Did you know 2017

 

 

2017:01 Neonatal hearing screening in South Africa

 

In 2014 it was reported that every day an estimated 17 babies in South Africa will be born with or acquire significant permanent bilateral hearing loss within the first few weeks of life.  Summary 1601 deals with successful screening of school age children using cellphone technology, a strategy that has the potential to make a significant difference in an environment in which EHDI (early hearing detection and intervention) is suboptimal, but this cannot be the sole strategy: we also need to address the matter of neonatal screening.  Unlike other congenital or early-onset disabilities, infants with hearing loss have the potential to develop speech and language skills, provided that the loss is identified and intervention initiated early enough.  Goals include screening shortly after birth, audiological and medical evaluations before 3 months of age, diagnosis by 4 months and initiation of intervention by 6 months of age.  In South Africa hearing loss appears to be detected ‘passively’ after 2 to 2½ years of age when parents become concerned about speech and language delays or unusual behaviour. Hearing aids and intervention programmes may be delayed until the 3rd or even 4th year of life.  Speech Pathologists/Audiologists have not been idle in this regard and in 2007 published an internationally-compliant comprehensive Position Statement through their designated Professional Board of the HPCSA (Health Professions Council of SA).  Unfortunately study after study has shown that what is effectively a best practice guideline is not achieving the desired outcomes in the country.  A subsequent survey showed that around 50% of private hospitals offered ‘some form’ of screening but only 15% offered true universal newborn screening. In the public sector less than 10% of hospitals had implemented some form of newborn screening.  An article in 2016 reviewed data from 117 children in three provinces in South Africa and found that only 19% had comprehensive assessments and the ‘guideline’ had not been followed in any of the cases analysed.  There are various possibilities for the failure to achieve desired screening rates ranging from a Position Statement not actually having the status of a guideline, to inadequate resources (human and technological) in the public sector  and failure of medical insurance/aid to cover the costs of screening in the private sector.  Sadly it has also been reported that in South Africa healthcare providers, and specifically Paediatricians, are often unsupportive of hearing screening and have played a role in influencing parents against having their neonate screened and/or returning for follow up if an abnormality is found.  On the positive side there is a study covering almost 7500 infants attending a community-based midwife obstetric unit successfully screened postnatally by a dedicated non-professional screener using auditory brainstem response or otoacoustic emission technology.  Further exploration of such a strategy in both the private and public sectors is probably worthwhile, in the meantime perhaps there should be initiatives to achieve buy-in for the position statement/guideline from the full range of health professionals involved in the comprehensive care of affected children.

Read more:

Int J Pediatr Otorhinolaryngol 2016;84:124-131;  2016;91:152-8;  2014;78:1197

S Afr J Child Health 2015; 9: 38-40

S Afr J Communic Disord 2014; http://dx.doi.org/10.4012/sajcd.v61i1.62

 

 

2017:02 Reducing group B streptococcal diasease in African settings

 

The previous summary alluded to the need for inter-professional collaboration in the matter of neonatal hearing screening.  An advocacy role for paediatricians was also mentioned in order to promote this important preventive health intervention.  Inter-professional collaboration is also highlighted in a recent article on strategies that should be considered in order to reduce neonatal infections with group B streptococcus (GBS).  Here paediatricians, vaccinologists and researchers into respiratory and meningeal pathogens jointly address the problem, but unless such a group also includes policy makers and various healthcare providers involved in antenatal care, the recommendations risk being ignored.  The authors of the article point out that in Africa the neonatal mortality rate of around 30/1000 live births is 4 to 5 times higher than that of the Americas and Europe.  Sepsis, meningitis and pneumonia contribute significantly to the ±3 million neonatal deaths worldwide each year, GBS being a leading pathogen.  Data from both high and low-income countries have shown maternal GBS carriage rates of 10-40% during pregnancy with South Africa measured at 28.4%.  As is well known, GBS infection may present as early or late-onset disease. Early onset disease (0-6 days of life) follows acquisition by the foetus or neonate from the rectovaginally-colonised mother. While up to 70% of newborns of colonized mothers are themselves colonized at birth, only 1-3% go on to develop early onset disease which may progress rapidly. The disease may be symptomatic at birth and 90% present within 24 hours of delivery, suggesting that most cases commence in utero.  In contrast, the role of maternal colonization, neonatal risk factors, mode of transmission and pathogenesis of late onset disease are less clear, with breast-feeding, hospital environment and even the community recognized as potential sources of infection.  Factors increasing the risk of maternal transmission and early onset disease include ‘density’ of maternal colonization, prolonged rupture of membranes, and GBS bacteriuria (which is an indicator of heavy genital tract colonization). Of interest is that maternal HIV infection has not been associated with higher rates of GBS colonization. In fact it has been shown that colonization rates are directly related to CD4 counts, and highest carriage rates were in HIV-infected women with counts of >500 cells/mm3.  It has been postulated that this apparent paradox is the result of ‘competitive exclusion’ of GBS in the altered microbial environment found in HIV-infected women.  In terms of preventive strategies for resource-poor settings, vaccines are being developed but will not be available in the short term.  Intrapartum antibiotic prophylaxis for women found to be colonised at 35-37 weeks of pregnancy, as practised in high-income countries, is not practical or affordable. Chlorhexidine vaginal douches, which were promoted some years back, have been shown in a Cochrane review to be ineffective. This leaves intra-partum antibiotic administration to high-risk women as the currently-preferred option, with high risk status assigned with factors such as preterm labour, prolonged rupture of membranes, intra-partum fever, bacteriuria during the pregnancy and/or a previous infant with invasive disease.  In the UK such a strategy has reduced the risk of early onset disease, probably by some 50%.  While intravenous intra-partum antibiotics are the standard of care, there is also a call for the study of intramuscular and oral antibiotics. If successful, such strategies would enable peripheral health facilities to provide care rather than having to refer high risk mothers to more-central facilities.

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Arch Dis Child 2017; 102: 72-7

J Matern Fetal Neonatal Med 2015; 28: 766-82

Vaccine 2013; 31: D20-6

 

 

2017:03 Mortality of HIV-infected infants despite access to antiretroviral therapy (ART)

 

Collaboration between 3 Johannesburg academic hospitals and 2 clinics treating infants with HIV enabled researchers from Witwatersrand and Columbia (New York) Universities to follow up a cohort of patients ≤24 months of age who were newly-diagnosed with HIV.  The outcomes of interest were ART initiation and mortality rates, and risk factors for mortality in the 6 months following enrolment.  Whereas South Africa has demonstrated success in preventing and treating paediatric HIV infection through its PMTCT (prevention of mother to child transmission) initiatives which have dropped transmission rates to around 3-4%, little is known about mortality of children who acquire HIV in the era of good access to ARTs.  The study was carried out between January and December 2011 and recruited infants with a positive PCR or HIV antibody test (depending on age). Various demographic details were obtained via a questionnaire, and blood was taken for viral load (mother and child) and CD4%.  Only ART-naïve subjects were included for analysis (n=272; median age at enrolment 6.2 months).  The majority (~70%) were identified during a hospital visit, ~21% at PMTCT follow-up and ~9% through immunization services.  Mean age at HIV testing was 3.7 months, with hospital cases being older than PMTCT follow up cases at the time of testing (median 6 months vs 1.6 months). Almost 20% of the 272 had died within 6 months of enrolment and almost 30% had been lost to follow up.  Kaplan-Meier analysis revealed that probability of death was 4.7% one week after enrolment, 9.6% one month later, 18.1% by 3 months and 23.5% by 6 months.  Not all infants received ART: 46 had not initiated treatment within 6 months of enrolment, and this group was at greater risk of death (~55% of those available for follow up vs ~16% of ART recipients available for follow up).  Other risk factors for mortality were later diagnosis i.e. in hospital vs at PMTCT follow up, and those with more advanced disease (specifically lower CD4 counts and lower weight-for-age z-scores).  Maternal risk factors for infant mortality included lower CD4 counts and non-exposure to ART/PMTCT.  It is likely that some patients who died without ART died before treatment initiation since in this study there were delays between testing and diagnosis, and diagnosis and ART initiation (4-6 weeks). Noting that this study covered children born in 2010 and 2011, that there have been advances in testing and lower thresholds for ART initiation, it is likely that currently more children are diagnosed, have access to treatment, and are at lower risk of dying. On the other hand, the frequently-observed loss to follow up in a subset encompassing the more-vulnerable remains a problem.

Read more:

Pediatr Inf Dis J 2017. doi:10.1097/INF.0000000000001507

PLoS one 2015; 10: e0125525

Curr Opin HIV AIDS 2013; 8: 443-6

 

 

2017:04 Grey matter volumes and psychiatric symptoms in very low birthweight (VLBW) infants

 

Since the advent of advanced neonatal care in the 1970’s and early 1980’s, and the increasing survival rates of VLBW and ELBW (extremely low birthweight) infants, there has been a considerable body of literature focusing on neurodevelopment and the longer term cognitive and motor outcomes. The indirect relationship between lower birthweight and risk of poor neurodevelopmental outcome is one of the realities of increased survival of these tiny infants. Additionally, several studies including a meta-analysis of >800 VLBW children and adolescents, have shown that extreme prematurity is associated with significantly lower total brain volume in comparison to infants born at term.  Over the past five years the focus has shifted to the relationship between VLBW and the risk of developing psychiatric problems which persist into adulthood.  These problems include anxiety disorders, attention problems, (including ADHD), social difficulties and autism spectrum disorders (ASDs).  One study suggests that ASDs are quite prevalent, with 23 of 84 children born at <27 weeks testing ASD-positive at 6.5 years.  These children had more neonatal complications than the ASD-negative children, and where structural morphometric studies were obtained, the ASD-positive group had significantly reduced volumes in the temporal, occipital, insular and limbic regions, and in the areas involved in social/behaviour and salience integration.  A more-recent study from Norway has added to the literature with a study of ~40 VLBW (mean birthweight 1204g; mean gestational age 29 weeks) born between 1986 and 1988, and ~60 38-42 week control subjects.  All were assessed and followed up at 15 and 19 years of age.  Assessments included MRIs using volume-calculating software, the KSADS diagnostic interview (Kids Schedule for Affective Disorders and Schizophrenia), and diagnosis according to DSM-IV.  Adolescents were further sub-categorised between 15 and 19 years of age into those whose psychiatric diagnosis developed or persisted, and those who had ‘become healthy’ or had been healthy throughout.  Additional assessments included the Children’s Global Assessment Scale, the ADHD Rating Scale-IV, an IQ score using the Wechsler Adult Intelligence Scale, and family socioeconomic status (SES) using the Hollingshead Index.  In 24 adolescents the psychiatric diagnosis developed or persisted, and in 30 subjects the diagnosis was either absent or had disappeared.  Notably the former sub-group had significantly lower mean birthweight (1096g vs 1269g), lower 1-minute Apgar (5.7 vs 7.6) and lower IQ at 19 years (80 vs 93).  Subcortical grey matter volume at 15 and 19 years was significantly reduced in VLBW subjects with persisting or developing diagnosis during adolescence. Where psychosocial problems (‘non-psychiatric’) were encountered within the VLBW group they were related to reduced grey matter volumes in the thalamus and parietal and occipital cortex, while inattention problems were predicted by smaller grey matter volumes in the parietal and occipital cortex.

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BMC Pediatrics 2017; 17: 45

Cereb Cortex 2015; Dec 21.pii: bhv300

Dev Med Child Neurol 2012; 54: 313-23                       

 

 

2017:05 Risk factors for hearing impairment in very low birth weight (VLBW) infants

 

Recent summaries in this series have made a case for greater access to hearing screening during infancy (summary 1701) and have correlated developmental and psychiatric problems in VLBW children and adolescents with reduced brain volumes (summary 1704).  Hearing impairment may occur together with developmental disorders in VLBW infants, and diagnosis may be delayed if poor language development is attributed to global delay and not recognized as being the result of auditory problems.  The incidence of hearing impairment in VLBW infants appears to be in the region of 0.4-5% and screening is recommended during the neonatal period and during neurodevelopmental follow-up.  Many articles have appeared over the years examining risk factors with some broadly identifying VLBW or neonatal ICU as the factors, while most go deeper into specific aetiologies and associations such as intrauterine or postnatal infections, perinatal asphyxia, requirement for prolonged supplemental oxygen or assisted ventilation, jaundice requiring exchange transfusion, congenital malformations or genetic abnormalities, and exposure to ototoxic medications such as furosemide, aminoglycosides and vancomycin.  Given the range of incidence figures it is probably incumbent on units treating VLBW infants to at some stage formally study where they are on the scale. One such report appeared recently from a Chinese NICU, and based on brainstem auditory evoked potentials (BAEP) documented hearing impairment in 12 of 309 VLBW infants (mean birthweight 1028g; mean gestational age 27.9 weeks). Univariate analysis of risk factors/associations identified birth asphyxia, craniofacial anomalies, ventilator dependence, PDA ligation and postnatal exposure to ototoxic agents.  Multivariate analysis revealed that the only independent risk factors were ototoxins, PDA ligation, craniofacial anomalies and prolonged requirement for supplemental oxygen.  While several early studies found the association between aminoglycoside treatment and hearing loss, some studies since the 1990s have suggested that controlled and monitored dosing does not result in ototoxicity.  This appears to have been confirmed again in a recent Swiss review in which gentamicin had been administered to 25 VLBW infants with hearing loss and also to controls matched for gender, birthweight, gestational age and year of birth.  Gentamicin was not considered to have played a role in the hearing loss because of similar rates of exposure in affected and control infants, but it should be noted that the study design would not have detected the possibility of gentamicin having acted in concert with or potentiated by other factors affecting VLBW neonates.  While much of the literature broadly categorises the hearing loss under discussion as ‘sensorineural hearing loss’ (SNHL), it is interesting to note that during the last decade much has been written about the Auditory Neuropathy Spectrum Disorder (ANSD) which is characterized by abnormal or absent auditory brainstem responses, but normal otoacoustic emissions and cochlear microphonics (voltages arising from hair cells).  These responses suggest cochlear outer hair cells are functioning normally while there is abnormal transmission of sound between inner hair cells and the brain. The risk factors described above for VLBW infants are strongly correlated with ANSD.

Read more:

Int J Pediatr Otorhinolaryngol 2017; 93: 123-7 and 2012; 76: 1668-70

PLOS One doi:10.1371/journal.pone.0158806

Canadian J Speech Lang Path Audiol 2016;40: 67-79

 

 

2017:06 Neurology of rotavirus in neonates, infants and children

 

Rotavirus remains an important cause of gastroenteritis in infants and children, even with access to vaccines. Since the introduction of rotavirus vaccine into the South African national programme in 2009 there has been a 45-65% reduction in diarrhoeal hospitalisation rates in infants and 40-50% reductions in those aged between 12 and 24 months. While dehydration is the most frequent complication of infection, there are other intestinal complications such as hepatitis and necrotising enterocolitis,and extra-intestinal complications, particularly neurological, have also been described. These include meningitis, encephalitis/encephalopathy, febrile seizures, and Guillain-Barre and Reyes syndromes.  It has been stated that rotavirus is the most common cause of benign infantile convulsions associated with gastroenteritis, and a recent article from Turkey has provided insight into characteristics of 16 affected children (mean age 13.8±5.98 months; 43.8% generalized tonic seizures; 50% generalized tonic-clonic; 6.3% focal seizures; mean duration of seizures 3.7±1.4 minutes; mean time between onset of clinical findings of rotavirus infection and seizures 31.5±12.2 hours). Neurological examinations were normal after the seizures and prognosis was generally benign in this small group. Importantly, where the impact of the rotavirus vaccine has been studied, norovirus is replacing rotavirus as the associated infectious agent in infants presenting with seizures and gastroenteritis.  Other rotavirus-related neurological presentations appear to be more sinister.  For example a Korean study reported on 30 neonates who presented with seizures at 2-7 days of age and cerebral white matter and corpus callosum changes on MRI.  Seizures were repetitive in all patients. Rotavirus was detected in stool samples from all 30 patients and enterovirus in 5. Focal and multifocal clonic seizures were observed in 28 with our without other seizure variants such as apneic episodes, subtle seizures and generalized tonic seizures. Prognosis on follow-up of these infants “was not always benign.” One study which reported on CSF levels of excitatory amino acids in febrile-seizure vs encephalopathic rotavirus-related cases showed levels to be significantly higher in the latter. These cases are likely part of the spectrum of ‘Encephalopathy with a Reversible Splenial lesion.’ If Mild the acronym is MERS, describing patients between 1 and 6 years of age with encephalopathy and/or seizure,s and a transient, obvious, high-signal-intensity lesion in the corpus callosum, possibly the result of intra-myelinic axonal oedema or local inflammatory cell infiltration. The majority of patients appear to achieve full recovery. Another study involved a nationwide survey of rotavirus-associated encephalopathy and sudden death in Japan and found 58 cases (median age 2.1 years) and 7 unexpected deaths (median age 1 year) between 2009 and 2011. Two-thirds had no sequelae while 26% were neurologically impaired (paralysis, epilepsy, psychomotor retardation, ataxia). CT scans showed brain oedema in 9/34 studied and MRI showed hyperintensity in various areas in 22 of the 34 studied. Interestingly most of the cases have been reported in the Far East (China, Korea, Japan) and a few from Australia.

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Acta Neurol Belg 2017 doi 10.1007/s13760-017-0747-1

BMC Infect Dis 2015; 15: 446

J Child Neurol 2015; 30: 1433-9

Brain Dev 2014; 36: 601-7

 

 

2017:07 Predicting parental cardiovascular mortality on the basis of birthweight of offspring

 

Predicting cardiovascular disease (CVD) in women is more difficult than in men, often because clinical presentation of CVD is different. It would therefore be of some value to have early identification of higher-risk women and the ability to monitor and introduce preventive strategies.  It is accepted that low birthweight of offspring is a predictor of parental (maternal>paternal) CVD and death, with highest risk observed with smaller babies.  Maternal risk declines by 25% with each standard deviation increase (~500g) in birthweight of the first child.  Common pregnancy complications responsible for this association are gestational diabetes mellitus, pre-eclampsia, foetal growth restriction and preterm delivery.  There are logical connections between these pregnancy complications and maternal pre-diabetes, diabetes, hypertensive disease and subsequent morbidity and mortality from CVD.  Apart from the maternal risks associated with lower birthweights, there are also the subsequent metabolic risks in mothers after the birth of macrosomic infants exposed to intrauterine hyperglycaemia, i.e. it is not only the small babies that confer risk, but also the larger ones.  In a large US cohort study it was estimated that around 30% of parous women have experienced one of the abovementioned pregnancy complications, each of which is associated with roughly a two-fold increase in the risk of CVD.  Therefore if 80% of women are parous and 30% have a ‘predictive’ pregnancy complication, then roughly 20-30% of women will be candidates for monitoring for future CVD.  Pursuing this line of investigation, Norwegian researchers studied neonatal and parental follow-up data for >700 000 families. Data were obtained from Birth and Person databases.  Firstborn singletons born between 1967 and 2002 were recorded together with parental mortality data until 2009.  Cardiovascular causes of death were essentially those coded as ischaemic heart disease and/or cerebrovascular disease/stroke.  Almost 2300 mothers and 10200 fathers died from cardiovascular causes during the follow-up. When hazard ratios were calculated according to absolute birthweight of the first offspring, lower birthweights were strongly associated with maternal cardiovascular mortality (HR 3.6; 95%CI 2.8-4.6), while the association was much weaker for fathers. Unexpectedly, there was no apparent association with high absolute birthweight. The authors confirmed the 25% reduction in risk of CVD for every 500g increase in birthweight (up to 3500g, after which there was no further reduction). More importantly, when the data were analysed according to birthweight/gestational age z-scores (-2.5 to +2.5) there was not only the expected risk for mothers of lower weight offspring, but also a strong relationship between higher birthweight (z-score>2.5) and mother’s subsequent cardiovascular mortality (HR 3.0; 95%CI 2.0-4.6). However this risk for CVD was apparently restricted to preterm births; for term babies the risk of heavier babies was restricted to risk of subsequent diabetes. The authors therefore conclude that women having relatively large preterm babies are at increased risk for cardiovascular mortality, and particular attention should be paid to assessing weight for gestational age, not only looking for those preterm infants who are small for gestational age but also those who are heavier.

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BJOG 2017; doi: 10.1111/1471-0528.14522

Epidemiol Rev 2014; 36: 57-70 

Circulation 2012; 125: 1367-80  

 

 

2017:08 Complications of adolescent Type 1 vs Type 2 diabetes mellitus

 

Summary 1623 deals with the fairly drastic intervention of bariatric surgery for the management of obesity and metabolic complications in adolescents with type 2 diabetes mellitus (DM2). The point is made in the summary that progression of disease appears to be far more aggressive among younger patients who as a group and  despite medical management develop comorbidities at a faster pace than for type 1 diabetes mellitus (DM1) and also appear to lose beta-cell function more rapidly than DM2 adults.  Complications present relatively early (e.g. a Japanese study showed that 24% of 1063 subjects were blind by 32 years of age) and adolescents with DM2 are predicted to lose 15 years from their remaining life expectancy when compared to non-diabetic peers.  Two recent articles, one from India, the other from the USA, compare DM2 complications and rates vs. DM1 in younger subjects.  The Indian study involved 108 DM1 and 90 DM2 patients diagnosed at 10 to 25 years of age. DM1 patients were 17.5±4.2 years old at the time of diagnosis vs. 21.6±3.6 years for DM2. Retinopathy risk was estimated to be similar (77.4 vs. 78.0/1000 person years for DM1 and 2 resp.), nephropathy 62.0 vs. 58.8/1000 person years, neuropathy 7.8 vs. 13.9 and ischaemic heart disease 1.2 vs. 5.4.  Overall the DM2 subjects were twice as likely to develop complications.  The American study involved 1746 DM1’s and 272 DM2’s: mean ages were 17.9 years for DM1 and 22.1 for DM2. Duration of diabetes was 7.9 years in both groups. Nephropathy was observed in 19.9% of DM2’s vs. 5.8%; retinopathy in 9.1% vs. 5.6%; and peripheral neuropathy in 17.7% vs. 8.5%.  Odds Ratios for the three complications were between 2.24 and 2.58.  These statistics are likely quite surprising to paediatricians who probably encounter DM1 to a greater extent than DM2 within the age spectrum seen by most practices As such, the young DM1 patients would typically be regarded as an at-risk group in which adherence to diet and treatment regimens is poor and hospital admissions are not uncommon. However it must be appreciated that adolescent DM2 is becoming more of a problem (currently the US and India both report around 50% of newly-diagnosed diabetes being DM2) and whereas paediatricians or paediatric endocrinologists may no longer be treating patients who have ‘graduated’ to their adult counterparts, once again there is an obligation on the former specialists to play a role in primary and secondary prevention i.e. to prevent overweight and obesity in children and adolescents, screen for pre-diabetes and DM2 where indicated, and aggressively intervene to manage lifestyles and control glucose and lipid levels in cases that are diagnosed as DM2.

Read more:

Diabetes Res Clin Prac 2017; 123: 1-8

JAMA 2017; 317: 825-35

Aust Fam Physician 2016; 45: 401-6

 

 

 

2017:09 Rotavirus genotype changes before and after vaccine introduction

 

Summary 1706 discusses a number of rotavirus-related neurological presentations in neonates, infants and children. The point is made that most of the literature on the subject has come from the Far East, raising the question of whether this is a true preponderance or the result of greater awareness and testing for rotavirus in patients presenting with gastroenteritis in that region. Literature cited for summary 1706 alludes to routine testing in some sites, and this also appears to be a factor in a recent article covering rotavirus genotype changes in three areas of Japan between the 2007/8 (pre-vaccine) and 2013/4 post-vaccine rotavirus seasons.  Whereas a number of countries introduced routine rotavirus vaccination into schedules in the late 2000’s, Japan has only relatively recently approved monovalent and pentavalent vaccines. While available within the country and routinely administered in some areas, vaccines were not part of a national programme at the time of the study.  The importance of gastroenteritis for the Japanese authorities is shown by the fact that in 1999, acute gastroenteritis was designated as a category V notifiable disease under the Communicable Disease Prevention Law. This requires 3000 designated paediatric sentinel sites to report weekly on the total number of patients by age and sex, following which the data are condensed to the National Epidemiological Surveillance of Infectious Disease (NESID) system.  This initiative was further developed to characterise the role of rotavirus through the establishment of RESG, the Rotavirus Epidemiology Study Group, which includes one laboratory and five medical in- and out-patient facilities in three different Japanese locations. Participating centres collect stool samples and test for rotavirus by means of commercially-available rapid antigen tests (e.g. Rapid-testa or ImmunoCard). For the research into genotype shifts, the stools were further tested by means of reverse-transcription PCR, confirming rotavirus infection in some 300 patients of which only 8 appear to have been immunized.  Significant changes were noted between the pre-vaccine and post-vaccine time periods, both in terms of an overall reduction in the number of rotavirus-related cases of gastroenteritis, and in the rotavirus genotypes identified. In two study areas genotype G3P[8] was dominant before vaccine introduction, but changed to dominance of G1P[8] and then to G2P[4] after an estimated vaccine coverage rate of 30-50% in the two areas. In the third region, in which vaccine coverage was closer to 100%, the genotype change was from G1P[8] to G9P[8]. While similar post-immunisation programme shifts in genotypes have been reported from Brazil, the USA and Australia, the authors do not attribute the genotype changes to the introduction of vaccines vs natural epidemiologic shifts, but do make the point that continuous monitoring is required in order to track and understand the shift, and also to ensure that vaccines continue to protect against prevailing pathogens.

Read more:

Jpn J Infect Dis 2017; doi: 10.7883/yoken.JJID.2016.286

Vaccine 2014; 32: 6396-402

 Hum Vaccin Immunother 2012; 8: 1022-8

 

 

 

2017:10 Does maternal sugar-containing beverage (SCB) intake during pregnancy affect childhood BMI?

 

Much has been made of research that has modeled the potential impact of a reduction in consumption of SCBs on population rates of obesity. Scientists have influenced policy-makers in various countries, and a tax on SCBs will likely be imposed on South Africans during 2017.  The statement from national Treasury is that the first 4g of sugar per 100ml of beverage would be exempt from the tax, as would 100% fruit juices and milk products.  In this regard one should review research recently published by epidemiologists in the Netherlands in which 3312 mother-child pairs were followed up as part of the Generation R Study. Their particular interest was whether maternal intake of SCBs during pregnancy would influence intrauterine programming of the child toward obesity. Previous research has indicated that no effects were observed within the first 6 months of life, but there has not been any research into consequences later on in childhood.  Singleton births between 2002 and 2006 were included and followed up until 6 years of age. Body mass index was calculated routinely and available for all 3312 subjects, while DEXA-scanning was used and results available for 2660 of the subjects and used to calculate fat mass- and fat-free mass indices (FMI and FFMI). Dietary assessments were obtained from mothers at antenatal clinic enrolment (median 13.4 weeks of gestation) and information obtained on SCBs, specifically ‘soda’ (soft drinks, sport drinks and energy drinks), concentrates (juice and lemonade concentrates with added sugar) and fruit juices (fresh or boxed 100% fruit juices).  Median intake of SCBs during early pregnancy was 1.9 servings per day, of which 1.0 was derived from fruit juices.  Mean birthweight of the infants was 3488±561g, and at 6 years of age 9.2% of the children were overweight or obese.  In a linear mixed-model analysis there was no association between maternal SCB intake and BMI trajectories of children between birth and 6yrs.  However after adjustment for child SCB intake, a significantly higher BMI was observed in children whose mothers had a higher SCB intake during pregnancy.  Furthermore, maternal fruit juice intake (vs soda and/or concentrate) appeared to be associated with higher FMIs in children, an effect that appeared to greater in girls. As for a proposed mechanism of action, the authors suggest that the epigenetics of the foetus are affected by SCB intake, leading to altered gene expression and greater susceptibility to a higher fat mass.  The focus on 100% fruit juices as the ‘prime suspects’ is interesting given that they will be exempted from the proposed South African sugar tax.

Read more:

Am J Clin Nutr 2017 doi: 10.3945/ajcn.116.147934

Biomed Res Int 2016 doi: 10.1155/2016/7574843

Exp Diabetes Res 2011:985135

 

 

 

2017:11 Intravitreal anti-VEGF (anti-vascular endothelial growth factor) and retinopathy of prematurity

 

Much has changed in the management of retinopathy of prematurity (ROP) since the 1990’s when treatment options were limited and it was still appropriate to report on the natural history of the condition. Interventions to prevent the consequences of neovascularization, retinal detachment and visual impairment have included cryotherapy, laser therapy and more recently, intravitreal bevacizumab (IVB) i.e. an injection of monoclonal antibody directed against VEGF.  Retinopathy of prematurity continues to be important in South Africa, reportedly accounting for 10.2% of children at schools for the blind.  Furthermore, while there have unquestionably been advances in survival rates of preterm babies in both the private and public sectors over the years, the country is still included among those encountering the ‘third epidemic’ of ROP. The first was during the mid-1900’s when preterm neonates were exposed to unrestricted oxygen; the second was encountered in the 1970’s when advances in neonatology resulted in the survival of second- and early-third trimester preterm infants at high risk for ROP, and the third epidemic is in developing countries where prematurity rates are high, survival is improving but neonatal monitoring is often inadequate.  These points are highlighted in a research report and an editorial in the South African Medical Journal focusing on outcomes in a public sector tertiary hospital in which IVB was used as an alternative to laser to treat qualifying infants.  Between 2013 and 2015 twenty-three patients were treated for active ROP and results were available for 22 (43 eyes), all of whom qualified for intervention according to criteria used in the 7000 patient ETROP study (Early Treatment of ROP).  Mean follow up was over 9 months (range 1-18) and 41 eyes showed complete regression or non-progression, while two eyes (one each in two patients) progressed to advanced disease.  A costing analysis based on private sector costs showed IVB to be substantially cheaper (R12 529 vs R25 916).  The editorial comment related to the article indicates that IVB is used by some 50% of ophthalmologists in South Africa, with ~30% regarding it as their primary treatment modality. While there are advantages as described in the article, there are also caveats ranging from IVB still being an ‘off-label’ intervention, to the risks of the antibody inhibiting peripheral retinal vascularization and a permanent avascular zone in some infants.  There are also concerns about the potential for the antibody to leak from the eye and have adverse systemic effects.  A recent review on the subject also expresses caution, stating that IVB should not be used in stage 1 or even stage 2 disease because of the risk of inhibiting necessary angiogenesis, and also not in stage 4 or 5 disease because of an increased risk of retinal detachment.  

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S Afr Med J 2017; March: 20-1  and 47-50

Arch Soc Esp Oftalmol 2015; 90: 81-6

Eye 1992; 6: 233-42         

 

 

 

2017:12 Non-operative management (NOM) of appendicitis in children

 

It is stated that acute appendicitis is one of the most common general surgical emergencies worldwide with a peak incidence in the second decade of life.  Acute abdominal pain is a common complaint among children and acute appendicitis is diagnosed in almost 10% of children presenting to emergency departments with the complaint.  In the USA as many as 70 000 children are hospitalized each year for management of appendicitis, tens of thousands of appendectomies are performed, the financial burden is substantial, and in recent years many surgeons have challenged the dogma that surgery is the mainstay of treatment.  There is a thus a growing body of literature supporting non-operative, antibiotic- and IV fluid-based management as a viable option, but unfortunately very little in the way of randomized controlled trials (RCTs). A meta-analysis of 10 eligible studies of NOM for uncomplicated appendicitis found only one RCT, 4 studies in which all children meeting entry criteria were treated with NOM, and 5 studies in which parents selected NOM or surgery after consultation with clinicians. The key feature of these latter studies is that they all refer to uncomplicated appendicitis (e.g. pain for <48 hours, absence of high C-reactive protein, appendicolith, perforation, rupture, abscess or mass). The articles covered 413 children and NOM was effective as initial treatment in 97% (although hospital stay was 0.5 days longer than if treated surgically).  No study reported adverse events related to NOM, 17/413 required appendectomy during their initial hospitalization, and at final follow-up (range 8 weeks to 4 years) a further 68 required appendectomy, predominantly for recurrent appendicitis. The overall long-term efficacy of NOM was 82% i.e. NOM resulted in some 4 of 5 every children not being exposed to the risks of anaesthesia or surgery, but the authors comment that the efficacy figure may actually be lower because some of the studies were of short duration.  Non-operative management is also regarded as an option for selected cases of complicated appendicitis in which the appendix may already have perforated, with or without the presence of an abscess or phlegmon.  Paradoxically, in several surgical units such cases are not routinely treated with immediate surgery but undergo ‘interval appendectomy’ within 6-8 week of presentation, i.e. they effectively have a fairly extended period of NOM. This has led to some studies giving the parents and patients a choice of interval surgery vs continued observation beyond the ‘interval.’ At this stage results are somewhat conflicting in the complicated cases with some showing early surgery is better than interval, others showing the opposite. In patients who elect to continue conservatively beyond the ‘interval’ period the appendicitis recurrence rate is higher than in NOM for uncomplicated appendicitis, but overall there may be a benefit for up to two-thirds of patients who choose the longer NOM option. Unfortunately RCTs are likely to prove difficult for non-operative management of complicated appendicitis as long as there is uncertainty about the risk of recurrence, so comparative trials will probably continue to be based upon management that depends on parental choice of, or their aversion to, surgical intervention.

Read more:

Pediatrics 2017; 139 (3): e20163003

Curr Opin Pediatr 2017, doi:10.1097/MOP0000000000000487

J Pediatr Surg 2016; 51: 1957-61

 

 

 

2017:13 Antenatal steroids for late preterm births

 

Summary 1613 commented on an Egyptian study comparing outcomes for neonates managed with or without antenatal steroids and delivered by caesarean section at 38-44 weeks. The question asked in that summary was whether it is appropriate to seek a preventive medical solution to a ‘problem’ that is often iatrogenic in nature viz. operative delivery prior to ≥39 weeks of gestation. A number of articles published in 2016 clarify the situation to some extent but probably require careful interpretation to avoid widespread use in our country with its extremely high private sector rate of elective caesarean sections that are often performed before 39 weeks.  The important starting point is the recognition that preterm neonates born at between 34 and 37 weeks (usually weighing more than 2kg) and previously regarded as being fairly mature and at low risk for morbidity and mortality should be categorized as ‘late preterm’ rather than as ‘near-term’ births. The reason for the change was the emergence of data showing that infants born even a few weeks before term are at higher risk for adverse outcomes such as respiratory distress, hypoglycaemia, feeding and thermoregulatory problems, jaundice, apnoea and seizures in the neonatal period. Such infants are also at risk for subsequent readmission, pulmonary disorders and subtle cognitive deficits and learning problems at school age.  Compounding the problem were trends towards more premature births which were not the result of advances in perinatology and greater numbers of VLBW and ELBW neonates, but births at 34-36 weeks. Epidemiologically this was associated with changes in peak gestational age at birth from 40 weeks in 1991 to 39 weeks in 2002.  These changes were also associated with an increase in medical interventions i.e. inductions or caesarean births in the absence of prolonged rupture of membranes and no obvious increase in the known causes of prematurity e.g. multiple gestation, pre-eclampsia or chorioamnionitis.  Two important initiatives and recommendations followed the categorization of births into late preterm (34-37 weeks) and early term (≥37-39 weeks).  The first, based on several studies that showed beneficial effects, was that steroids should be administered to women at risk for imminent late preterm delivery. This has been endorsed by bodies such as the American Congress of Obstetricians and Gynecologists (ACOG), but with caveats and concerns that indicate that short term problems such as hypoglycaemia, and possible long-term neurodevelopmental and metabolic effects still require follow up and evaluation.  The second important intervention applied to the early term group and ACOG recommendations to avoid non-medically indicated early term deliveries before 39 weeks. This initiative appears to have been responsible for a significant reduction in clinician-initiated obstetric interventions and early term birth rates in the US between 2006 and 2014.  It is important to separate the two strategies (late preterm vs early term) to ensure that fetuses at risk for imminent late preterm birth are afforded the benefits of steroids while procedures such as elective caesarean section are performed at term rather than before, and fetuses should not  be unnecessarily exposed to the risks associated with immaturity and/or the drug.

Read more:

Pediatrics 2017; 139, 3: e20163331

Am J Obstet Gynecol 2016; 215: B13-15   and 215: 423-30

N Engl J Med 2016; 374: 1311-20     

 

 

 

2017:14 Upper airway obstruction as a cause of nocturnal enuresis in children

 

Some 35 years ago a relationship between nocturnal enuresis (NE) and upper airway obstruction (UAO) and/or sleep apnoea was noted in case reports when the NE resolved immediately after surgery for the upper airway problem. A New Hampshire study published in 1991 presented results in 115 children and adolescents aged between 3 and 19 years with symptoms of both NE and UAO. Surgical resolution of the UAO led to a significant cure of NE in 76% of the group. Systematic reviews of the subject have confirmed the association. For example an article published in 2012 reported on 7 studies covering 1360 children in which there was a clinically significant relationship between NE and intermittent UAO during sleep, and a more recent publication identified 74 studies that confirmed the frequent coexistence of the conditions, with both conditions characterized by an altered arousal response and sleep fragmentation.  The pathophysiology is seemingly linked to nocturnal obstructive events in the airway that lead to changes in intrathoracic and intra-abdominal pressures, effects on systemic blood pressure, and resultant induction of natriuresis and polyuria due to changes in levels of antidiuretic hormone (ADH) and atrial and brain natriuretic peptides. In this regard it has been shown that in affected children with NE and sleep-disordered breathing, adenotonsillectomy normalizes levels of the hormones and urinary electrolytes.  While UAO is by no means the underlying cause of all NE, its prevalence is demonstrated by another recent report which was published in the European Archives of Otorhinolaryngology and analysed data from 225 children and adolescents with NE referred from a urology clinic over a period of one year for assessment of UAO. Mean age of the study population was around 9.3±2.8 years. About 50% of the group had monosymptomatic NE and these 112 showed significantly more in the way of snoring, adenoidal hypertrophy and septal deviation than the ‘controls’.  Whereas the spontaneous resolution rate of all NE is usually stated to be around 15% per annum, in this study NE resolved in 71.5% of children who underwent adenoidectomy.  The significance of this association between NE and UAO is that when clinicians who treat children with NE take a history they should specifically include questions relating to UAO such as snoring and recurrent otitis or upper respiratory tract infections. In this regard it is worth noting that while a resource such as UpToDate© includes UAO in a list of conditions to be considered when assessing a child with NE, recent consensus guidelines from the UK and Europe make no mention of the relationship.

Read more:

Eur Arch Otorhinolaryngol 2017 doi 10.1007/s00405-017-4558-z

Swiss Med Weekly 2017; 147: w14400

Urology 2015; 86: 158-61

 

 

 

2017:15 Management of patent ductus arteriosus (PDA)

 

The automatic and immediate response of most readers may well be to not read any further than the title. After all, every doctor working with neonates encounters patients with a PDA and there are almost invariably policies, guidelines or algorithms that are followed, so why the need to read more?  The issue is where each neonatal unit is in terms of its approach to PDA management e.g. early and/or late administration, prophylactic vs rescue administration, medical and/or surgical intervention. Much often depends on the haemodynamic significance of the PDA and how that is assessed, whether on clinical grounds, biochemically or by means of echocardiography.  Not surprisingly, although pharmacological and surgical interventions have been applied for several decades, there are wide variations in hospital practices, likely due to uncertainty about key issues such as the natural history of PDA, lack of evidence for a causal relationship between PDA severity and adverse outcomes, and reports of adverse outcomes of treatment, whether medical or surgical.  The likelihood of the ductus closing spontaneously, even in the most premature neonates, adds to the confusion around the need to intervene. Overall the debates have resulted in clinicians being more circumspect in the administration of drugs or resorting to ligation. An example of a change in practice appears in a study from California in which 134 hospitals in the CPQCC (California Perinatal Quality Care Collaborative) submitted data on 28 025 VLBW infants for the 7 years between 2008 and 2014. Diagnostic criteria for PDA changed between early and later years e.g. echocardiographic or 1 of a number of clinical criteria in 2008 vs. echocardiographic plus ≥2 clinical criteria in 2011, and then a ‘loosening’ again in 2012 to the 2008 criteria but also including ‘any who were recorded as having been treated’. Patent ductus was diagnosed in 42.8% of the total group, but over the review period decreased from 49.2% in 2008 to a nadir of 35.4% in 2011 (probably coinciding with the tighter diagnostic criteria) and then settling at around 39% towards 2014.  Over the period there was not only a tendency to make the diagnosis less frequently but also to intervene differently: between 2008 and 2014 fewer received pharmacological intervention (30.5% vs. 15.7%) and fewer had both pharmacological and surgical intervention (6.9% vs 2.9%), while the rate of primary ligation increased from 2.2% to 3.0%.  While this review shows that there is indeed a tendency to both diagnose and treat fewer PDA’s, as pointed out in a recent American Academy of Pediatrics Clinical Report, the ‘waters are still muddied.’  There is good evidence that early, routine treatment in the first two weeks of life does not improve long-term outcomes, but there is still a need to identify high-risk infants, for example by combining echocardiographic scores with serum biomarkers (e.g. natriuretic peptides) and haemodynamic monitoring, and then to study the role of ductal closure in the management of such infants. Such an approach would likely result in even fewer neonates being treated, and in treatment being directed more towards those in greatest need.

Read more:

Pediatrics 2017; doi.10.1542/peds.2016-2390  and doi 10.1542/peds.2015-3730

Am J Perinatol 2015; 32: 379-86

J Pediatr 2005; 147: 38-42

 

 

 

2017:16 Outcomes in children treated for attention deficit/hyperactivity disorder (ADHD)

 

A recent article in JAMA Pediatrics demonstrates once again the ability to produce excellent research if/when one has access to large volumes of standardized, routinely-collected data merged from a number of sources. The focus of the study was educational and health outcomes in Scottish children and adolescents treated for ADHD, a condition that is estimated by the World Health Organisation to affect some 39 million people worldwide.  Pooled estimates from meta-analyses suggest that around 6.5% of children are affected, with more boys being affected than girls.  On the health side the databases used in the Scottish study included a medicines/prescribing database that allowed identification of children receiving medication/s for ADHD, a maternity database that provided maternal, obstetric and neonatal information, and hospitalization databases of admissions to acute and/or psychiatric hospitals. On the educational side the databases provided information on any special educational needs of children, approved or unapproved absences or exclusions from school, examination attainment data and status of pupils 6 months after leaving school (i.e. unemployment, employment or further education or training).  The database provided data on 766 244 singleton children who had attended a Scotland school at some point between 2009 and 2013. Of these, 7413 received ADHD medication (1.0%).  Treated children were more likely than non-treated controls to be male, socioeconomically deprived and born to a mother who was younger, parous and smoked during pregnancy. They were born at earlier gestation than controls and had lower Apgar scores and birthweight. Learning disability was recorded in 12.9% vs 2.5% in controls, autistic spectrum disorder in 11.5% vs 1.0%, or both in 3.3% vs 0.3%. Nearly two-thirds (64.3%) left school before age 16 years vs. 28.4% of controls. They also showed more absences and exclusions from school. ADHD-treated subjects were also more likely to be admitted to hospital (Hazard Ratio 1.47: 95% CI 1.40 – 1.54), the most common reason being injury.  These results are deeply worrying but should be seen in the context of the low ADHD prevalence rate of 1%. In the UK the recommendations for drug treatment of ADHD are more stringent than in the US and elsewhere, with pharmacologic management being reserved for severe cases and those who have failed conservative treatment (e.g. family or group therapy). Given that the worldwide prevalence is around 6%, the Scottish study that focused on patients receiving drug treatment suggests that the results apply particularly to the worst cases. As such they should be noted, but also put into context in a country such as ours in which the prevalence has been quoted as around 10%. The ‘diagnosis’ is often made by school teachers, who tend to overdiagnose the condition, and referral is frequently to doctors who have a low threshold for initiation of treatment. As such our ADHD rate almost certainly includes milder cases for which the outlook is probably more positive.

Read more:

JAMA Pediatrics

Int J Environ Res Public Health 2015; 12:n 3042-59

Health24 ADHD; 23 August 2016    

 

 

 

2017:17 Risk of motor vehicle accident (MVA) in medically-treated vs. untreated ADHD

 

Further to the previous summary (1716) which indicated that treated patients with attention deficit hyperactivity disorder (ADHD) were more likely than controls to be admitted to hospital for treatment of injuries, there is a USA-based study carried out by a Swedish-American collaboration into the risk of MVA in treated vs. untreated subjects. It is stated that globally around 1.25 million people die each year as a result of MVAs. In the US almost 35 000 died from MVAs in 2014 and an additional 2.4 million visited an emergency department for treatment. The study under review utilized MarketScan® which is an enormous database of de-identified inpatient, outpatient and medicines claims from more than 100 US insurers providing employer-sponsored commercial health insurance.  The research covered a 10-year period from 2005 and ultimately included almost 2.5 million patients over 18 years of age with a diagnosis of ADHD.  The list of prescribed medications included all standard treatments and the researchers were able to link dates of prescriptions to emergency department visits for treatment of an MVA.  Having access to such a large database allowed the authors to collect an equally-sized group of matched controls. Overall, subjects with ADHD were around 1.5 times more likely to be involved in one or more emergency department visits for an MVA than controls. This risk changed depending on whether subjects were on or off medication, increasing to twice the risk vs. controls if not on medication. For subjects with ADHD, at the population level, whether male or female, medication use was associated with a ±13% reduction in the risk of MVA. When analysed at the level of individual subjects (i.e. using each as her/his own control) the reduction in risk with medication was much greater (around 40%: 38% for males and 42% for females). It should be noted that the results may underestimate the MVA rates because many incidents will not result in an emergency department visit, but in general they support previous research and meta-analyses. However it is also important to consider the actual MVA event rate of ≥1 emergency visit which was similar in males and females at 0.5% (5-6000 MVAs for ADHD populations of 1.1 and 1.2 million respectively). So, one is looking at a rate of 0.33% in controls and of 0.5% in ADHD. This introduces an interesting issue: the authors of the article state that ethical clearance was not required because the data were anonymized. However, given that the results could influence health insurers to increase premiums for ADHD members or deny coverage irrespective of medicine use, one could argue that consent for the study should have been obtained.

Read more:

JAMA Psychiatry 2017; doi:10.1001/jamapsychiatry.2017.0659 (article and commentary)

J Clin Psychopharmacol 2012; 32: 225-30

J Consult Clin Psychol 2016; 84: 1078-93

 

 

 

2017:18 Efficacy of zinc as an adjunct to treatment of severe pneumonia in infants and children

 

There cannot be any doubt about the importance of pneumonia as a cause of morbidity and mortality during childhood, particularly in developing countries where it is said to be responsible for about one-fifth of deaths in children below 5-years of age.  Micronutrient deficiencies (e.g. vitamin A and zinc deficiency) are known to exist in resource-poor environments and extensive research has been undertaken over the years regarding the role of micronutrient supplementation in the prevention and/or treatment of childhood infections such as diarrhoea, pneumonia and malaria.  The role of vitamin A supplementation has been established for treatment of measles pneumonia, while studies, including a Cochrane review, concluded that vitamin A adjunctive treatment does not reduce mortality or duration of hospital stay in non-measles pneumonia. In fact high-dose supplementation may result in worsening of the disease.  On the other hand, a number of studies have provided micronutrients in combination and have noted beneficial effects on symptoms and hospital stay in children with pneumonia.  Isolated zinc supplementation has also been studied in the context of pneumonia in infants and children, and two Cochrane reviews covering subjects aged 2-59 months have concluded a) that data are insufficient to recommend zinc as an adjunct to standard antibiotic therapy for pneumonia, but b) that daily zinc supplements in this age group may reduce the incidence and prevalence of pneumonia.  The rationale for supplementation is that such children might not have received sufficient zinc from mothers prenatally and/or as a group are less able to absorb zinc which is known to play a central role in the immune system. Deficiency may impair secretion of proinflammatory cytokines, lymphocyte proliferation, T-cell function and the integrity of respiratory epithelial cells.  While the Cochrane review of 2011 did not find a role for zinc supplementation in the management of pneumonia, a recent meta-analysis from China reported otherwise.  This latter review included six eligible studies covering 2216 children aged between 2-60 months.  In addition to standard antibiotic therapy, zinc was administered to ~50% and placebo to the remainder.  Cumulative zinc dose was variable, ranging from 70-280mg and duration of treatment from 7-14 days.  Main outcomes were treatment failure (e.g. change of antibiotic therapy, clinical deterioration) and mortality.  Different combinations of the six studies were used to report on the above outcomes. While no effects of zinc were found for treatment failure as defined above, there was a significant reduction in mortality in the supplemented subjects (Relative Risk 0.43; p0.01).  As is usually the case, validity of the results is confounded by the heterogeneity of the data, once again making the case for larger, standardized, multicentre studies.

Read more:

Clin Resp J 2017. doi: 10.1111/crj.12646

Cochrane Database Syst Rev doi: 10.1002/14651858.CD005978.pub3  and CD007368.pub2

Int J Epidemiol 2010; 39: 795-808

 

 

 

2017:19 Role of rhinovirus in the acquisition and transmission of Streptococcus pneumoniae

 

Rhinoviruses are a major cause of upper and lower respiratory tract infections in young children, accounting for around 50% of all respiratory tract infections. At the same time, the pneumococcus is an important cause of acute otitis media, pneumonia, meningitis and sepsis. Nasopharyngeal colonization with pneumococci, a prerequisite for pneumococcal diseases, has been reported to occur in 87% of children at least once during the first two years of life.    Co-infection with rhinovirus and S. pneumoniae is common in children. For example rhinovirus has been detected in 32% of pneumococcus-positive sputum samples from children with community acquired pneumonia, and in children with acute otitis media and pneumococcus detected in the middle ear fluid, 24-36% have been found to test positive for rhinovirus in the nasopharynx and/or middle ear fluid. However, the role of rhinovirus infection in transmission of pneumococci remains poorly characterized and it is unclear how much rhinovirus infection predisposes to pneumococcal acquisition and transmission vs. promotion of growth of existing S. pneumoniae in the upper respiratory tract.  In a carefully-planned study in Finland (albeit with small numbers), researchers set out to explore the role of rhinoviruses in community-acquired vs. intra-family acquisition of the pneumococcus. Thirty-one families with at least two children were recruited to this study during autumn of 2011-2012. Parents of families with at least two children were instructed to obtain nasal swab samples at home from the first onset of symptoms of a respiratory tract infection in any family member. Swabs were then taken from each participant within the family for three weeks. Symptoms were documented on a daily basis. Samples were tested for rhinoviruses, enteroviruses and respiratory syncytial virus, and for pneumococcus and subtypes.  In the 29 families included in the analyses, rhinovirus was detected in 38 (30%) subjects at the onset and in 86 (67%) subjects during the follow-up. S. pneumoniae was detected on the first day in 9 (7%) and during follow-up in 38 (30%) subjects. Compared to children without rhinovirus infection, children with infection had a 4.3-fold rate of pneumococcal acquisition from the community (95% confidence interval, 1.1-15.4) and a 14.8-fold rate of within-family transmission (95% confidence interval, 3.1-69.6). Possible reasons for the rhinovirus-induced predisposition to bacterial colonization are diverse.  For example viral infection of the donor might increase respiratory excretion and density of pneumococci in droplets, thus promoting transmission, or viral infection of the recipient may change the conditions in the respiratory epithelium making it more susceptible to bacterial adherence and colonization. This may occur by epithelial damage or by upregulation or exposure of receptors for bacterial adhesion.  Specifically, upregulation of platelet-activating factor receptor has been suggested as one of the ways in which rhinovirus might promote the adherence of pneumococcus. Finally, rhinovirus infection may impair the innate immune response. Pneumococcal within-family acquisition was associated with symptomatic rhinovirus infection of the recipient but not with asymptomatic rhinovirus infection, or with symptoms in rhinovirus negative children. These results are in line with prior research but are not specific to rhinoviruses as parainfluenza and influenza virus infections have also been shown to increase children’s risk of acquiring pneumococcal infection.

Read more:

Am J Resp Crit Care Med 2017  doi: 10.1164/rccm.201702-0357OC

Clin Infect Dis; 58: 1369-76

Pediatr Infect Dis J 2011; 30: 11-8

 

 

 

2017:20 Association between non-cow milk (NCM) intake and lower height during childhood

 

This summary may once again attract the “First World problem” response from readers, although it should be acknowledged that where NCM is prescribed in the Third World it is usually for an underlying medical problem which may independently be associated with impaired growth.  In the current context the focus is on a Canadian study that explored growth (i.e. height) in children without medical problems whose parents elect to feed with NCM during early life because of perceived health benefits. Height is an important indicator of children’s overall nutritional status, health, and development, and cow’s milk, a staple for most North American children, is an important source of dietary protein and fat which are essential for optimal growth. A previous meta-analysis has shown that children who consume cow’s milk on a daily basis are taller than those who do not, possibly because milk proteins (casein and whey) and insulin-like growth factor 1 (IGF-1) in cow’s milk enhance linear growth. Many parents (~12% in Canada) are replacing cow’s milk with NCM with soy, rice or almond milk, most likely because of perceived health benefits. However, NCM contains different proteins than cow milk and lacks IGF-1, suggesting that it may not have the same effect on height.  More importantly, unlike for cow’s milk, there are no legislative requirements for standardizing the nutritional content of NCM under the FDA or the Food and Drug Regulations of Canada. The protein and fat content of NCM milk beverages is highly variable, so children who consume NCM may receive less dietary protein and fat than peers fed cow’s milk. To explore the issue further, children aged 24–72 months seen at their annual well-child visits were recruited from 9 primary health care practices in Toronto between December 2008 and September 2015. Data included daily intake/s of cow’s milk and/or NCM, and the primary outcome was height-for-age z-score. Potential confounders included age, gender, BMI, and maternal ethnicity, income, and height.  The study group included 5034 children, of which 88% drank cow’s milk exclusively and 12% drank NCM (not necessarily exclusively). Mean ages of the groups were similar at around 39 months, and gender, ethnicity and socio-economic status were similarly distributed. There was a dose-dependent association between higher NCM consumption and lower height (p<0.0001). For each daily cup of NCM consumed, children were 0.4 cm shorter. The authors are careful to point out that they have demonstrated an association and not evidence of a causative relationship between NCM and growth (i.e. height), and that understanding the relation between NCM consumption and height in childhood may help inform parents, clinicians, and policymakers when choosing the optimal type of milk for children.

Read more:

Am J Clin Nutr 2017 doi: 10.3945/ajcn.117.156877

Econ Hum Biol 2012; 10: 299-309

Arch Pediatr 2014; 21: 483-8

 

 

 

2017:21 What's the optimal oxygen range for the smallest preterm infants?

 

Controversy persists regarding the optimal oxygen saturation range in preterm infants. Several large multicentre trials have randomized preterm infants (<28 weeks) to a lower (85%-89%) vs higher (91%-95%) oxygen saturation target, and documented a decrease in the incidence of severe retinopathy of prematurity but with an unexpected increase in mortality in the lower target group. As a result, some clinicians are avoiding the lower oxygen target. To explore the situation further, researchers carried out additional analyses on a sub-cohort of infants enrolled in the original Surfactant Positive Pressure and Oxygen Trial (SUPPORT) who had been randomized to lower vs higher oxygen saturation targets. Of particular interest was their previous observation that infants born small for gestational age (SGA) had a higher mortality than infants born appropriate for gestational age (AGA), with the highest mortality seen in the SGA infants who were randomized to the lower oxygen saturation target. In the original study, oxygen saturation was sampled continuously every 10 seconds with an oximeter. Infants who survived until 3 days of age were included in this study. There were 1054 infants with oxygen saturation data of acceptable integrity for analysis. Overall a lower 90-day survival rate was associated with lower birthweight (P < .0001) and younger gestational age (P < .0001). Infants born SGA in the lower target group had the lowest achieved oxygen saturation levels and highest incidence of longer intermittent hypoxemia during the first 3 days of life vs. AGA infants with a lower saturation target, and vs. both SGA and AGA infants with a higher target. Furthermore, being in the lowest quartile for median oxygen saturation during the first 3 days of life was associated with decreased infant survival at 90 days for both SGA and AGA infants, with those born SGA with the lowest oxygen saturation having a particularly low survival (54.3%). Possible contributors to the increased mortality include impaired pulmonary vascular growth and/or pulmonary vasoconstriction, as well as suppression of the ventilatory response to acute hypoxaemia. The results of this study suggest that the optimal achieved oxygen saturation during the first few days of life to improve survival in preterm infants, and especially infants born SGA, may be an oxygen saturation of >92%, but achievement of this in clinical practice may be unrealistic given the multitude of studies showing the challenge of keeping infants within any given range.  While there has already been a move from the measurement of partial pressure of oxygen to oxygen saturation, there is currently a recommendation that oxygen saturation within tissues rather than within pulsatile vessels may be the best measure of oxygen demand vs. supply..

Read more:

J Pediatr 2017; 186: 49-56

JAMA Pediatr 2016; 170: 292-4

Pediatrics 2017 DOI: 10.1542/peds.2016-1117

 

 

 

2017:22 Morbidity and mortality of very low birthweight (VLBW) infants according to time of birth

 

A review of 2013 United States time-of-birth data for 41 states and the District of Columbia covered 90% of all US births. Results were perhaps as expected e.g. <20% of births occurred between midnight and 07h00, caesarean section (CS) deliveries were least likely to occur during the evening and early morning hours, non-induced vaginal deliveries were more likely than induced deliveries to occur between 23h00 and 07h00, and induced vaginal deliveries rose in the morning hours, peaked at 15h00 and then declined, particularly after 18h00.  These figures seem to speak to active management of delivery during the day and less intervention during the night, particularly between midnight and 07h00, and the question has often been asked whether the lack of management/intervention at night is associated with adverse consequences for the affected foetuses and neonates. In this regard several epidemiological studies have raised concern that delivery during ‘off-peak hours’ may increase mortality risk among preterm infants, and recent data, largely from academic centres, suggest that any increased risk is due to differences in ‘case-mix’ or illness severity among infants born during the day vs. the night.  In a recently-published study, researchers from Pennsylvania reviewed outcomes for almost 50 000 500-1499g infants born between 2002 and 2009. As per the 2013 findings, around 20% were born during ‘off-peak’ hours, defined here as between midnight and 06h59. Study outcomes included a) death; b) among survivors, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) and severe (grade 3 or 4) intraventricular haemorrhage (IVH); and c) composites of death and the various morbidities.  While the frequencies of all outcomes were higher for infants born during off-peak hours, after adjusting for maternal, hospital and infant characteristics, off-peak delivery was associated with increased odds of IVH in survivors, and with composite outcomes of death/severe IVH, or death/major morbidity. The highest odds ratio was for IVH in survivors (1.39; 95% CI 1.23 – 1.57). The authors add that there was no evidence of effects based on mode of delivery, hospital ICU ‘level’, VLBW delivery volumes or weekday vs. weekend deliveries. As such they do no more than identify the association, however in their discussion tend towards case-mix differences by pointing out that mothers of the infants born off-peak had more in the way of chorioamnionitis, placental abruption, premature rupture of membranes and precipitous labour, and the authors also cite literature showing that infants born overnight are at greater risk of perinatal asphyxia as evidenced by umbilical cord pH<7.1.  In terms of being able to respond to high-risk situations during off-peak hours the authors refer to lower staffing levels, staff fatigue and longer response times for CS. These results should be read in conjunction with those of the South African ‘saving babies’ initiatives as published by Pattinson and Rhoda in 2014 in which similar factors for adverse outcomes are explored.

Read more:

J Pediatr 2017; 186: 41-8  and pp 7-9

NCHS data brief, no. 200, 2015

Saving babies 2012-3; ISBN: 978-0-620-63308-6

 

 

 

2017:23 Osteoporosis in children and adolescents

 

This summary is the first of two covering an important but neglected topic in paediatric practice.

Osteoporosis is increasingly being recognized in children and teens. A major determinant of the lifetime risk for osteoporosis is the magnitude of peak bone strength achieved by early adulthood. Bone strength is determined by the peak bone mass (PBM) acquired as well as bone size, geometry, and microarchitecture established through the growing years. Heritable factors account for 60– 80% of the variability in bone strength, but achieving one’s genetic potential requires optimal bone health through the first two decades. While primary osteoporosis occurs among children (e.g. osteogenesis imperfecta), secondary osteoporosis as more common as a consequence of chronic disease and the medications used for treatment. Inflammatory bowel disease, rheumatologic disorders, malignancy, transplantation, cerebral palsy, Duchenne muscular dystrophy, cystic fibrosis, and anorexia nervosa are among the common diagnoses linked to bone fragility. These diverse disorders share one or more common skeletal risk factors including nutritional deficits, reduced mobility, increased inflammatory cytokines, sex steroid or growth hormone deficiency, and exposure to osteotoxic drugs. The net result is reduced bone formation, which may be compounded by more rapid bone resorption. Growing children have the potential to restore bone strength through bone modeling and remodeling if risk factors can be reversed. Early identification and treatment of high-risk children are required to capitalize on this opportunity for recovery. In older adults, low bone mineral density (BMD) relative to younger norms is the cornerstone of diagnosis, but this definition should not be applied to children and teens because they have not yet reached PBM and because a ‘fracture threshold’ for BMD has not been established. This reflects the fact that BMD standard deviation scores for age (i.e. Z-scores) vary, depending upon the pediatric normative data used. In addition, fragility fractures can occur despite BMD values within the normal range for age. International guidelines define pediatric osteoporosis as ≥1 vertebral compression fractures (VF) occurring without major trauma or local disease, or the presence of low bone mineral content (BMC) or BMD for age, plus a history of a clinically-significant long bone fracture. These criteria indicate that fragility fractures can occur at a relatively better BMC or BMD, particularly in patients treated with glucocorticoids (GC). There is also differing clinical significance of fractures according to site. For example, fractures of long bones but not fingers and toes are important in decision-making about treatment. Clinical signs of osteoporosis include chronic bone pain, vertebral or long bone fractures, loss of height, skeletal deformity, and premature loss of ambulation. An estimated 40% of VFs are asymptomatic, underscoring the need for routine screening for these important indicators of bone fragility. VFs can also be detected using vertebral fracture assessment (VFA) software available on newer dual energy x- ray absorptiometry (DXA) equipment. This method offers the advantage of much lower radiation exposure, but whether the precision and accuracy of VFA to identify VF in younger patients is sufficient has been controversial. For BMD, DXA is the method of choice because of its availability, precision, speed, low radiation dose, and robust normative data. Total body less head and lumbar spine are the preferred regions of interest in pediatric patients, and BMD at these differing sites may be helpful for specific chronic diseases. For example, total body BMD has proven to be a better predictor of fracture than spine BMD in patients with Duchenne muscular dystrophy, by contrast, spine BMD is more closely associated with VFs in patients on chronic GC therapy. Newer three-dimensional (3D) densitometric techniques including peripheral quantitative computerized tomography (pQCT) and high-resolution pQCT (HRpQCT) can measure volumetric bone mineral density (vBMD), distinguish trabecular from cortical compartments, and determine bone geometry. This information provides valuable insights into the geometric and microarchitectural parameters that determine bone strength. Urine and blood biochemical markers of bone turnover have proven less useful surrogate measures of bone health, but may be useful to monitor for over-suppression of bone turnover during pharmacologic therapy. The most commonly measured parameters are procollagen type I N-terminal propeptide (PINP; a marker of bone formation) and serum collagen type I cross-linked C-telopeptide (CTx; a marker of bone resorption).

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Curr Osteoporos Res 2017 DOI 10.1007/s11914-017-0371-2

Osteoporosis Int 2016; 27:2147-79

Nat Rev Rheumatol 2913; 9: 465-75

 

 

 

2017:24 Relationship between childhood illnesses and osteoporosis

 

Chronic glucocorticoid (GC) therapy administered for a variety of conditions is a leading cause of osteoporosis in both adults and children. GCs decrease the function and lifespan of osteoblasts and osteocytes and increase the survival of osteoclasts, thus disrupting the balance between bone resorption and formation. There is also decreased intestinal calcium absorption and increased urinary calcium loss, leading to increased parathyroid hormone levels. By creating growth hormone resistance, altering growth plate cellular activity, and decreasing the production of sex steroids, GCs also impair skeletal growth. The negative skeletal effects of GCs appear to be dose and age-dependent, but a safe lower threshold has not been established. In one review of records of >37,000 children (aged 4–17), humerus fracture rates doubled for those prescribed ≥4 short courses vs. controls. GCs were prescribed primarily for respiratory disorders for a mean duration of only 6.4 days, and fracture risk returned to normal once GCs were stopped. Studies have also documented an increase in vertebral fractures (VFs) in young patients treated with GCs for acute lymphoblastic leukaemia (ALL) and rheumatologic disorders. The adverse effects of GC’s are confounded by risk factors associated with the underlying disease for which they are prescribed, and in general, GCs alone appear to have fewer deleterious effects on bone in the absence of malnutrition, immobilization and chronic inflammation. Deficits in muscle and bone develop in severe, long-standing inflammatory diseases in which inflammatory cytokines have adverse effects similar to those of GCs, reducing bone formation and increasing resorption.  Malnutrition, decreased ambulation (related to pain or ‘sarcopaenia’) and other osteotoxic medications such as immunosuppressives are additional threats. Rheumatologic and inflammatory bowel disease (IBD),  especially Crohn’s disease, have been studied most extensively, but other condition such as cystic fibrosis, chronic pulmonary infections and coeliac disease share common risk factors for bone fragility. Patients with IBD may present with VF at diagnosis as a result of undernutrition and inflammation. Patients with rheumatologic disorders demonstrate a similar high risk for VF, underscoring the importance of routine surveillance for VF.  In acute lymphoblastic leukaemia fractures of the hip, vertebrae, or other long bones may be the presenting feature. Bone fragility at diagnosis is hypothesized to be due to increased bone resorption  in response to cytokines released from leukaemic cells. Anorexia nervosa (AN) is also associated with many threats to bone metabolism including chronic undernutrition, high cortisol level, growth hormone resistance, and hypogonadotropic hypogonadism. Restrictions on activity imposed during weight rehabilitation may further compromise bone health. MRI studies in girls with AN have observed an increased conversion of red to yellow bone marrow in the distal femur and proximal tibial metaphyses, suggesting a shift in differentiation from osteoblasts towards adipocytes, a process seen commonly with aging. These changes may be reversible with recovery from AN, however despite weight rehabilitation and resumption of menstrual cycles with treatment, bone deficits may persist] and the lifetime risk of fractures is increased.

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Curr Osteoporos Res 2017 DOI 10.1007/s11914-017-0371-2

J Clin Endocrinol Metab 2015; 100: 3408-17

J Bone Miner Res 2010; 25: 298-304

 

 

 

2017:25 Management of secondary osteoporosis in children and adolescents

 

Management of bone health for any of the osteoporosis-related chronic disorders requires understanding of the presence or absence of ongoing risk factors and degree of bone fragility. For example, an asymptomatic young child with acute leukaemia who will discontinue glucocorticoid (GC) therapy at the end of chemotherapy will have time to recover from threats to bone health. By contrast, a teen with a chronic inflammatory condition likely to require long-term GC therapy is one in whom pharmacotherapy may be needed. Initial blood studies include blood count, blood chemistry (creatinine, U&E, calcium, phosphorus, magnesium, alkaline phosphatase and 25-hydroxyvitamin D.   Evaluation of muscle function may be appropriate for patients with immobilization disorders such as muscular dystrophy. Optimal nutrition involves achievement of a ‘healthy’ body mass index (since both overweight and underweight have been linked to pediatric fractures). This includes optimal intake of calories, protein, calcium, and vitamin D. Increase in lean body mass has been shown to improve BMD in anorexia nervosa even before the resumption of menses. If the serum 25OHD is <20 ng/ml, high-dose vitamin D supplementation should be administered. Higher doses may be needed in patients with obesity, cystic fibrosis, or other malabsorption disorders. Activity should be encouraged as tolerated, but may not be feasible in those with immobilization disorders.  Control of the underlying chronic disease is key to improving bone health. Targeting inflammatory cytokines using biologics instead of GCs holds promise as a way to reduce bone fragility. For example, anti-TNF-α therapy increases both trabecular BMD and cortical area of the tibia in patients with Crohn’s disease, and increases in spine BMD z-scores have been seen in juvenile idiopathic arthritis. Sex steroid replacement is appropriate for those with gonadal failure from chemotherapy, but the benefits of sex steroid therapy to increase BMD or reduce fractures for ‘hypothalamic amenorrhea’ (e.g. anorexia nervosa or exercise-associated amenorrhea) remain controversial. Use of pharmacologic agents to treat osteoporosis in children and teens is more challenging than in adults because the number of drugs available to treat bone fragility is limited and none is FDA-approved for use in the pediatric population. The ideal agent to treat bone fragility would be an anabolic drug since the cause is typically inadequate gains in bone mass and quality and bone turnover is frequently low in the childhood chronic illnesses. Antiresorptive agents such as bisphosphonates (BPs) have been used most extensively on an off-label basis. Most studies of BP efficacy have been short term, and because of a paucity of randomized controlled trials, controversies persist about the optimal agent, dose, and duration of drug use. Intravenous agents appear to be more effective than oral agents to reduce vertebral fractures, and children with persistent risk factors for bone fragility generally need continuous BP treatment until final height is reached to avoid fractures that  can occur with a ‘drug holiday’ where newly-formed bone added during bone growth (i.e. endochondral bone formation) is untreated and has lower density. This sets up a density differential between previously treated and newly formed untreated bone, and thereby a nidus for fracture.

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Curr Osteoporos Res 2017 DOI 10.1007/s11914-017-0371-2

Expert Opin Emerg Drugs 2014; 19: 385-95

Horm Res Pediatr 2013; 80: 179-84

 

 

 

2017:26 What are the risks of polio epidemics as we progress into the 21st century?

 

The short answer to the above question is that we hope the risks are quite low, but are we sure? For practical purposes WHO regards wild type 2 poliovirus as having been eradicated, and because the Sabin 2 vaccine strain causes most circulating vaccine-derived poliovirus cases and about one-third of all vaccine associated poliomyelitis cases, WHO recommended in 2015 that Sabin 2 be removed from the trivalent oral vaccine (tOPV) as used in >100 countries.  As such, global cessation of tOPV took place in April 2016, replacing it with bivalent bOPV containing live types 1 and 3, and following up with one dose of inactivated trivalent polio vaccine (IPV). South Africa is currently following the guideline, administering bOPV at birth and 6 weeks and trivalent IPV thereafter. Part of the WHO strategy is to stockpile monovalent type 2 (mOPV2) vaccine for outbreak response in the event of detection of type 2 (essentially vaccine-derived disease) transmission post-cessation.  In this regard a recent paper from BMC Infectious Diseases reported that since 2003 there have been 35 outbreaks of vaccine-derived disease, 10 of which were in Nigeria and the Democratic Republic of Congo, with the majority being type 2. To assess the risk of transmission of type 2 virus in a study simulating one year of tOPV cessation, change to bOPV and subsequent exposure to type 2 vaccine-derived virus, researchers from Bangladesh and the US followed children, household contacts and communities after a mOPV2 intervention to ~30% of eligible children. Sixty-seven villages were studied: 22 were randomly assigned to receive tOPV, 23 to bOPV and two doses IPV, and 22 to bOPV and two doses IPV.  The switch from tOPV to bOPV/IPV facilitated transmission of Sabin 2 after the mOPV2 challenge and increased the quantity of virus shed (albeit in only ~5% of subjects). This also occurred in a small number of contacts who did not receive the mOPV2 challenge. However, modelling showed that immunity in household contacts limited the transmission, and as a result of prior immunity, transmission was not increased in the community as a whole. This study mainly highlights the potential for type 2 to spread if somehow reintroduced after cessation of tOPV once population immunity has waned.  Reverting to comments made above regarding polio outbreaks in Africa, the article referred to indicates that South Africa is regarded as being at medium risk for polio as a result of factors such as population displacement and high migration numbers and also  diarrhoeal disease in susceptible areas. The latter appears to play an independent role, possibly due to reduced efficacy of OPV as a result of interference from other enteroviruses and/or infection with other pathogens and enteropathy.

Read more:

BMC Infect Dis 2017; 17: 367

Lancet Infect Dis 2017 http://dx.doi.org/10.1016/S1473-3099(17)30358-4

J Glob Health. 2016; 6: 20406      

 

 

 

2017:27 Is folic acid (FA) supplementation during pregnancy completely benign?

 

It sounds impressive when one speaks of folic acid supplementation having been around for prevention of neural tube defects and anencephaly since the last century. However the reality is that the intervention has only been recommended for the past ±25 years, so this is a relatively recent addition to materno-foetal care.  Apart from the role in spinal development, FA is important for optimal structural and functional brain development. This is through its role in a number of processes including synthesis, repair and methylation of DNA; amino acid metabolism; formation of myelin; and neurotransmitter synthesis.  Apart from the risk of neural tube defects there is also evidence that lower folate status in mothers not taking FA supplements during periconception has implications for offspring in terms of subsequent behavioural problems. Conversely it appears that FA supplementation in early pregnancy is associated with better neuropsychological development in childhood.  But what about excessive FA supplementation?  The recommended dose of 400µg/day has an established ‘track record’ but higher doses may be prescribed, e.g. where medical conditions interfere with FA metabolism, and also sometimes taken knowingly or otherwise by women without the knowledge of their treating healthcare provider.  It appears that neither the impact of overdosage during the first trimester nor of normal dosage beyond that period have been studied to significant extent. To address the former of the two deficits, researchers in Spain studied a mother-child cohort from four regions. Folic acid intake (both dietary and supplementary) was assessed by means of a comprehensive questionnaire at 10-13 weeks of pregnancy and again at 28-32 weeks.  Typical dosages were categorised as <400µg/day, 400-999µg/day and ≥1000µg/day.  For this study the data from 1682 mother-child pairs were available when the children were followed up at 4-5 years of age.  Neuropsychological development was assessed using the McCarthy Scales of Children’s Abilities, and sophisticated adjustment was employed during analyses to compensate for variations in maternal characteristics between the various study regions.  Inter-rater reliability between assessors of development was high.  During the periconceptional period one-third of women took dosages of FA ≥1000µg/day.  This was negatively associated with several neuropsychological outcomes, in particular global verbal and verbal memory scores.  While there are a number of limitations to the study, health professionals should note the results, pay some attention to the actual dosage of FA consumed by women during the first trimester, and further study the effects of high dosage where identified.

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Am J Clin Nutr 2017 doi: https://doi.org/10.3945/ajcn.117.152769

JAMA Pediatr 2014; 168:e142611

J Nutr Sci Vitaminol (Tokyo) 2011; 57; 130-7

 

 

 

2017:28 The 'Double Burden of Malnutrition' (DBM) in Africa

 

In South Africa we are probably all aware our much-publicised quadruple burden of disease (HIV/TB; maternal and child mortality; violence and injury; and NCDs i.e. non-communicable diseases). Furthermore, with inroads into HIV/AIDS mortality rates and consequential increases in the nation’s life expectancy, we are seeing increases in the NCDs. Children and adolescents are included when one considers sub-groups at-risk for NCDs, mainly for type 2 diabetes mellitus. Perhaps we are not (yet) seeing the extremes as reported in summary 1623 which discusses bariatric surgery for treatment of obese adolescents with diabetes, but we are seeing increasing concern about overweight and obesity in a sub-group of stunted children. This sub–group of stunted obese/overweight children has apparently now earned its own acronym, DBM, which stands for ‘double burden of malnutrition.’ The phenomenon has been covered in the literature for at least 20 years, is acknowledged to be a public health problem with potential adverse effects attributable to both the stunting and the obesity, but not much progress is being made in addressing the problem. In several countries the stunting rates are decreasing but researchers are reporting increasing rates of obesity in the stunted children. For example summary 1603 refers to an Indonesian study of under-5s in which stunting rates decreased from ~50 to ~36% between 1993 and 2007, while obesity rates increased from ~11 to ~17%, particularly in the stunted children. In a recent South African study 68.4% of obese children were stunted vs. 13.6% in children who were underweight or of normal weight.  The language and science around the problem become ever-more sophisticated, for example the stunting-obesity problem is regarded as the result of the ‘nutrition transition’ in LMICs (low- and middle-income countries), and a recent paper calculates nutritional risk according to ‘urbanicity gradients.’ The latter study finds stunting to predominantly arise in peri-urban areas whereas DBM occurs in the urban and peri-urban. In one of the more-recent studies into the epidemiology of the phenomenon in Ghana it was concluded that ‘contextual’ factors such as (higher) income resulted in obesity among the stunted. Other studies have shown that maternal overweight and lower educational status also play a role. In contrast to the ‘contextual’ factors, a Brazilian study makes a case for a metabolic variation and abnormal fat oxidation in stunted children, rendering them more susceptible to obesity. At an educational level, whereas we ensure that our medical students are able to assess risk according to growth charts and z-scores in order to identify stunting and wasting, are we alerting them sufficiently to the risks of early obesity, and particularly obesity affecting stunted children (and their families).

Read more:

BMC Pediatrics 2017; 17: 177

J Nutr 2016; 146: 1257-67

Eur J Clin Nutr 2007; 61: 623-32

 

 

 

2017:29 Association between maternal vitamin D levels and babies born small for gestational age (SGA)

 

It has been stated that vitamin D deficiency or insufficiency has become a global public health issue, especially for pregnant women. A Norwegian multi-ethnic cohort study of 748 pregnant women in Oslo measured 25-hydroxyvitamin D at 15 weeks of gestation and found severe deficiency in 45% of women from South Asia, 40% from the Middle East and 26% from sub-Saharan Africa. These figures differ dramatically from those of the European participants in the study (1.3% displayed severe deficiency). These findings highlight the well-known risk factors for D deficiency viz. limited access to sunlight, minimal outdoor activity, cultural practices, traditional clothing and higher levels of skin pigmentation, circumstances no doubt placing susceptible women at even greater risk when they relocate to climates with lower annual sunlight exposure.  Additional factors in the ethnic minority women were that they were younger, with higher parity and lower education than Western European women. Women with the lowest vitamin D levels were referred to their usual caregivers for supplementation and levels rose when measured again at 28 weeks In this regard it is noteworthy that globally there is a lack of consensus about the optimal dose of vitamin D supplementation during pregnancy. Scandinavia and the UK recommend 400IU per day but recommendations differ in other countries and there is also debate about the optimal concentration of vitamin D during pregnancy. Most Western countries recommend supplementation during pregnancy as there are concerns about the potential impact of deficiency on the foetus and neonate (e.g. preterm birth, low birth weight, abnormal bone mass, postnatal hypocalcaemia), infant (hypocalcaemia, rickets) and mother (preeclampsia, gestational diabetes). In this regard there have been several studies and a few meta-analyses that have examined the relationship between maternal D deficiency during pregnancy and infants born small for gestational age (SGA). A recent addition to the list of meta-analyses is a study from China. Using only data from cohort studies, the authors initially extracted 1734 studies for review but finally included only 13 studies covering 28285 singleton pregnancies between 2010 and 2016 emanating from the USA, Netherlands, China, Korea, Singapore, Ireland and New Zealand.  Prevalence of maternal D deficiency ranged from 13.2% to 77.3% and the authors found that maternal D deficiency was significantly associated with risk of SGA (pooled Odds Ratio 1.59; 95%CI 1.14-2.22; p<0.001). Because there was a degree of heterogeneity in the studies the authors carried out additional subgroup and sensitivity analyses, none of which made much difference to the pooled odds ratio. However their subgroup analyses did not take ethnicity into account due to lack of the data in some of the studies. While the authors go into some detail as to the possible mechanisms for the relationship between vitamin D deficiency and SGA (e.g. through a possible effect on proinflammatory cytokines, leading to oxidative stress), a possible weakness of the study is that vitamin D is reviewed in isolation and it is not clear whether one is dealing with a single deficiency or a deficiency that is associated with other nutrient imbalances. In terms of the impact of supplementation in women diagnosed as being D deficient during pregnancy, limited data exist regarding the ability of supplementation to lower the risk of SGA births, but three studies that have been reported do not make a convincing case.

Read more:

BMJ Open 2017;7:e016404  doi:10.1136/bmjopen-2017-016404

BMC Pregnancy Childbirth 2016 doi: 10.1186/s12884-016-0796-0

Fertil Steril 2015; 103: 1278-88

 

 

 

 

2017:30 Birth asphyxia, cerebral palsy and the placenta

 

At the recent 2017 United South African Neonatal Association (USANA) biennial conference, several keynote speakers directly and indirectly referred to the importance of the placenta in the context of birth asphyxia, hypoxic ischaemic encephalopathy (HIE) and cerebral palsy (CP) in the full-term infant.  The point was made that as a foetal organ the placenta can provide information that may retrospectively guide clinicians in determining whether an insult that resulted in HIE and the diagnosis of birth asphyxia occurred intrapartum or prior to the initiation of the birth process. In the context of CP, term-born children account for 50-65% of children with CP and they tend to be more- severely impaired than those with CP who were born preterm. In the developed world the incidence of CP is between 1 and 2%, but rates are acknowledged to be higher in developing countries in which antenatal and maternity services may be less than ideal. Sentinel events around the time of birth are nevertheless responsible for a relatively small proportion of CP cases, even in the developing world. More typically, risk factors and multiple events interact in a cascade with additive effects. Most likely, when a newborn is delivered with low Apgar scores and requires urgent resuscitation, little attention is paid to the placenta beyond the usual recording of macroscopic appearance and number of umbilical vessels, and submission of the placenta for histology is not routinely considered. However, placental function may be assessed prior to birth even without the formal examination of the placenta. For example, in a recent study from Australia, data from 308 nulliparous women who subsequently gave birth to AGA infants were studied. Ultrasound data at 28 and 36 weeks were utilized to estimate foetal weight (EFW). EFW growth velocity was correlated with three clinical indicators of placental insufficiency viz. cerebroplacental ratio (which measures foetal blood redistribution to the brain and is a response to hypoxia), neonatal acidosis after labour (pH <7.15), and neonatal body fat percentage (reflecting intrauterine nutritional reserve). Results showed that for each one centile reduction in EFW growth velocity between 28 and 36 weeks, even in AGA infants there was a 2.4% increase in the odds of cerebral redistribution and neonatal acidosis, and a 3.3% increase in the odds of low body fat percentage. These findings indicate a reduction in both foetal and placental reserves, placing the foetus at risk during the stresses of labour.  A decline in EFW of >35 centiles was associated with a relative risk of 3.51 for neonatal acidosis.  In a systematic review of risk factors for CP in 6297 term children (vs ~3.8m children without CP) Australian researchers identified placental abnormalities as being high on the list of 10 factors, with several if not most of the others (e.g. meconium aspiration) likely representing the consequences of an underlying problem and not the cause. Perhaps along similar lines, Madhi and coworkers in South Africa are studying causes of stillbirth and finding evidence of foetal infections when the placenta, foetus and/or fluids are cultured. The ability to link birth asphyxia/HIE and subsequent CP to placental pathology would likely assist in dealing with the plethora of medicolegal cases currently plaguing obstetricians, paediatricians and others involved in maternity services i.e. if the placenta were to be routinely sent for pathology/histology following birth of a term or near-term asphyxiated infant requiring full resuscitation. This may be problematic in the South African private sector because of the reluctance of medical aid schemes to pay for the investigations, but even if paid for by the doctors concerned would likely provide a return on the investment if the results point to a problem that antedated the birth.

Read more:

BMC Medicine 2017; doi 10.1186/s12916-017-0928-z

BJOG 2015; 122: 1437-45

Dev Med Child Neurol 2013; 55: 409-508

 

 

 

 

2017:31 More on predicting hypoxic problems at birth and after neonatal hypoxia/asphyxia

 

In the previous summary, attention was drawn to the ability of measures of slow intrauterine growth to assist with prediction of problems at birth, even in neonates born within the normal range of weight for gestational age. In a study from Turkey, while the research only focused on IUGR babies (born between 24 and 34 weeks), it was found that circulating neural injury markers (NIMs) correlated with neonatal morbidity and mortality. The markers studied were s100B protein and neurone-specific enolase (NSE) in 32 IUGR and 29 non-IUGR deliveries. Umbilical venous s100B and NSE were significantly higher in the IUGR group, and correlated significantly with perinatal mortality, necrotizing enterocolitis and need for intubation.  In another study from Turkey, researchers looked at a number of inflammatory and injury markers as predictors of neurological damage and outcome in neonates with hypoxic ischaemic encephalopathy (HIE) treated with either selective head or total body cooling. Markers studied included IL-1β, IL-6, NSE, brain-specific creatine kinase (CK-BB), TNF-α, and protein s100B. Urinary s100B and urinary lactate/creatinine (L/C) ratio were also measured. Infants were assessed at 1 year using the Bayley Scales of Infant Development. There were no differences in biomarker levels between the two types of therapeutic hypothermia. In this study, of all the biomarkers measured, only higher IL-6 and L/C ratio at 6 and 72 hours correlated with death or disability at 12 months, while L/C ratio differentiated mild from moderate and severe HIE.  Clearly more work needs to be done in the case of neonates in terms of establishing whether the NIMs i.e. NSE and s100B have a prognostic role to play, while there are numerous studies in adults that have shown a robust relationship between elevated NSE and s100B serum levels and neurological outcome.  Studies that have been done in infants, children and adolescents include a retrospective study from Germany into the prognostic value of NSE and s100B in 95 subjects who suffered cardiac arrest and were resuscitated.  Primary outcome was neurological outcome at discharge as assessed by the Paediatric Cerebral Performance Category (PCPC) scale, a 6-point scale in which 1 represents a normal neurological outcome and 6 represents death. The majority of patients were post-operative cardiac patients who experienced in-hospital cardiac arrest.  Results showed different kinetic release patterns for NSE and s100B, the latter peaking 12 hours after cardiac arrest in patients with unfavourable neurological outcome, then declining, but remaining elevated for 48 hours.  NSE peaked later, plateaud 24 hours after cardiac arrest and remained significantly elevated in the unfavourable outcome group.  After cardiac arrest, peak NSE and 12-hour s100B were found to discriminate outcomes precisely with levels of 134.8µg/L and 2.3µg/L respectively.  However in multivariate analysis it was 24-hour NSE together with duration of CPR and patient age that best determined unfavourable outcome. 

Read more:

Resuscitation 2017; doi 10.1016/j.resuscitation.2017.09.012

J Obstet Gynecol 2015; 35: 555-60

Ital J Pediatr 2015; 10.1186/s13052-015-0188-5   

 

 

 

2017:32 Medical marijuana (MM) in South Africa

 

Perhaps one has to worry when our leading newspapers quote the managing director of a South African phytopharmacological company with the statement that “Medicinal cannabis can be thought of as the gold rush of our time.” In monetary terms the current global market for marijuana products is estimated to be $3bn with the potential to rise to $56bn, with the abovementioned company anticipating a significant share of that market. The foundations have already been laid through the acquisition of a licence to produce MM in Lesotho, and then to deliver to countries in which MM and recreational marijuana have been legalized. While the South African media have recently given a fair amount of coverage to legislative processes around both MM and recreational marijuana use, it is interesting to note what has been happening behind the scenes. In March 2017 the Medicines Control Council (MCC, soon to be replaced by the South African Health Products Regulatory Authority Board) issued Guidelines for comment. The 32 page document covered processes that would regulate the growing, extraction and testing of cannabis as well as the manufacture of medicines containing cannabis.  The MCC and Department of Health would grant permission to qualifying applicants, who would also have to meet stringent requirements in terms of product security and production.  These guidelines were in anticipation of the government making progress in legalising MM. In this context, on 28 July 2017 the Government Gazette indicated that cannabidiol oil had been rescheduled as a Schedule 6 drug. Previously available through various outlets, but often of questionable quality and purity, the rescheduling for therapeutic purposes introduces an element of control. Apparently a few days later the Schedule 6 status was ‘downgraded’ to Schedule 4 by the MCC. Other cannabinoids may follow, but to recap what one is dealing with here: Marijuana is chemically complex, comprised of >480 compounds, including 70 distinct cannabinoids. The two main types of cannabinoids are tetrahydrocannabinol (THC) which is primarily responsible for the drug’s psychoactive properties, and cannabidiol (CBD). Purified CBD, or hemp oil, has been commercially available, with emerging evidence of medicinal properties.  It usually contains minimal THC. Cannabinoid receptors are widely distributed in the body, with CB-1 receptors primarily in the central and peripheral nervous system and CB-2 primarily in the immune system (e.g. B lymphocytes and natural killer cells). CBD is purported to have components with multiple actions ranging from reduction of inflammation, inhibition of cancer cell growth and enhanced bone growth, to pain reduction, enhanced sleep, appetite stimulation and reduction in nausea and vomiting.  Overall it is fairly clear that efforts to legitimize and legalise cannabis are enjoying some success, and as such it is appropriate that medical professionals consider if and when to prescribe the drug for their patients.  In the US, while cannabis is still banned at federal level, some 29 states and Washington DC have legalized MM and nine have legalized recreational marijuana for adults. MM does not specifically refer to particular derivatives of marijuana but rather to the use of the drug for medical purposes. In the US all the aforementioned states allow the use of MM for children with cancer or a terminal condition. Apart from CBD which has been commercially available, the US FDA has approved a couple of synthetic THC products for treatment of chemotherapy-induced nausea and vomiting. In terms of research attesting to the value of cannabinoids in paediatrics, the subject has recently been reviewed by clinicians from New York and Boston. On balance it would appear that the staunch opposition of the American Academy of Pediatrics to legalization and use of MM in paediatrics is not without foundation, as the evidence is thin for effectiveness in treating cancer, nausea and vomiting, anorexia and pain. On the other hand there may be a place for management of refractory seizures, although the rate of adverse events appears to be fairly high, ranging from somnolence and diarrhea to status epilepticus.

Read more:

Pediatr Blood Cancer 2017; e26826

Government Gazette 28/07/2017

http://www.mccza.com/documents/547f30142.44_Cannabis_growth_Feb2017_v1.1_for_comment.pdf

 

 

 

2017:33 Paediatric Multiple Sclerosis

 

Multiple sclerosis is a dynamic inflammatory demyelinating disease of the CNS that peaks in incidence in young adulthood. There is an association with HLA polymorphisms, which supports the theory that it is an antigen-related disease of immune dysregulation. Studies have indicated that up to 10% of all patients ultimately diagnosed with MS experience the onset of symptoms before 18 years of age. Paediatric patients often exhibit a more-inflammatory disease course within the first years of diagnosis, associated with greater frequency of clinical relapses in addition to higher T2- and T1-weighted lesion volumes on MRI.  Paediatric patients tend to have good recovery after attacks, with lack of marked disability progression, but peak of disease and irreversible disability are achieved at a younger age than with adult-onset disease.  A diagnosis of MS can be made in children at the time of the first clinical ADEM (acute disseminated encephalomyelitis) attack, provided that MRI at the time demonstrates the necessary evidence of both ‘dissemination in time’ (i.e. presence of a clinically-silent gadolinium-enhancing lesion with simultaneous non-enhancing lesions) and ‘dissemination in space’ (i.e. presence of at least one T2-hyperintense lesion in at least two of four CNS areas – periventricular, juxta-cortical, brainstem or cerebellum, and spinal cord). If these criteria are not met at the time of the first demyelinating event, diagnosis may be made on follow-up imaging which should show the presence of a new T2 or gadolinium-enhancing lesion.  These criteria are sensitive and specific if the patient is older than 11, but positive predictive value diminishes when applied to younger children. Positive family history and concordant twin studies confirm that there is a genetic basis for the condition, but it is apparent that it is the interplay between genes and environment that is important in the expression of MS, and much epidemiological and basic research is being carried out to assist with future risk modification and disease prevention. Interestingly, geography of residence in childhood, and particularly latitude, come into play i.e. research has shown a positive relationship between latitude and prevalence of MS at a global level that is independent of the genetic distribution of high-risk alleles.  Migrants moving from a high-risk area to a lower-risk location prior to 16 years of age have an associated decrease in risk of disease, and adults moving from a low- to a high-risk area retain the risk of their country of origin, but their children exhibit a risk approaching that of the host country.  Latitude therefore appears to exert its greatest influence during childhood.  Geographic latitude may act through an association with sunlight and vitamin D, which has been shown to be protective against development of MS, although it is not absolutely clear whether beneficial effects are due to ultraviolet radiation and/or vitamin D.  Higher average annual hours of sunlight exposure are not only associated with a lower prevalence of MS in a population, but also with lower mortality rates in individuals with the disease. Vitamin D studies have shown lower risk of MS with increasing 25-hydroxyvitamin D levels, strongest in those <20 years of age.  In a study based on neonatal levels, lower levels were associated with more MS, but the risk decreased by 30% for every 25nmol/l increase in 25-hydroxyvitamin D. Currently there is conflicting research into the role of supplemental vitamin D in preventing relapse.  Past infections with the Ebstein-Barr virus has been shown to be associated with MS, although it is not clear whether the virus confers risk or MS increases susceptibility to EBV infection.  On the other hand, past cytomegalovirus infection appears to play a protective role.  Smoking, both active and passive, appears to not only increase the risk for development of MS, but also to influence disability progression.  On the nutritional front, lack of breast-feeding, the gut biome and obesity before 20 years of age have all been implicated.  Obesity may be linked to other risk factors as it is not only now regarded as an inflammatory condition, but is also associated with low vitamin D status.  Drug treatment of paediatric MS typically involves the same approach as in adults and appears to be safe and tolerable, with similar efficacy.  Most specialists consider interferon-beta and glatiramer acetate to be ‘first line’ treatment, with progression to other disease modifiers if the latter fail.  Attention should probably also be paid to modifiable risk factors. In this regard some clinicians consider supplemental vitamin D to achieve a serum 25-OH D level of 50-80ng/ml, and it appears to be prudent to counsel patients and parents about limiting exposure to cigarette smoke  (active and/or passive).  Diet, lifestyle and prevention or management of obesity should also come into the equation.

Read more:

Pediatr Neurol 2017; 75: 17-28

Neurology 2017; 88: 44-51

New Engl J Med 2007; 356: 2603-2613

 

 

 

2017:34 Update on diagnosis and outcome of hypoxic ischaemic encephalopathy (HIE)

 

Summary 1731 covers research being done on neural injury markers NIMs). Adding to that is an excellent review in a recent issue of the Journal of Pediatrics on the subject of diagnosis, management and outcome of HIE. Diagnosis will be covered in this summary and neuroprotective strategies in the next. The developing brain responds to injury in a gestational age–dependent manner. During the third trimester white matter injury is most common, while in term infants grey matter injury predominates. HIE occurs in 1.5-2.0/1000 births in developed countries and almost 20 times more in resource-limited settings (26/1000 live births). The presence of infection/inflammation can sensitize the brain, resulting in more severe brain injury. The coexistence of inflammation with HIE may stimulate different mechanisms of brain injury with a resulting difference in response to therapeutic approaches. Without treatment, 20-50% of newborns with HIE die within the newborn period, and up to 25% of survivors will have permanent neuropsychological handicaps including intellectual disability, cerebral palsy, epilepsy, sensorineural hearing loss or vision loss. HIE is estimated to be the underlying cause of 23% of the 2.8 million neonatal deaths that occur annually, most of which occur in low-resource settings. Therapeutic hypothermia has improved outcomes of neonates with HIE and has become standard of care in the developed world.  Brain injury after hypoxia ischemia occurs in multiple phases. Immediately after hypoxia, anaerobic metabolism leads to decreased adenosine triphosphate production and primary energy failure with lactic acidosis, failure of cell membrane pumps, an influx of sodium and calcium, cellular swelling and death. Secondary energy failure occurs after reperfusion, with accumulation of excitotoxic glutamate, activation of N-methyl-D-aspartate (NMDA), alpha-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid, and kainite receptors, free radical formation, nitric oxide production, oxidative stress, and delayed cell death. Injury continues in the tertiary phase with ongoing inflammation, impaired neurogenesis, and alteration in synaptogenesis and axonal growth. The mechanism of cell death changes from necrosis early on to apoptosis later, with a continuum of phenotypes emerging in the developing brain (the apoptosis–necrosis continuum). Brain injury detected by MRI evolves over time. Early evaluation is more sensitive while later evaluation is more specific. Many sites choose to study infants with HIE after rewarming at around 4-6 days. Two main patterns of injury can be seen with moderate-to-severe HIE.  Deep nuclear grey matter injury (25%- 75% of cases) involves the deep grey nuclei and peri-rolandic cortex, extending further into the cortex when severe. Watershed injury (15%-45% of cases), involves injury at the watershed areas between the anterior and middle cerebral arteries anteriorly, and the middle and posterior cerebral arteries posteriorly. Deep grey matter injury is associated with more severe neurodevelopmental impairments. The watershed pattern of injury is associated with predominantly cognitive impairments, with fewer functional motor deficits. Magnetic resonance spectroscopy (MRS) can provide additional prognostic information: N-acetyl aspartate (NAA) is found primarily in neurons, so a reduction in NAA peak is thought to reflect neuronal injury or loss. Choline is a cell membrane component and also is present in the neurotransmitter acetylcholine. Lactate may be elevated after asphyxia and anaerobic glycolysis. Ratios of NAA/choline or NAA/lactate may therefore provide important prognostic information regarding extent and severity of brain injury.  Biomarkers that accurately reflect the timing, severity, evolution of injury, and response to therapy have the potential to improve the clinical management of newborns with HIE. Circulating candidate biomarkers in neonatal HIE can be subdivided into four categories: neural injury–specific, neuro-inflammatory, oxidative by-products, and metabolism-related markers. Each of these markers peaks differently after an injury, so the timing of when they are studied is critical. Neuron-specific cytoplasmic proteins considered to be potential biomarkers include neuron-specific enolase, spectrin breakdown products, and ubiquitin carboxyl-terminal hydrolase isoenzyme L1. Axon-related proteins include neurofilament light polypeptide (contained in large-calibre myelinated axons) and total tau, a biomarker of injury to thin non-myelinated axons. Amyloid precursor protein and amyloid-b are produced in axon terminals and might be involved in synaptic activity and plasticity. Astrocyte-specific proteins include S100-B and glial fibrillary acidic protein, so astrocytic injury is reflected by increased concentrations of these proteins in both cerebrospinal fluid and blood. Neuroinflammation and astrocytosis can lead to increased production of interleukins, particularly IL-6, IL-8, and IL-1β. At this time no biomarker has the capability to diagnose the severity of disease in timely fashion, however a prospective study in paediatric traumatic brain injury (TBI) is currently evaluating the predictive value of a combined biomarker panel (glial fibrillary acidic protein, S100B, neurogranin, brain-derived neurotrophic factor, metallothionine 3, neuron-specific enolase, intracellular adhesion molecule 5, and beta synuclein). Novel biomarkers like microRNA have also been investigated and recent studies have shown upregulation of microRNA 21 as a marker of severe TBI, neonatal HIE, and a predictor of 6-month outcomes. Metabolomics is the quantitative analysis of low-molecular-weight metabolites, including intermediates, signaling molecules, and components of metabolic pathways. Metabolomics has created an opportunity to assess the net biochemical changes occurring in HIE. In animal studies of HIE, arachidonic, butanoic, citric, fumaric, propionic and succinic acid as well as lactate and malate correlated with early and long-term neurodevelopmental outcomes. In another recent study, umbilical cord serum from newborns with HIE has shown that four metabolites (3-hydroxybutyrate, glycerol, O-phosphocholine, and succinate) predicted HIE severity and correlated with clinical outcomes at 3 years.

Read more:

J Pediatr doi.1016/j.peds.2017.08.031

J Clin Neurosci 2017, 38: 37-42

Clin Chim Acta 2015; 450: 282-97

 

 

 

2017:35 Where are we in terms of neuroprotection in neonates with hypoxic ischaemic encephalopathy?

 

Therapeutic hypothermia is the standard of care used to treat neonates with moderate-to-severe HIE when initiated within 6 hours of birth, and has decreased death or significant neurodevelopmental impairment from approximately 65% to 40%-50%. However 40%-50% death or disability is still unacceptable and additional treatments are being sought to reduce morbidity and mortality. Furthermore, as therapeutic hypothermia has not been shown to provide benefit in low- and middle-income countries (LMICs) in which HIE is most common, alternative or supplementary therapies might provide realistic treatment options. In summary 1634 the potential role of erythropoietin (Epo) was discussed. Epo and its receptor (EpoR) are required for normal brain development. Astrocytes are the main source of brain Epo, and many cell types express the receptor, including neurons, oligodendrocytes, and epithelial cells. The EpoR is expressed in hippocampal and cerebral cortical neurons. Both Epo and EpoR decline postnatally in brain but remain present at lower levels throughout adulthood. Prolonged hypoxic exposure leads to upregulation of EpoR. In the absence of Epo to bind these up-regulated EpoRs, neurons and oligodendrocytes have a greater risk of apoptotic cell death. Animal studies have shown that Epo reduces neuronal loss and learning impairment after brain injury, and it is currently undergoing clinical trials for neuroprotection of term infants with HIE and as a prophylactic neuroprotective treatment for extremely preterm neonates. The anti-inflammatory, anti-excitotoxic, antioxidant, and regenerative effects are relevant to promoting brain development and minimizing brain injury in both age groups. Since Epo has been studied extensively in neonates and children for other purposes, has a robust safety profile and is relatively inexpensive, one can expect much in the way of research in this field. Results from various studies to date include less injury on early MRI; decreased incidence of moderate-to-severe disability or death at 18 months; decreased seizure activity; improved neurodevelopmental outcomes at 6 months, and reduced cerebral palsy rates and seizure burden on follow up. Melatonin is another naturally-occurring hormone that may have a role in neuroprotection. It is a strong antioxidant capable of scavenging free radicals and stimulating several enzymes including glutathione, glutathione reductase, peroxidase, and superoxide dismutase. It has been studied in animal models of neonatal HIE with promising results including reduction in infarct area, improved neuronal survival, reduced reactive gliosis and less white matter injury. In piglets, combined melatonin and hypothermia showed greater neuroprotective effects than hypothermia alone. Phase I and II trials are ongoing to test neuroprotection for HIE. Melatonin also holds potential as an antenatal therapy that could be administered to pregnant mothers with at-risk fetuses. Possibly losing favour to some extent is xenon. Summary 1331 commented on studies being done in the UK at that time which showed that xenon appeared to reduce seizures in asphyxiated neonates, and as such might also act to reduce post-asphyxial brain damage. The gas binds to NMDA glutamate receptors and decreases apoptosis. Preclinical trials demonstrated benefit, but a number of current human trials are still grappling with questions around the concentration of administered xenon (25/30/50%) and the appropriate timing and duration of administration. Additional limitations include the cost of the gas and the problem that if high concentrations are required in oxygen-dependent neonates, then the xenon concentration must be reduced. So at this time this does not appear to be the solution for LMICs.  Moving on to more exotic interventions, which again do not appear to be helpful for LMICs, work has been done on stem cell therapy. Stem cells ranging from neural stem cells, embryonic stem cells, umbilical cord blood (UCB) stem cells, bone marrow derived mesenchymal stem cells (MSCs), and inducible pluripotent stem cells have been used in studies and have been effective in providing significant neuroprotection and improvement in functional outcomes in animal models of neonatal hypoxia ischemia, CP, and stroke.  In recent years, focus has shifted to MSC, especially UCB-MSCs. Preclinical studies have shown that MSCs do not engraft but rather respond to signals of local injury by secreting trophic factors, thereby increasing progenitor cell proliferation, survival of neurons, reduction of inflammation, stimulation of axonal sprouting and proliferation of oligodendrocyte precursors. Currently, there are ongoing phase I and phase II trials in neonates with severe HIE. These studies will help us understand the optimal dose, duration of therapy, therapeutic window, and dose response to the treatment. Further work is required to assess the long-term outcomes of stem cell therapy. Other agents that are being studied include N-acetyl-L-cysteine (NAC) which is a potent thiol-containing antioxidant, precursor of glutathione and a scavenger of free radicals; and lithium, which in animal studies has shown reduced neonatal brain injury by reduction in apoptosis and inflammation, and induction of neurogenesis. Work is also being done on polyphenols which are natural molecules with variable phenolic structures that are enriched in vegetables, fruits, tea, wine, and other foods. Most polyphenols have antioxidant, anti-inflammatory, and anti-apoptotic properties. Those that have been studied include resveratrol, which is found in grapes, soybeans, and pomegranates, and seems to play an important role in neuroprotection in models of ischaemia and brain, and spinal cord injury. Resveratrol has also been investigated as preventive treatment for neonatal brain injury as it crosses the placenta, so maternal supplementation may lead to reduction in tissue loss and decreased apoptosis in neonatal brains. Curcumin, which is also a polyphenol, like resveratrol and Epo, works on multiple pathways affecting brain injury and has a potential to be an effective treatment. To date, most neuroprotection work with polyphenols has been done in adult models of injury. One major limitation of polyphenols and other potentially protective compounds is poor bioavailability. Delivery methods are being studied to circumvent this issue and nanomedicine has emerged as an important field for delivering drugs to specific targets using nanoparticles such as polymeric dendrimers which can bind drugs, target their uptake by specific cell types, and modulate drug delivery by modifying speed of release. Clearly, while there is much happening in this field of research there is little that can be introduced in LMICs to prevent asphyxial damage. In terms of cost and safety one might focus on a role for Epo while simultaneously enhancing strategies to reduce hypoxic ischemic encephalopathy in LMICs and establishing effective therapeutic hypothermia facilities where possible.

Read more:

J Pediatr doi.1016/j.peds.2017.08.031

Brain Behav Immun 2011; 25: 1342-8

BMJ 2010; 340: c363

 

 

 

2017:36 Back to multiple sclerosis (MS); does the 'hygiene hypothesis' play a role?

 

In summary 1733 reference is made to a role for infections in relation to MS. The Ebstein-Barr virus appears to be associated with risk for development of MS, whereas past cytomegalovirus appears to be protective. There is also reference to the ‘biome’ possibly playing a role. Adding to this aspect of MS risk is a recent article from Norway that reviews the evidence for the ‘hygiene hypothesis’ playing a part.  Studies from ~20 years ago suggested an inverse relationship between various infectious diseases and immune-mediated conditions such as allergy and auto-immune diseases in industrialised countries.  Some argue that the terminology is misleading and that the “microbial deprivation hypothesis” would be a more correct term.  Another tweak was the “old friends hypothesis” which proposes that exposure to micro- and macro-organisms such as saprophytes (e.g. mycobacteria and lactobacilli) and helminthic parasites is important for the development of normal immunoregulation.  Some 50 years ago it was shown that risk of MS may be higher in individuals with higher sanitation standards during childhood, and 10 years ago it was pointed out that there is an inverse correlation between MS rates and geographic Trichuris trichuria distribution (with Trichuris being a possible surrogate marker for infections with other parasites as well). In terms of specific infections, two large meta-analyses have shown that infection with H. pylori is negatively correlated with MS, especially in Western countries, and in an animal MS model, infection with H. pylori has been shown to reduce the severity of disease. Helminths, which have immune-modulatory abilities, exert their actions by modulating cells of both the innate and adaptive immune systems. In MS it is postulated that they have a protective effect through down-modulation of inflammatory responses and enhancement of immune regulation.  Animal studies have shown reduced disease severity after immunization with helminth ova, while a small human study (24 patients) reported that helminth-infected individuals with MS had fewer relapses and lower MRI activity than uninfected patients.  The same study showed that anti-helminthic treatment to infected patients resulted in increased clinical and radiological disease.  In terms of attempts to use the research data and actually treat auto-immune disease with helminths, most studies introduce the non-pathogenic whipworm, Trichuris suis, or the hookworm Necator americanus (which may be pathogenic).  Several studies are ongoing, at this time with some showing results such as reduction in the number of gadolinium-enhancing MRI lesions during T. suis treatment.  Whether any of the above has relevance in childhood MS in terms of causation and/or treatment remains to be seen.

Read more:

Acta Neurol Scand 2017; 136 (Suppl. 201): 26-30

Mult Scler Relat Disord 2016; 7: 92-7

Neurology 2006; 67: 2085-6

 

 

 

2017:37 Management of Adult Congenital Heart Disease

 

There are various areas in paediatric practice where paediatric specialists are relieved- or deprived-of management of the long-term ‘consequences’ of ‘successful’ clinical outcomes in neonates, infants and children. The latter statement might sound oxymoronic, i.e. how can there be a ‘consequence’ of ‘successful’ treatment? But here one is referring to the management of serious medical and/or surgical conditions such as birth asphyxia, diaphragmatic hernia and congenital heart disease, where there are risks not only of mortality, but also of long-term morbidity after various interventions and discharge from hospital.  Paediatricians and various paediatric subspecialists may follow up and manage such patients until late adolescence or early adulthood, but at some stage there has to be transfer to specialists who are competent to manage the transition and assume care of the adult patient. With conditions such as type 1 diabetes the transition might be smoother in terms of pathophysiology in children and adults, but for specialists trained in adult cardiology, congenital heart disease is generally a foreign entity and one requires a unique solution. In the USA for example, subspecialisation in the field of Adult Congenital Heart Disease (ACHD) is a certification programme available to Board certified adult or paediatric cardiologists, and formally accredited ACHD clinics and services are being led and provided by these subspecialists. Some data from the USA and Europe indicate that advances in diagnosis and management of congenital heart disease now routinely offer a 90% chance of survival into adulthood. This success rate, which also reflects improved survival of complex congenital heart disease, has reportedly resulted in a doubling of ACHD-related hospital admissions between 1998 and 2005 (from 35 992 to 72 656) and a concomitant increase in mean hospital charges from $19 186 to $43 496 per admission.  Others have shown average length of stay has also increased, also in relation to severity and complexity of the underlying lesion/s. In order to better manage the increasing burden of ACHD on the healthcare system and appropriately and supportively manage the patients, it has been recognized that there must not only be an ACHD team to take over care, but there must also be an active transition programme. The outcome of one such programme in California has recently been reported, showing that only 39% of 73 patients were successfully transferred to the ACHD facility. Other studies also report disappointing transfer rates of between 30-40%, but one study stands out with a rate of 86%. Factors apparently responsible for this success include unique logistics of the system such as a single database of all patients, initiation of transfer at 16 years, and a single and shared location of care for paediatric and adult patients.  The consequences of patients opting out of continuous care appear to be dire, with various researchers showing an increased likelihood of emergency department (ED) visits among such patients, a higher risk of urgent admission from the ED compared to adolescent patients, the  emergence of ‘new,’ symptomatic cardiac diagnoses, and the need for urgent catheterisation on re-presentation.  Recent studies have also shown that there is an increased number of ED visits, even for simple lesions, whereas for patients adherent to care in the ACHD environment there are reductions in morbidity and mortality.  In our country which is burdened with an increase in non-communicable disease and in which adult cardiologists have their hands, rooms and theatres full of patients it is probably wishful thinking that national ACHD training  or establishment of clinics would gain much traction, but morally, ethically and medically, paediatric cardiologists almost certainly feel an obligation to ensure that the excellent work initiated by themselves and their cardiothoracic surgical colleagues is continued as their patients enter and traverse adulthood.

Read more:

Congen Heart Dis 2017; doi: 10.1111/chd.12549

Clin Cardiol; 2016; 39: 391-8

J Am Coll Cardiol; 2011; 57: 2368-74

 

 

 

2017:38 Benefits of antenatal care in low- and middle-income countries (LMICs)

 

There is no questioning that the consistency of the elements within the dataset and the size of the database provide a high level of credibility to the results of a recent study published in the British Medical Journal. Analysts from Germany and the USA reviewed data from 193 Demographic and Health Surveys (DHSs) from 69 LMICs for the period 1990 to 2013. The data from the DHS, available at http://dhsprogram.com, are cross-sectional household surveys that use a ‘harmonised’ questionnaire to facilitate inter-country comparisons. Data collected since 1985 include nationally-representative health and welfare data for women of reproductive age (15-49 years), their offspring and households. Essentially the authors are going deeper into previous data which showed that globally, during the period 2010-2015, 85% of pregnant women attended at least one antenatal visit with a skilled provider. This statistic dropped to around 77% in the least developed countries, and the researchers sought to differentiate between no antenatal care, at least one visit, and multiple visits. Their sample consisted of >750 000 pregnancies resulting in a live birth, and provided results for neonatal and infant mortality, low birth weight, stunting and underweight.  Compared to no visits, at least one antenatal visit was associated with a 1.04% reduced probability of neonatal mortality and a 1.07% lower probability of infant death.  At least four visits, with at least one to a skilled provider, further reduced the probability by 0.56% and 0.42% respectively (not a huge difference). More impressive effects are seen for the other outcome variables: one visit reduced low birthweight probability by 3.82%, stunting by 4.11% and underweight by 3.26%, whereas at least four visits with ≥1 to a skilled provider reduced the probability by an additional 2.83%, 1.41% and 1.90% respectively.  Importantly, the authors point out that as good as the data in the database are, there is insufficient ‘granularity’ to identify which elements of antenatal care are responsible for the improved outcomes, and they state that the analysis does not allow a causal interpretation of the results i.e. improved access in various areas may be a proxy for other important socio-economic and other factors.  Therefore one should always be aware of the flaw in directly relating pregnancy outcome to number of visits. In many cases the fact that the woman is looking after herself, and the pregnancy is going well, simply gives her time to attend clinics ≥4 times, so the clinic might actually have little to do with the favourable outcome. Notably, the research only includes live births, so one has no idea of the relationship between care and outcome in the case of abortions or stillbirths. The challenge is always to not only find the women who don’t attend at all, but also to identify and manage those in the group that ‘books’ early and then has problems that result in a foetal loss or preterm baby and consequential adverse outcomes.

Read more:

BMJ Open 2017; doi; 10.1136/bmjopen-2017-017122

Int J Gynaecol Obstet 2016; 133: 164-7

Pediatr Perinat Epidemiol 1994; 8: 86-97

 

 

 

2017:39 HIV confirmatory testing in early infant diagnosis programmes

 

Health economists and health economics have earned their rightful places in discussions about cost effectiveness and other metrics that inform policy makers, healthcare providers, consumers/patients and product manufacturers. In many cases the economists assist by analyzing actual data (e.g. in the comparison of product A vs B and/or C in the management of a particular condition), but increasingly the economists make use of increasingly-sophisticated mathematical modelling.  In this regard we in South Africa can look to the recently-approved tax on sugar-containing drinks, and the relative speed with which the legislation was passed.  This was based to a large extent on models of the impact of assumed reductions in sugar intake on obesity. Whether the models are/were accurate will take years to measure.  In the case of confirmatory HIV testing after first test at 6 weeks, a plethora of researchers in the USA, Europe and Cape Town utilized high quality data from South Africa to estimate the clinical and economic value of performing the repeat (confirmatory) test vs. missing out on the test and possibly continuing with treatment when some of the recipients have had false positive first test results. According to a survey carried out by the WHO, while confirmatory testing is recommended and is policy in many countries (including South Africa), 38% of high-burden countries do not include such a recommendation and other countries might ignore it, often on the basis of cost. One expects that for the most part South Africa is compliant with respect to re-testing, but no doubt the country’s data were used because of its quantity and high quality.  This allows researchers to make various assumptions in developing a mathematical model. In the model reported in a recent issue of PLOS Medicine the following were assumed and simulated: first test at 6 weeks, infants infected prenatally, intrapartum or at least four weeks prior to testing; MTCT rate of 4,9% at 12 months; ART initiation of 100% after positive first test (i.e. including false positives); infants retained in care for 10 years in the case of false positives or lifelong for true positives; and life expectancy(LE) and per-person lifetime HIV-related costs. Their results showed that with or without confirmatory testing, LE was 26.2 years for HIV-infected infants and 61.4 years for HIV-exposed infants. The 26.2 year figure is interesting, considering that it is likely derived from data that antedate the testing and treatment policy under consideration here (and is ±50% of the figure expected by HIV/AIDS units).  The assumption that treatment in the false positives would have been stopped after 10 years is also interesting i.e. why stop treatment if the underlying assumption after a first (albeit false) positive test is that the infant is infected and should continue treatment for life?  This brings one to the core of the re-test debate: Current guidelines recommend testing and immediate treatment for all positives, then re-testing and cessation of treatment in the false positives. Once one has missed the opportunity of a re-test in infants on treatment, then blood tests are not helpful in differentiating the treated infected infants from those who are uninfected.  The authors estimated that without confirmatory testing 128/1000 ART initiations were in falsely-diagnosed infants. This reduced to 1/1000 with re-testing, and because the latter averted costly HIV care in uninfected infants there was a cost saving ($1790 with re-test vs. $1830 without confirmatory testing). These savings did not include costs of adverse effects of (unnecessary) treatment in false-diagnosed infants.  So the bottom line: it’s better to follow the SA guideline and re-test. One of the other important points from the article is that the lower the incidence of paediatric HIV as a result of access to ARTs, the lower the positive predictive value of diagnostic assays, leading to a greater number of uninfected infants potentially receiving false positive diagnoses and initiation of ART at 6 weeks.   

Read more:

PLOS Med 2017; 14(11):e1002446

AIDS 2015; 29: 1053-60

Lancet Infect Dis 2015; 15: 803-9

 

 

 

2017:40 Antenatal steroids for near-term elective caesarean delivery

 

Summary 1613 of this series dealt with this topic in the context of the South African private sector in which caesarean section (c/s) rates often exceed 60% of all deliveries. This is much higher than the c/s rate in many countries, but even the increase from 9% to 22% in England between 1980 and 2003 caused alarm, particularly because many elective c/s deliveries lacked ‘medical justification’. Even at term the incidence of respiratory problems in infants delivered by c/s is higher than that of vaginally-delivered infants, and this prompted research in 2005 into benefits of administering maternal steroids (betamethasone) prior to elective c/s. Results of the latter randomized controlled trial were positive, showing fewer neonatal admissions to special/intensive care for respiratory problems. Similar studies have been reported over the years, some with dexamethasone, with elective c/s taking place over a gestational range from 34 to 44 weeks, but most do not include c/s after 39 weeks. The studies show diminishing rates of respiratory distress as gestation progresses above 34 weeks, but odds ratios usually still favour infants born to mothers who have received steroids. The problem is in interpreting the results which show for example that steroids reduce the risk of respiratory problems by 50%. However one must look at the actual incidences as well as the risk reduction particularly at higher gestations i.e. take into account the clinical value or significance of reducing the risk of the problem from 4 per 100 babies to 2 per 100 babies. Should one treat 100 in order to prevent 2 cases? The ‘problem’ is to some extent compounded because obstetricians are almost encouraged to administer steroids by guidelines, for example by those published by the Royal College of Obstetricians which states in the section on “women undergoing elective caesarean section” that corticosteroids should be given for elective c/s prior to 38+6 weeks of gestation. The College counters that a little with a preceding statement that elective c/s should normally be performed at or after 39 weeks to reduce respiratory morbidity, but an interesting point here is that the recommendation to give steroids up to 39 weeks is given a higher ‘evidence level’ of ‘A’ vs. the lower level of ‘C’ that recommends delaying delivery until 39 weeks. Consequently, as stated in 2014 by researchers from the UK, antenatal glucocorticoid administration has become common practice in the UK for late preterm/early term caesarean deliveries. The Royal College guideline also stated that there is an absence of evidence available for the safety of antenatal steroids for babies born after 36 weeks. Some critics have challenged such a statement because it can be interpreted as the existence of data, but no evidence of adverse effects. The critics state that one should rather speak of ‘evidence of absence’, but perhaps there is some evidence of evidence after all. There has been a concern that the synthetic steroids (beta- and dexamethasone) cross the placenta because they are resistant to the placental enzyme 11β-hydroxysteroid dehydrogenase which normally prevents maternal steroids from crossing to the foetus. However the foetal brain has high, ‘protective’ levels of the enzyme, especially in areas that undergo rapid growth in the third trimester. The enzyme is supposedly protective against physiological increases in endogenous cortisol that occur in late gestation. Exogenous non-metabolisable steroids could therefore potentially have a deleterious effect on the late preterm/early term brain, possibly accounting for findings of significantly lower academic achievement in the steroid-exposed children in a follow-up of the 2005 trail of steroids for elective c/s. Perhaps evidence such as this will actually have an impact and reduce the number of elective c/s cases ‘protected’ by antenatal steroids in favour of cases that are delayed until at least 39 weeks gestation or the onset of labour. 

Read more: 

Arch Dis Child Fetal Neonatal Ed 2017; 102 F284-5

JAMA Pediatrics 2014; 168: 507-8 

Royal College of Obstetricians and Gynaecologists 2014 Green-top Guideline No.7 

 
Articles from other years 

Index | 2019 | 2018 |  2016 |  2015 |  2014

- Author Prof Alan Rothberg

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