Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may result in severe bleeding, particularly fetal and neonatal intracranial haemorrhage (ICH). As a result, FNAIT requires prompt identification ...and treatment; subsequent pregnancies need close surveillance and management. An international panel convened to develop evidence‐based recommendations for diagnosis and management of FNAIT. A rigorous approach was used to search, review and develop recommendations from published data for: antenatal management, postnatal management, diagnostic testing and universal screening. To confirm FNAIT, fetal human platelet antigen (HPA) typing, using non‐invasive methods if quality‐assured, should be performed during pregnancy when the father is unknown, unavailable for testing or heterozygous for the implicated antigen. Women with a previous child with an ICH related to FNAIT should be offered intravenous immunoglobulin (IVIG) infusions during subsequent affected pregnancies as early as 12 weeks gestation. Ideally, HPA‐selected platelets should be available at delivery for potentially affected infants and used to increase the neonatal platelet count as needed. If HPA‐selected platelets are not immediately available, unselected platelets should be transfused. FNAIT studies that optimize antenatal and postnatal management, develop risk stratification algorithms to guide management and standardize laboratory testing to identify high risk pregnancies are needed.
Several strategies can be used to manage fetal or neonatal alloimmune thrombocytopenia (FNAIT) in subsequent pregnancies. Serial fetal blood sampling (FBS) and intrauterine platelet transfusions ...(IUPT), as well as weekly maternal IV immunoglobulin infusion (IVIG), with or without additional corticosteroid therapy, are common options, but optimal management has not been determined. The aim of this systematic review was to assess antenatal treatment strategies for FNAIT. Four randomized controlled trials and 22 nonrandomized studies were included. Pooling of results was not possible due to considerable heterogeneity. Most studies found comparable outcomes regarding the occurrence of intracranial hemorrhage, regardless of the antenatal management strategy applied; FBS, IUPT, or IVIG with or without corticosteroids. There is no consistent evidence for the value of adding steroids to IVIG. FBS or IUPT resulted in a relatively high complication rate (consisting mainly of preterm emergency cesarean section) of 11% per treated pregnancy in all studies combined. Overall, noninvasive management in pregnant mothers who have had a previous neonate with FNAIT is effective without the relatively high rate of adverse outcomes seen with invasive strategies. This systematic review suggests that first-line antenatal management in FNAIT is weekly IVIG administration, with or without the addition of corticosteroids.
•The systematic review suggests that first-line antenatal management in FNAIT is weekly IVIG administration.•Noninvasive management is effective without the relatively high rate of adverse outcomes seen in invasive strategies.
In general, transfusion guidelines for non-neonatal pediatric patients are similar to those for adults. However, some differences do exist and certain precautions may be necessary particularly in the ...setting of massive transfusions. We review these differences as they apply to general pediatric surgery outside of the neonatal period, with respect to the transfusion of red blood cells (RBCs), platelets, fresh-frozen plasma (FFP), and cryoprecipitate. We include a discussion of the indications for transfusion and practical considerations such as dosing and administration. Finally, we briefly review the use of directed donations and specialized (irradiated, CMV seronegative) blood components.
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Introduction. Hydroxyurea treatment has proven safety, feasibility, and efficacy for children with sickle cell anemia living in sub-Saharan Africa. Even in malaria endemic regions, hydroxyurea is ...safe and has been shown to reduce vaso-occlusive events and lower mortality. The optimal dosing regimen is not known, however, and specifically whether a fixed dose at 15-20 mg/kg/day is better than escalation to maximum tolerated dose (MTD) at 25-30 mg/kg/day. Particularly in low-resource settings, additional drug-related toxicities and monitoring costs associated with dose escalation could outweigh potential laboratory and clinical benefits.
Methods. Children with sickle cell anemia previously enrolled in NOHARM (NCT01976416) received hydroxyurea at ~20 mg/kg/day during the open-label portion of that trial, after which they transitioned to commercial supply at that same daily dose. All were then offered enrollment in the NOHARM MTD trial (NCT03128515), a double-blinded trial with 1:1 randomization between continuing fixed-dose oral hydroxyurea (20 ± 2.5 mg/kg/day) versus dose-escalation to MTD (30 ± 2.5 mg/kg/day), using hydroxyurea tablets donated by Addmedica. The primary study outcome was the proportion of study participants who achieved either hemoglobin ≥9.0 g/dL or fetal hemoglobin ≥20% after 24 months of treatment. Secondary outcomes included sickle-related clinical adverse events, malaria events, and laboratory toxicities. We now present the main results of the NOHARM MTD trial.
Results. A total of 187 children enrolled and began study treatment: 94 children (4.8 ± 0.9 years, 55 males) received hydroxyurea at fixed dose versus 93 who received hydroxyurea with dose escalation (4.6 ± 1.0 years, 47 males). At Month 6 of study treatment the average doses were 19.3 ± 1.7 mg/kg/day and 29.0 ± 3.5 mg/kg/day, respectively, and these dose differences were continued through Month 12 and Month 18. The trial was terminated prematurely by the independent Data Safety Monitoring Board after 146 children had reached Month 18, when the clinical complications and interventions were significantly fewer among children randomized to MTD compared to fixed-dose. The incidence rate ratio (IRR) with 95% confidence intervals (CI) included the following: all sickle-related Adverse Events IRR = 0.43, CI = (0.34, 0.56), P<0.00001; vaso-occlusive crises IRR = 0.43, CI = (0.33, 0.56), P<0.00001; acute chest syndrome/pneumonia IRR = 0.27, CI = (0.11, 0.55), P=0.001; transfusions IRR = 0.29, CI = (0.20, 0.43), P<0.00001; and hospitalizations IRR = 0.21, CI = (0.13, 0.34), P<0.00001. The rates of Laboratory Adverse Events were similar between treatment arms IRR = 0.83, CI = (0.60, 1.15), P=NS and dose-limiting toxicities were equivalent IRR = 1.01, CI = (0.66, 1.54), P=NS without any episodes of severe neutropenia or thrombocytopenia. Superior laboratory benefits were observed in the dose-escalation arm, with higher hemoglobin (8.7 versus 8.3 g/dL, P=0.006) and fetal hemoglobin (30.5 versus 18.2%, P<0.0001), and lower reticulocyte counts (157 versus 261 x 109/L, P<0.0001) and neutrophil counts (3.4 versus 5.1 x 109/L, P<0.0001). At the time of study closure, more children on the dose-escalation arm had achieved the primary study endpoint compared to those on fixed-dose hydroxyurea (86% versus 37%, P<0.0001).
Conclusion. NOHARM MTD is the first randomized controlled clinical trial to compare hydroxyurea at fixed-dose versus escalation to MTD in either high- or low-resource settings. Hydroxyurea escalated to MTD at ~30 mg/kg/day had superior clinical and laboratory efficacy compared to fixed-dose treatment at ~20 mg/kg/day in this high-risk population, without any increase in toxicity. Optimal hydroxyurea dosing to MTD at ~30 mg/kg/day is therefore recommended for children with sickle cell anemia living in sub-Saharan Africa, which represents an important paradigm shift from the concept of low-dose daily treatment. Increasing access to hydroxyurea at optimal doses will require concerted efforts that include training and implementation strategies, to enable safe and effective hydroxyurea dose escalation for children in low-resource settings.
Ware:Bristol Myers Squibb: Other: Research Drug Donation; Addmedica: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB.
In children with severe sepsis or septic shock, the optimal red blood cell transfusion threshold is unknown. We analyzed the subgroup of patients with sepsis and transfusion requirements in a ...pediatric intensive care unit study to determine the impact of a restrictive vs. liberal transfusion strategy on clinical outcome.
Subgroup analysis of a prospective, multicenter, randomized, controlled trial.
Multicenter pediatric critical care units.
Stabilized critically ill children (mean systemic arterial pressure >2 sd below normal mean for age and cardiovascular support not increased for at least 2 hrs before enrollment) with a hemoglobin ≤ 9.5 g/dL within 7 days after pediatric critical care unit admission.
One hundred thirty-seven stabilized critically ill children with sepsis were randomized to receive red blood cell transfusion if their hemoglobin decreased to either <7.0 g/dL (restrictive group) or 9.5 g/dL (liberal group).
In the restrictive group (69 patients), 30 patients did not receive any red blood cell transfusion, whereas only one patient in the liberal group (68 patients) never underwent transfusion (p < .01). No clinically significant differences were found for the occurrence of new or progressive multiple organ dysfunction syndrome (18.8% vs. 19.1%; p = .97), for pediatric critical care unit length of stay (p = .74), or for pediatric critical care unit mortality (p = .44) in the restrictive vs. liberal group.
In this subgroup analysis of children with stable sepsis, we found no evidence that a restrictive red cell transfusion strategy, as compared to a liberal one, increased the rate of new or progressive multiple organ dysfunction syndromes. Furthermore, a restrictive transfusion threshold significantly reduced exposure to blood products. Our data suggest that a hemoglobin level of 7.0 g/dL may be safe stabilized for children with sepsis, but further studies are required to support this recommendation.
Summary
ACS (ACS) is a serious complication of sickle cell anaemia (SCA). We set out to describe the burden, presentation and organisms associated with ACS amongst children with SCA attending Mulago ...Hospital, Kampala, Uganda. In a cross‐sectional study, 256 children with SCA and fever attending Mulago Hospital were recruited. Chest X‐rays, blood cultures, complete blood count and sputum induction were performed. Sputum samples were investigated by Ziehl‐Nielsen staining, culture and DNA polymerase chain reaction (PCR) for Chlamydia pneumoniae. Of the 256 children, 22·7% had ACS. Clinical and laboratory findings were not significantly different between children with ACS and those without, besides cough and abnormal signs on auscultation. Among the 83 sputum cultures Streptococcus pneumoniae (12%) and Moraxella spp (8%), were the commonest. Of the 59 sputa examined with DNA PCR, 59·3% were positive for Chlamydia pneumoniae. Mycobacterium tuberculosis was isolated in 6/83 sputa. These results show that one in 5 SCA febrile children had ACS. There were no clinical and laboratory characteristics of ACS, but cough and abnormalities on auscultation were associated with ACS. The high prevalence of Chlamydia pneumoniae in children with ACS in this setting warrants the addition of macrolides to treatment, and M. tuberculosis should be differential in sub‐Saharan children with ACS.
Background: Children with sickle cell anemia (SCA) have a high predisposition to a range of infections and gastrointestinal disorders. Studies of children living in low income countries have shown ...high levels of infection with Helicobacter Pylori (H.pylori), however, there are no reports in Ugandan children with SCA.
Objectives: We aimed to describe the prevalence and factors associated with H. pylori infection among children with SCA at Mulago Hospital.
Methods: A cross-sectional study was conducted on 340 children with SCA aged 5-18 years. Assessments included recurrent abdominal pain(RAP), dyspeptic symptoms, relevant medical and social histories. Stool samples were collected and an antigen test carried out to determine H. pylori infection. H. pylori prevalence and its associated factors were determined.
Results: Helicobacter pylori infection was detected in 49%(168/340); (95%Confidence interval (CI): 44.1, 54.7) of the study subjects. Having epigastric pain was independently associated with H. pylori infection; (Adjusted odds ratio aOR = 1.89; 95%CI: 1.1, 3.6; p= 0.048). Pneumococcal vaccination; (aOR=0.425; 95%CI: 0.2, 0.9; p=0.019) and appetite loss; (aOR=0.588; 95%CI: 0.3, 0.9; p=0.046) were negatively associated with H. pylori infection. RAP was not associated with H.pylori infection.
Conclusions: H. pylori infection was common among children with SCA and independently associated with epigastric pain but not recurrent abdominal pain. Pneumococcal vaccination and appetite loss were protective against the infection. Screening for H. pylori should be carried out in SCA children with epigastric pain.
Keywords: Recurrent abdominal pain; Sickle cell anemia; Dyspeptic symptoms.
Sickle cell disease (SCD) is associated with significant mortality and morbidity that can be decreased by neonatal diagnosis. Although 44 American states have implemented such programs, there are no ...provincially funded universal or targeted newborn screening programs for SCD in Canada.
To report a critical appraisal of a hospital-based neonatal screening program targeting at-risk infants over a 15-year period.
The cord blood of infants born at Sainte-Justine University Health Centre (Sainte-Justine UHC, Montreal, Quebec) whose mother or father was black was collected at birth and analyzed for the presence of hemoglobin (Hb) S by liquid chromatography or isoelectric focusing. Samples with positive results underwent confirmatory testing.
A total of 9619 infants were screened: 8142 (84.6%) had a normal phenotype, 1012 (10.5%) had sickle cell trait and 386 (4.0%) had HbC trait. Seventy-two infants were diagnosed with SCD: 37 (0.4%) were classified as HbSS or HbS-beta-thalassemia and 35 (0.4%) had HbSC disease. Of these 72 infants, 67 (93.1%) were immediately enrolled in a multidisciplinary SCD follow-up clinic. The five remaining children not initially enrolled were later referred to the clinic. A chart study revealed that six patients with SCD born at Sainte-Justine UHC were not identified by neonatal screening.
The screening program was clinically effective because it identified 92.3% of at-risk patients born at Sainte-Justine UHC. These infants received appropriate medical care before 10 weeks of age as opposed to a median of 12 months for infants not identified by the screening program. It is proposed that either a targeted or a universal neonatal screening for SCD should be available in Canada.
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