Northwestern Medicine investigators have discovered how proteins expressed in umbilical cord blood at birth evolve during gestational development and could serve as biomarkers to inform new precision care strategies for infants born prematurely, according to a recent study published in Scientific Reports.
Increasing advances in medical technology and neonatology have improved care for infants born prematurely. Nonetheless, preterm infants still remain at increased risk for medical complications, including invasive infections and sepsis, many of which are poorly predicted in real time or not at all by current diagnostic tools.
“Understanding the pathophysiology, what is the developmental state of a baby when they’re born so early and what’s going on from a molecular standpoint, can give us more insight into not just keeping them alive, but optimizing their health outcomes in a more precise way,” said Leena Mithal, ’08 MD, ’16 MSCI, associate professor of Pediatrics in the Division of Infectious Diseases and lead author of the study.
To better understand the biologic state of a baby born prematurely versus at full term, the scientists studied umbilical cord blood samples from 150 infants born between 25 to 42 weeks at Northwestern Prentice Women’s Hospital from 2008 to 2019.
Compared to standard blood samples, umbilical cord blood gives a unique window into the state of the fetus at the time of birth, Mithal said.
“You get a snapshot of the proteome at birth, at that specific point in gestational development that’s not impacted by all the events that happen after the baby is born, transitioning to postnatal life and often unstable,” said Mithal, who is also director of Feinberg’s Master of Science in Clinical Investigation program.
Using mass spectrometry proteomics techniques, the scientists characterized the proteome, or expressed proteins, in the cord blood samples and found that there are gestational age-related changes in an abundance of different proteins.
For example, proteins that support structural development and growth (extracellular matrix organization, lipid particle remodeling and blood vessel development) are more abundant earlier in gestation. Proteins involved in immune response and inflammatory pathway signaling, including complements and calcium-binding proteins, were more highly expressed later in gestation.
“This characterizes how the proteins that function in the immune system change over gestational development and can help us understand what’s lacking in a baby that’s born very early and compared to the immune state of full-term infants,” Mithal said.
Ultimately, these biomarkers could also help clinicians better understand why preterm infants are more susceptible to infection, brain bleeds and other preterm-related health complications, which could help clinicians tailor more effective care strategies and treatments.
“If we understand what’s lacking in babies that are born early, we can use that information to develop therapeutic interventions to mediate those differences and to optimize the environment and clinical state of those babies,” Mithal said. “If we can do a better job of understanding the health state and specific risks for each baby, tailoring our therapies, and being able to give the parents a little bit better of an idea what to expect short term and long term, I think that would go a long way for these families.”
The next steps for this work, according to Mithal, include validating newly identified biomarkers to improve timely, accurate diagnosis of early-onset sepsis in newborn infants. The biomarkers could provide clarity on which infants are more likely benefit from antibiotic treatment and which infants could be spared antibiotics and may benefit from other types of treatment, Mithal said.
“The goal is a cord blood diagnostic test at the time of birth to help us risk stratify for early-onset infection and provide a precision medicine approach to targeted antibiotic therapy,” Mithal said.
Co-authors include Ted Ling-Hu, a former student in the Driskill Graduate Program in Life Sciences (DGP); Sebastian Otero, a research coordinator in Pediatric Infectious Diseases; Judd Hultquist, PhD, assistant professor of Medicine in the Division of Infectious Diseases and of Microbiology-Immunology; Denise Scholtens, PhD, chief of Biostatistics in the Department of Preventive Medicine; and Patrick Seed, MD, PhD, the Children’s Research Fund Professor of Basic Science and president and chief research officer of Stanley Manne Children’s Research Institute.
This work was supported by National Institute of Allergy and Infectious Diseases grant K23AI139337the Gerber Foundation, Friends of Prentice, the Thrasher Research Fund, the Northwestern University Clinical and Translational Sciences Institute (grant UL1TR001422), and the NUCord Biorepository (supported by the Perinatal Origins of Disease Research Program at Lurie Children’s the National Heart, Lung, and Blood Institute grant K23HL093302).
