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Am J Perinatol 2025; 42(02): 238-249
DOI: 10.1055/a-2347-3751
Original Article

Genomic Differences between Spontaneous versus Indicated Extreme Preterm Birth

Namasivayam Ambalavanan 
1   Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
,
C. Michael Cotten
2   Department of Pediatrics, Duke University, Durham, North Carolina
,
Stephen W. Erickson
3   Genomics Research Center, RTI International, Research Triangle Park, North Carolina
,
Ravi Mathur
3   Genomics Research Center, RTI International, Research Triangle Park, North Carolina
,
Dara Torgerson
4   Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California
,
Philip L. Ballard
5   Department of Pediatrics, University of California San Francisco, San Francisco, California
6   National Institute of Child Health and Human Development, Bethesda, Maryland
,
for the Eunice Kennedy Shriver NICHD Neonatal Research Network and the TOLSURF Study Group › Author Affiliations Funding The National Institutes of Health, the Eunice Kennedy Shriver NICHD (grants U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689) and the National Center for Research Resources (General Clinical Research Center grants M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587) provided grant support for the NRN's Glutamine trial which included the Genomic Study through cooperative agreements. In addition, J.C.M. received assistance for the GENEVA study from the National Human Genome Research Institute (U01 HG4423). The validation cohort TOLSURF was supported by the National Institutes of Health/National Heart, Lung and Blood Institute (U01-HL094338 and U01HL094355) and the UCSF Clinical and Translational Sciences Institute (UL1TR000004). ONY, Inc., provided the Infasurf, and IKARIA, Inc., provided the inhaled nitric oxide for TOLSURF.
Participating NRN sites collected data and transmitted it 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, RTI International had full access to all of the data in the study, and with the NRN Center Principal Investigators, takes responsibility for the integrity of the data and accuracy of the data analysis. 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 NICHD, the National Institutes of Health, the Department of Health and Human Services, or the U.S. Government.
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Abstract

Objective Extremely preterm infants are at high risk of neonatal mortality and morbidity. Extreme preterm birth (PTB) may result from spontaneous preterm labor or preterm premature rupture of membranes or may be indicated due to preeclampsia, eclampsia, hypertension, or other causes. Our objective was to identify single nucleotide polymorphisms (SNPs) and biological pathways associated with spontaneous versus indicated extreme PTB using the neonatal genome.

Study Design We evaluated 523 spontaneous births and 134 indicated births weighing 401 to 1,000 g at birth from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Genomics dataset by genome-wide association study (GWAS) and pathway analysis. The TOLSURF cohort was used to replicate the results.

Results In the NRN GWAS, no statistically significant results were found, although the Manhattan plot showed one almost significant peak (rs60854043 on chromosome 14 at p = 1.03E-07) along with many other modest peaks at p = 1–9E-06, for a total of 15 suggestive associations at this locus. In the NRN pathway analysis, multiple pathways were identified, with the most significant being “GO_mf:go_low_density_lipoprotein_particle_receptor_activity” at p = 1.14E-06. However, these results could not be replicated in the TOLSURF cohort.

Conclusion Genomic differences are seen between infants born by spontaneous versus indicated extreme PTB. Due to the limited sample size, there is a need for larger studies.

Key Points

  • Genomic differences are seen between infants born by spontaneous versus indicated very PTB.

  • Future studies with large sample sizes evaluating extreme PTB are necessary.

  • Spontaneous PTB is more common than indicated extreme PTB.

Keywords

prematurity - genomics - preeclampsia - preterm labor

Authors' Contributions

N.A.: conception, design of work, drafting the work, acquisition, analysis, and interpretation of data for the work.


C.M.C., S.W.E., R.M., D.T.: design of work, analysis, revising the work critically for important intellectual content, and interpretation of data for the work.


P.L.B.: revising the work critically for important intellectual content, and interpretation of data for the work.


Data Availability

Genotypes and a subset of subject information inclusive of key characteristic and outcome phenotype data have been stored, with no identifying links, in the National Human Genome Research Institute Database of Genotypes and Phenotypes (dbGaP Study Accession: phs000353.v1.p1).


Patient Consent

Written informed consent was obtained from the parent(s) of enrolled infants. The studies were approved by the Institutional Review Boards at the multiple participating centers of the Eunice Kennedy Shriver NICHD NRN and TOLSURF that are listed in the “Acknowledgments” section.


# A complete list of study group members appears in the Acknowledgments.


Supplementary Material



Publication History

Received: 09 February 2024

Accepted: 13 June 2024

Accepted Manuscript online:
18 June 2024

Article published online:
10 July 2024

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