Staffan K. Berglund

Palovarotene is approved in several countries for reducing heterotopic ossification (HO) in patients with fibrodysplasia ossificans progressiva (FOP), an ultra-rare, severely debilitating, genetic disorder. Approval was based on interim phase III MOVE trial (NCT03312634) analyses at month 18 (IA3), the most complete dataset considering subsequent clinical holds for futility and study restart; however, long-term data remain limited. We report exploratory, post hoc analyses of once daily palovarotene over the 48-mo MOVE trial, including time on and off treatment. The primary efficacy outcome was annualized change in new HO volume, per low-dose whole-body CT. Safety was assessed throughout. Post-baseline HO volume measurements were available for 97 palovarotene-treated patients from MOVE and 101 untreated patients from a natural history study (NHS; NCT02322255). Across 48 mo, mean annualized new HO volume was numerically lower (46.4%) in palovarotene-treated patients compared with untreated patients; however, this difference was not significant (nominal p = .0585). In patients who paused and stopped or paused and restarted palovarotene, mean annualized new HO volume appeared lower when patients received palovarotene compared with when they did not (significance not assessed). The proportions of patients with new HO and number of affected body regions were similar in palovarotene-treated patients and untreated patients (significance not assessed); flare-up rates were consistent with published literature. Adverse events were predominantly retinoid-associated mucocutaneous events. In 80 patients aged <18 yr in MOVE, palovarotene treatment occurred for a mean (SD) of 166.0 (75.2) wk; 24 (30.0%), all aged <14 yr, had premature physeal closure events. Computational analyses showed a significantly increased risk of radiographically-observed, asymptomatic new-onset vertebral deformities with palovarotene treatment. Overall, these exploratory analyses reaffirm the MOVE IA3 findings but should be interpreted with caution; potential efficacy must be weighed against the safety profile of palovarotene, particularly in growing patients. Clinical trial registration number: NCT03312634 (MOVE), NCT02322255 (NHS), and NCT02279095 (phase II OLE).

Objectives: The aim of this follow‐up was to investigate how reduced iron concentration and added bovine lactoferrin in infant formula affect neurodevelopment, iron status, and growth at 12 months of age. Methods: Swedish healthy term formula‐fed infants ( n = 180) were randomly assigned to receive, from 6 weeks to 6 months of age, a low‐iron formula (2 mg/L) fortified with bovine lactoferrin (1.0 g/L) (Lf+, n = 72), the same formula without lactoferrin fortification (Lf−, n = 72) or a control standard formula with 8 mg/L and no lactoferrin (CF, n = 36). Breast‐fed infants were recruited as a reference ( n = 72). At 12 months of age, Bayley Scales of Infant and Toddler Development‐III (BSID‐III), iron status, and anthropometrics were assessed. Results: There were no intervention effects on BSID‐III. Explored outcomes were unaffected by lactoferrin and the two low‐iron groups (Lf+ and Lf−) were combined. The low‐iron group had lower hepcidin (37.8 vs. 49.4 ng/mL, p = 0.027), compared to the CF group. Furthermore, they had iron status indicators more similar to the breast‐fed reference group. The prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) was low with no significant differences among groups. Weight and length were unaffected by intervention, however head circumference was minimally higher in infants fed low‐iron formula compared to CF with mean difference (95% confidence interval) of 0.3 (0.0–0.6) standard‐deviation‐scores, p = 0.03. Conclusions: Infant formula iron concentration at 2 mg/L was adequate in this population of infants with low risk of ID. Adding bovine lactoferrin did not affect the explored long‐term clinical outcomes.

Aim: To examine how reduced iron content and added bovine lactoferrin in infant formula affect the antibody response following routine immunisation.Methods: In this randomised controlled trial, 180 Swedish formula‐fed infants received, from 6 weeks to 6 months of age, a 2 mg/L iron formula with (n = 72) or without (n = 72) bovine lactoferrin, or a control formula with 8 mg/L iron and no lactoferrin (n = 36). Another 72 infants were recruited as a breastfed reference. Serum immunoglobulin G (IgG) levels against Haemophilus influenzae type b (Hib), diphtheria and tetanus were assessed at four, six and 12 months of age.Results: With an equal gender distribution, 180 + 72 term infants were included with a mean age of 7.0 ± 0.7 weeks. At 12 months, infants fed low iron formula showed a significantly higher geometric mean Hib IgG (1.40 μg/mL [1.07–1.83]) compared to the control formula infants (0.67 μg/mL [0.42–1.07]). For all three vaccines, breastfed infants had significantly lower IgG levels at six and 12 months of age.Conclusion: Except for higher Hib IgG levels at 12 months in infants fed low iron formula, the interventions did not affect vaccine IgG response. Unexpectedly, breastfed infants had significantly lower vaccine IgG levels compared to formula‐fed infants.

AimTo evaluate red flags as an instrument to distinguish other medical conditions from Functional Gastrointestinal Disorders (FGID) in children with long-term abdominal pain.MethodsIn a retrospective follow-up, data were collected from 317 children who were referred for medical assessment due to long-term abdominal pain between the years 2011 and 2012 at three Swedish paediatric open clinic units in Sweden. Throughout the review of medical records, any documented red flags at the primary consultation and finally set diagnosis after 1 year were noted for all cases.ResultsA non-FGID disease was diagnosed in 32 cases (10.1%). The sensitivity of red flags to predict inflammatory bowel disease (IBD) was 100% and the specificity 64.1%. The sensitivity of red flags to predict celiac disease was 45.5% and the specificity 63.7%. The sensitivity of red flags to predict any non-FGID disease was 59.4%, and the specificity was 65.6%.ConclusionThe use of red flags is a sensitive instrument to identify patients with IBD but less applicable when identifying celiac disease and other organic diseases. Specificity is generally low and future biomarkers for assessing children with long-term abdominal pain is needed.

Background: Erythroferrone (ERFE) has been identified as a hepcidin-regulating hormone synthetized by erythroblasts correlating to the erythropoietic activity and the needs for iron substrate in bone marrow of adults. The present study aimed to assess the ERFE serum concentrations and its predictors in infants. Methods: ERFE was explored at 4 time points during the first year of life in 45 healthy, breastfed, normal birth weight (NBW) infants, and 136 marginally low birth weight infants (LBW, 2000–2500 g) receiving iron (N = 58) or placebo (N = 78) between 6 weeks and 6 months of age. Results: ERFE concentrations were low at birth, increasing gradually during the first year of life. In NBW infants, reference ranges (5th to 95th percentile) were at 6 weeks <0.005–0.99 ng/mL and at 12 months <0.005–33.7 ng/mL. ERFE was higher in LBW infants at 6 weeks but lower at 12 months compared to NBW and minimally affected by iron supplementation among LBW infants. Correlations of ERFE with erythropoietic and iron status markers were weak and inconsistent. Conclusions: The role of ERFE in the crosstalk of erythropoiesis and iron homeostasis remains unclear in infants and further studies on ERFE in infants and older children are warranted within the framework of the erythropoietin–ERFE–hepcidin axis. Impact: Normal range of erythroferrone in healthy infants is described for the first time. Erythroferrone in infants lacks correlation to iron status and markers of erythropoiesis. The findings indicate differences in infant regulation of iron homeostasis as compared to adults. The findings point to a need to study infant erythropoiesis separately from its adult counterpart. The findings may have clinical impact on management strategies of iron-loading anemia in infancy.

Purpose of review: Iron deficiency is the most common micronutrient deficiency and infants are at particular risk. The purpose of this review is to summarize recent studies that explored the metabolism of iron in infants as well as the risks and benefits of iron supplementation in different populations. Recent findings: The ability of infants to regulate iron homeostasis is not fully known but most likely different from adults. Reducing iron deficiency has beneficial effects on neurodevelopment but iron overload may have adverse functional effects including diarrhea and even poor neurodevelopment. Recent studies have confirmed benefits of delayed cord clamping and supplementation of infants in risk groups while iron supplementation to pregnant women has shown limited effect in the offspring with regard to iron status and neurodevelopment. Further support is given to the recommendation that exclusive breast feeding, without supplementation, is safe for normal birth weight infants until 6 months whereafter an iron-rich diet should be given. Summary: Iron deficiency negatively impacts global health but efforts to identify optimal interventions are progressing. Yet, questions remain, particularly regarding long-term risks, benefits and optimal interventions for low birth weight infants as well as the level of iron fortification in infant formula.

Many infant formulas are fortified with iron at 8–14 mg/L whereas breast milk contains about 0.3 mg/L. Another major difference between breast milk and infant formula is its high concentration of lactoferrin, a bioactive iron-binding protein. The aim of the present study was to investigate how reducing the iron content and adding bovine lactoferrin to infant formula affects iron status, health and development. Swedish healthy full-term formula-fed infants (n = 180) were randomized in a double-blind controlled trial. From 6 weeks to 6 months of age, 72 infants received low-iron formula (2 mg/L) fortified with bovine lactoferrin (1.0 g/L) (Lf+), 72 received low-iron formula un-fortified with lactoferrin (Lf−) and 36 received standard formula with 8 mg of iron/L and no lactoferrin fortification as controls (CF). Iron status and prevalence of iron deficiency (ID) were assessed at 4 and 6 months. All iron status indicators were unaffected by lactoferrin. At 4 and 6 months, the geometric means of ferritin for the combined low-iron groups compared to the CF-group were 67.7 vs. 88.7 and 39.5 vs. 50.9 µg/L, respectively (p = 0.054 and p = 0.056). No significant differences were found for other iron status indicators. In the low-iron group only one infant (0.7%) at 4 months and none at 6 months developed ID. Conclusion: Iron fortification of 2 mg/L is an adequate level during the first half of infancy for healthy term infants in a well-nourished population. Adding lactoferrin does not affect iron status.

Background We aimed to evaluate whether serum hepcidin is a useful indicator of iron status in infants. Methods Term infants (n = 400) were randomized to delayed (≥180 s) or early (≤10 s) cord clamping (CC). Iron status was assessed at 4 and 12 months. In all cases with iron depletion or iron deficiency (ID) (as defined in “Methods”) (n = 30) and 97 randomly selected iron-replete infants, we analyzed hepcidin and explored its correlation to the intervention, iron status, and perinatal factors. Results Serum hepcidin concentrations were significantly lower in the early CC group at both time points and in ID infants at 4 months. Median (2.5th–97.5th percentile) hepcidin in non-ID infants in the delayed CC group (suggested reference) was 64.5 (10.9–142.1), 39.5 (3.5–157.7), and 32.9 (11.2–124.2) ng/mL in the cord blood and at 4 and 12 months, respectively. The value of 16 ng/mL was a threshold detecting all cases of iron depletion/ID at 4 months. No similar threshold for ID was observed at 12 months. The strongest predictor of hepcidin at both ages was ferritin. Conclusions Hepcidin is relevant as iron status indicator in early infancy and may be useful to detect ID. Levels <16 ng/mL at 4 months of age indicates ID. Impact Serum hepcidin is a relevant indicator of iron status in early infancy. Normal reference in healthy infants is suggested in this study. Serum hepcidin may be useful in clinical practice to detect iron deficiency.

Being born with very low birth weight (P=0.004), lower VMI-scores (96.5 vs. 100, P=0.028) and lower total mean TEA-Ch scores, (8.5 vs. 9.7, P=0.006), compared to controls. Also, the marginally LBW children had a higher proportion of children below −1SD for VMI and TEA-Ch. Marginally LBW children had lower verbal comprehension IQ, lower visual-motor integration, and lower attention performance than NBW children, suggesting an increased risk of cognitive difficulties in early school age.

Background: Low birth weight (LBW) (≤2500 g) is associated with iron deficiency in infancy and high blood pressure (BP) later in life.