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Am J Perinatol 2024; 41(S 01): e221-e229
DOI: 10.1055/a-1877-6191
Original Article

DLK1: A Novel Biomarker of Placental Insufficiency in Stillbirth and Live Birth

Jessica M. Page 
1   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah Health Sciences, Salt Lake City, Utah
2   Division of Maternal-Fetal Medicine, Intermountain Health Care, Murray, Utah
,
Amanda A. Allshouse
1   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah Health Sciences, Salt Lake City, Utah
,
Jessica E. Gaffney
3   Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center Oregon Health and Science University, Portland, Oregon
,
Victoria H. J. Roberts
3   Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center Oregon Health and Science University, Portland, Oregon
,
Vanessa Thorsten
4   RTI International, Research Triangle Park, North Carolina
,
Karen J. Gibbins 
13   Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon
,
Donald J. Dudley
5   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia
,
George Saade
6   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston
,
Robert L. Goldenberg
7   Department of Obstetrics and Gynecology, Columbia University, New York, New York
,
Barbara J. Stoll
8   Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, Texas
,
Carol J. Hogue
9   Rollins School of Public Health, Emory University, Atlanta, Georgia
,
Radek Bukowski
10   Department of Women's Health, Dell Medical School, University of Texas at Austin, Austin, Texas
,
Corette Parker
4   RTI International, Research Triangle Park, North Carolina
,
Deborah Conway
11   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, Texas
,
Uma M. Reddy
12   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Yale School of Medicine, New Haven, Connecticut
,
Michael W. Varner 
1   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah Health Sciences, Salt Lake City, Utah
2   Division of Maternal-Fetal Medicine, Intermountain Health Care, Murray, Utah
,
Antonio E. Frias
13   Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon
,
Robert M. Silver
1   Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah Health Sciences, Salt Lake City, Utah
2   Division of Maternal-Fetal Medicine, Intermountain Health Care, Murray, Utah
› Author Affiliations Funding This analysis was supported by Oregon Health and Science University through grant no.: U01-HD087182 for Ms. Gaffney's effort. This investigation was supported by the University of Utah Study Design and Biostatistics Center, with funding in part from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant no: 8UL1TR000105 (formerly grant no.: UL1RR025764). This work, including the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review and approval of the manuscript, was supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, grant no.: U10-HD045953, Brown University, RI; grant no.: U10-HD045925 Emory University, GA; grant no.: U10-HD045952 University of Texas Medical Branch at Galveston, TX; grant no.: U10-HDO45955 University of Texas Health Sciences Center at San Antonio, TX; rant no.: U10-HD045944 University of Utah Health Sciences Center, UT; and grant no.: U01-HD045954 RTI International, RTP.
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Abstract

Objective Delta-like homolog 1 (DLK1) is a growth factor that is reduced in maternal sera in pregnancies with small for gestational age neonates. We sought to determine if DLK1 is associated with stillbirth (SB), with and without placental insufficiency.

Study Design A nested case-control study was performed using maternal sera from a multicenter case-control study of SB and live birth (LB). SB and LB were stratified as placental insufficiency cases (small for gestational age <5% or circulatory lesions on placental histopathology) or normal placenta controls (appropriate for gestational age and no circulatory lesions). Enzyme-linked immunosorbent assay (ELISA) was used to measure DLK1. The mean difference in DLK1 was compared on the log scale in an adjusted linear regression model with pairwise differences, stratified by term/preterm deliveries among DLK1 results in the quantifiable range. In exploratory analysis, geometric means were compared among all data and the proportion of “low DLK1” (less than the median value for gestational age) was compared between groups and modeled using linear and logistic regression, respectively.

Results Overall, 234 SB and 234 LB were analyzed; 246 DLK1 values were quantifiable within the standard curve. Pairwise comparisons of case and control DLK1 geometric means showed no significant differences between groups. In exploratory analysis of all data, adjusted analysis revealed a significant difference for the LB comparison only (SB: 71.9 vs. 99.1 pg/mL, p = 0.097; LB: 37.6 vs. 98.1 pg/mL, p = 0.005). In exploratory analysis of “low DLK1,” there was a significant difference between the odds ratio of having “low DLK1” between preterm cases and controls for both SB and LB. There were no significant differences in geometric means nor “low DLK1” between SB and LB.

Conclusion In exploratory analysis, more placental insufficiency cases in preterm SB and LB had “low DLK1.” However, low DLK1 levels were not associated with SB.

Key Points

  • Maternally circulating DLK1 is correlated with placental insufficiency.

  • Maternally circulating DLK1 is not correlated with SB.

  • DLK1 is a promising marker for placental insufficiency.

Keywords

stillbirth - placental insufficiency - biomarker - growth restriction

Note

This study was conducted at 59 hospitals in portions of five states: Rhode Island, Massachusetts, Georgia, Texas, and Utah.




Publication History

Received: 26 January 2022

Accepted: 26 May 2022

Accepted Manuscript online:
16 June 2022

Article published online:
22 August 2022

© 2022. Thieme. All rights reserved.

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