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

The underlying biology is straightforward but consequential. Bilirubin is the yellow pigment produced when the heme portion of hemoglobin is catabolized, and every molecule of bilirubin generated corresponds to one molecule of carbon monoxide released as heme oxygenase does its work. In newborns, whose livers are still maturing and whose red cell lifespan is shorter than in older children and adults, any acceleration of red cell destruction can push bilirubin concentrations upward rapidly. When bilirubin crosses the blood-brain barrier in sufficient quantities, it can cause acute bilirubin encephalopathy and permanent kernicterus, a devastating outcome that modern screening and phototherapy are designed to prevent. Identifying hemolysis early therefore gives clinicians a chance to intervene before bilirubin levels reach neurotoxic territory.

The study at the center of the dispute, conducted by Burch and colleagues, compared the direct antiglobulin test, commonly known as the DAT or Coombs test, against end-tidal carbon monoxide corrected for ambient carbon monoxide, abbreviated ETCOc, across three threshold levels. The DAT has long been the traditional tool for flagging immune-mediated hemolysis, particularly in infants whose mothers have antibodies that cross the placenta and coat the fetal red cells. It detects antibody bound to the infant’s red blood cells, which is an indirect and imperfect proxy for whether red cells are actually being destroyed at an accelerated rate. Many infants with clinically significant hemolysis test negative, and many DAT-positive infants never develop problematic bilirubin elevations.

The performance numbers cited in the correspondence are striking. Schutzman endorses the Burch group’s finding that the DAT had a sensitivity of only 13 percent for identifying hemolysis as a neurotoxicity risk factor, meaning the vast majority of hemolyzing infants went undetected by the blood test. ETCOc, by contrast, achieved a sensitivity of 88 percent at a correction threshold of 2.1 parts per million. The logic of the breath test follows directly from heme catabolism: because carbon monoxide is exhaled in proportion to bilirubin production, measuring it in the terminal portion of the infant’s exhaled breath, after subtracting background carbon monoxide in the ambient air, provides a direct physiological readout of the rate of red cell destruction. The approach has been refined over decades, and nomograms establishing reference ranges for term and late-preterm infants, including work in Chinese newborn populations, have helped define what constitutes abnormal heme catabolism in the first days of life.

Where Schutzman parts company with the original study is in its conclusion that ETCOc screening would lead to overdiagnosis, overtreatment, and higher costs. He argues that this conclusion rests on prevalence-dependent quantities, specifically the rates of indicated testing and phototherapy observed in the study cohort, and that those rates cannot be generalized to routine screening. Although all nursery admissions were nominally eligible for the Burch study, the authors themselves acknowledged that their cohort was enriched with DAT-positive and hyperbilirubinemic infants. In other words, the sample was not representative of an ordinary well-baby nursery population, and any cost or treatment projections drawn from it inherit that bias.

The magnitude of the bias, as Schutzman lays it out, is considerable. The Burch cohort showed a phototherapy rate of 9 percent, which he notes is more than fourfold the 2.1 percent rate reported in the same eight-hospital network when an unselected population of 22,455 infants was examined in earlier work by Sarathy and colleagues. That earlier study, published in Pediatrics, examined bilirubin measurement and phototherapy use after the American Academy of Pediatrics issued its 2022 newborn hyperbilirubinemia guideline, providing a large benchmark for what phototherapy utilization actually looks like across a broad, unselected nursery population. A selective sample, Schutzman contends, simply cannot support conclusions about what would happen if ETCOc were adopted for routine or universal screening.

To make the counterpoint concrete, the correspondence points to the only study to date that evaluated a large, continuous cohort of all admissions to a well-baby nursery. That investigation, by Wells and colleagues and published in the Journal of Perinatology in 2025, examined end-tidal carbon monoxide monitoring for significant hemolysis in the routine management of newborn hyperbilirubinemia. Its findings ran in the opposite direction from the overdiagnosis concern: when ETCOc was used across an unselected population, it was associated with reductions in serum bilirubin sampling, in phototherapy use, and in readmissions. The mechanistic explanation is plausible. If a breath test reliably identifies which infants are truly hemolyzing, clinicians can reserve blood draws and treatment for those who need them, while confidently observing infants whose bilirubin production is normal, rather than reflexively testing and treating based on an insensitive proxy.

The correspondence also situates the debate within a broader effort to establish a definitive reference standard for neonatal hemolysis. A 2023 review by Christensen, Stevenson, Bhutani, and coauthors asked whether any test could serve as a gold standard for diagnosing and quantifying hemolysis in neonates and infants, highlighting the inherent difficulty of the problem. Hemolysis is a dynamic process, its rate changing hour by hour in the first days of life, and no single static measurement captures it perfectly. Earlier collaborative work by Bhutani, Maisels, Schutzman, and colleagues published in Acta Paediatrica in 2018 addressed the identification of risk for neonatal hemolysis directly, helping to frame ETCOc as a physiologically grounded candidate for that role. The current exchange is thus not an isolated squabble over a single study but part of a decade-long effort to replace indirect markers with a direct measure of heme catabolism.

What hangs on this methodological dispute is far from academic. Severe neonatal hyperbilirubinemia remains one of the most common reasons for newborn readmission, and kernicterus, while rare in well-resourced settings, is entirely preventable when at-risk infants are recognized in time. A screening strategy that misses nearly nine out of ten hemolyzing infants, as a 13 percent sensitivity implies, leaves a substantial reservoir of risk undetected, particularly among infants whose hemolysis is not immune-mediated and would never be flagged by a DAT. Conversely, an approach that indiscriminately expands testing and treatment burdens families and health systems. The correspondence argues that the evidence points toward the breath test as the more faithful instrument, and that fears of overtreatment rest on a biased sample rather than on data from the populations in which routine screening would actually be deployed.

For now, the field awaits the kind of large, unselected, prospective studies that both sides agree would settle the question. The correspondence itself declares no funding, and its author discloses only an unpaid advisory role with a company in the field, Capnia, Inc., alongside affiliations with Jefferson Einstein Philadelphia Hospital, Thomas Jefferson University Hospital, and Nemours Children’s Hospital Delaware. Whether ETCOc moves from research tool to standard nursery practice will depend on whether the reductions in blood sampling, phototherapy, and readmissions seen in the Wells cohort can be replicated at scale. But the core physiological insight at the heart of the debate, that every bilirubin molecule announces itself in a puff of exhaled carbon monoxide, continues to make the breath test a compelling candidate for catching the hemolyzing newborn before jaundice becomes dangerous.

Subject of Research: Comparison of the direct antiglobulin test and end-tidal carbon monoxide measurement for detecting hemolytic hyperbilirubinemia in newborns

Article Title: Hemolytic hyperbilirubinemia

Article References: Schutzman, D. L. (2026). Hemolytic hyperbilirubinemia. Journal of Perinatology. https://doi.org/10.1038/s41372-026-02919-z

Image Credits: AI Generated

DOI: 10.1038/s41372-026-02919-z

Keywords: neonatal jaundice, hyperbilirubinemia, hemolysis, end-tidal carbon monoxide, direct antiglobulin test, phototherapy, newborn screening, bilirubin, kernicterus, neonatology, Journal of Perinatology, diagnostic sensitivity