Study Links Low Birth Weight to Long-Term Disease Risk

Babies born smaller than expected may carry a biological signature at birth that increases their risk of developing heart, lung, and metabolic diseases decades later, according to a new study.

Researchers identified a group of proteins in umbilical cord blood that could help explain why some low-birth-weight babies experience long-term health problems, offering new clues about the origins of chronic disease.

The study, published in Nature Communications, found that about one-third of babies born small for gestational age (SGA) had unusually high levels of proteins involved in early nerve and organ development. Those same proteins were later linked to poorer lung function in adulthood, suggesting they may influence how multiple organs develop before birth.

“Low birth weight is one of the most important risk factors for the development of chronic diseases,” said Dr. Fernando Martinez, director of the Asthma and Airway Disease Research Center at the University of Arizona. “We’ve known about an association between lower birth weight and smaller lungs, as well as later lung dysfunction, but we don’t understand the biological mechanism behind the effect.”

What did scientists discover?

Small for gestational age describes babies who weigh less than expected for the number of weeks they have spent developing in the womb. While many grow up healthy, they are statistically more likely to develop cardiovascular disease, diabetes, and respiratory conditions later in life.

To investigate why, researchers analyzed stored umbilical cord blood samples collected from multiple U.S. birth cohorts that have followed participants from birth into adulthood since the 1980s through the Children’s Allergy and Asthma Data Repository (CADRE).

They compared babies born SGA with babies of average birth weight across five U.S. cities representing different environments and genetic backgrounds.

The researchers found that approximately one-third of SGA babies consistently showed elevated levels of axon guidance proteins.

These proteins are best known for helping guide the growth of nerve cells in the developing brain. However, they also play a critical role in branching morphogenesis, the process that shapes organs such as the lungs, blood vessels, and possibly other organs before birth.

“It was surprising that we saw this in one-third of the babies in every cohort,” said Dr. Anthony Bosco, associate professor of immunobiology at the University of Arizona. “We thought that this might be very different in different cohorts and environments, especially with different socioeconomic factors.”

Why should these proteins matter?

Think of organ development like building a tree. The trunk forms first, then branches spread outward in carefully organized patterns. Axon guidance proteins help direct this branching process, ensuring organs and nerve connections develop properly.

If these molecular signals become disrupted during pregnancy, scientists believe several organs may not develop optimally, potentially increasing disease risk years later.

The team tracked participants into their 40s and found that higher levels of axon guidance proteins in cord blood were associated with poorer adult lung function.

Researchers then strengthened their findings in two additional ways. They analyzed large genome-wide association studies (GWAS), which linked variations in axon guidance genes to differences in lung development and function. They also used a sheep model, where single-cell sequencing showed these genes were active during fetal development in the brain, heart, and lungs of both low- and normal-birth-weight animals.

“We have results from three studies providing a unified hypothesis to explain how low birth weight affects multiple organs through the axon guidance pathway and increases risk for multiple diseases,” Bosco said.

What does this mean for future research?

The findings do not mean every baby born with a low birth weight will develop chronic disease. Instead, the researchers say they have identified one possible biological pathway that may explain why some children face greater long-term health risks than others.

“The mystery is, why do these chronic heart, lung, and metabolic conditions often cluster together?” Martinez said. “Since the axon guidance mechanism is so important in the development of lungs and possibly all organs, we’re proposing that a dysregulation in the system probably affects many body functions.”

The researchers plan to investigate these genes and proteins further to determine whether they could eventually become targets for treatments that improve lifelong health outcomes.

“This could be a fundamental biological system that may impact all body systems,” Martinez said. “We’re excited about the possibilities.”

The study suggests that some of the biological foundations for adult chronic diseases may be established before birth, with molecular signals in umbilical cord blood potentially offering an early window into future health risks.