Physical Activity, Fitness, and Cardiovascular Disease Risk in Adolescent Childhood Cancer Survivors Compared to Controls: The Physical Activity in Childhood Cancer Survivors Study.

Purpose: Childhood cancer survivors have increased risk of cardiac late effects that can be potentially mitigated by physical activity and fitness. We aimed to (1) compare cardiovascular disease (CVD) risk between survivors and controls, and (2) examine whether the associations of moderate-to-vigorous physical activity (MVPA), cardiorespiratory fitness (CRF), and musculoskeletal fitness (MSF) with CVD risk factors differed between survivors and controls. Methods: Within the Physical Activity in Childhood Cancer Survivors (PACCS) study, we assessed CVD risk factors (android fat mass, systolic blood pressure [SBP], total cholesterol/high-density lipoprotein [HDL]-cholesterol, and glycosylated hemoglobin) in 157 childhood cancer survivors and 113 age- and sex-matched controls aged 9-18 years. We used multivariable mixed linear regression models to compare CVD risk factors between survivors and controls, and assess associations of MVPA, CRF, and MSF with CVD risk factors. Results: Compared with controls, survivors had more android fat mass (861 vs. 648 g, p = 0.001) and lower SBP (114 vs. 118 mmHg, p = 0.002). MVPA, CRF, and MSF were associated with lower levels of android fat mass and total cholesterol/HDL-cholesterol, and higher SBP in survivors. Associations of MVPA, CRF, and MSF with CVD risk factors were similar in survivors and controls (Pinteraction > 0.05), except the associations of CRF and MSF with android fat mass, which were stronger in survivors than in controls (Pinteraction ≤ 0.001). Conclusion: Owing to higher levels of android fat mass and its stronger association with physical fitness in childhood cancer survivors compared with controls, survivors should get targeted interventions to increase fitness to reduce future risk of CVD.

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen: A Nonrandomized Controlled Trial.

Importance: Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. Objective: To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). Design, Setting, and Participants: This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. Interventions: Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. Main Outcomes and Measures: The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. Results: Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. Conclusions and Relevance: This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT01356290.

Physical Activity Among Adolescent Cancer Survivors: The PACCS Study.

OBJECTIVES: Physical activity (PA) may modify risks of late effects after cancer. We aimed to examine levels of PA and sedentary time (ST) in a large, international sample of adolescent childhood cancer survivors in relation to sociodemographic and cancer-related factors and compare levels of PA and ST to reference cohorts. METHODS: Survivors from any cancer diagnosis who had completed cancer treatment ≥1 year ago, aged 9 to 16 years, were eligible for the multicenter Physical Activity in Childhood Cancer Survivors study. PA and ST were measured by ActiGraph GT3X+ accelerometers. We performed linear regression analyses to assess factors associated with moderate-to-vigorous PA (MVPA) and ST, and compared marginal means of total PA, MVPA, and ST in 432 survivors to sex- and age-stratified references (2-year intervals) using immediate t-tests for aggregated data. RESULTS: Among survivors, 34% fulfilled the World Health Organization's PA recommendation of ≥60 min of daily MVPA on average and their ST was 8.7 hours per day. Being female, older, overweight, a survivor of central nervous system tumor, or having experienced relapse were associated with lower MVPA and/or higher ST. Generally, male survivors spent less time in MVPA compared with references, whereas female survivors had similar levels. Both male and female survivors had higher ST than references in nearly all age groups. CONCLUSIONS: The low PA and high ST in this large sample of adolescent childhood cancer survivors is worrisome. Combined, our results call for targeted interventions addressing both PA and ST in follow-up care after childhood cancer.

Systolic myocardial function measured by echocardiographic speckle-tracking and peak oxygen consumption in pediatric childhood cancer survivors-a PACCS study.

Background: Cancer therapy-related cardiotoxicity is a major cause of cardiovascular morbidity in childhood cancer survivors. The aims of this study were to investigate systolic myocardial function and its association to cardiorespiratory fitness in pediatric childhood cancer survivors. Methods: In this sub-study of the international study "Physical Activity and fitness in Childhood Cancer Survivors" (PACCS), echocardiographic measures of left ventricular global longitudinal strain (LV-GLS) and right ventricular longitudinal strain (RV-LS) were measured in 128 childhood cancer survivors aged 9-18 years and in 23 age- and sex-matched controls. Cardiorespiratory fitness was measured as peak oxygen consumption achieved on treadmill and correlated to myocardial function. Results: Mean LV-GLS was reduced in the childhood cancer survivors compared to the controls, -19.7% [95% confidence interval (CI) -20.1% to -19.3%] vs. -21.3% (95% CI: -22.2% to -20.3%) (p = 0.004), however, mainly within normal range. Only 13% of the childhood cancer survivors had reduced LV longitudinal strain z-score. Mean RV-LS was similar in the childhood cancer survivors and the controls, -23.2% (95% CI: -23.7% to -22.6%) vs. -23.3% (95% CI: -24.6% to -22.0%) (p = 0.8). In the childhood cancer survivors, lower myocardial function was associated with lower peak oxygen consumption [correlation coefficient (r) = -0.3 for LV-GLS]. Higher doses of anthracyclines (r = 0.5 for LV-GLS and 0.2 for RV-LS) and increasing time after treatment (r = 0.3 for LV-GLS and 0.2 for RV-LS) were associated with lower myocardial function. Conclusions: Left ventricular function, but not right ventricular function, was reduced in pediatric childhood cancer survivors compared to controls, and a lower left ventricular myocardial function was associated with lower peak oxygen consumption. Furthermore, higher anthracycline doses and increasing time after treatment were associated with lower myocardial function, implying that long-term follow-up is important in this population at risk.

Polyneuropathy in Adolescent Childhood Cancer Survivors: The PACCS Study.

BACKGROUND: Childhood cancer survivors (CCS) are at risk of polyneuropathy due to chemotherapy, but studies in young survivors are scarce and diagnosis is challenging. We aimed to study the presence of polyneuropathy and the possible effect of cumulative doses of chemotherapeutic agents in a representative group of adolescent survivors. METHODS: CCS aged nine to 18 years and age- and sex-matched controls were recruited from the cross-sectional Physical Activity and Fitness among Childhood Cancer Survivors (PACCS) study. CCS with various cancer diagnoses who had ended cancer treatment one year or more before study were included. Polyneuropathy was evaluated clinically and with nerve conduction studies (NCSs) in three motor and five sensory nerves. We used mixed-effects linear regression models to compare CCS and controls, and investigate possible associations between cumulative chemotherapy doses and NCS amplitudes. RESULTS: A total of 127 CCS and 87 controls were included, with 14% CCS having probable or confirmed polyneuropathy. NCS amplitudes were lower in survivors compared with controls in all nerves. The largest mean difference was 3.47 µV (95% confidence interval [CI], 2.18 to 4.75) in the tibial plantar medial sensory and 1.91 mV (95% CI, 0.78 to 3.04) in the tibial motor nerve. The cumulative dose of platinum derivatives was associated with lower tibial motor nerve amplitude (-0.20; 95% CI, -0.35 to -0.04 mV for 100 mg/m2 dose increase) but not in other nerves. We found no significant associations between vinca alkaloids cumulative dose and amplitudes. CONCLUSIONS: CCS without clinical signs or symptoms of polyneuropathy may have subtle nerve affection. The clinical long-term impact of this novel observation should be evaluated in larger, longitudinal studies.

Device-measured physical activity and cardiovascular disease risk in adolescent childhood cancer survivors. A physical activity in childhood cancer survivors (PACCS) study.

Objectives: We aimed to compare cardiovascular disease (CVD) risk factors in childhood cancer survivors (CCS) with age- and sex-stratified reference material and examine the association between physical activity (PA) intensities and CVD risk factors in CCS. Materials and methods: Within the cross-sectional, multicenter Physical Activity in Childhood Cancer Survivors (PACCS) study, we collected data on CVD risk factors [VO2-peak (mL⋅kg-1⋅min-1), body mass index (BMI, kg/m2), systolic blood pressure (SBP, mmHg), and total-cholesterol/HDL-cholesterol (Total/HDL)] among CCS aged 9-18 years. CVD risk factors were compared to references with immediate t-tests. We transformed CVD risk factors into z-scores based on international references and generated an individual CVD risk score: [inverse ZVO2-peak + Z BMI + Z SBP + Z Total/HDL )/4]. Multivariable mixed linear regression models were used to analyze the associations between device-measured PA intensities and CVD risk factors. Results: We included 157 CCS aged on average 13.4 years at inclusion and 8.2 years from diagnosis. Male CCS had lower VO2-peak compared to references (45.4 vs. 49.4 mL⋅kg-1⋅min-1, P = 0.001), higher diastolic BP (67 vs. 63 mmHg, P < 0.001), lower HDL (1.35 vs. 1.44 mmol/L, P = 0.012), as well as a tendency to higher CVD risk score (z-score=0.14 vs. 0.00, P = .075). Female CCS' CVD risk factors were comparable to references. Vigorous-intensity PA (VPA) was associated with CVD risk factors. A 10-min increase in VPA was associated with higher VO2-peak (ß = 4.9, 95% CI, 2.1-7.7), lower Total/HDL (ß = -0.3, 95% CI, -0.6 to -0.1) and a lower CVD risk score (ß = -0.4, 95% CI, -0.6 to -0.2). Conclusion: Male adolescent CCS had less favorable values of CVD risk factors compared to references. VPA in adolescent CCS is associated with clinically meaningful favorable values of CVD risk factors.

The Physical Activity and Fitness in Childhood Cancer Survivors (PACCS) Study: Protocol for an International Mixed Methods Study.

BACKGROUND: Survivors of childhood cancer represent a growing population with a long life expectancy but high risks of treatment-induced morbidity and premature mortality. Regular physical activity (PA) may improve their long-term health; however, high-quality empirical knowledge is sparse. OBJECTIVE: The Physical Activity and Fitness in Childhood Cancer Survivors (PACCS) study comprises 4 work packages (WPs) aiming for the objective determination of PA and self-reported health behavior, fatigue, and quality of life (WP 1); physical fitness determination (WP 2); the evaluation of barriers to and facilitators of PA (WP 1 and 3); and the feasibility testing of an intervention to increase PA and physical fitness (WP 4). METHODS: The PACCS study will use a mixed methods design, combining patient-reported outcome measures and objective clinical and physiological assessments with qualitative data gathering methods. A total of 500 survivors of childhood cancer aged 9 to 18 years with ≥1 year after treatment completion will be recruited in follow-up care clinics in Norway, Denmark, Finland, Germany, and Switzerland. All participants will participate in WP 1, of which approximately 150, 40, and 30 will be recruited to WP 2, WP3, and WP 4, respectively. The reference material for WP 1 is available from existing studies, whereas WP 2 will recruit healthy controls. PA levels will be measured using ActiGraph accelerometers and self-reports. Validated questionnaires will be used to assess health behaviors, fatigue, and quality of life. Physical fitness will be measured by a cardiopulmonary exercise test, isometric muscle strength tests, and muscle power and endurance tests. Limiting factors will be identified via neurological, pulmonary, and cardiac evaluations and the assessment of body composition and muscle size. Semistructured, qualitative interviews, analyzed using systematic text condensation, will identify the perceived barriers to and facilitators of PA for survivors of childhood cancer. In WP 4, we will evaluate the feasibility of a 6-month personalized PA intervention with the involvement of local structures. RESULTS: Ethical approvals have been secured at all participating sites (Norwegian Regional Committee for Medical Research Ethics [2016/953 and 2018/739]; the Oslo University Hospital Data Protection Officer; equivalent institutions in Finland, Denmark [file H-19032270], Germany, and Switzerland [Ethics Committee of Northwestern and Central Switzerland, project ID: 2019-00410]). Data collection for WP 1 to 3 is complete. This will be completed by July 2022 for WP 4. Several publications are already in preparation, and 2 have been published. CONCLUSIONS: The PACCS study will generate high-quality knowledge that will contribute to the development of an evidence-based PA intervention for young survivors of childhood cancer to improve their long-term care and health. We will identify physiological, psychological, and social barriers to PA that can be targeted in interventions with immediate benefits for young survivors of childhood cancer in need of rehabilitation. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35838.

Impaired gross motor development in infants with higher PFAS concentrations.

Industrial produced perfluoroalkyl substances (PFAS) are environmentally persistent and found in humans around the globe. PFAS is transferred from mother to child during pregnancy and lactation and PFAS concentrations are high in infants. PFAS exposure in early life has been linked to a range of negative health effects. In the present study we have investigated PFAS concentrations in mothers (pregnancy week 18, 28 and 36 and six weeks, four and six months postpartum, n = 114) and in infants at six months age (n = 94), and studied the effects of PFAS status on infant gross motor development by Alberta Infant Motor Scale (AIMS) at age six months. PFAS concentrations declined in the mothers during pregnancy and postpartum period, and the highest concentrations were seen in infants aged six months. Parity was a strong negative predictor and fish intake a strong positive predictor of maternal PFAS status, while maternal concentrations of PFAS in pregnancy week 18 and months of exclusive breastfeeding determined the PFAS concentrations in infants at six months. Infants who scored below the median on gross motor development had higher PFAS concentrations than infants with a better gross motor development. Ninety percent of the women reported having fish for dinner at least once a week, with fatty fish as the most popular choice (72%). A higher maternal fish intake in pregnancy week 18 was associated with a poorer gross motor development in the infants at six months. Infant gross motor development is a marker of later cognitive outcome and our findings indicate that higher PFAS concentrations in young infants and maternal fatty fish intake may impair neurodevelopment.

Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

Children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor in Norway from 1974 through 2013: Unexplainable regional differences in survival.

BACKGROUND: A previous study based on Norwegian Cancer Registry data suggested regional differences in overall survival (OS) after treatment for medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET) in Norway. The purpose of the present study was to confirm in an extended cohort whether there were regional differences in outcome or not, and if so try to identify possible explanations. MATERIAL AND METHODS: Data from patients aged 0-20 years diagnosed with and treated for MB/CNS-PNET at all four university hospitals in Norway from 1974 to 2013 were collected and compared. RESULTS: Of 266 identified patients, 251 fulfilled inclusion criteria. MB was diagnosed in 200 and CNS-PNET in 51 patients. Five-year OS and event-free survival (EFS) were 59% and 52%, respectively. There was a significant difference in five-year OS and EFS between MB and CNS-PNET patients; 62% versus 47% (P =  0.007) and 57% versus 35% (P < 0.001). In multivariable analysis, two factors were found to significantly contribute to improved five-year OS and EFS, whereas one factor contributed to improved five-year OS only. Gross total resection (GTR) versus non-GTR (hazard ratio [HR] 0.53, P =  0.003; HR 0.46, P < 0.001) and cerebrospinal irradiation (CSI) versus non-CSI (HR 0.24, P < 0.001; HR 0.28, P < 0.001) for both, and treatment outside Oslo University Hospital for OS only (HR 0.64, P =  0.048). CONCLUSION: Survival was comparable with data from other population-based studies, and the importance of GTR and CSI was confirmed. The cause for regional survival differences could not be identified.

Maternal Serum Cobalamin at 18 Weeks of Pregnancy Predicts Infant Cobalamin Status at 6 Months-A Prospective, Observational Study.

Background: An adequate maternal cobalamin status is crucial for fetal and infant neurodevelopment. Pregnancy-induced physiologic changes make evaluation of maternal cobalamin status in pregnancy difficult. Objective: We have investigated maternal cobalamin status during pregnancy in order to establish a maternal cobalamin concentration which secures an optimal infant cobalamin status during the first 6 mo of life. Methods: In an observational, prospective study, markers of cobalamin status including serum cobalamin, plasma total homocysteine (tHcy), and plasma methylmalonic acid (MMA) were assessed in healthy pregnant women (n = 114) from week 18 of pregnancy through 6 mo postpartum and related to infant cobalamin status at 6 mo. Healthy, never-pregnant women aged 18-40 y (n = 123) were included as controls. Results: Compared to controls, all markers of cobalamin status were lower in pregnant women. Median serum cobalamin concentration progressively decreased from week 18 to week 36 of pregnancy (356 to 302 pmol/L, P < 0.001) and increased by >40% by 6 wk postpartum (518 pmol/L). The metabolic markers increased from week 18 of pregnancy to 6 wk postpartum: median plasma tHcy 3.9 to 7.7 µmol/L (P < 0.001), and MMA 0.13 to 0.17 µmol/L (P < 0.001). The serum cobalamin concentration of infants at age 6 mo correlated with maternal serum cobalamin concentration during pregnancy and postpartum (rho = 0.36-0.55, P < 0.001). A maternal serum cobalamin concentration <394 pmol/L during week 18 of pregnancy was associated with an increased risk (OR: 4.2; 95% CI: 1.5, 11.5) of infant biochemical cobalamin deficiency at 6 mo (defined as tHcy ≥6.5 µmol/L). Conclusions: The maternal serum cobalamin concentration in early pregnancy is a strong predictor for later maternal and infant cobalamin status. To secure an optimal infant cobalamin status during the first 6 mo of life, we recommend a maternal serum cobalamin concentration >394 pmol/L at week 18 of pregnancy. This should be confirmed in an intervention study. This trial was registered at clinicaltrials.gov as NCT03272022.

Impact of Maternal Selenium Status on Infant Outcome during the First 6 Months of Life.

Pregnant women and infants are at risk for selenium deficiency, which is known to have negative effects on immune and brain function. We have investigated selenium levels in 158 healthy never-pregnant women and in 114 pregnant and lactating women and their infants at age 6 months and related this to clinical outcomes during the first 6 months of life. Neurodevelopment was assessed with the parental questionnaire Ages and Stages (ASQ) at 6 months. A maternal selenium level ≤0.90 µmol/L in pregnancy week 18 was negatively related to infant neurodevelopment at 6 months (B = -20, p = 0.01), whereas a selenium level ≤0.78 µmol/L in pregnancy week 36 was associated with an increased risk (odds ratio 4.8) of having an infant infection during the first 6 weeks of life. A low maternal selenium status in pregnancy was found to be associated with an increased risk of infant infection during the first 6 weeks of life and a lower psychomotor score at 6 months. We suggest a cutoff for maternal serum selenium deficiency of 0.90 µmol/L in pregnancy week 18 and 0.78 µmol/L in pregnancy week 36. This should be reevaluated in an intervention study.

Development of the SIOPE DIPG network, registry and imaging repository: a collaborative effort to optimize research into a rare and lethal disease.

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.

Motor development related to duration of exclusive breastfeeding, B vitamin status and B12 supplementation in infants with a birth weight between 2000-3000 g, results from a randomized intervention trial.

BACKGROUND: Exclusive breastfeeding for 6 months is assumed to ensure adequate micronutrients for term infants. Our objective was to investigate the effects of prolonged breastfeeding on B vitamin status and neurodevelopment in 80 infants with subnormal birth weights (2000-3000 g) and examine if cobalamin supplementation may benefit motor function in infants who developed biochemical signs of impaired cobalamin function (total homocysteine (tHcy) > 6.5 µmol/L) at 6 months. METHODS: Levels of cobalamin, folate, riboflavin and pyridoxal 5´-phosphate, and the metabolic markers tHcy and methylmalonic acid (MMA), were determined at 6 weeks, 4 and 6 months (n = 80/68/66). Neurodevelopment was assessed with the Alberta Infants Motor Scale (AIMS) and the parental questionnaire Ages and Stages (ASQ) at 6 months. At 6 months, 32 of 36 infants with tHcy > 6.5 µmol/L were enrolled in a double blind randomized controlled trial to receive 400 µg hydroxycobalamin intramuscularly (n = 16) or sham injection (n = 16). Biochemical status and neurodevelopment were evaluated after one month. RESULTS: Except for folate, infants who were exclusively breastfed for >1 month had lower B vitamin levels at all assessments and higher tHcy and MMA levels at 4 and 6 months. At 6 months, these infants had lower AIMS scores (p = 0.03) and ASQ gross motor scores (p = 0.01). Compared to the placebo group, cobalamin treatment resulted in a decrease in plasma tHcy (p < 0.001) and MMA (p = 0.001) levels and a larger increase in AIMS (p = 0.02) and ASQ gross motor scores (p = 0.03). CONCLUSIONS: The findings suggest that prolonged exclusive breastfeeding may not provide sufficient B vitamins for small infants, and that this may have a negative effect on early gross motor development. In infants with mild cobalamin deficiency at 6 months, cobalamin treatment significantly improvement cobalamin status and motor function, suggesting that the observed impairment in motor function associated with long-term exclusive breastfeeding, may be due to cobalamin deficiency. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01201005.

Targeted program for provision of mother's own milk to very low birth weight infants.

OBJECTIVE: Evaluate the effect of an evolving targeted program to encourage mothers to provide own milk (MM) to their very low birth weight (VLBW) infants in a traditional open-bay NICU. METHODS: Retrospective review of medical records on all VLBW infants (birth weight <1500 g) born in a geographical region of Norway in 1986/1987, 1996, and 2007/2008 (n = 203). Types of nutrition and data on maternal and infant health were prospectively and similarly recorded during all time periods. Between each period, targeted programs were initiated to encourage provision of MM. RESULTS: The rates of providing MM (exclusively MM in parenthesis) for the 3 periods were 55% (33%), 85% (60%), and 89% (62%) when achieving full enteral feeds; 48% (11%), 76% (39%), and 92% (60%) at discharge; 15%, 42%, and 62% at 2 to 4 months' corrected age; and 10%, 40%, and 53% at 6 to 8 months' corrected age (P < .001 at all end points). Neither maternal or pregnancy disorders nor neonatal morbidity had significant effects on provision of MM, but smoking was associated with a lower rate after discharge. CONCLUSIONS: Both early and long-term provision of MM for their VLBW infants were strongly associated with targeted programs to encourage provision. We suggest that almost all mothers are able to provide their own milk if given targeted encouragement and guidance, even in crowded open-bay NICUs.

Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study.

BACKGROUND: During infancy, minor developmental delays and gastrointestinal complaints are common, as is a biochemical profile indicative of impaired cobalamin status. OBJECTIVE: We investigated whether cobalamin supplementation can improve development or symptoms in infants with biochemical signs of impaired cobalamin function and developmental delay or feeding difficulties. DESIGN: Infants <8 mo of age (n = 105) who were referred for feeding difficulties, subtle neurologic symptoms, or delayed psychomotor development were assessed for cobalamin status [by the measurement of serum cobalamin, plasma total homocysteine (tHcy), and plasma methylmalonic acid (MMA)]. Infants with biochemical signs of impaired cobalamin function, defined as a plasma tHcy concentration ≥6.5 µmol/L (n = 79), were enrolled in a double-blind, randomized controlled trial to receive 400 µg hydroxycobalamin intramuscularly (n = 42) or a sham injection (n = 37). Motor function [Alberta Infants Motor Scale (AIMS)] and clinical symptoms (parental questionnaire) were recorded at entry and after 1 mo. RESULTS: During follow-up, cobalamin supplementation changed all markers of impaired cobalamin status (ie, plasma tHcy decreased by 54%, and MMA decreased by 84%), whereas no significant changes were seen in the placebo group (P < 0.001). The median (IQR) increase in the AIMS score was higher in the cobalamin group than in the placebo group [7.0 (5.0, 9.0) compared with 4.5 (3.3, 6.0); P = 0.003], and a higher proportion showed improvements in regurgitations (69% compared with 29%, respectively; P = 0.003). CONCLUSIONS: In infants with biochemical signs of impaired cobalamin function, 1 intramuscular injection of cobalamin resulted in biochemical evidence of cobalamin repletion and improvement in motor function and regurgitations, which suggest that an adequate cobalamin status is important for a rapidly developing nervous system. This trial was registered at clinicaltrials.gov as NCT00710359 and NCT00710138.

Biochemical signs of impaired cobalamin function do not affect hematological parameters in young infants: results from a double-blind randomized controlled trial.

BACKGROUND: Whereas iron deficiency is considered the leading cause of anemia in infants, cobalamin deficiency is foremost characterized by developmental delay, and the typical macrocytic anemia is confined to severe and longstanding cobalamin deficiency in this age group. Hematological parameters were investigated in 4-mo-old infants with biochemical signs of impaired cobalamin function who participated in a randomized controlled cobalamin intervention study at 6 wk. METHODS: One hundred and seven infants were randomly assigned to receive either an intramuscular injection with 400 µg cobalamin or no intervention at 6 wk. Hematological parameters, and cobalamin and folate status were determined at inclusion and 4 mo. RESULTS: Cobalamin supplementation improved all markers of impaired cobalamin function but had no effect on hematological cell counts at 4 mo (P > 0.18). Signs indicative of an iron-restricted erythropoiesis were observed at 6 wk and 4 mo. At 4 mo, the strongest predictors of low iron status were male gender and a high percentage weight increase from birth. CONCLUSION: In infants with biochemical signs of impaired cobalamin function, supplementation does not improve hematological cell counts. Variations in erythrocyte parameters seem to be foremost associated with iron status in this age group.

Evaluating iron status and the risk of anemia in young infants using erythrocyte parameters.

BACKGROUND: Correct evaluation of iron status is important in young infants because both iron deficiency and excess may have negative effects on development, growth, and morbidity. METHODS: We evaluated iron status using erythrocyte parameters, including reticulocyte hemoglobin content (CHr) in infants with birth weight <3,000 g (n = 80). Blood samples and infant characteristics were recorded at 6 wk and at 4 and 6 months. Infants with a birth weight ≤2,500 g (n = 36) were recommended for iron supplementation. RESULTS: Despite a significantly poorer status at 6 wk, iron-supplemented infants had significantly higher hemoglobin level (Hb): 12.2 (SD = 0.8) g/dl and CHr: 28.3 (SD = 1.4) pg at 6 mo, as compared with nonsupplemented infants, Hb: 11.7 (SD = 1.0) g/dl, P = 0.02 and CHr: 26.5 (SD = 2.5) pg, P < 0.001. Prolonged exclusive breastfeeding, high weight gain, and male gender were the predisposing factors for a low iron status at 6 mo. A CHr cutoff level of 26.9 pg at 4 mo proved to be a sensitive predictor for anemia at 6 mo. CONCLUSION: Signs of an iron-restricted erythropoiesis were observed in nonsupplemented infants (birth weight 2,501-3,000 g), and CHr was a useful tool for evaluating iron status. The need for iron supplementation in certain infant risk populations should be further evaluated.

Increased yet iron-restricted erythropoiesis in postpartum mothers.

Iron deficiency in the postpartum period is common and associated with impaired quality of life. Interpretation of ordinary laboratory parameters is considered to be simple in postpartum women, as normalization of pregnancy induced physiological changes is assumed to take place in the early postpartum period. We have studied changes in erythrocyte and iron parameters during the first 11 postpartum months. Erythrocyte parameters and iron markers, serum ferritin, and soluble transferrin receptor (sTfR), and an inflammation marker, neopterin, were investigated in healthy mothers 6 weeks (n = 104), 4 months (n = 100), and 11 months (n = 43) after giving birth to a term infant. Healthy nonpregnant and nonlactating women (n = 61) were included as controls. The hemoglobin level increased throughout the first 11 postpartum months and was significantly higher from 4 months on, compared to control women. At all time points, the mothers had significantly lower mean corpuscular volume (MCV) and higher erythrocyte count and percentage of hypochromic erythrocytes. sTfR levels were significantly higher over the whole serum ferritin distribution during the first 4 postpartum months compared to the controls, indicative of an increased cell production. At 6 weeks, postpartum mothers had higher neopterin levels and this was associated with markers of a low iron status, not including sTfR. Substantial changes in erythrocyte and iron parameters were observed in the postpartum period, consistent with an increased, but iron restricted erythropoiesis. The increased erythropoietic activity was reflected in higher sTfR concentrations. Given the vital role for iron in both mothers and infants, further studies are warranted for establishing proper cut off levels for sTfR as an iron marker in postpartum women.

Common metabolic profile in infants indicating impaired cobalamin status responds to cobalamin supplementation.

OBJECTIVE: A metabolic profile consistent with impaired cobalamin status is prevalent in breastfed infants. We investigated whether this profile reflects immature organ systems or impaired cobalamin status. METHODS: In a single-center, randomized, placebo-controlled trial, we studied 107 six-week-old infants. The infants were randomly assigned to receive either an intramuscular injection of 400 mug of cobalamin or no intervention. Concentrations of cobalamin and folate in serum and total homocysteine, methylmalonic acid, and cystathionine in plasma were determined at enrollment and at the age of 4 months. RESULTS: There were no significant differences between the intervention group (n = 54) and the control group (n = 53) in the concentrations of any vitamin marker at baseline (6 weeks). At 4 months, the supplement-treated infants had a 75% higher median serum cobalamin level and remarkable reductions in median plasma total homocysteine (from 7.46 to 4.57 micromol/L) and methylmalonic acid (from 0.58 to 0.20 micromol/L) levels, whereas levels of both metabolites were essentially unchanged during the follow-up period in the control group. CONCLUSIONS: Cobalamin supplementation changed all markers of impaired cobalamin status (low cobalamin, high total homocysteine, and high methylmalonic acid levels) toward a profile observed in cobalamin-replete older children and adults. Therefore, the high total homocysteine and methylmalonic acid levels reported for a large fraction of infants reflect not immature metabolism but rather insufficient cobalamin levels to fully sustain cobalamin-dependent reactions fully.