Fetal Haemoglobin Crash in the Tiniest Newborns Is Linked to Transfusions and Serious Disease

Every baby is born carrying a molecular relic of life in the womb: fetal haemoglobin, the oxygen-transporting protein that allowed their blood to snatch oxygen from their mother’s circulation across the placenta. For infants born at term, this fetal form of haemoglobin is steadily replaced over the first year of life by the adult version, which releases oxygen more readily into tissues. But for babies born months early, that carefully choreographed molecular handover is thrown into disarray, and a new study suggests the consequences may be far more serious than scientists previously appreciated.

A large retrospective cohort study conducted at the Sophia Children’s Hospital of Erasmus University Medical Centre in Rotterdam, The Netherlands, and published in eClinicalMedicine, has produced the most detailed picture yet of how fetal haemoglobin behaves after very early birth. The researchers, led by Jip H. van Daelen and colleagues, analysed routine blood gas measurements from 856 newborns admitted to the neonatal intensive care unit between February 2020 and February 2024, spanning gestational ages from 24 to 42 weeks. Within this group, they assembled a longitudinal sub-cohort of 458 infants born before 30 weeks of gestation, generating more than 9,400 paired haemoglobin and fetal haemoglobin measurements for modelling.

The first finding concerns what normal looks like. By analysing measurements taken within the first 24 hours after birth, before any transfusion had occurred, the team established gestational age-specific reference values for fetal haemoglobin. The results were striking in their consistency: for babies born between 24 and 35 weeks of gestation, median fetal haemoglobin remained at or above 85 percent of total haemoglobin, with relatively little variation between individuals. Only from around 35 weeks onward did levels begin to fall, reaching a median of roughly 74 percent at 40 weeks, the point at which the natural fetal-to-adult haemoglobin switch is preparing for life outside the womb.

That stability ends abruptly at birth for the most premature infants. Using mixed-effects statistical models with spline terms to capture non-linear change over time, the researchers showed that fetal haemoglobin declines steeply during the first 40 postnatal days across all groups of infants born before 30 weeks, with the sharpest fall seen in those born at 24 to 25 weeks of gestation. Interestingly, the data revealed a modest spontaneous rebound after about day 40 in the youngest infants, with a median rise of 7 percent from the nadir. Yet this recovery fell well short of restoring the levels seen in slightly more mature infants at the same age, suggesting that the endogenous capacity to regenerate fetal red blood cells is limited after such an early exit from the protective uterine environment.

The dominant force accelerating this decline, the study found, is blood transfusion. Half of the infants in the longitudinal cohort received at least one red blood cell transfusion, and these transfusions come from adult donors, meaning the infused cells carry almost exclusively adult haemoglobin. The modelling showed a clear dose-response relationship: infants who received no transfusions maintained adjusted fetal haemoglobin values above 75 percent throughout early follow-up, while those receiving four or more transfusions plummeted to nadir levels of approximately 17 percent. By the end of the observation period, adjusted fetal haemoglobin levels were roughly 28 percentage points lower in the one-to-three transfusion group and 50 percentage points lower in the four-or-more group compared with untransfused infants, independent of gestational age and total haemoglobin concentration.

The physiological logic behind why this matters is rooted in the distinct biochemistry of the two haemoglobin types. Fetal haemoglobin binds oxygen with high affinity and interacts weakly with 2,3-bisphosphoglycerate, the molecule that normally prompts haemoglobin to release oxygen into tissues. This high affinity is ideal in the womb, where oxygen must be extracted from maternal blood. Adult haemoglobin, by contrast, releases oxygen more readily. When adult donor cells flood the circulation of a premature infant, the oxygen dissociation curve shifts to the right within a short interval, delivering more free oxygen to tissues such as the immature retina and lung that are poorly equipped to handle oxidative stress. Excess oxygen free radicals generated in these vulnerable organs are thought to contribute to some of the most feared complications of prematurity.

The clinical data lend weight to that framework. Among the 458 infants born before 30 weeks, 44 percent developed at least one severe prematurity-related outcome: retinopathy of prematurity requiring laser or anti-VEGF treatment, severe bronchopulmonary dysplasia defined by oxygen or ventilatory dependence at 36 weeks postmenstrual age, necrotizing enterocolitis of at least stage II, or death before discharge. In the outcome models, baseline fetal haemoglobin at birth did not differ between infants who later developed these complications and those who did not. But over time, the trajectories diverged dramatically: infants who developed severe disease or died showed a significantly steeper postnatal decline in fetal haemoglobin, with the signal strongest for treated retinopathy of prematurity and severe bronchopulmonary dysplasia, both reaching statistical significance at p less than 0.001.

The authors are careful to frame these as descriptive associations rather than proof of causation. Infants who required more intensive clinical support naturally underwent more frequent blood gas analyses and more transfusions, and residual confounding by illness severity, oxygen exposure, infection, and other treatments cannot be excluded. Fetal haemoglobin decline may therefore reflect a broader vulnerability profile rather than a single causal pathway. The researchers also note technical caveats: fetal haemoglobin was measured with a blood gas analyser rather than the gold-standard high-performance liquid chromatography method, which introduces a modest systematic positive bias, though this is unlikely to distort the longitudinal trajectory findings. The single-centre design and the overlap of the study period with the COVID-19 pandemic add further limitations to generalisability.

Nevertheless, the study arrives at a moment of genuine therapeutic momentum. The randomised BORN trial recently demonstrated that transfusions using red blood cells derived from umbilical cord blood of healthy term newborns, which are rich in fetal haemoglobin, successfully preserved circulating fetal haemoglobin levels in extremely preterm infants, with encouraging per-protocol findings including reduced severity of retinopathy and lung disease. The Rotterdam team’s reference values and trajectory curves now provide exactly the physiological benchmark that such HbF-preserving strategies need, helping define what levels to target and how to interpret deviations. The authors also highlight unresolved questions, including how the timing and spacing of transfusions shape the decline, and whether time-varying models of cumulative exposure would refine predictions. As the search continues for ways to shield the smallest newborns from the oxidative hazards of early extrauterine life, the humble fetal haemoglobin molecule has moved from a developmental curiosity to a central player in neonatal medicine, and preserving it may prove to be one of the most elegant interventions yet conceived.

Subject of Research: Fetal haemoglobin trajectories and transfusion exposure in neonates born before 30 weeks of gestation

Article Title: Gestational age references and trajectory of fetal haemoglobin in relation to outcome in neonates born before 30 weeks of gestation: a single-centre retrospective cohort study in The Netherlands

Article References: van Daelen, J. H., Gangaram-Panday, N. H., Huisman, E. J., Taal, H. R., Klei, T. R., Lopriore, E., Reiss, I. K., Tintu, A. N., & Snijder, P. M. (2026). Gestational age references and trajectory of fetal haemoglobin in relation to outcome in neonates born before 30 weeks of gestation: a single-centre retrospective cohort study in The Netherlands. eClinicalMedicine, 100, Article 104256. https://doi.org/10.1016/j.eclinm.2026.104256

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104256

Keywords: fetal haemoglobin, preterm infants, red blood cell transfusion, retinopathy of prematurity, bronchopulmonary dysplasia, neonatal intensive care, oxygen affinity, cord blood transfusion, haemoglobin switch, oxidative stress, necrotizing enterocolitis, gestational age