Hydroxyurea is an oral medication taken once daily that works by coaxing the body to produce more fetal haemoglobin, the oxygen-carrying protein normally made by babies in the womb. Fetal haemoglobin has a crucial biochemical property: it prevents red blood cells from adopting the rigid, crescent-shaped sickle form that gives the disease its name. Sickled cells block small blood vessels, causing the excruciating pain crises, organ damage and chronic ill health that characterise sickle cell anaemia. By reactivating fetal haemoglobin production, hydroxyurea reduces these complications at their source. The drug has been recommended treatment in high-income countries for years, but its uptake in much of sub-Saharan Africa, where the vast majority of patients live, has lagged behind for a specific and understandable reason.

That reason concerns the immune system. Hydroxyurea suppresses the bone marrow to some degree, reducing the number of neutrophils, the white blood cells that form the first line of defence against bacterial and viral pathogens. In a hospital with ready access to blood counts, antibiotics and intensive care, this side effect can be monitored and managed. In rural clinics with limited laboratory capacity, doctors have worried that lowering neutrophil counts could tip vulnerable children into severe or fatal infections, including malaria, which is endemic at all four of the trial sites. Malaria is a particular concern because the parasite attacks red blood cells directly, and sickle cell patients already face heightened vulnerability to infection-related complications. Until now, this theoretical risk had not been examined in detail in the settings where it mattered most.

The new analysis addresses that gap with unusual statistical power. Recruitment of children aged one to ten took place between 2014 and 2016, and participants have been followed up every two to three months in the years since, generating more than 5,000 patient years of observation. Children began hydroxyurea at a fixed dose for six months and were then escalated to the maximum dose they could tolerate, the regimen now widely considered optimal. Most infections during the trial were reported retrospectively, usually through clinical history alone rather than real-time laboratory testing, a pragmatic approach that reflects how infections are actually diagnosed in routine care across much of the region.

The results pointed firmly in the opposite direction from the feared harm. Rather than increasing infections, higher hydroxyurea doses were associated with falling infection rates. The risk of malaria dropped by 51 percent with increasing dose, and the risk of non-malarial infections fell by 38 percent. The incidence and severity of infections did not increase over more than a decade of treatment, and in many cases declined. The study authors interpret this pattern as consistent with the drug’s broader benefit: by reducing sickling, vaso-occlusion and the chronic inflammation and organ dysfunction that accompany untreated disease, hydroxyurea appears to leave children better able to withstand the infectious threats around them, not weaker.

Professor Tom Williams of Imperial College London’s Institute of Global Health Innovation, the study lead, emphasised how directly the findings speak to clinical hesitation. He noted that many doctors are cautious of using hydroxyurea because they worry it will increase the risks of severe or fatal infections, particularly in low-income settings with limited medical resources. In the huge study covering more than 5,000 patient years of follow-up, he reported, the team found no increase in illness or death from infections, even when hydroxyurea was used at the maximum tolerated dose. Senior author Professor Russell Ware of Cincinnati Children’s Hospital Medical Center added that the findings provide long-awaited data on the long-term safety of maximum tolerated dose hydroxyurea in low-income settings, with incidence and severity of infections not increasing over ten years of treatment and often decreasing.

The scale of the unmet need behind this research is difficult to overstate. Sickle cell anaemia is the most common and severe inherited blood disease in humans, and approximately 80 percent of cases occur in sub-Saharan Africa. Around 550,000 children are born with the condition every year, facing complications that include chronic pain, vulnerability to life-threatening bacterial and viral infections, and progressive organ damage. Bacterial and viral infections are among the most common and dangerous complications of the disease, yet in many affected countries newborn screening, preventive antibiotics and comprehensive specialist care remain scarce. A cheap, oral, once-daily drug that can be escalated to the right dose with modest monitoring represents one of the few realistic routes to changing that trajectory at scale.

The REACH programme itself has been running for more than a decade and has already demonstrated that hydroxyurea therapy is both safe and highly effective in reducing most sickle-related complications. What this extended analysis adds is the infection-specific evidence that had been missing. Earlier REACH results established the drug’s efficacy against pain crises and other classic complications, but the question of whether immune suppression would translate into real-world infectious harm in malaria-endemic, resource-limited environments remained open. By closing that gap with long-term, dose-escalated follow-up across four countries, the study removes the principal scientific rationale for withholding the drug from the children who need it most.

The study authors’ recommendation is unambiguous: children with sickle cell anaemia living in low-resource settings should receive treatment with hydroxyurea at the maximum tolerated dose. Professor Williams said the results provide strong reassurance that the incidence and severity of infections are not increased with long-term or maximum dose hydroxyurea treatment, and that the findings support the wider use of hydroxyurea as standard of care. For an estimated half a million children born each year into a disease that has historically been undertreated precisely where it is most prevalent, the message from this decade of African-led evidence is clear: the safest option is not to avoid the drug, but to give it, and to give it at the dose the child can tolerate.

Subject of Research: Safety and efficacy of hydroxyurea treatment for children with sickle cell anaemia in low-income African settings

Article Title: Children living with sickle cell can be treated safely using hydroxyurea

Article References: Children living with sickle cell can be treated safely using hydroxyurea. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: sickle cell anaemia, hydroxyurea, REACH trial, fetal haemoglobin, malaria, pediatric haematology, sub-Saharan Africa, infection risk, global health, The Lancet Haematology, neutrophils, maximum tolerated dose

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