Recent advances: Paediatrics–I: Infancy and early childhood
BMJ 1997; 314 doi: https://doi.org/10.1136/bmj.314.7083.801 (Published 15 March 1997) Cite this as: BMJ 1997;314:801
- John Pearn, professora
- a Department of Paediatrics and Child Health Royal Children's Hospital Brisbane Queensland 4029 Australia
Introduction
Children born in the last decade of the 20th century have been healthier, and will be longer lived, than ever before.1 Recent advances in paediatrics have seen national infant mortality rates fall below 5.0 per 1000 live births. The countries in which this has been achieved–Hong Kong, Taiwan, and Japan–have thus set benchmarks for the century ahead. In the context of world medicine, all who care for children rejoice in the momentum of advanced technology, which is saving hitherto unsavable individual children2 3; yet we are seeing the failings of delivery of health systems whose principles have been proved for decades. The major killers of the 13 million children who die annually before their fifth birthday4 remain pneumonia,5 gastroenteritis,4 malaria,6 measles,7 and trauma.8 The potentiating effects of malnutrition contribute to more than 80% of child deaths from infectious disease.9
One of the signal advances in paediatrics is the recognition that children's safety8 and health, indeed the very existence of whole races of children10 is a responsibility for all who practise in a contracting world.
Neonates and infants
Mortality
Current best paediatric practice uses neonatal mortality rates specific to birth weight as a combined index of antenatal care and obstetric and paediatric care. In affluent countries these rates continue to fall and show no evidence of plateauing.1 The current United Kingdom neonatal death rate (deaths per 1000 live births in the first 28 days of life) for infants above the median birth weight of 3500 g is 0.9. The international benchmark for all infants who are not premature (those born weighing more than 2500 g) is a rate below 2.0 per 1000 live births.
The new treatments that have made this possible include the use of exogenous surfactant, high frequency ventilation, extracorporeal membrane oxygenation (ECMO),11 12 with the promise of nitric oxide and partial liquid ventilation of otherwise unsavable preterm infants.13 Extracorporeal membrane oxygenation has been an accepted rescue treatment for otherwise fatal neonatal and infantile respiratory failure for the past five years,11 and its provision in selected high technology centres has enabled survival of an increasing number of infants with acute, catastrophic myocardial or respiratory failure.12
New treatments have made it possible to save preterm infants who previously would have died.
Such splendid results have a downside: over 30% of survivors who weighed less than 1000 g at birth will manifest severe significant neurological disabilities such as cerebral palsy, intellectual impairment, and deafness or blindness.14 Best practice policy is not to intervene below 22 weeks of gestation but to do so at 25-26 weeks.2 Such treatment, and the allocation of resources to achieve such survival statistics, remains a source of tension among doctors, parents, judges, and policymakers. Analysis of resource use indices show that most tiny premature babies who die do so quickly; and the medical resources allocated to non-survivors are relatively small and independent of birth weight.15
Follow up of children conceived by in vitro fertilisation has shown that they do not have increased rates of minor or major malformations16 and do not differ in mean percentiles for weight or head circumference from their peers conceived in the usual way.
Recent advances in paediatrics
Child mortality
Infant mortality rates are the lowest they have ever been, falling below 5.0/1000 live births in Japan and in Hong Kong
The major killers of children remain pneumonia, gastroenteritis, malaria, measles, and trauma
13 million children a year die before their fifth birthday; malnutriton contributes to 80% of such deaths
Neonatal care
Birthweight specific neonatal mortality rates are the lowest ever in affluent countries; the international benchmark of best practice is a neonatal death rate below 2.0 for infants above 2500 g at birth
Exogenous surfactant, high frequency ventilation, and extracorporeal membrane oxygenation (ECMO) enables premature infants with otherwise fatal respiratory and myocardial failure to be saved
Best current neonatal policy attempts to save premature infants of 25-26 weeks' gestation but not those of 22 weeks' gestation.
Transplantation
Placental blood banking is now in place on four continents; these banks are a potential lifelong rescue source for neonate donors who later develop cancer or require a transplant during childhood or in later life
Selected centres now offer children transplants of livers, hearts, heart-lungs, liver-intestines, and small intestines; child liver transplant recipients now have a median 10 years of good quality life
Genetics and gene therapy
Genes for cystic fibrosis, Duchenne muscular dystrophy, fragile X syndrome, spinal muscular atrophy, and phenylketonuria are now defined
Gene therapy is now the central tenet of medical science in paediatrics
Immunisation
Less than 60% of children are fully immunised in parts of the United States, Australia, Africa, and Europej
Protection by herd immunity against disease preventible by vaccination varies with individual diseases
Parents are refusing to have their children immunised not because of cost, any difficulty with access, or the presence of intercurrent illness at the scheduled time for immunisation, but because of a lack of perceived risk, concern about side effects, and the inadeqacy of tracking or reminder systems
Placental blood banks
Placental blood banking is now an exciting reality in paediatrics. Cord blood, unlike adult blood, contains immunogenetically naive B lymphocytes. Transfusion of such leucocytes, and of stem cells, engenders a lower incidence of graft versus host disease in recipients, irrespective of age. This fact allows a broader range of recipients, who need be only partially matched on standard tissue markers17 and thus offers rescue to a wider range of marrow-ablated, non-related donors.18 Such banked blood is a potential source of premutational stem cells for the donor children themselves when they grow to adult life and develop neoplasms. Special precautions are needed–the neonate donor must be screened for genetic and infectious diseases (including HIV), and relatively large amounts of blood are required, with the potential danger of neonatal anaemia.19 Several companies now exist to harvest and store such stem cells–in the United States, the United Kingdom, and Germany.20
As one third of us will die from neoplasia, the possibility of citizens of the future having their own, neonatally collected, pluripotential stem cells which are stored and banked for postablative rescue and hopefully for engraftment and cure is an exciting development. It is the ultimate form of gene therapy for acquired mutational disorders. By mid-1996, the Australian Cord Blood Bank (based at the Royal Hospital for Women in Sydney) was publicly advertising for neonatal blood donations.21
Gastrostomy feeding
Gastrostomy (enteral) feeding has been used increasingly in the past two years.22 23 It avoids the need for of recurrent nasogastric tube feeding for long periods. Children with many life threatening diseases 24 and congenital abnormalities25 26 are subject to malnutrition–which raises the risk of death or morbidity from the primary disease. Gastrostomy feeding arrests this deteriorating vicious spiral and allows catch up growth.22 After the surgical operation to create a gastrostomy port,23 27 enteral feeding is used in children gravely ill from generalised disease24; children with conditions such as corrosive injury to the oesophagus,28 severe gastro-oesophageal reflux with chronic, destructive acid and enzymatic pneumonitis (the “pickled lungs” of severe gastro-oesophageal reflux),29 or dysmorphogenetic conditions with congenital airway obstruction25; and in selected children with severe neurological impairment.26 29
The principal complications of prolonged gastrostomy nutrition include perigastrostomy infection,27 diarrhoea, bloating, and reflux.23 Gastro-oesophageal fundoplication has become one of the most common major operations performed on infants and children by paediatric surgeons.29
Preventing childhood illness
The past decade has seen a shift in focus away from the central role of hospital in the care of ill children. Throughout much of the affluent world, the momentum in children's health care is encapsulated in such phrases as “partnerships with parents,” “child friendly hospitals,” and “day hospital admission only” and an emphasis on primary care for children. The median duration of hospital inpatient stay is now less than 48 hours in most major children's hospitals.
Child abuse
Deaths from child abuse have been reduced in some centres, but the overall rate of reporting of suspected child abuse continues to rise in all centres where better surveillance systems have been incorporated, recognising the different syndromes of unlawful child killing.30 Hundreds of cases of child abuse deaths have appeared in the literature of the past two years from Europe, Asia, Australasia, and the United States.31 32 33. Research into prevention is notoriously difficult, both clinically and methodologically.30 Most child homicide victims in Europe, Asia, and Australasia die as a result of blunt injury,34 the “shaken baby syndrome,” or drowning. Recent research has highlighted two unmet needs in the domain of child abuse. The first is the better identification of the child victim who is subject to prolonged crescendo assaults, about whom society still does not seem to be able to offer protection.30 The second is the unmet need of siblings of identified abused children, who are also at major and sometimes fatal risk.34
Genetics and gene therapy
The human genome organisation has, using semi-industrial techniques concentrated in a few large genomic centres, produced a human transcript map. The human genome is now known to harbour between 50 000 and 100 000 genes, of which half have been sampled to date in the form of expressed sequence tags. Some 16 000 human genes have been mapped relative to a framework map that contains 1000 polymorphic genetic markers.35
Some 80% of children in hospital have diseases which have genetic or familial implications. In recent years the genes for the most common genetic diseases have been defined, including those for cystic fibrosis,36 phenylketonuria,37 the fragile X syndrome,38 Duchenne muscular dystrophy,39 and spinal muscular atrophy. Molecular diagnosis, especially molecular prenatal diagnosis, has begun to supplant biochemical and cytogenetic diagnosis for many inherited diseases. One holy grail of prenatal diagnosis–the selective harvesting and diagnosis of fetal cells from the maternal circulation (from blood taken by simple venepuncture at the first antenatal visit)–remains an unrealised hope.
In spite of many setbacks,40 41 more than 500 patients are currently being treated by insertional gene therapy.41 And, of course, a more crude form of gene therapy, using whole tissue or whole organ transplants, has seen signal success. Transplants of hearts, heart-lung complexes, livers, liver and intestines, and intestines are now options in a variety of centres.42 Median survival after childhood liver transplants now exceeds 10 years. Allogenic bone marrow transplantation remains the most effective treatment for patients with inherited metabolic diseases.
Gene therapy has become one of the central tenets of medical science. The first human trial was begun in September 1990 at the US National Institutes of Health when a 4 year old girl was treated for adenosine deaminase deficiency. For patients with homozygous familial hypercholesterolaemia it has been shown that liver derived, autologous, ex vivo gene therapy (using recombinant, retrovirus encoded gene inserts) produces no harm, at least in the short term. Gene transfer agents have included retroviruses, adenoviruses, liposomes, cationic lipids, and even naked DNA.
Two types of childhood diseases in particular are candidates for gene therapy–immunodeficiency diseases and diseases in which epithelial cells carry metabolic deficits which might be selectively targeted by corrective viruses carrying DNA. Genetically corrected cells of patients with primary immunodeficiency diseases have a selective survival advantage, thus making these diseases a principal focus of the current clinical attempts at human gene therapy.43
In the past two years research trials of gene therapy have been accepted as a treatment of last resort for life threatening conditions; current limitations are scarce resources on the one hand and biological problems such as host rejection of the inserted gene product on the other.40 To date, human gene therapy treatment for severe combined immune deficiency, hypercholesterolaemia, Duchenne dystrophy,39 and cystic fibrosis36 have all indicated some degree of gene transfer and even prolonged gene expression. At least one child with adenosine deaminase deficiency, treated by gene transfer, has been disease free for three years. However, no published evidence has yet been presented of a long term therapeutic effect.
Immunisation
Compliance rates
Two hundred years after Jenner's discovery of practical and safe immunisation compliance rates remain unacceptably low. Protective immune status in the early childhood years ranges from less than 20% in war torn countries10 to 50-70% in the United States,44 60-77% in Australia,45 80-90% in Switzerland,46 and over 90% in Italy, where vaccination is compulsory.47 Immunisation rates exceed 90% in the United Kingdom for the tetanus-diphtheria-pertussis (TPD) triad and for Haemophilus influenzae type b (Hib) vaccine.48 49
In the United Kingdom, over 90% of children are immunised with TDP and Hib vaccines
The immunisation rate needed for herd immunity is disease specific. A seroconversion rate of 60% is adequate to confer herd immunity to diphtheria,50 but a rate of 95% is needed against measles.7
All nations, particularly affluent ones, have been concerned by the suboptimal levels of childhood immunisation evident by 1997. In Australia pertussis has been epidemic since 1994, with 9890 new cases notified in the two years 1994 and 1995. In 1993, 6335 new cases of pertussis were reported in the United States.51 Urgent rescue programmes have been mounted in many countries, one of the most high profile ones being President Clinton's Vaccine for Children programme.52 In several countries the responsible authorities now ensure that children admitted to government preschool classes have evidence of current immunisation or an exemption by a medical practitioner. The United Kingdom, Australia, New Zealand, and the United States have undertaken public health campaigns in the past year.
Parents are refusing to have their children immunised, not because of cost, access, or intercurrent illness but because they see no risk to their children in an otherwise healthy society; because of concerns about side effects53; and because of lack of tracking and reminder systems.54 Influential antimedical, anti-immunisation lobby groups have evolved in all affluent countries, and anti-immunisation beliefs are receiving much publicity. The fact that some vaccines, particularly those against pertussis, are only 70% effective 55 is often used by groups in their campaigns against immunisation programmes. Countering this disturbing trend remains an unmet challenge for all health professionals.
A recent nationwide case-control study has shown unequivocally that immunisation of infants is not linked with any increased risk of the sudden infant death syndrome.56
New vaccines
Acellular pertussis vaccines, introduced in the past two years, are efficient and have reduced the number of reactions by over 50% compared with whole cell vaccine.51 57 The complications with these new vaccines are fever (4%), persistent severe crying (5%), and local swelling at the injection site (24%); the risk of convulsions is less than 0.1%.57
Immunisation against hepatitis B has been progressively introduced in all countries since universal immunisation was adopted as national policy in the United States in November 1991.58 Infants in Asia and Africa and the indigenous populations of Australia, New Zealand, Papua New Guinea, and the Americas are at high risk. In the United States the three dose compliance rate at 12 months increased from 1% in 1989 to 50% by 1993.58 In low risk countries (such as the Netherlands, where only 0.44% of the population is positive for hepatitis B surface antigen59) current practice is routine antenatal screening for hepatitis B, with selective immunisation of infants born to positive mothers. Early and urgent immunisation of infants of such mothers will protect 70% of these high risk children from contracting the infection.60
H influenzae type b immunisation rates of 40-70% have been achieved in most Western countries.45 The incidence of invasive haemophilus disease has decreased by 80% since 1992, when the vaccine became available,46 and in some countries (particularly in Japan and Scandinavia) invasive haemophilus disease has all but disappeared.
In 1988, the 41st World Health Assembly committed the World Health Organisation to the global eradication of poliomyelitis by the year 2000.61 The technical feasibility of this goal is supported by the availability of easily administered, inexpensive oral vaccines and by the epidemiological characteristics of poliomyelitis and the successful experience in the Americas62 and in Australasia, where wild poliomyelitis infection has been completely eradicated. Infants and children from developed countries travelling to endemic areas in Africa, Europe, and Asia also remain at risk.
Immunisation generally is one of the four most cost effective stratagems for reducing mortality in childhood. This, together with better acute management of sick children, improved preterm and delivery care, and better family planning,63 remains the responsibility of all who wish to see not just equality of opportunity for the world's children, but life itself.
References
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