Abstract
Background
Low birth weight in term-born individuals correlates with adverse cardiometabolic outcomes; excess glucocorticoid exposure has been linked to these relationships. We hypothesized that cortisol and adrenal androgens would correlate inversely with birthweight and directly with markers of cardiometabolic risk in school-aged children born extremely preterm; further, preterm-born would have increased cortisol and adrenal androgens compared to term-born children.
Methods
Saliva samples were obtained at age 6 from 219 preterm-born children followed since birth and 40 term-born children and analyzed for dehydroepiandrosterone (DHEA) and cortisol. Cortisol was also measured at home (awakening, 30′ later, evening).
Results
For preterm-born children, cortisol and DHEA correlated inversely with weight and length Z-scores at 36 weeks PMA and positively with systolic BP. DHEA was higher in preterm-born than term-born children (boys p < 0.01; girls p = 0.04). Cortisol was similar between preterm-born and term-born at study visit; however, preterm-born children showed a blunted morning cortisol. In term-born children, DHEA correlated with BMI (p = 0.04), subscapular, and abdominal skinfold thicknesses (both p < 0.01).
Conclusion
Cortisol and DHEA correlated inversely with early postnatal growth and directly with systolic BP in extremely preterm-born children, suggesting perinatal programming. Blunted morning cortisol may reflect NICU stress, as seen after other adverse childhood experiences (ACEs).
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Acknowledgments
The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Heart, Lung, and Blood Institute (NHLBI) provided grant support for the Neonatal Research Network’s Extended Follow-up at School Age for the SUPPORT Neuroimaging and Neurodevelopmental Outcomes (NEURO) Cohort through cooperative agreements. NHLBI provided support for this study (R01HL117764). While NICHD staff had input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of the NICHD. Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. On behalf of the NRN, Drs. Abhik Das (DCC Principal Investigator), Marie Gantz, Lisa Wrage, and Helen Cheng (DCC Statisticians) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study.
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K.W. made substantial contributions to conception and design of the study, acquisition, analysis, and interpretation of data. She drafted the initial manuscript, revised it, and has given final approval of the version to be published. S.H. provided resources for the study, made substantial contributions to the investigation, reviewed and edited the manuscript, and has given final approval of the version to be published. B.D. made substantial contributions to the formal analysis and interpretation of the data, writing and review of the manuscript, and has given final approval of the version to be published. B.V. made substantial contribution to the investigation, review and editing of the manuscript, and has given final approval of the version to be published. J.L. made substantial contribution to the methodology and investigation, reviewed and edited the manuscript, and has given final approval of the version to be published. J.N. made substantial contribution to the study methodology, provided supervision/oversight, reviewed and edited the manuscript, and has given final approval of the version to be published. D.W. made substantial contribution to conception and design of the study and its methodology, data curation and analysis, review and editing of the manuscript, and has given final approval of the version to be published. C.L. made substantial contribution to the conception, design and methodology of the study, provided supervision and oversight, reviewed and edited the manuscript, and has given final approval of the version to be published. E.D. made substantial contribution to the methodology of the study, reviewed and edited the manuscript, and has given final approval of the version to be published. D.G. made substantial contribution to the study methodology and data curation, provided supervision/oversight, participated in writing and editing of the manuscript, and has given final approval of the version to be published. S.S. provided substantial contribution to the study methodology, provided supervision/oversight, reviewed and edited the manuscript, and has given final approval of the version to be published. A.P. provided substantial contribution to the study investigation, participated in writing and editing of the manuscript, and has given final approval of the version to be published. R.H. provided substantial contribution to the conception and design of the study, supervision/oversight for the investigation, review and editing of the manuscript, and has given final approval of the version to be published.
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D.A.G. is founder and chief scientific and strategy advisor at Salimetrics LLC and Salivabio LLC. The nature of those relationships is managed by the policies of the committees on conflict of interest at the Johns Hopkins University School of Medicine and the University of California at Irvine. All the remaining authors declare no competing interests.
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Appendix
Appendix
NRN Steering Committee Chairs
Alan H. Jobe, MD PhD, University of Cincinnati (2003-2006).
Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine (2006–2011).
Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University, (2011-present).
Abbot R. Laptook, MD; Angelita M. Hensman, MS RNC-NIC; Elisa Vieira, RN BSN; Emilee Little, RN BSN; Katharine Johnson, MD; Barbara Alksninis, PNP; Mary Lenore Keszler, MD; Andrea M. Knoll; Theresa M. Leach, MEd CAES; Elisabeth C. McGowan, MD; Victoria E. Watson, MS CAS—Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904).
Michele C. Walsh, MD MS; Avroy A. Fanaroff, MD; Deanne E. Wilson-Costello, MD; Nancy S. Newman, RN; Bonnie S. Siner, RN; Arlene Zadell, RN; Julie DiFiore, BS; Monika Bhola, MD; Harriet G. Friedman, MA; Gulgun Yalcinkaya, MD—Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80).
Ronald N. Goldberg, MD; C. Michael Cotten, MD MHS; Kathryn E. Gustafson, PhD; Ricki F. Goldstein, MD; Patricia Ashley, MD; Kathy J. Auten, MSHS; Kimberley A. Fisher, PhD FNP-BC IBCLC; Katherine A. Foy, RN; Sharon F. Freedman, MD; Melody B. Lohmeyer, RN MSN; William F. Malcolm, MD; David K. Wallace, MD MPH—Duke University School of Medicine, University Hospital, and Duke Regional Hospital (U10 HD40492, M01 RR30).
David P. Carlton, MD; Barbara J. Stoll, MD; Ira Adams-Chapman, MD; Susie Buchter, MD; Anthony J. Piazza, MD; Sheena Carter, PhD; Sobha Fritz, PhD; Ellen C. Hale, RN BS CCRC; Amy K. Hutchinson, MD; Maureen Mulligan LaRossa, RN; Yvonne Loggins, RN, Diane Bottcher, RN—Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory Crawford Long Hospital (U10 HD27851, RR25008, M01 RR39).
Stephanie Wilson Archer, MA—Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Brenda B. Poindexter, MD MS; Gregory M. Sokol, MD; Heidi M. Harmon, MD MS; Lu-Ann Papile, MD; Abbey C. Hines, PsyD; Leslie D. Wilson, BSN CCRC; Dianne E. Herron, RN; Lucy Smiley, CCRC—Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750).
Kathleen A. Kennedy, MD MPH; Jon E. Tyson, MD MPH; Andrea F. Duncan, MD MSClinRes; Allison G. Dempsey, PhD; Janice John, CPNP; Patrick M. Jones, MD MA; M. Layne Lillie, RN BSN; Saba Siddiki, MD; Daniel K. Sperry, RN—McGovern Medical School at The University of Texas Health Science Center at Houston and Children’s Memorial Hermann Hospital (U10 HD21373).
Carol J. Blaisdell, MD, Victoria Pemberton RNC, MS, CCRC—National Heart, Lung, and Blood Institute.
Abhik Das, PhD; Dennis Wallace, PhD; Marie G. Gantz, PhD; Jeanette O’Donnell Auman, BS; Jane A. Hammond, PhD; W. Kenneth Poole, PhD (deceased)—RTI International (U10 HD36790).
Krisa P. Van Meurs, MD; David K. Stevenson, MD; M. Bethany Ball, BS CCRC; Maria Elena DeAnda, PhD; Gabrielle T. Goodlin, BAS—Stanford University and Lucile Packard Children’s Hospital (U10 HD27880, UL1 RR25744, M01 RR70).
Ivan D. Frantz III, MD; John M. Fiascone, MD; Elisabeth C. McGowan, MD; Anne Kurfiss, MPH; Brenda L. MacKinnon, RNC; Ellen Nylen, RN BSN; Ana Brussa, MS OTR/L; Cecelia Sibley, PT MHA—Tufts Medical Center, Floating Hospital for Children (U10 HD53119, M01 RR54).
Waldemar A. Carlo, MD; Namasivayam Ambalavanan, MD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN; Vivien A. Phillips, RN BSN; Kristy Domanovich, PhD; Sally Whitley, MA OTR-L FAOTA; Leigh Ann Smith, CRNP; Carin R. Kiser, MD—University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32).
Neil N. Finer, MD; Donna Garey, MD; Maynard R. Rasmussen; MD; Paul R. Wozniak, MD; Yvonne E. Vaucher, MD MPH; Martha G. Fuller, PhD RN; Natacha Akshoomoff, PhD; Wade Rich, BSHS RRT; Kathy Arnell, RNC; Renee Bridge, RN—University of California – San Diego Medical Center and Sharp Mary Birch Hospital for Women (U10 HD40461).
Edward F. Bell, MD; Tarah T. Colaizy, MD MPH; John A. Widness, MD; Jonathan M. Klein, MD; Karen J. Johnson, RN BSN; Michael J. Acarregui, MD; Diane L. Eastman, RN CPNP MA; Tammy L. V. Wilgenbusch, PhD—University of Iowa (U10 HD53109, UL1 TR442, M01 RR59).
Robin K. Ohls, MD; Janell Fuller, MD; Conra Backstrom Lacy, RN; Rebecca A. Thomson, RN BSN; Sandra Brown, RN BSN—University of New Mexico Health Sciences Center (R01 HL117764, U10 HD53089, M01 RR997).
Pablo J. Sánchez, MD; Roy J. Heyne, MD; Charles R. Rosenfeld, MD; Walid A. Salhab, MD; Luc Brion, MD; Sally S. Adams, MS RN CPNP; James Allen, RRT; Laura Grau, RN; Alicia Guzman; Gaynelle Hensley, RN; Elizabeth T. Heyne, PsyD PA-C; Jackie F. Hickman, RN; Lizette E. Lee, RN; Melissa H. Leps, RN; Linda A. Madden, RN CPNP; Melissa Swensen Martin, RN; Nancy A. Miller, RN; Janet S. Morgan, RN; Araceli Solis, RRT; Catherine Twell Boatman, MS CIMI; Diana M Vasil, MSN BSN RNC-NIC—University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689, M01 RR633).
Bradley A. Yoder, MD; Roger G. Faix, MD; Shawna Baker, RN; Karen A. Osborne, RN BSN CCRC; Carrie A. Rau, RN BSN CCRC; Sarah Winter, MD; Sean D. Cunningham, PhD; Ariel C. Ford, PsyD—University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children’s Medical Center (U10 HD53124, M01 RR64).
Athina Pappas, MD; Beena G. Sood, MD MS; Rebecca Bara, RN BSN; Thomas L. Slovis, MD (deceased); Laura A. Goldston, MA; Mary Johnson, RN BSN—Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (U10 HD21385).
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Watterberg, K.L., Hintz, S.R., Do, B. et al. Adrenal function links to early postnatal growth and blood pressure at age 6 in children born extremely preterm. Pediatr Res 86, 339–347 (2019). https://doi.org/10.1038/s41390-018-0243-1
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DOI: https://doi.org/10.1038/s41390-018-0243-1
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