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Association Between Blood Spot Transforming Growth Factor-β and Patent Ductus Arteriosus in Extremely Low-Birth Weight Infants

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Abstract

Permanent ductal closure involves anatomic remodeling, in which transforming growth factor (TGF)-β appears to play a role. Our objective was to evaluate the relationship, if any, between blood spot TGF-β on day 3 and day 7 of life and patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. Prospective observational study involving ELBW infants (n = 968) in the National Institute of Child Health and Human Development Neonatal Research Network who had TGF-β measured on filter paper spot blood samples using a Luminex assay. Infants with a PDA (n = 493) were significantly more immature, had lower birth weights, and had higher rates of respiratory distress syndrome than those without PDA (n = 475). TGF-β on days 3 and 7 of life, respectively, were significantly lower among neonates with PDA (median 1,177 pg/ml [range 642–1,896]; median 1,386 pg/ml [range 868–1,913]) compared with others without PDA (median 1,334 pg/ml [range 760–2,064]; median 1,712 pg/ml [range 1,014–2,518 pg/ml]). The significant difference persisted when death or PDA was considered a composite outcome. TGF-β levels were not significantly different among subgroups of infants with PDA who were not treated (n = 51) versus those who were treated medically (n = 283) or by surgical ligation (n = 159). TGF-β was not a significant predictor of death or PDA (day 3 odds ratio [OR] 0.99, 95 % confidence interval [CI] 0.83–1.17; day 7 OR 0.88, 95 % CI 0.74–1.04) on adjusted analyses. Our results suggest that blood spot TGF-β alone is unlikely to be a reliable biomarker of a clinically significant PDA or its responsiveness to treatment.

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Abbreviations

PDA:

Patent ductus arteriosus

ELBW:

Extremely low birth weight

TGF:

Transforming growth factor

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Acknowledgments

Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Department of Health and Human Services (Grants No. U10 HD21385, U10 HD40689, U10 HD 27871, U10 HD21373, U10 HD36790, U10 HD40461, U10 HD34216, U10 HD21397, U10 HD27904, U10 HD40492, U10 HD27856, U10 HD40521, U10 HD27853, U10 HD27880, U10 HD27851, and R03 HD054420) and from the National Institutes of Health (Grants No. GCRC M01 RR 08084, M01 RR 00125, M01 RR 00750, M01 RR 00070, M01 RR 0039-43, M01 RR 00039, and 5 M01 RR00044). The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Centers for Disease Control and Prevention provided grant support for recruitment for 1999 through 2001 and data analysis for the Neonatal Research Network’s Cytokines Study. The funding agencies provided overall oversight for study conduct, but all data analyses and interpretation were independent of the funding agencies. Data collected at participating NRN sites were transmitted to RTI International, the data-coordinating center (DCC) for the NRN, which stored, managed, and analyzed the data for this study. On behalf of the network, Abhik Das (DCC PI) and Scott A. McDonald (DCC statistician) had full access to all of 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 as well as the infants and their parents who agreed to take part in this study.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Girija Natarajan & Seetha Shankaran

  2. Department of Statistics and Epidemiology, RTI International, Research Triangle Park, Durham, NC, USA

    Scott A. McDonald

  3. Department of Statistics and Epidemiology, RTI International, Rockville, MD, USA

    Abhik Das

  4. Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA

    Richard A. Ehrenkranz

  5. Department of Pediatrics, Duke University, Durham, NC, USA

    Ronald N. Goldberg

  6. Department of Pediatrics, Emory University, Atlanta, GA, USA

    Barbara J. Stoll

  7. Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX, USA

    Jon E. Tyson

  8. Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA

    Rosemary D. Higgins

  9. National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA

    Diana Schendel

  10. Section of Neonatal Screening and Hormones, Department of Clinical Biochemistry and Immunology, Statens Serum Institut, 2300, Copenhagen, Denmark

    David M Hougaard & Kristin Skogstrand

  11. Department of Obstetrics and Gynecology, Lillebaelt Hospital, Kolding, Denmark

    Poul Thorsen

  12. Rollins School of Public Health, Emory University, Atlanta, GA, USA

    Poul Thorsen

  13. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    Waldemar A. Carlo

Authors
  1. Girija Natarajan
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  2. Seetha Shankaran
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  3. Scott A. McDonald
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  4. Abhik Das
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  5. Richard A. Ehrenkranz
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  6. Ronald N. Goldberg
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  7. Barbara J. Stoll
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  8. Jon E. Tyson
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  9. Rosemary D. Higgins
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  10. Diana Schendel
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  11. David M Hougaard
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  12. Kristin Skogstrand
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  13. Poul Thorsen
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  14. Waldemar A. Carlo
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Corresponding author

Correspondence to Girija Natarajan.

Additional information

On behalf of the NICHD Neonatal Research Network.

Appendix: NICHD Neonatal Research Network

Appendix: NICHD Neonatal Research Network

The following investigators participated in this study:

NRN Steering Committee Chair: Alan H. Jobe, MD PhD, University of Cincinnati.

Centers for Disease Control and Prevention (IAA Y1-HD-5000-01)—Diana E. Schendel, PhD.

Cincinnati Children’s Hospital Medical Center University of Cincinnati Hospital and Good Samaritan Hospital (GCRC M01 RR8084, U10 HD27853)—Edward F. Donovan, MD; Vivek Narendran, MD MRCP; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Jody Hessling, RN; Marcia Worley Mersmann, RN CCRC; Holly L. Mincey, RN BSN.

Duke University University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (GCRC M01 RR30, U10 HD40492)—C. Michael Cotten, MD MHS; Kathy J. Auten, MSHS.

Emory University Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory Crawford Long Hospital (GCRC M01 RR39, U10 HD27851)—Ellen C. Hale, RN BS CCRC.

Eunice Kennedy Shriver National Institute of Child Health and Human Development—Linda L. Wright, MD; Sumner J. Yaffe, MD; Elizabeth M. McClure, MEd.

Indiana University Indiana University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (GCRC M01 RR750, U10 HD27856)—Brenda B. Poindexter, MD MS; James A. Lemons, MD; Diana D. Appel, RN BSN; Dianne E. Herron, RN; Leslie D. Wilson, BSN CCRC.

Rainbow Babies & Children’s Hospital (GCRC M01 RR80, U10 HD21364)—Avroy A. Fanaroff, MD; Michele C. Walsh, MD MS; Nancy S. Newman, RN; Bonnie S. Siner, RN.

RTI International (U01 HD36790)—W. Kenneth Poole, PhD; Betty K. Hastings; Kristin M. Zaterka-Baxter, RN BSN; Jeanette O’Donnell Auman, BS; Scott E. Schaefer, MS.

Stanford University Lucile Packard Children’s Hospital (GCRC M01 RR70, U10 HD27880)—David K. Stevenson, MD; Krisa P. Van Meurs, MD; M. Bethany Ball, BS CCRC.

Statens Serum Institut—Kristin Skogstrand, PhD; David M. Hougaard, MD DSc.

University of Aarhus Department of Epidemiology and Social Medicine, Denmark—Poul Thorsen, MD PhD.

University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (GCRC M01 RR32, U10 HD34216)—Namasivayam Ambalavanan, MD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN.

University of California—San Diego Medical Center and Sharp Mary Birch Hospital for Women (U10 HD40461)—Neil N. Finer, MD; Maynard R. Rasmussen MD; David Kaegi, MD; Kathy Arnell, RNC; Clarence Demetrio, RN; Wade Rich, BSHS RRT.

University of Miami Holtz Children’s Hospital (GCRC M01 RR16587, U10 HD21397)—Charles R. Bauer, MD; Shahnaz Duara, MD; Ruth Everett-Thomas, RN MSN.

University of New Mexico Health Sciences Center (GCRC M01 RR997, U10 HD27881)—Lu-Ann Papile, MD; Conra Backstrom Lacy, RN.

University of Tennessee (U10 HD21415)—Sheldon B. Korones, MD; Henrietta S. Bada, MD; Tina Hudson, RN BSN.

University of Texas Southwestern Medical Center at Dallas Parkland Health & Hospital System and Children’s Medical Center Dallas (GCRC M01 RR633, U10 HD40689)—Abbot R. Laptook, MD; Walid A. Salhab, MD; Susie Madison, RN.

University of Texas Health Science Center at Houston Medical School, Children’s Memorial Hermann Hospital, and Lyndon B. Johnson General Hospital (U10 HD21373)—Kathleen Kennedy, MD MPH; Brenda H. Morris, MD; Esther G. Akpa, RN BSN; Patty A. Cluff, RN; Claudia Y. Franco, RN BSN MSN NNP; Anna E. Lis, RN BSN; Georgia E. McDavid, RN; Patti L. Tate, RCP.

Wake Forest University Baptist Medical Center, Forsyth Medical Center, and Brenner Children’s Hospital (GCRC M01 RR7122, U10 HD40498)—T. Michael O’Shea, MD MPH; Nancy J. Peters, RN CCRP.

Wayne State University Hutzel Women’s Hospital and Children’s Hospital of Michigan (U10 HD21385)—G. Ganesh Konduri, MD; Rebecca Bara, RN BSN; Geraldine Muran, RN BSN.

Women & Infants Hospital of Rhode Island (U10 HD27904)—William Oh, MD; Lewis P. Rubin, MD; Angelita M. Hensman, RN BSN.

Yale University Yale-New Haven Children’s Hospital (GCRC M01 RR6022, U10 HD27871)—Patricia Gettner, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN.

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Natarajan, G., Shankaran, S., McDonald, S.A. et al. Association Between Blood Spot Transforming Growth Factor-β and Patent Ductus Arteriosus in Extremely Low-Birth Weight Infants. Pediatr Cardiol 34, 149–154 (2013). https://doi.org/10.1007/s00246-012-0404-7

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