The answer, according to a growing body of work and a recent perspective published in the Journal of Perinatology, increasingly points to a noninvasive breath test. For every mole of bilirubin generated by the metabolism of hemoglobin, exactly one mole of carbon monoxide is produced, and this reaction accounts for roughly 80 percent of the body’s endogenous carbon monoxide production. Because carbon monoxide diffuses readily into the airway and can be captured in the exhaled breath, the concentration of end-tidal carbon monoxide corrected for ambient carbon monoxide, abbreviated ETCOc, provides a direct and quantitative readout of the rate of red cell destruction. Christensen and colleagues have gone so far as to designate ETCOc as the gold standard for diagnosing and quantifying hemolysis in neonates and infants, a designation that reflects both the stoichiometric elegance of the measurement and its precision in practice.

The technology behind the measurement has matured considerably. The CoSense device, manufactured by Capnia of Redwood City, California, has been in clinical use for more than a decade and allows ETCOc to be measured noninvasively at the bedside, often within minutes. During that decade, a substantial literature has accumulated describing the use of ETCOc to gauge the degree of hemolysis in newborns, spanning studies of jaundiced infants, preterm populations, and infants at risk for hemolytic disease. The test requires no blood draw, no centrifugation, and no laboratory turnaround time, which makes it uniquely suited to the fast-moving environment of a well-baby nursery where decisions about discharge and phototherapy must often be made within hours.

The clinical stakes are highest for infants in the well-baby nursery. The 2022 guideline notes that significant hemolysis is the only neurotoxicity risk factor for those infants, because any newborn with the other listed risk factors would already be cared for in an intensive care nursery. The guideline also observes that a rapid rate of rise of bilirubin suggests hemolysis and that ETCOc may be useful for quantifying it. In the first table of the guideline, hemolysis appears as a risk factor for developing significant hyperbilirubinemia; in the second, its presence lowers the hour-specific bilirubin level at which phototherapy should begin. A reliable hemolysis measurement therefore translates directly into a treatment decision, potentially triggering earlier phototherapy in an infant whose red cells are being destroyed at an alarming rate.

Traditionally, the standard approximation for significant hemolysis has been a positive direct antibody test, a laboratory assay that detects antibody-coated red blood cells. That test, however, is an imperfect surrogate: it identifies the immunologic potential for hemolysis rather than its actual rate. Before the advent of practical breath testing, it was also simply difficult to measure a newborn’s degree of hemolysis quickly and easily. In conventional statistics, a significant value is one that lies two standard deviations above the mean, or at the 95th percentile, of a distribution for a given population. Applying that logic to ETCOc would mean defining significant hemolysis as an exhaled carbon monoxide level exceeding the 95th percentile of a well-characterized reference population, but the difficulty lies in establishing what that population and its distribution actually look like.

Here the evidence base becomes more complicated than it first appears. Although numerous studies have measured ETCOc in many different groups of infants, the perspective argues that only one study to date has evaluated a large, consecutive cohort of infants with an exclusive hospitalization in the well-baby nursery, excluding infants only for a NICU stay unrelated to phototherapy. Wells and colleagues evaluated 1,029 consecutive admissions to a well-baby nursery and found a mean ETCOc of 1.7 plus or minus 0.5 parts per million for the entire group. Because the cohort had reasonable ethnic diversity, with subgroup means of 1.7 or 1.8 plus or minus 0.5 parts per million, the author of the perspective suggests that an ETCOc of 2.7 parts per million might be a reasonable starting point as an indicator of significant hemolysis in the United States.

Other studies illustrate why a single universal threshold has been so elusive. Bao and colleagues evaluated 499 Chinese infants but excluded those born weighing less than 2,500 grams and did not include the ETCOc values of the 44 infants with hemolysis in their nomogram. Cheng and colleagues studied 386 infants but enrolled only those already at risk for hyperbilirubinemia. One study by Christensen and colleagues measured ETCOc only in infants whose bilirubin exceeded the 95th percentile on the Bhutani nomogram, while another established a reference range from just 30 newborns. Yang and colleagues evaluated 2,500 Chinese infants but included only those with bilirubin levels above the 40th percentile on the Bhutani nomogram. Bhutani and colleagues studied 283 infants across five sites, finding an overall ETCOc of 1.74 plus or minus 0.88 parts per million, with site means ranging from 1.60 plus or minus 0.39 to 1.91 plus or minus 0.49. Bhatia and colleagues restricted enrollment to infants with G6PD deficiency, ABO incompatibility, or a need for phototherapy. Each of these designs answers a different question, and none provides the clean, inclusive reference distribution that a universal cutoff would require.

Population differences compound the problem. The United States accounts for only about 4.2 percent of the world’s population, roughly 349 million of 8.3 billion people, and there may well be different 95th percentiles for ETCOc in other regions of the world, or in subgroups not represented in the Wells cohort. There is also a matter of clinical temperament. Some providers may feel anxious about adopting a value as high as the 95th percentile as the determinant of significant hemolysis, since by definition it would label one in twenty newborns as hemolyzing significantly. For those clinicians, the 75th percentile may feel like a more comfortable and more conservative indicator, accepting a higher false-positive rate in exchange for greater sensitivity to infants at risk.

The perspective’s proposed solution is pragmatic rather than universal: let each unit define its own threshold. Every nursery could measure ETCOc in an inclusive cohort of 200 to 500 consecutive infants admitted to its well-baby service, establishing the local mean and standard deviation for the measurement. The unit could then choose whether to use the 95th percentile, the 75th percentile, or some other value as its indicator of significant hemolysis, tailoring the cutoff to its own population and risk tolerance. This approach acknowledges that ETCOc distributions differ across backgrounds and that the meaning of significance is partly a local decision, while still anchoring that decision in quantitative, unit-specific data rather than in a single borrowed number from a study conducted elsewhere.

What emerges from this analysis is a picture of a technology whose diagnostic power has outpaced its standardization. ETCOc appears to be the best available means of determining the degree of hemolysis in a newborn and of identifying the neurotoxic risk factor that would justify starting phototherapy at a lower bilirubin level. The measurement is noninvasive, rapid, and grounded in a clear biochemical relationship between heme catabolism and carbon monoxide production. What remains missing is an agreed-upon ETCOc level that defines significant hemolysis across populations. Until such consensus emerges, the perspective concludes that appropriate levels for each institution can be readily determined and implemented, allowing nurseries to manage jaundiced newborns safely with the tools and thresholds that best fit the infants in their care.

Subject of Research: End-tidal carbon monoxide measurement for identifying significant hemolysis in newborn jaundice

Article Title: End tidal carbon monoxide and significant hemolysis

Article References: Schutzman, D. L. (2026). End tidal carbon monoxide and significant hemolysis. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02921-5

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02921-5

Keywords: end-tidal carbon monoxide, ETCOc, neonatal hyperbilirubinemia, hemolysis, phototherapy, American Academy of Pediatrics guideline, jaundice, bilirubin, well-baby nursery, CoSense, neurotoxicity risk, perinatology