Semin Perinatol. 2006 Feb;30(1):24-7. doi: 10.1053/j.semperi.2006.01.014. — View Citation

Linnet KM, Wisborg K, Agerbo E, Secher NJ, Thomsen PH, Henriksen TB. Gestational age, birth weight, and the risk of hyperkinetic disorder. Arch Dis Child. 2006 Aug;91(8):655-60. doi: 10.1136/adc.2005.088872. Epub 2006 Jun 5. — View Citation

McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol. 2008 Jan;111(1):35-41. doi: 10.1097/01.AOG.0000297311.33046.73. — View Citation

Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med. 2008 Jul 17;359(3):262-73. doi: 10.1056/NEJMoa0706475. — View Citation

Neu J. Gastrointestinal maturation and feeding. Semin Perinatol. 2006 Apr;30(2):77-80. doi: 10.1053/j.semperi.2006.02.007. — View Citation

Raju TN, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late-preterm (near-term) infants: a summary of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics. 2006 Sep;118(3):1207-14. doi: 10.1542/peds.2006-0018. — View Citation

Rubaltelli FF, Dani C, Reali MF, Bertini G, Wiechmann L, Tangucci M, Spagnolo A. Acute neonatal respiratory distress in Italy: a one-year prospective study. Italian Group of Neonatal Pneumology. Acta Paediatr. 1998 Dec;87(12):1261-8. doi: 10.1080/080352598750030951. — View Citation

Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, Barfield W, Weiss J, Evans S. Risk factors for neonatal morbidity and mortality among "healthy," late preterm newborns. Semin Perinatol. 2006 Apr;30(2):54-60. doi: 10.1053/j.semperi.2006.02.002. — View Citation

Stutchfield P, Whitaker R, Russell I; Antenatal Steroids for Term Elective Caesarean Section (ASTECS) Research Team. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ. 2005 Sep 24;331(7518):662. doi: 10.1136/bmj.38547.416493.06. Epub 2005 Aug 22. — View Citation

Tita AT, Landon MB, Spong CY, Lai Y, Leveno KJ, Varner MW, Moawad AH, Caritis SN, Meis PJ, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, O'Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, Mercer BM; Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl J Med. 2009 Jan 8;360(2):111-20. doi: 10.1056/NEJMoa0803267. — View Citation

Tomashek KM, Shapiro-Mendoza CK, Weiss J, Kotelchuck M, Barfield W, Evans S, Naninni A, Declercq E. Early discharge among late preterm and term newborns and risk of neonatal morbidity. Semin Perinatol. 2006 Apr;30(2):61-8. doi: 10.1053/j.semperi.2006.02.003. — View Citation

Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics. 2004 Aug;114(2):372-6. doi: 10.1542/peds.114.2.372. — View Citation

Yoder BA, Gordon MC, Barth WH Jr. Late-preterm birth: does the changing obstetric paradigm alter the epidemiology of respiratory complications? Obstet Gynecol. 2008 Apr;111(4):814-22. doi: 10.1097/AOG.0b013e31816499f4. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Neonatal Composite Outcome	Need for respiratory support: Continuous positive airway pressure (CPAP) or humidified high-flow nasal cannula (HHFNC) for greater than or equal to 2 hours or more in the first 72 hours, or fraction of inspired oxygen (FiO2) greater than or equal to 0.30 for 4 hours or more in the first 72 hours, or mechanical ventilation in the first 72 hours, or Extracorporeal membrane oxygenation (ECMO) Stillbirth, or neonatal death less than 72 hours of age	72 hours of life
Secondary	Number of Neonates With Severe Respiratory Complication,	A severe respiratory complication was defined as any of the following occurrences within 72 hours after birth: CPAP or high-flow nasal cannula for at least 12 hours, supplemental oxygen with a fraction of inspired oxygen of 0.30 or more for at least 24 hours, mechanical ventilation, stillbirth or neonatal death, or the need for ECMO. Except for the duration of CPAP or high-flow nasal cannula and the duration of a fraction of inspired oxygen of 0.30 or more, the criteria for a severe respiratory complication overlap with those of the primary outcome.	72 hours of life
Secondary	Neonates Needing Immediate Resuscitation After Birth	Need for resuscitation after birth: any intervention in the first 30 minutes other than blow-by oxygen	Within the first 30 minutes of birth
Secondary	Number of Neonates With Respiratory Distress Syndrome	Respiratory distress defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis) with an oxygen requirement and a chest x-ray that shows hypoaeration and reticulogranular infiltrates	Delivery
Secondary	Number of Neonates With Transient Tachypnea of the Newborn	TTN is defined as signs of respiratory distress, specifically tachypnea, that are resolved by 72 hours of age. TTN may be diagnosed in the absence of a chest X-ray or with a chest X-ray that is normal or shows signs of increased perihilar interstitial markings	by 72 hours after delivery
Secondary	Number of Infants With Neonatal Apnea	Neonatal apnea with respiratory pauses of more than 20 seconds duration resulting in bradycardia or oxygen desaturation below baseline.	72 hours of life
Secondary	Number of Infants withChronic Lung Disease / Bronchopulmonary Dysplasia (BPD) Requiring Supplemental Oxygen	Infants requiring supplemental oxygen of more than 0.21 for the first 28 days of life	28 days of life
Secondary	Neonates With Pneumonia	Neonatal pneumonia	by 72 hours of life
Secondary	Number of Neonates Needing Surfactant Administration	Administration of surfactant for neonatal respiratory treatment	Delivery
Secondary	Neonatal Outcome Composite	Transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and apnea	72 hours of life
Secondary	Number of Neonates With Pulmonary Air Leak	Neonatal pulmonary air leak syndrome	72 hours post delivery
Secondary	Neonatal Death After 72 Hours of Delivery	Neonatal death after 72 hours of life but before hospital discharge.	72 hours after delivery through hospital discharge up to 3 weeks
Secondary	Birth Weight	Weight in grams at delivery	Delivery
Secondary	Birth Weight Less Than 10th Percentile	Neonates whose birth weight is less than the 10th percentile at delivery	Delivery
Secondary	Gestational Age at Delivery	Number of neonates delivered at = 34 weeks 6 days, between 35 weeks 0 days and 35 weeks 6 days, between 36 weeks 0 days and 36 weeks 6 days, between 37 weeks 0 days and 38 weeks 6 days, or on or after 39 weeks 0 days	Delivery
Secondary	Number of Neonates With Necrotizing Enterocolitic (NEC)	Defined as modified Bell Stage 2 or 3. Stage 2: Clinical signs and symptoms with pneumatosis intestinalis on radiographs. Stage 3: Advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation.	Delivery
Secondary	Number of Infants With Neonatal Sepsis	Clinical suspicion of systemic infection with a positive blood, cerebral spinal fluid, or catheterized/suprapubic urine culture; or, in the absence of positive cultures, clinical evience of cardiovascular collapse or an X-ray confirming infection.	Delivery
Secondary	Number of Neonates With Intraventricular Hemorrhage	Grade 3 or 4 Intraventricular Hemorrhage	Delivery
Secondary	Neonatal Morbidity Composite	A composite endpoint of morbidities known to be affected by steroid administration will also be evaluated. Specifically, this composite will include RDS, intraventricular hemorrhage (IVH), and NEC	Delivery
Secondary	Number of Neonates With Hypoglycemia	Glucose < 40 mg per deciliter (2.2 mmol per liter) at any time	Delivery through hospital discharge up to 3 weeks
Secondary	Time Until First Neonatal Feeding	Median length of time from delivery until the first neonatal feeding	Delivery to 36 hours post delivery
Secondary	Neonatal Feeding Difficulty	Inability of the neonate to take all feeds (po), i.e. requiring gavage feeds or IV supplementation.	Delivery to 36 hours post delivery
Secondary	Neonatal Hyperbilirubinemia	Peak total bilirubin of at least 15 mg% or the use of phototherapy.	Delivery
Secondary	Number of Neonates With Hypothermia	Rectal temperature < 36 C at any time	Delivery through discharge up to 3 weeks
Secondary	Length of NICU or Nursery Stay	Includes need for NICU or intermediate care admission and length of stay if admitted. For analysis purposes, death before discharge is assigned maximum rank	Delivery through hospital discharge up to 3 weeks
Secondary	Median Length of Hospital Stay	Median length of maternal hospital stay following delivery	Duration of hospital stay following delivery up to 2 weeks
Secondary	Maternal Outcomes (Participant-based)	Chorioamnionitis: clinical diagnosis and a body temperature of at least 100.4 degrees F., Endometritis: persistent postpartum temperature greater than 100.4 degrees F with uterine tenderness, cesarean delivery	Labor and delivery through 72 hours post partum
Secondary	Hours From Randomization to Delivery	Median interval of hours from randomization to delivery	Randomization through delivery
Secondary	Median Length of Maternal Hospital Stay	Median length of maternal hospital stay in days	Delivery through hospital discharge

External Links

•   (The public website of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Units (MFMU) Network)