New Insights Into Preterm Infant Immunity Could Inform Care

Preterm babies are fragile. This is especially true for infants born just six to seven months into a pregnancy. Called extremely preterm infants, these children essentially finish developing outside the uterus. Studying this vulnerable population is challenging because standard tests—such as blood draws—can be life-threatening for these small patients who have too little blood to support the amount needed in standard assays.

That’s starting to change. New methodology developed at Yale School of Medicine (YSM), combined with techniques that analyze multiple types of molecular information, is allowing researchers to more safely gain insight into the immune systems of extremely preterm babies.

Researchers suspect that early exposures to infection and other environmental factors can shape immunity later in life. Now, by analyzing just two drops of blood collected from 10 preterm babies, researchers know that preterm babies have unique immune systems that respond to threats, potentially both before and after birth. The findings were reported March 5 in Science Translational Medicine.

This study is the first step toward understanding extremely preterm infants' immune systems, which is key to providing better care for this population, says Liza Konnikova, MD, PhD, an associate professor of pediatrics, immunobiology, and reproductive sciences at YSM and senior author of the study.

The United States has one of the highest rates of preterm birth among developed nations. Pregnancy typically lasts around 40 weeks. Yet around 10% of babies in the United States are born before 37 weeks of pregnancy.

With their organs still developing, preterm babies can have trouble breathing, eating, and even regulating their internal temperature. For extremely premature infants, the risks are even greater. “The more premature an infant is, the more complications there are,” says Konnikova.

How premature birth impacts the immune system is somewhat an open question. It was once thought that infant immune systems were immature. However, more and more data suggest that full-term babies are born with working immune systems, albeit different from those of adults.

But researchers have faced challenges in determining whether that’s true in preterm infants. Immune studies require blood samples, and most studies use around 10 to 50 milliliters of blood. Collecting the same amount from preterm babies “would exsanguinate them [drain them of blood],” explains Konnikova.

To learn about the immune system of extremely premature babies, Konnikova and her colleagues had to find a way to get results from the minimum amount of blood. By combining a protocol from a group of researchers in Sweden with newly available molecular techniques, Konnikova’s team was able to collect large amounts of data from just two drops of blood.

In collaboration with Yale’s NOURISH team led by Sarah Taylor, MD, professor of pediatrics (neonatal-perinatal medicine) at YSM and co-author of the study, the researchers collected blood samples from 10 extremely premature infants between their first week and 2 months of life. They then simultaneously compared protein expression and cell types within these samples to that of adults and full-term infants.

They learned that preterm babies have the full array of immune cells that are found in adult and full-term infants. They even have memory T and B cells, which are used by the immune system to respond to threats that have been previously encountered. This suggests that the preterm babies in the study were not only responding to exposures in their new environments but may also have learned immunity while still residing within their mothers’ wombs.

However, the development of immune cells in preterm infants differed from that of full-term infants, the researchers found. Protein pathways and cell types related to inflammation were more active in extremely preterm infants and persisted far longer than in full-term infants. Around half of the preterm cohort had also been exposed to an infection of the placenta before birth. These babies had even higher persistent levels of inflammatory cells in their blood compared to those who hadn’t been exposed to such an infection before birth.

What this means for the long-term health of preterm infants is unknown, says Konnikova. Large-scale epidemiological studies suggest that early life exposures to pathogens or other immune triggers may increase the risk of later developing conditions such as asthma and irritable bowel syndrome. Conversely, some early life exposures are protective against the development of numerous diseases, such as diabetes. These conditions are impacted by the immune system, but this cohort is too small and hasn’t been followed long enough to show a link, says Konnikova.

But she hopes to change that. The research team has now enrolled around 250 preterm infants in their study and is recruiting a comparable full-term infant group that they can follow for at least a year. They are also beginning to collect other samples that might shed light on early life immune system development such as stool, skin, and nasal swabs. “Our goal is to determine how long early-exposure impacts last, and whether they change your risk one way or another,” says Konnikova.

The new findings, meanwhile, offer good news, she says. Parents should feel reassured that infants have the ability to fight infections and develop immunity, even when they arrive in the world ahead of schedule.

The research reported in this news article was supported by the National Institutes of Health (awards R21TR002639, R21HD102565, R01AI171980, R01DK129552, R01HL163043, KL2TR001862, and K08DK133687). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.