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Original Investigation |

Association of Antenatal Corticosteroids With Mortality, Morbidity, and Neurodevelopmental Outcomes in Extremely Preterm Multiple Gestation Infants

Nansi S. Boghossian, PhD, MPH1; Scott A. McDonald, BS2; Edward F. Bell, MD3; Waldemar A. Carlo, MD4; Jane E. Brumbaugh, MD3; Barbara J. Stoll, MD5; Abbot R. Laptook, MD6; Seetha Shankaran, MD7; Michele C. Walsh, MD8; Abhik Das, PhD9; Rosemary D. Higgins, MD10 ; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
[+] Author Affiliations
1Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia
2RTI International, Research Triangle Park, North Carolina
3Department of Pediatrics, University of Iowa, Iowa City
4Department of Pediatrics, University of Alabama at Birmingham
5Department of Pediatrics, University of Texas Health Science Center at Houston
6Department of Pediatrics, Warren Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island, Providence
7Department of Pediatrics, Wayne State University, Detroit, Michigan
8Department of Pediatrics, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, Ohio
9RTI International, Rockville, Maryland
10Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
JAMA Pediatr. 2016;170(6):593-601. doi:10.1001/jamapediatrics.2016.0104.
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Importance  Little is known about the effects of antenatal corticosteroids (ANS) on extremely preterm multiples.

Objective  To examine if use of ANS is associated with improvement in major outcomes in extremely preterm multiples.

Design, Setting, and Participants  Infants with a gestational age between 22 and 28 weeks born at a National Institute of Child Health and Human Development Neonatal Research Network center were studied between January 1998 and December 2013. Generalized estimating equation models were used to generate adjusted relative risks (aRR) controlling for important maternal and neonatal variables.

Exposure  Antenatal corticosteroids.

Main Outcomes and Measures  In-hospital mortality and the composite outcome of neurodevelopmental impairment at 18 to 22 months’ corrected age or death before assessment.

Results  A total of 6925 multiple-birth infants were studied; 5775 of 6925 (83.4%) were twins, and 4276 (61.7%) were white. Of the total study population, 6094 (88%) were born to women who received ANS. In-hospital mortality was lower among infants with exposure to ANS vs no exposure (aRR = 0.87; 95% CI, 0.78-0.96). Neurodevelopmental impairment or death was not significantly lower among those exposed to ANS vs no exposure (aRR = 0.93; 95% CI, 0.84-1.03). Other adverse outcomes that occurred less frequently among infants of women receiving ANS included severe intraventricular hemorrhage (aRR = 0.68; 95% CI, 0.58-0.78) and the combined outcomes of necrotizing enterocolitis or death and severe intraventricular hemorrhage or death. Subgroup analyses indicated that exposure to ANS was associated with a lower risk of mortality and a lower composite of neurodevelopmental impairment or mortality among nonsmall for gestational age multiples (aRR = 0.82; 95% CI, 0.74-0.92; and aRR = 0.89; 95% CI, 0.80-0.98, respectively) and a higher risk among small for gestational age multiples (aRR = 1.40; 95% CI, 1.02-1.93; and aRR = 1.62; 95% CI, 1.22-2.16, respectively). Antenatal corticosteroids were associated with higher neurodevelopmental impairment or mortality among multiple-birth infants of mothers with diabetes (aRR = 1.55; 95% CI, 1.00-2.38) but not among infants of mothers without diabetes (aRR = 0.91; 95% CI, 0.83-1.01).

Conclusions and Relevance  Compared with no exposure, exposure to ANS was associated with a lower risk of mortality in extremely preterm multiples, with no significant differences in the composite of neurodevelopmental impairment or death. Future research should investigate the increased risks of mortality and the composite of neurodevelopmental impairment or death associated with exposure to corticosteroids among small for gestational age multiples.

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Figure 1.
Frequency of Exposure to Antenatal Corticosteroids (ANS) by Gestational Age and Year of Birth Among Multiples

Cells with fewer than 20 infants per gestational age per year of birth are not reported.

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Figure 2.
Adjusted Relative Risks (RRs) of Outcomes by Gestational Age (GA) at 22 to 28 Weeks

Models adjusted for center, year of birth, maternal age (≤19 vs ≥20 years), sex, race/ethnicity (black, white, or other), marital status, diabetes, hypertension, small for gestational age, and rupture of membrane more than 24 hours before birth. Regression for neurodevelopmental impairment or death also adjusts for epoch and maternal education. The error bars indicate 95% CIs.

aNot adjusted for center; model did not converge with center included.

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