Preterm Babies’ Exhaled Breath May Hold Clues to Neonatal Disease

Exhaled breath may be helpful in predicting disease in newborns, specifically those born preterm.

“Premature babies develop distinct diseases that full-term babies do not,” says Hany Aly, MD, Chair of Neonatology at Cleveland Clinic Children’s. “One mechanism could be their different metabolism. For example, premature babies have difficulty handling sugar early in life and tend to show symptoms in a way similar to what we see in adults with diabetes, sometimes requiring insulin therapy. If we can identify metabolic differences like this, perhaps we can predict future disease and take steps to alleviate it.”

Diseases such as retinopathy of prematurity and chronic lung disease are not present at birth but can develop weeks later in premature infants, he notes.

Metabolites — or volatile organic compounds (VOCs) — are end products of metabolic processes that can enter the bloodstream and be excreted through respiration. VOCs are detectable in the exhaled breath of adults. Studies have linked certain levels of VOCs with stroke, heart failure, cirrhosis and other diseases.

Dr. Aly and a research team at Cleveland Clinic Children’s have begun to explore whether the same concept can apply to preterm newborns.

In a recent feasibility study, published in the Journal of Perinatology, the team found two notable things:

It is possible to assess VOCs in newborns’ exhaled breath collected from a breathing tube or air inside an incubator.

Preterm newborns have different levels of some VOCs compared with full-term infants.

Assessing 22 VOCs in exhaled breath condensate

In a pilot study, the research team evaluated 20 newborns in Cleveland Clinic Children’s Neonatal Intensive Care Unit, 10 born full term (≥ 37 weeks of gestational age) and 10 born preterm (< 30 weeks of gestational age). All infants had received full enteral feeds for at least 24 hours. None were intubated or receiving invasive mechanical ventilation.

For each infant, 50 mL of exhaled breath gas was collected from either a noninvasive breathing circuitor ambient air in the incubator. The breath samples were analyzed by mass spectrometry.

VOCs were detectable in all of the breath samples. Of all 22 VOCs measured, researchers found:

• Preterm infants had higher levels of 3-methylhexane compared to full-term infants.
• Full-term infants had higher levels of 12 VOCs: 2-propanol, acetaldehyde, acetone, acetonitrile, benzene, ethanol, isoprene, pentane, 2-nonene, ethane, triethylamine and trimethylamine.

“This study showed the feasibility of collecting breath samples noninvasively in newborns and being able to measure VOCs in them,” Dr. Aly says. “Additionally, we found that VOC concentrations were different for preterm and full-term infants. Now we have a new opportunity to explore what it all means.”

For example, isoprene can be expressed during cholesterol synthesis, pentane during lipid metabolism and ethanol during bacterial metabolism.

Can VOCs identify disease before it occurs?

VOCs also are detectable in neonates’ blood, urine and stool, however those tests — which can be difficult and slower to conduct and depend on biologic samples that are challenging or inconvenient to collect — have never been used to predict disease.

“Today, we can diagnose disease in preterm infants only when it happens. We cannot reliably predict it,” Dr. Aly says. “However, collecting and assessing VOCs in breath samples could be a safe, noninvasive way to diagnose or monitor disease even before symptoms arise.”

Which compound at which level will indicate pending eye disease or lung disease? That is the type of question that Dr. Aly and his colleagues will attempt to answer next.

“In adults, Dr. Raed Dweik and his research team at Cleveland Clinic Integrated Hospital Care Institute, have established that certain VOCs in breath indicate a certain disease, but we see this in adults who already have developed the disease,” Dr. Aly says. “Premature babies aren’t born with disease. They develop it later. If we can use their VOCs to understand what’s happening in their bodies, we may be able to identify some neonatal diseases before they occur and then work to prevent them. That will be the exciting part of this research — like predicting the future and then trying to change it.”

Adding, he says, “We appreciate this opportunity to collaborate on this work by bringing together neonatal and adult researchers.”