Infants affected by Rh sensitization: A 2-year Canadian National Surveillance Study.

INTRODUCTION: Rh sensitization occurs when Rh(D)-negative women develop anti-Rh(D) antibodies following exposure through pregnancy or transfusion. Rh disease may cause jaundice, anemia, neurological impairment, and death. It is rare in countries where Rh Immune Globulin (RhIg) is used. Canadian Rh sensitization and disease rates are unknown. METHODS: This survey-based study was conducted using a Canadian Paediatric Surveillance Program questionnaire sent to Canadian paediatricians and paediatric subspecialists to solicit Rh disease cases from May 2016 to June 2018. Paediatricians reported Rh-positive infants ≤ 60 days of age, born to Rh-negative mothers with RhD sensitization. RESULTS: Sixty-two confirmed cases of infants affected by Rh(D) sensitization were reported across Canada. The median gestational age of neonates was term, age at presentation was 2 hours, and hemoglobin at presentation was 137.5 g/L (33 to 203 g/L). The median peak bilirubin and phototherapy duration were 280 µmol/L (92 to 771 µmol/L), and 124 hours, respectively. Thirty (48%) infants received Intravenous immune globulin (IVIG) (median two doses). Seventeen (27%) received one to three simple transfusions; 10 (16%) required exchange transfusions. Six (10%) infants presented with acute bilirubin encephalopathy, and less than five presented with seizures. Fourteen mothers with affected infants were born outside of Canada. DISCUSSION: Rh disease continues to exist in Canada. Additional efforts are needed to raise awareness of Rh disease, prevent disease, and minimize sequelae when it does occur. The ongoing global burden of Rh Disease, as well as the possibility of emerging Rh immunoglobulin refusal are among factors that could be taken into consideration in future prevention efforts.

Changes in circulating red cell volume during the first 6 weeks of life in very-low-birth-weight infants.

BACKGROUND: Little is known about the change in circulating red cell volume (RCV) of very-low-birth-weight (VLBW) infants during the first weeks of life. METHODS: RCV was measured during the first 5 d in 35 VLBW infants using chromium-51 labeling of the infants' red blood cells (RBCs). RCV was measured again at 6 wk of age in 12 infants, and the volumes of RBCs lost by phlebotomy and those gained by transfusion were recorded between the RCV measurements. In six infants, the volume of waste blood on materials contaminated with blood during phlebotomy, which would usually be discarded, was measured by radioactive counting. RESULTS: The mean RCV in the first several days of life was 39.6 ml (35.7 ml/kg; range: 20.1-58.7 ml/kg). Of the 12 infants whose RCV was measured twice, all but one had a decrease in absolute RCV. The mean RCV initially and at 6 wk were 37.3 and 26.6 ml, respectively. The mean volume of RBCs lost through phlebotomy was 29.2 ml, and the mean volume of RBCs given by transfusion was 34.5 ml. CONCLUSION: During the first 6 wk of life, when the anemia of prematurity is evolving, the RCV falls despite complete replacement of RBCs lost by diagnostic phlebotomy with transfused RBCs.

Origins of leukaemia in children with Down syndrome.

Transient megakaryoblastic leukaemia is found in 10% of newborns with Down syndrome, characterized by constitutional trisomy 21. Although in most cases the leukaemic cells disappear spontaneously after the first months of life, irreversible acute megakaryoblastic leukaemia develops in 20% of these individuals within 4 years. The leukaemic cells typically harbour somatic mutations of the gene encoding GATA1, an essential transcriptional regulator of normal megakaryocytic differentiation. Leukaemia that specifically arises in the context of constitutional trisomy 21 and somatic GATA1 mutations is a unique biological model of the incremental process of leukaemic transformation.

Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels.

BACKGROUND: Rhesus (Rh) disease and extreme hyperbilirubinemia (EHB) result in neonatal mortality and long-term neurodevelopmental impairment, yet there are no estimates of their burden. METHODS: Systematic reviews and meta-analyses were undertaken of national prevalence, mortality, and kernicterus due to Rh disease and EHB. We applied a compartmental model to estimate neonatal survivors and impairment cases for 2010. RESULTS: Twenty-four million (18% of 134 million live births ≥ 32 wk gestational age from 184 countries; uncertainty range: 23-26 million) were at risk for neonatal hyperbilirubinemia-related adverse outcomes. Of these, 480,700 (0.36%) had either Rh disease (373,300; uncertainty range: 271,800-477,500) or developed EHB from other causes (107,400; uncertainty range: 57,000-131,000), with a 24% risk for death (114,100; uncertainty range: 59,700-172,000), 13% for kernicterus (75,400), and 11% for stillbirths. Three-quarters of mortality occurred in sub-Saharan Africa and South Asia. Kernicterus with Rh disease ranged from 38, 28, 28, and 25/100,000 live births for Eastern Europe/Central Asian, sub-Saharan African, South Asian, and Latin American regions, respectively. More than 83% of survivors with kernicterus had one or more impairments. CONCLUSION: Failure to prevent Rh sensitization and manage neonatal hyperbilirubinemia results in 114,100 avoidable neonatal deaths and many children grow up with disabilities. Proven solutions remain underused, especially in low-income countries.

The Programme for Global Paediatric Research.

When it comes to global health, there is no 'them'... only 'us.'" - Global Health Council There is a major anomaly in child health research. The majority of pediatric research resources and expertise is located in the developed world, whereas the vast majority of childhood disease and mortality is in the developing world. This disequilibrium has been referred to as the "10/90 gap", suggesting that only 10% of global health research dollars are devoted to conditions that account for 90% of the global disease burden (Global Forum for Health Research). The Programme for Global Paediatric Research (PGPR) began as an effort to include, in a major pediatric research conference, topics dealing with diseases of children in the developing world in order to engage more interest and more research dollars. It has evolved into a program educating and linking professionals, and developing global networks of colleagues working collaboratively to solve major childhood health problems.

Hemolytic disease of the fetus and newborn due to Rh(D) incompatibility: A preventable disease that still produces significant morbidity and mortality in children.

In the mid-20th century, Hemolytic Disease of the Fetus and Newborn, caused by maternal alloimmunization to the Rh(D) blood group antigen expressed by fetal red blood cells (i.e., "Rh disease"), was a major cause of fetal and neonatal morbidity and mortality. However, with the regulatory approval, in 1968, of IgG anti-Rh(D) immunoprophylaxis to prevent maternal sensitization, the prospect of eradicating Rh disease was at hand. Indeed, the combination of antenatal and post-partum immunoprophylaxis is ~99% effective at preventing maternal sensitization to Rh(D). To investigate global compliance with this therapeutic intervention, we used an epidemiological approach to estimate the current annual number of pregnancies worldwide involving an Rh(D)-negative mother and an Rh(D)-positive fetus. The annual number of doses of anti-Rh(D) IgG required for successful immunoprophylaxis for these cases was then calculated and compared with an estimate of the annual number of doses of anti-Rh(D) produced and provided worldwide. Our results suggest that ~50% of the women around the world who require this type of immunoprophylaxis do not receive it, presumably due to a lack of awareness, availability, and/or affordability, thereby putting hundreds of thousands of fetuses and neonates at risk for Rh disease each year. The global failure to provide this generally acknowledged standard-of-care to prevent Rh disease, even 50 years after its availability, contributes to an enormous, continuing burden of fetal and neonatal disease and provides a critically important challenge to the international health care system.

Rhesus disease: a global prevention strategy.

After nearly five decades of effective prophylaxis in high-income countries, the incidence of rhesus haemolytic disease (also known as haemolytic disease of the fetus and newborn) has substantially decreased, and as a result, clinical experience of the disease among health-care providers is insufficient. By contrast, a worldwide study found that rhesus haemolytic disease continues to be a public health problem in low-income and middle-income countries, affecting annually in more than 150 000 children, and causing thousands of stillbirths, neonatal deaths, and cases of hyperbilirubinaemia with its sequelae (kernicterus and bilirubin-induced neurological dysfunction). Solutions to this problem will require the combined and integrated effort of physicians and other health-care workers, international agencies, manufacturers of the prophylactic agent (rhesus immunoglobulin), health policy makers, and governments of low-income and middle-income countries.

Impact of Rhesus disease on the global problem of bilirubin-induced neurologic dysfunction.

Clinical experience with Rhesus (Rh) disease and its post-icteric sequelae is limited among high-income countries because of nearly over four decades of effective prevention care. We hypothesized that Rh disease is prevalent in other regions of the world because it is likely that protection is limited or non-existent. Following a worldwide study, it has been concluded that Rh hemolytic disease is a significant public health problem resulting in stillbirths and neonatal deaths, and is a major cause of severe hyperbilirubinemia with its sequelae, kernicterus and bilirubin-induced neurologic dysfunction. Knowing that effective Rh-disease prophylaxis depends on maternal blood-type screening, healthcare afforded to the high-risk mothers needs to be free of bottlenecks and coupled with unfettered access to effective Rh-immunoglobulin. Future studies that match the universal identification of Rh-negative status of women and targeted use of immunoprophylaxis to prevent childhood bilirubin neurotoxicity are within reach, based on vast prior experiences.

Setting global research priorities for integrated community case management (iCCM): Results from a CHNRI (Child Health and Nutrition Research Initiative) exercise.

AIMS: To systematically identify global research gaps and resource priorities for integrated community case management (iCCM). METHODS: An iCCM Child Health and Nutrition Research Initiative (CHNRI) Advisory Group, in collaboration with the Community Case Management Operational Research Group (CCM ORG) identified experts to participate in a CHNRI research priority setting exercise. These experts generated and systematically ranked research questions for iCCM. Research questions were ranked using a "Research Priority Score" (RPS) and the "Average Expert Agreement" (AEA) was calculated for every question. Our groups of experts were comprised of both individuals working in Ministries of Health or Non Governmental Organizations (NGOs) in low- and middle-income countries (LMICs) and individuals working in high-income countries (HICs) in academia or NGO headquarters. A Spearman's Rho was calculated to determine the correlation between the two groups' research questions' ranks. RESULTS: The overall RPS ranged from 64.58 to 89.31, with a median score of 81.43. AEA scores ranged from 0.54 to 0.86. Research questions involving increasing the uptake of iCCM services, research questions concerning the motivation, retention, training and supervision of Community Health Workers (CHWs) and concerning adding additional responsibilities including counselling for infant and young child feeding (IYCF) and treatment of severe acute malnutrition (SAM) ranked highly. There was weak to moderate, statistically significant, correlation between scores by representatives of high-income countries and those working in-country or regionally (Spearman's ρ = 0.35034, P < 0.01). CONCLUSIONS: Operational research to determine optimal training, supervision and modes of motivation and retention for the CHW is vital for improving iCCM, globally, as is research to motivate caregivers to take advantage of iCCM services. Experts working in-country or regionally in LMICs prioritized different research questions than those working in organization headquarters in HICs. Further exploration is needed to determine the nature of this divergence.

Global action plan for childhood diarrhoea: Developing research priorities: Report from a Workshop of the Programme for Global Paediatric Research.

BACKGROUND: Childhood diarrhoea remains a major public health problem responsible for the deaths of approximately 800 000 children annually, worldwide. The present study was undertaken to further define research priorities for the prevention and treatment of diarrhoea in low and middle income countries. We used the Child Health and Nutrition Research Initiative (CHNRI) process for defining research priorities. This provided a transparent, systematic method of obtaining the opinions of experts regarding research priorities in childhood diarrhoea. The present report describes the deliberations of a workshop that reviewed these research priorities by stakeholders including colleagues from: government agencies, academic institutions, major funding agencies and non-governmental organizations. METHODS: The workshop included 38 participants, divided into four groups to consider issues in the categories of description, delivery, development and discovery. Each group received 20 to 23 questions/research priorities previously identified by the CHNRI process. Deliberations and conclusions of each group were summarized in separate reports that were further discussed in a plenary session including all workshop participants. RESULTS: THE REPORTS OF THE WORKING GROUPS EMPHASIZED THE FOLLOWING FIVE KEY POINTS: 1) A common theme was the need to substantially increase the use of oral rehydration salts (ORS) and zinc in the prevention and treatment of diarrhoea. There is a need for better definitions of those factors that supported and interfered with the use of these agents; 2) There is an urgent need to determine the long-term effects of chronic and recurrent bouts of diarrhoea on the physical and intellectual development of affected children; 3) Improvements in water, sanitation and hygiene facilities are critical steps required to reduce the incidence and severity of childhood diarrhoea; 4)Risk factors enhancing the susceptibility and clinical response to diarrhoea were explored; implementation research of modifiable factors is urgently required; 5) More research is required to better understand the causes and pathophysiology of various forms of enteropathy and to define the methods and techniques necessary for their accurate study. CONCLUSIONS: The participants in this workshop determined that use of the CHNRI process had successfully defined those research priorities necessary for the study of childhood diarrhoea. The deliberations of the workshop brought these research priorities to the attention of stakeholders responsible for the implementation of the recommendations. It was concluded that the deliberations of the workshop positively supplemented the research priorities developed by the CHNRI process.

A global need for affordable neonatal jaundice technologies.

Globally, health care providers worldwide recognize that severe neonatal jaundice is a "silent" cause of significant neonatal morbidity and mortality. Untreated neonatal jaundice can lead to death in the neonatal period and to kernicterus, a major cause of neurologic disability (choreo-athetoid cerebral palsy, deafness, language difficulty) in children who survive this largely preventable neonatal tragedy. Appropriate technologies are urgently needed. These include tools to promote and enhance visual assessment of the degree of jaundice, such as simpler transcutaneous bilirubin measurements and readily available serum bilirubin measurements that could be incorporated into routine treatment and follow-up. Widespread screening for glucose-6-phoshate dehydrogenase deficiency is needed because this is often a major cause of neonatal jaundice and kernicterus worldwide. Recognition and treatment of Rh hemolytic disease, another known preventable cause of kernicterus, is critical. In addition, effective phototherapy is crucial if we are to make kernicterus a "never-event." Finally it is essential that we conduct appropriate population-based studies to accurately elucidate the magnitude of the problem. However, knowledge alone is not sufficient. If we are to implement these and other programs and technologies to relegate severe neonatal jaundice and its sequelae to the history books, screening and interventions must be low cost and technologically appropriate for low and middle income nations.

Long-term results of an ultra low-dose cytarabine-based regimen for the treatment of acute megakaryoblastic leukaemia in children with Down syndrome.

Children with acute megakaryoblastic leukaemia (AMKL) and Down syndrome (DS) show a favourable response to chemotherapy, probably due to increased sensitivity of the leukaemic blasts to cytarabine. In contrast, dose-intensive approaches have resulted in disproportionate treatment-related mortality in this group. The survival of children with AMKL and DS was retrospectively compared following treatment with a low-dose chemotherapy protocol, consisting of cytarabine (10 mg/m2/dose), retinylpalmitate and vincristine or standard chemotherapy. Event-free (67 +/- 11%) and overall survival (77 +/- 10%) at 5 years were not significantly different in both groups. Further reduction of treatment intensity in AMKL of children with DS, therefore, appears feasible.

A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481.

A unique transient leukemia (TL) has been described in newborns with Down syndrome (DS; or trisomy 21 mosaics). This leukemia has a high incidence of spontaneous remission; however, early death and subsequent development of acute megakaryoblastic leukemia (AMKL) have been reported. We prospectively evaluated 48 infants with DS and TL to determine the natural history and biologic characteristics of this disease, identify the clinical characteristics associated with early death or subsequent leukemia, and assess the incidence of subsequent leukemia. Blast cells associated with TL in DS infants exhibited FAB M(7) morphology and phenotype. Most infants (74%) had trisomy 21 (or mosaicism) as the only cytogenetic abnormality in the blast cells. Most children were able to spontaneously clear peripheral blasts (89%), normalize blood counts (74%), and maintain a complete remission (64%). Early death occurred in 17% of infants and was significantly correlated with higher white blood cell count at diagnosis (P < .001), increased bilirubin and liver enzymes (P < .005), and a failure to normalize the blood count (P = .001). Recurrence of leukemia occurred in 19% of infants at a mean of 20 months. Development of leukemia was significantly correlated with karyotypic abnormalities in addition to trisomy 21 (P = .037). Ongoing collaborative clinical studies are needed to determine the optimal role of chemotherapy for infants at risk for increased mortality or disease recurrence and to further the knowledge of the unique biologic features of this TL.

Congenital abnormalities and childhood cancer.

BACKGROUND: The examination of specific characteristics of neoplasms diagnosed in children have suggested that a significant proportion can be attributed to a genetic mutation or genetic predisposition. Although the study of a genetic predisposition to cancer in children remains in the early stages, congenital abnormalities could provide essential information for mapping predisposing lesions in children with cancer. METHODS: In the current study, 2 large cohorts of children with and without congenital abnormalities were followed for the occurrence of cancer and death up to 18 years. Through this study, the risk of developing cancer by age at diagnosis, effects of birth characteristics on cancer risk, and possible associations between specific anomalies and tumor types were examined. RESULTS: Based on the follow-up of 90,400 children, the risk of developing cancer during the first year of life was found to be nearly 6 times higher in children with anomalies (rate ratio [RR] of 5.8; 95% confidence interval [95% CI], 3.7-9.1). Children with birth defects were found to be at a higher risk for developing leukemia (RR of 2.7; 95% CI, 2.1-3.6), tumors of the central nervous system (RR of 2.5; 95% CI, 1.8-3.4), sympathetic nervous system tumors (RR of 2.2; 95% CI, 1.4-3.4), and soft tissue sarcomas (RR of 1.9; 95% CI, 1.0-3.5). Among children with birth defects, children with Down syndrome, nervous system anomalies, and anomalies of the urinary system had the highest incidence rates of cancer. In the presence of birth defects, other factors such as birth weight, gestational age, age of the mother, and birth order were not found to be associated significantly with the risk of cancer. CONCLUSIONS: The significant relative risks found in the current study provided evidence of links between the presence of abnormalities and the development of cancer. Some "cancer-prone" abnormalities were identified in the current study. Such anomalies may be markers of other exposures or processes that increase the risk of developing cancer.