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Am J Perinatol
DOI: 10.1055/s-0043-1774312
Original Article

Genetic Predisposition to Adverse Neurodevelopmental Outcome of Extremely Low Birth Weight Infants

Michael W. Varner 
1   Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah
,
Elizabeth A. Thom   *
2   Biostatistics Coordinating Center, George Washington University, Washington, District of Columbia
,
C. Michael Cotten
3   Department of Pediatrics, Duke University, Durham, North Carolina
,
Susan R. Hintz
4   Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California
,
Grier P. Page
5   Social, Statistical and Environmental Sciences Unit, RTI International, Atlanta, Georgia
,
Dwight J. Rouse
6   Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama
,
Brian M. Mercer
7   Case Western Reserve University-MetroHealth Medical Center, Cleveland, Ohio
8   University of Tennessee, Memphis, Tennessee
,
Maged M. Costantine 
9   Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio
,
Yoram Sorokin
10   Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan
,
John M. Thorp Jr.
11   Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina
,
Susan M. Ramin
12   Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston-Children's Memorial Hermann Hospital, Houston, Texas
,
Marshall W. Carpenter
13   Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island
,
Mary J. O'Sullivan
14   Department of Obstetrics and Gynecology, University of Miami, Miami, Florida
,
Alan M. Peaceman
15   Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
,
George R. Saade
16   Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas
,
Donald J. Dudley
17   Department of Obstetrics and Gynecology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas
,
Steve N. Caritis
18   Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
,
for the Eunice Kennedy Shriver National Institute of Child Health Human Development Maternal-Fetal Medicine Units Network Neonatal Research Network › Author Affiliations Funding This study is supported by U10 grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; HD36790, HD21364, HD21373, HD21385, HD21397, HD21415, HD27851, HD27853, HD27856, HD27871, HD27880, HD27881, HD27904, HD34216, HD40461, HD40492, HD40498, HD40689, HD27869, HD34208, HD34116, HD40544, HD27915, HD34136, HD21414, HD27917, HD27860, HD40560, HD40545, HD40485, HD40500, HD27905, HD27861, HD34122, HD40512, HD53907, HD34210, HD21410, U01 HD36801, HD19897), MO1-RR-000080, and by the National Institute of Neurological Disorders and Stroke (NINDS). The National Center for Research Resources provided grant support for the Neonatal Research Network's Glutamine trial, which included the Genomic Study through cooperative agreements (General Clinical Research Center M01 grants RR30, RR32, RR39, RR70, RR80, RR633, RR750, RR997, RR6022, RR7122, RR8084, RR16587). Comments and views of the authors do not necessarily represent views of the NICHD, the National Institutes of Health, the Department of Health and Human Services, or the U.S. Government.
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Abstract

Objective This study aimed to evaluate whether there are genetic variants associated with adverse neurodevelopmental outcomes in extremely low birth weight (ELBW) infants.

Study Design We conducted a candidate gene association study in two well-defined cohorts of ELBW infants (<1,000 g). One cohort was for discovery and the other for replication. The discovery case–control analysis utilized anonymized DNA samples and evaluated 1,614 single-nucleotide polymorphisms (SNPs) in 145 genes concentrated in inflammation, angiogenesis, brain development, and oxidation pathways. Cases were children who died by age one or who were diagnosed with cerebral palsy (CP) or neurodevelopmental delay (Bayley II mental developmental index [MDI] or psychomotor developmental index [PDI] < 70) by 18 to 22 months. Controls were survivors with normal neurodevelopment. We assessed significant epidemiological variables and SNPs associated with the combined outcome of CP or death, CP, mental delay (MDI < 70) and motor delay (PDI < 70). Multivariable analyses adjusted for gestational age at birth, small for gestational age, sex, antenatal corticosteroids, multiple gestation, racial admixture, and multiple comparisons. SNPs associated with adverse neurodevelopmental outcomes with p < 0.01 were selected for validation in the replication cohort. Successful replication was defined as p < 0.05 in the replication cohort.

Results Of 1,013 infants analyzed (452 cases, 561 controls) in the discovery cohort, 917 were successfully genotyped for >90% of SNPs and passed quality metrics. After adjusting for covariates, 26 SNPs with p < 0.01 for one or more outcomes were selected for replication cohort validation, which included 362 infants (170 cases and 192 controls). A variant in SERPINE1, which encodes plasminogen activator inhibitor (PAI1), was associated with the combined outcome of CP or death in the discovery analysis (p = 4.1 × 10−4) and was significantly associated with CP or death in the replication cohort (adjusted odd ratio: 0.4; 95% confidence interval: 0.2–1.0; p = 0.039).

Conclusion A genetic variant in SERPINE1, involved in inflammation and coagulation, is associated with CP or death among ELBW infants.

Key Points

  • Early preterm and ELBW infants have dramatically increased risks of CP and developmental delay.

  • A genetic variant in SERPINE1 is associated with CP or death among ELBW infants.

  • The SERPINE1 gene encodes the serine protease inhibitor plasminogen activator inhibitor.

Keywords

candidate genes - extremely low birth weight - mental developmental delay - neurodevelopmental delay - preterm birth - polymorphisms - psychomotor delay - single-nucleotide polymorphisms

* Deceased.


# A list of other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network and Neonatal Research Network are listed in the [ Supplemental Material ] (available in online version).


Supplementary Material



Publication History

Received: 04 September 2022

Accepted: 01 August 2023

Article published online:
19 September 2023

© 2023. Thieme. All rights reserved.

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