Unwell Infants Research Articles

Critically unwell infants and children with mitochondrial disorders diagnosed by ultra-rapid genomic sequencing

To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultra-rapid genomic testing as part of a national program. Ultra-rapid genomic sequencing was performed in 454 families (genome sequencing: n=290, exome sequencing +/- mitochondrial DNA sequencing: n=164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria. A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD following broader analysis. Gene-agnostic analysis led to the discovery of two novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another four individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation. Ultra-rapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.

Wales Infants’ and childreN’s Genome Service (WINGS): providing rapid genetic diagnoses for unwell children

IntroductionThis study reviews the first 3 years of delivery of the first National Health Service (NHS)-commissioned trio rapid whole genome sequencing (rWGS) service for acutely unwell infants and children in...

‘Baby Liberation’ – Developing and implementing an individualised, developmentally-supportive care bundle to critically unwell infants in an Australian Paediatric Intensive Care Unit

BackgroundInfants requiring high acuity care within a Paediatric Intensive Care Unit are at multifactorial risk of neurological injury to the immature brain, resulting in long-term developmental difficulties. In 2020, Queensland Children's Hospital implemented an individualised family-centred developmental care program, ‘Baby Liberation’, to address an identified service gap for critically unwell infants, aimed at optimising early neuroprotective strategies and minimising risk of suboptimal developmental outcomes. AimTo implement Baby Liberation for infants admitted to a quaternary paediatric intensive care referral centre. Secondary aims were to describe environmental changes, enablers and limitations related to implementation. Study designA single-centre, prospective implementation pilot study investigated the feasibility of implementing Baby Liberation. Subjects included infants less than six months of age admitted to Queensland Children's Hospital Paediatric Intensive Care Unit. Outcome measuresPrimary measures comprised data collected during the implementation period, including number of eligible patients and number of developmental care plans provided. Environmental audit data were collected pre and post implementation to inform secondary outcomes. ResultsBaby Liberation was feasibly implemented into the Queensland Children's Hospital Paediatric Intensive Care Unit. During implementation, 181 individualised care plans were provided to 313 eligible infants (57.8 %). Environmental audits showed improvements in all areas of developmental care, with greatest improvements noted in pain and stress management (+95 %) and staff support and development (+83.3 %). ConclusionImplementation of Baby Liberation was feasible within a large quaternary paediatric intensive care unit and has potential to be expanded into other clinical areas providing acute infant care.

Maternal intrapartum fluids and neonatal weight loss in the breastfed infant

Background/Aims Significant weight loss during early life can be of serious concern and assessing weight is key in decisions regarding supplementation. However, supplementation is a significant risk factor for early breastfeeding cessation. Recognising differential causes of weight loss supports identification of genuinely unwell infants and targets practices that support exclusive breastfeeding appropriately. This study's aim was to identify whether maternal fluid balance/load is associated with neonatal weight loss. Methods The databases CINAHL, MEDLINE, EMBASE, EMCARE were searched for relevant literature. Data were extracted using a structured form based on the Cochrane handbook. Meta-analysis was not possible because of the heterogeneity of all aspects of study design and outcome definitions. Results Eight studies presented original data. Four reported an association between maternal intravenous fluid intake and neonatal weight loss, and four did not. No two studies collected the same outcome data at the same time, using the same comparator or intervention. Conclusions Further research is required to clarify the relationship between maternal fluid intake and neonatal weight loss in a clinically useful way.

Parents and healthcare professionals' attitudes to Kangaroo Care for preterm infants in the United Kingdom.

To explore the attitudes of parents and healthcare professionals (HCPs), and facilitators and barrier to implementation of Kangaroo Care (KC) in the United Kingdom. Online cross-sectional survey; distributed via the British Association of Perinatal Medicine, Bliss (UK-based charity), social media. Sixty HCPs responded. 37 (62%) were nurses/nurse practitioners. 57 (95%) regularly implement KC. The most important factor that supported KC implementation was the team's belief in benefits of KC. Increased workload, staff shortage and fear about safely of KC in unwell infants were recognised as the challenges preventing implementation. Five hundred eighteen parents responded. 421 (81%) had a preterm baby within 3 years. 338 (80%) were familiar with KC. The main facilitator was the belief that their baby enjoyed it. Excess noise and crowding on the unit were the most frequently reported barriers. Lack of opportunity and limited staff support were the main reasons why they had been unable to practice KC. We found that most HCPs and parents believe that KC is beneficial and would like to practice it. Lack of resources to enable effective implementation is the main barrier. Service development and implementation research is required to ensure that KC is delivered in all UK neonatal units.

Forehead monitoring of heart rate in neonatal intensive care.

Heart rate is an extremely important physiological parameter to measure in critically unwell infants, as it is the main physiological marker that changes in response to a change in infant condition. Heart rate is routinely measured peripherally on a limb with a pulse oximeter. However, when infants are critically unwell, the blood supply to these peripheries is reduced in preference for central perfusion of vital organs such as the brain and heart. Measurement of heart rate with a reflection mode photoplethysmogram (PPG) sensor on the forehead could help minimise this problem and make it easier for other important medical equipment, such as cannulas, to be placed on the limbs. This study compares heart rates measured with a forehead-based PPG sensor against a wrist-based PPG sensor in 19 critically unwell infants in neonatal intensive care collecting 198h of data. The two heart rates were compared using positive percentage agreement, Spearman's correlation coefficient and Bland-Altman analysis. The forehead PPG sensor showed good agreement with the wrist-based PPG sensor with limits of agreement of 8.44bpm, bias of -0.22bpm; positive percentage agreement of 98.87%; and Spearman's correlation coefficient of 0.9816. The analysis demonstrates that the forehead is a reliable alternative location for measuring vital signs using the PPG.

Prevalence of anaemia in acutely unwell infants.

Nil.

Addressing Suffering in Infants and Young Children Using the Concept of Suffering Pluralism.

Despite the central place of suffering in medical care, suffering in infants and nonverbal children remains poorly defined. There are epistemic problems in the detection and treatment of suffering in infants and normative problems in determining what is in their best interests. A lack of agreement on definitions of infant suffering leads to misunderstanding, mistrust, and even conflict amongst clinicians and parents. It also allows biases around intensive care and disability to (mostly unconsciously) affect medical decision-making on behalf of infants. In this paper, I propose the concept of suffering pluralism, which is a novel multidimensional view of infant suffering based on subjective and objective components. The concept of suffering pluralism is more inclusive of the multiple ways in which infant suffering can occur. It acknowledges and defines a subjective component to infant suffering, while also focusing moral attention on objective well-being by describing it using the language of suffering. This concept allows us to better weigh up subjective and objective components of well-being. It also encourages clarity and consistency in claiming suffering, which is likely to improve communication and reduce conflict in medical decision-making for unwell infants and children. I will end by exploring possible critiques and limitations of this concept.

Rapid exome sequencing: revolutionises the management of acutely unwell neonates.

Diagnosing acutely unwell infants with a potential genetic diagnosis can be challenging for healthcare professionals. Evidence suggests that up to 13% of critically unwell infants on the neonatal intensive care unit (NICU) have an underlying molecular diagnosis and when identified directly affects treatment decisions in 83%. On 1st October 2019, the National Health Service England (NHSE) launched a nationally commissioned service so that rapid whole-exome sequencing can be offered to critically unwell babies and children with a likely monogenic disorder who are admitted to NICU and paediatric intensive care unit (PICU). We present 7 cases from two neonatal units in the West Midlands (UK), where rapid exome sequencing has revealed a genetic diagnosis. Early genetic diagnosis in this cohort has influenced management in all (100%) cases, and in 57% (4 in 7 cases), it has helped in the decision to reorientate care. In some cases, early diagnosis has reduced the need for invasive and unnecessary investigations and avoided the need for post-mortem investigations. The genetic diagnosis has helped in counselling the families regarding the recurrence risk for future pregnancies. In some cases, this has provided parents with the reassurance of a low recurrence. In others, it has resulted in the offer of prenatal diagnosis or assisted conception technologies. What is Known:• Rapid whole-exome sequencing was commissioned in the UK in October 2019.• It is available for critically unwell babies with a likely monogenic aetiology.What is New:• It helps management planning for rare genetic disorders and future pregnancies counselling.• It can reduce the need for invasive investigations and overall intensive care costs.

Parental experiences of ultrarapid genomic testing for their critically unwell infants and children

PurposeTo explore parental experiences of ultrarapid genomic testing for their critically unwell infants and children. MethodsParents of critically unwell children who participated in a national ultrarapid genomic diagnosis program were surveyed >12 weeks after genomic results return. Surveys consisted of custom questions and validated scales, including the Decision Regret Scale and Genomics Outcome Scale. ResultsWith 96 survey invitations sent, the response rate was 57% (n=55). Most parents reported receiving enough information during pretest (n=50, 94%) and post-test (n=44, 83%) counseling. Perceptions varied regarding benefits of testing, however most parents reported no or mild decision regret (n=45, 82%). The majority of parents (31/52, 60%) were extremely concerned about the condition recurring in future children, regardless of actual or perceived recurrence risk. Parents whose child received a diagnostic result reported higher empowerment. ConclusionThis study provides valuable insight into parental experiences of ultrarapid genomic testing in critically unwell children, including decision regret, empowerment, and post-test reproductive planning, to inform design and delivery of rapid diagnosis programs. The findings suggest considerations for pre- and post-test counseling that may influence parental experiences during the testing process and beyond, such as the importance of realistically conveying the likelihood for clinical and/or personal utility.

Group B Streptococcal Disease in England (1998 – 2017): A Population-based Observational Study

Group B Streptococcus (GBS) is the leading cause of sepsis and meningitis in infants <90 days. In this study, the burden of GBS disease and mortality in young infants in England was assessed. Using linked hospitalization records from every National Health Service (NHS) hospital from April 1, 1998 to March 31, 2017, we calculated annual GBS incidence in infants aged <90 days and, using regression models, compared their perinatal factors, rates of hospital-recorded disease outcomes, and all-cause infant mortality rates with those of the general infant population. 15 429 infants aged <90 days had a hospital-recorded diagnosis of GBS, giving an average annual incidence of 1.28 per 1000 live births (95% CI 1.26-1.30) with no significant trend over time. GBS-attributable mortality declined significantly from 0.044 (95% CI .029-.065) per 1000 live births in 2001 to 0.014 (95% CI .010-.026) in 2017 (annual percentage change -6.6, 95% CI -9.1 to -4.0). Infants with GBS had higher relative rates of visual impairment (HR 7.0 95% CI 4.1-12.1), cerebral palsy (HR 9.3 95% CI 6.6-13.3), hydrocephalus (HR 17.3 95% CI 13.8-21.6), and necrotizing enterocolitis (HR 18.8 95% CI 16.7-21.2) compared with those without GBS. Annual rates of GBS disease in infants have not changed over 19 years. The reduction in mortality is likely multifactorial and due to widespread implementation of antibiotics in at-risk mothers and babies, as well as advances in managing acutely unwell infants. New methods for prevention, such as maternal vaccination, must be prioritized.

Untargeted lipidomics using liquid chromatography-ion mobility-mass spectrometry reveals novel triacylglycerides in human milk

Human milk provides the infant with the essential nutritive and non-nutritive factors required for health, growth and development. The human milk lipidome is complex, but comprises predominantly triacylglycerides. Historically, the fatty acid profile of the entire human milk lipidome has been investigated, and many relationships have been identified between infant health and fatty acids. Most of these fatty acids are, however, delivered to the infant as triacylglycerides. Using liquid chromatography-ion mobility-mass spectrometry, the objective of this study was to characterise the triacylglyceride profile of human milk and elucidate relationships between the triacylglyceride profile and infant outcomes in a cohort of 10 exclusively breastfeeding woman-infant dyads. 205 triacylglycerides were identified, including 98 previously not reported in human milk. The dose of specific triacylglycerides differed in relation to infant health, such as lauric acid containing TAGs, which were delivered in significantly higher dose to healthy infants compared to unwell infants.

Biological basis of child health 3: development of the cardiovascular system and congenital heart defects.

This article is the third in a series on the biological basis of child health. It outlines how the cardiovascular system develops during gestation and how congenital heart defects (CHDs) may arise in the process. The article details the pathophysiology and treatment of some of the common CHDs, including patent ductus arteriosus, atrial septal defect, ventricular septal defect and transposition of the great arteries. It explains the possible causes of CHDs and explains how these defects are detected and diagnosed. The article also provides an overview of the initial management of acutely unwell infants and children who present with a CHD. The first two articles in the series looked at cells and genetics, and embryology.

Repair of isolated atrial septal defect in infants less than 12 months improves symptoms of chronic lung disease or shunt-related pulmonary hypertension.

Infants with isolated atrial septal defects are usually minimally symptomatic, and repair is typically performed after infancy. Early repair may be considered if there is high pulmonary blood flow and reduced respiratory reserve or early signs of pulmonary hypertension. Our aim was to review the characteristics and outcomes of a cohort of patients who underwent infant repair at our institute. The study included 56 infants (28 female, 19 trisomy 21) with isolated atrial septal defect (age: 8 months (1.5-12), weight: 6 kg (2.8-7.5), echo Qp/Qs: 1.9 ± 0.1) who underwent surgical closure (20 fenestrated). Three groups were identified: 1) chronic lung disease and pulmonary hypertension (group A: n = 28%); 2) acutely unwell infants with pulmonary hypertension but no chronic lung disease (group B: n = 20, 36%); and 3) infants with refractory congestive heart failure without either pulmonary hypertension or chronic lung disease (group C: n = 9, 16%). Post-operatively, pulmonary hypertension infants (47/56) showed improvement in tricuspid annular plane systolic excursion z-score (p < 0.001) and right ventricular systolic/diastolic duration ratio (p < 0.05). All ventilator (14.3%) or oxygen-dependent (31.6%) infants could be weaned within 2 weeks after repair. One year later, weight z-score increased in all patients and by +1 in group A, +1.3 in group B and +2 in group C. Over a median follow-up of 1.4 years, three patients died, four patients continued to have pulmonary hypertension evidence and two remained on targeted pulmonary hypertension therapy. Atrial septal defect repair within the first year may improve the clinical status and growth in infants with early signs of pulmonary hypertension or those requiring respiratory support and facilitate respiratory management.

Can H2 receptor antagonists (H2RA) prevent gastrointestinal bleeding in unwell term or near-term infants?

Can H2 receptor antagonists (H2RA) prevent gastrointestinal bleeding in unwell term or near-term infants?

Are there changes to regional tissue oxygenation and circulation following umbilical artery catheter placement? A prospective cohort study in newborn infants.

The use of umbilical arterial catheters (UACs) is a standard of care in monitoring critically unwell infants. Serious vascular complications are rare but when they do occur, they can be associated with significant morbidity, risking limb loss or even death. Near infra-red spectroscopy has the potential to monitor limb perfusion. Our study investigates changes in tissue oxygenation and perfusion in the abdominal and leg circulation following UAC insertion. A prospective observational study performing ultrasound pulsed Doppler measurements in the coeliac, superior mesenteric artery, renal arteries and the femoral arteries as well as near infrared spectroscopy measurements of both thighs at three time points (immediately before = Time 1, 1 h after = Time 2 and 24 h after UAC insertion = Time 3). We monitored 30 infants, the mean gestational age was 30 weeks (24-41) and the mean birthweight was 1720 g (600-4070 g). We observed statistically significant changes (P < 0.05) in pulse Doppler measurements in coeliac (mean peak systolic velocity (PSV): Time 1 = 70.51, Time 2 = 61.75; resistive index (RI): Time 1 = 0.75, Time 2 = 0.67), superior mesenteric (PSV: Time 1 = 41.72, Time 2 = 36.10; RI: Time 1 = 0.92, Time 2 = 0.87), renal (same side end-diastolic velocity: Time 1 = 1.98, Time 2 = 3.80; RI: Time 1 = 0.93, Time 2 = 0.87; opposite side end-diastolic velocity: Time 1 = 2.62, Time 2 = 3.84; RI: Time 1 = 0.92, Time 2 = 0.85) and femoral arteries (same side PSV: Time 1 = 72.75, Time 2 = 62.18; opposite side PSV: Time 1 = 81.89, Time 2 = 62.74). Tissue oxygenation in lower limbs remained unaffected (same side (mean): Time 1 = 68.59, Time 2 = 68.99, Time 3 = 66.40, opposite side: Time 1 = 67.72, Time 2 = 66.92, Time 3 = 65.40). All infants on clinical examination had normal lower limb perfusion, lower limb arterial pulses and normal perfusion to the gluteal region before and after insertion of UAC. While sub-clinical changes in perfusion occur in abdominal and leg circulation, these changes are not consistent across vessels and regional tissue oxygenation remains unaffected.

Early diagnosis of Pearson syndrome in neonatal intensive care following rapid mitochondrial genome sequencing in tandem with exome sequencing.

Rapid genomic testing is a valuable new diagnostic tool for acutely unwell infants, however exome sequencing does not deliver clinical-grade mitochondrial genome sequencing and may fail to diagnose mitochondrial disorders caused by mitochondrial DNA (mtDNA) variants. Rapid mitochondrial genome sequencing and analysis are not routinely available in rapid genomic diagnosis programmes. We present two critically ill neonates with transfusion-dependent anaemia and persistent lactic acidosis who underwent rapid mitochondrial genome sequencing in tandem with exome sequencing as part of an exome sequencing-based rapid genomic diagnosis programme. No diagnostic variants were identified on examination of the nuclear exome data for either infant. Mitochondrial genome sequencing identified a large mtDNA deletion in both infants, diagnosing Pearson syndrome within 74 and 55 h, respectively. Early diagnosis in the third week of life allowed the avoidance of a range of other investigations and appropriate treatment planning. Rapid mitochondrial genome analysis provides additional diagnostic and clinical utility and should be considered as an adjunct to exome sequencing in rapid genomic diagnosis programmes.

Learning from diagnostic error when primary care services are located in or alongside emergency departments: a theory generating mixed-methods study

BackgroundNew healthcare service models are being introduced to help manage increasing demand on emergency healthcare systems including the provision of primary care services in or alongside emergency departments. There is little research evidence to guide decisions about how service models can be most effective and safe.AimFocusing on diagnostic error, the aim was to learn why errors occur to identify priority interventions.MethodTwo data sources were used to identify diagnostic error reports including: coroners’ reports to prevent future deaths; and the National Reporting and Learning System (NRLS). A cross-sectional, mixed-methods theory-generating study which used a multi-axial PISA classification system based on the recursive model for incident analysis, was carried out.ResultsNine Coroners’ reports (from a total of 1347 community and hospital reports, 2013–2018) and 217 NRLS reports (from 13 million, 2005–2015) were identified describing diagnostic error with learning relevant to primary care services in or alongside emergency departments. Clinical presentations included musculoskeletal injuries; unwell infants; headaches; and chest pains. Findings highlighted a difficulty identifying appropriate patients for the primary care service; underinvestigation; misinterpretation of diagnostic tests; underuse of safeguarding protocols; and inadequate communication and referral pathways between the services.ConclusionPriority areas to minimise risk of diagnostic error when primary care services are located in or alongside emergency departments include clinical decision support to triage and stream patients to the appropriate care setting; contextualised, workplace-based education and training for primary care staff; and standardised computer systems, communication and referral pathways between emergency and primary care services.

How Sensitive are Dipstick Urinalysis and Microscopy in Making Diagnosis of Urinary Tract Infection in Children?

Background:Urinary tract infection (UTI) is a common reason for referral to the emergency department (ED) especially in unwell infants. Upper UTIs are particularly at risk of significant complications later in life. Rapid dipstick urinalysis and microscopy are often used in unwell children as a screening tool to guide early diagnosis and treatment. This study aims to evaluate the sensitivity of dipstick urinalysis and microscopy in the diagnosis of UTI.Methods:A retrospective review of children aged 16 years and below with positive urine culture (UC) over a 3-year period was done. The results of urine dipstick and microscopy were compared with the positive UC and sensitivities calculated.Results:Dipstick urinalysis and microscopy of 262 children were studied. Female-to -male ratio of 1.8:1. Median age was 0.79 (range: 0.02–15.95) years. The sensitivity of nitrite, blood, and leukocyte esterase (LE) were 0.54, 0.74, and 0.86 (95% confidence interval [CI] = 0.46–0.62, 0.68–0.80, and 0.82–0.91), respectively. The sensitivity of pyuria of ≥100 cells/mm3 was 0.92 (95% CI = 0.89–0.95). The presence of any of the 3 dipstick parameters increased the sensitivity to 0.97 (95% CI = 0.95–0.99). The lowest sensitivity 0.49 (95% CI = 0.40–0.58) was found with combined positive LE and nitrite. There was a significant comparison between positive LE dipstick test and pyuria (P = 0.000004).Conclusions:Dipstick urinalysis may not be reliable in ruling out UTI in children. However, considering both positive dipstick and pyuria will be more useful in making the diagnosis.

Infection control and treatment guidelines and neonatal mortality in a rural hospital in Uganda

ABSTRACTBackground: The neonatal mortality rate in Uganda has been 24–27/1000 live births for the last 14 years.Aim: To determine the impact on neonatal mortality of the introduction of infection prevention and treatment guidelines in a resource-poor setting.Methods: A prospective study was undertaken in Kagando Hospital, a rural hospital in Western Uganda of infants live-born in hospital and those admitted from the community or other hospitals between 2013 and 2017. Guidelines were developed from a literature review and informed by local doctors and nurses and a visiting paediatrician. The guidelines highlighted that unwell infants should be admitted to the neonatal unit which was a section of the paediatric ward, emphasised hand hygiene, the separation of infants with and without sepsis and that unwell infants should be treated with evidence-based antibiotic regimens and enteral feeds withheld from unwell infants. Mortality within 28 days of birth was audited for 3 months before and after the intervention; the audit was repeated 3 and 5 years later.Results: Pre-intervention, there were 137 neonatal admissions and 79 neonatal deaths in 3 months (0.58 deaths per admission). Post-intervention there were 187 admissions and the death rate was lower (0.26 deaths per admission, p < 0.001). Three years after the intervention, there were 60 deaths among 233 admissions (0.26 deaths per admission, p < 0.001) and, at 5 years, 53 deaths among 315 admissions (0.17 deaths per admission, p < 0.001).Conclusion: These data suggest that the introduction of infection, prevention and treatment guidelines can reduce neonatal mortality in a resource-poor setting.