Article Text

This article has a correction. Please see:

Prevention of acquired neurological impairment in the perinatal period
  1. A D Edwards,
  2. J Patel,
  3. D Azzopardi
  1. Department of Paediatrics and Neonatal Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Rd, London
  1. Professor A D Edwards, Department of Paediatrics and Neonatal Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Rd, London W12 0NN, UK.

Statistics from Altmetric.com

Cerebral palsy

Neurological impairments acquired before or around birth make an important contribution to the total burden of neurological disease in the community. The multiple aetiologies of these disorders are imperfectly understood, and tend to be grouped under the broad heading of cerebral palsy.

Cerebral palsy is usually defined as a non-progressive neurological syndrome caused by injury to the immature brain, although recent data have questioned whether the pathological progress is genuinely non-progressive.1 The predominant feature is motor impairment, although about half of the affected population will have significant cognitive or intellectual impairment, and these children comprise about 50% of the total number of those with severe mental retardation in the community.2 Associated features such as visual impairment, hearing loss, or feeding problems are common.

The birth prevalence of cerebral palsy shows geographical variations, but is generally in the range of 1.5-3 per 1000 live births.3 Trends in prevalence over time have been somewhat contradictory; a fall from 2.24 to 1.9 per 1000 occurred in Sweden between 1954-8 and 1967-70,4 whereas in Western Australia a significant rise from 2.2 to 2.5 per 1000 occurred over a similar period.5 However, in the past two decades most investigators have found a significant increase in the birth prevalence of cerebral palsy, due largely to an increase in the rates recorded for extremely small or preterm infants.6 There is some evidence that this increase is now being reversed.7

Epidemiological analysis has defined a large number of risk factors for cerebral palsy, including low birth weight, preterm birth, multiple pregnancy, neurological disorder in mother or sibling, thyroid disease or therapy during pregnancy, thyroid hormone deficiency in preterm infants, low placental weight, chorioamnionitis, birth asphyxia, and neonatal hyperbilirubinaemia. During the past decade it has become clear that, contrary to previous views, birth asphyxia does not account for the overwhelming number of cases of cerebral palsy8; rather, interuterine events and the sequelae of preterm birth make the largest contributions to the overall prevalence. In the Oxford Regional Register of Impairment 28% of infants were born under 2000 g and 37% were born at term and required intensive care at birth, whereas 34% had unremarkable perinatal histories and were of normal birthweight (figure).9 Recent data from Western Australia suggest that about 30% of cerebral palsy is associated with preterm delivery, 10% with multiple pregnancy, 10% with hypoxic-ischaemic encephalopathy in term infants, and 10% with postneonatal insults such as road traffic accidents and child abuse. The remaining 40% of infants are born uneventfully at term, and are assumed to have had a prenatal insult.7

These epidemiological data. together with clinical investigation and basic research, suggest areas in which progress towards primary or secondary prevention of acquired neurological impairment could be made.

Neurological injury during fetal life

Barker et al have emphasised the relation between disorders during the fetal period and disease in adult life, and many studies have shown a population relation between fetal abnormalities, such as impaired growth, and cerebral palsy.10 Yet in an individual case direct proof of a fetal cause for neurological injury is often lacking and most children diagnosed as having cerebral palsy of fetal origin have no documented history of fetal abnormalities. This poorly understood group probably provides most cases of fetal neurological injury, and further research in this area is urgently needed. However, there is a series of well demonstrated fetal conditions directly or indirectly linked to neurological impairment, which might be the targets for intervention.

INTRAUTERINE GROWH RETARDATION

Infants small for gestational age born after 32 weeks have an excess risk of cerebral palsy.10 Current data suggest that this is mediated by chronic intrauterine undernutrition and hypoxia, which can be detected both by fetal blood sampling showing acidosis or increased concentrations of erythropoetin,11 and as redistribution of fetal blood flow, shown by Doppler ultrasonography. Fetal acidaemia has been associated with impaired neurological outcome.12 Improvements in the management of the small for gestational age fetus is a tantalising goal for research.

PREGNANCY INDUCED HYPERTENSION (PRE-ECLAMPSIA)

Maternal hypertension is associated with an increased risk of cerebral palsy in infants born at greater than 32 weeks, but a reduced risk in infants born at lower gestational ages (F Stanley, personal communication). The mechanism for this effect is unclear, but is probably related to two effects: stress induced by short term placental insufficiency improves lung maturation and is thus beneficial to preterm infants at high risk of cerebral injury associated with lung disease, whereas long term placental problems are injurious in infants born at term.

Attempts to treat pre-eclampsia with diuretic, antihypertensive, or antithrombotic agents have generally aimed at reducing the risk of eclampsia or preterm birth, and have not focused on fetal morbidity.13 Further research into the treatment of pre-eclampsia, including a thorough assessment of fetal neurodevelopmental outcome, is urgently needed.

Cerebral palsy by birthweight and admission to special care baby unit. Infants of less than 2000 g are predominantly preterm births. Of infants born at more than 2000 g, those requiring special care may have had a perinatal insult, whereas those who did not are usually assumed to have had cerebral injury earlier during interuterine life. Data redrawn from Macfarlane et al.9

A recent retrospective study has suggested that treatment of pre-eclampsia with magnesium leads to a significant reduction in the incidence of cerebral palsy in infants born under 33 weeks gestation.14 Magnesium ions block the N-methyl-D-aspartate class of glutamate receptors, which can mediate the cytotoxic effects of acute hypoxia, and thus a plausible biological mechanism for this association is available. However, these data may be affected by sampling bias, as the patients who received magnesium all had a condition (pre-eclampsia) which has a protective effect on cerebral palsy in preterm infants, and would not have had another (infection) which carries an increased risk. Thus the results may be due to factors other than magnesium, which may explain why some other groups have not been able to show similar effects (N Paneth, personal communication). Until a prospective randomised controlled trial has been carried out, magnesium cannot be recommended for prevention of neurological injury in preterm infants.

MULTIPLE PREGNANCY

In Western Australia the birth prevalence of cerebral palsy in singletons is three per 1000 live births, whereas for twins it is nine per 1000 and for triplets 30 per 1000.15 Most of this excess morbidity is related to an increased incidence of preterm birth, but even accounting for this multiple pregnancies have an excess of neurological injury. The risk seems to be higher in monchorial than dichorial twins, and is particularly high with feto-fetal transfusion syndrome or if one twin dies in utero. This seems to point to a haemodynamic or immunological cause for the cerebral injury, and there is scope for prevention of these injuries by reducing multiple pregnancies (particularly by improved management of in vitro fertilisation programmes) and better understanding of fetal haemodynamics and immunology.

CONGENITAL INFECTION

The incidence of congenital infection varies. Significant sequelae of congenitial cytomegalovirus infection can be seen in about 0.03% of live births, and congenital toxoplasmosis is said to occur in one in 10 000 births in Britain, but is more common among societies that prize raw meat, such as France. The success in reducing the incidence of congenital rubella to some 20-30 cases per year by vaccination suggests that interventions might be attempted but screening and vaccination policies would need rigorous assessment, as the rarity of the diseases militates against significant success.16 However, HIV, which causes significant neurological syndromes in affected children, is now endemic in many parts of the world and is a clear candidate for intervention. Some minor success has been achieved by treatment of seropositive mothers.17

Bacterial infection in the mother is significantly associated with an increased risk of cerebral palsy.18 Maternal infection is a potent cause of preterm delivery, but there is an additional risk associated with maternal and fetal infection, particularly for the development of periventricular leucomalacia.19 Prevention or treatment of bacterial infection is a potential route for reducing necrological injury. Specific treatment in labour of mothers carrying group B Streptococcus has been shown to reduce the risk of serious fetal infection. Unfortunately treatment earlier in labour has no effect as the patient is prone to recolonisation.20

NUTRITIONAL DEFECTS

Folate deficiency early in pregnancy is generally accepted as an aetiological factor in spinal dysraphism, and a randomised controlled trial has shown that periconceptual vitamin supplementation effectively reduces the incidence of spinal malformations.21 Iodine deficiency is a well described cause of intrauterine cerebral injury, and intervention to prevent this has successfully prevented neurological impairment.22 The role of calorie and protein malnutrition in interuterine growth retardation and other neurological injures is less clear, but the strong social class gradient in the incidence of cerebral palsy seen in almost all studies suggests that attention to maternal nutrition is likely to be beneficial.

TOXINS

Maternal alcohol ingestion of 40 g a day increases the chance of neurological injury, but it is unclear that moderate drinking has any definite deleterious effects.23 Opiate addiction is also associated with cerebral palsy, but it is unclear if this is due to the opiate or associated circumstances. Cocaine, on the other hand, leads to specific cerebral injury, due at least in part to its vasoconstrictor action and cerebral infarction is sometimes detectable by ultrasonography at birth.24 Mercury poisoning has also been shown to lead to fetal injury.25 Prevention of these and similar toxic neurological syndromes requires complex social as well as medical manipulation.

Preterm birth

Preterm birth is the factor most consistently associated with cerebral palsy. In studies of populations as far apart as Liverpool, Sweden, and Western Australia the relative risk of neurological injury is an order of magnitude higher in very preterm infants compared to their term counterparts, with a strong relation between the lower gestational age and increased relative risk of cerebral palsy.4 6 26

The major reduction in the mortality of extremely preterm infants achieved over recent decades has been accompanied by a pronounced rise in the birthweight specific prevalence of cerebral palsy for low birthweight infants; in Western Australia, this rose from a 12-fold to a 26-fold relative risk between 1961 and 1975; in the Mersey region, the birth prevalence increased from 14 per 1000 live births to 64 per 1000. It is important to remember that values for relative risk hide the fact that many preterm infants who would previously have died now survive neurologically intact, as about 80%–90% of preterm survivors do not have cerebral palsy. However, the data show that the risks associated with preterm birth and neonatal intensive care are high.

The most recent figures from Western Australia have shown a significant reduction in the birth specific prevalence rates of cerebral palsy among low birthweight infants so that the total birth prevalence is falling. The cause for this is as unclear as was the aetiology of the previous rise, but changes in medical care are likely to be important to this vulnerable and dependent population.7

PREVENTION OF PRETERM DELIVERY

The high risk of mortality and morbidity associated with preterm delivery has led to many attempts to prevent preterm labour by pharmacological means. This policy is predicated on the belief that in this population the greater risk of cerebral injury occurs after delivery; data acquired using cerebral ultrasonography immediately after birth support this view.27

Administration of oral β-mimetic agents as prophylaxis to prevent preterm birth has been shown to be of no value, whereas intravenous treatment for preterm labour is highly effective at postponing delivery in the short term. By themselves, these drugs do not seem to have a beneficial effect for the fetus, but by allowing time for administration of treatments such as dexamethasone, or transfer of the mother to a centre with adequate facilities, they have an important role in the management of preterm delivery.28

Prostaglandin synthase inhibitors also delay preterm delivery and are often used.29 However, there is evidence that indomethacin has deleterious effects on cerebral perfusion,30 and its use has been associated with cerebral lesions in preterm infants.31 Further research into specific inhibitors of the isoform of the cyclooxygenase enzyme responsible for prostaglandin synthesis in labour but not constitutively expressed elsewhere may help overcome this problem.

The high incidence of infection as a cause of preterm delivery has prompted research into the inflammatory aspects of labour. The treatment of asymptomatic bacteruria with antibiotics has not been shown to reduce preterm delivery,32 but the treatment of bacterial vaginosis may be useful.33 Cervical cerclage to treat cervical incompetence probably has a benefit, the number needing to be treated being about 20 to prevent one preterm birth.34

PRETERM DELIVERY

Research has shown that administration of dexamethasone to mothers in preterm labour significantly reduces the mortality and morbidity of preterm birth, probably in large part due to its beneficial effect on lung maturation. The risk of periventricular haemorrhage is significantly less in treated infants (odds ratio 0.45, 95% confidence interval (95% CI) 0.22-0.88).35 Studies of thyroid hormone treatment before birth have been conflicting, but the largest trial available showed no benefit.36 Work in this important area is continuing.

Postnatal cerebral injury

PRETERM INFANT

Modern neonatal intensive care has been spectacularly successful in reducing the mortality of preterm birth, but at the cost of increased gestational age specific increases in morbidity in the most immature infants. In one sense this is hardly surprising, as the mortality of these extremely preterm infants was previously almost 100%. However, there is now justified reluctance to assume that a therapy which improves mortality will also improve morbidity until long term follow up data have been accumulated. For many of the newer therapies, such data are not available.

Several studies have shown that infants have a better chance of survival if delivered and cared for in a large specialist perinatal centre,37 and that transfer to such centres before delivery reduces mortality.38 There are few data on the relative rates of neurological impairment between specialist centres and smaller units, largely because although systematic data are available on neurological outcome of the graduates of large units, this is often not true for smaller ones.

Mechanical ventilation is a life saving therapy for many small infants, and it is assumed that by improving oxygenation it can also reduce neurological morbidity; as there is a relation between the severity of neonatal lung disease and the incidence of neurological problems. Circumstantial evidence supports this belief; cerebral haemorrhage is declining in incidence in all major neonatal units around the world over the past decade as ventilation strategies have become more complex. However, proof that adequate ventilation reduces the gestation specific rate of cerebral injury in very preterm infants is lacking.

Administration of surfactant replacement compounds significantly reduces the mortality of preterm infants.39 However, it does not reduce the incidence of cerebral haemorrhage in these infants, and the important data on long term neurological morbidity are still being compiled.

Indomethacin administered on the first day of life reduces the number of periventricular haemorrhages in preterm infants.40However, the drug also decreases cerebral blood flow and intracellular oxygen availability in newborn infants,30 and it is not clear that it will not increase ischaemic injury in these infants. Other prostaglandin inhibitors, such as ibuprofen, which do not affect global cerebral blood flow are being investigated.41

Recent evidence has suggested that low concentrations of thyroid hormone in the perinatal period are associated with an increased risk of cerebral palsy.42 Trials of thyroid replacement therapy are needed to determine if treatment of this condition is of benefit.

Adequate nutrition is probably important for neurological development, and preterm infants have to achieve this without the benefit of a normal placental nutrient supply. There is evidence that specific nutrients may be required, including long chain polyunsaturated fatty acids, taurine, and iron, and also that feeding with breast milk or particular optimised formulas improves the neurodevelopmental outcome of infants at 18 months and 8 years of age.43 The particular components of breast milk that allow improved neurodevelopment are unknown, but breast milk is rich in growth factors and cytokines as well as conventional nutrients. A large body of research is under way into the neurodevelopmental effects of diet which may provide clear guidelines in the future.

BIRTH ASPHYXIA IN INFANTS BORN AT TERM

Hypoxic-ischaemic encephalopathy at term still accounts for between 10% and 30% of cerebral palsy in developed countries. Estimates from Nepal44 suggest that the incidence in the developing world is similar.

Considerable effort has gone into the obstetric prevention of birth asphyxia, and it is likely that the historical fall in cerebral palsy seen in some western countries is in part due to this. However, it has been surprisingly difficult to show that complex modern fetal monitoring reduces the incidence of fetal death or neonatal encephalopathy, and the value of fetal monitoring for predicting events leading to cerebral palsy is uncertain.45 Fetal monitoring has been shown to reduce he incidence of some surrogate measures of fetal injury, such as low APGAR score, or neonatal seizures.46 Unfortunately these are not always appropriate surrogates; the APGAR score correlates poorly with neurodevelopmental outcome, and neonatal seizures are difficult to diagnose without EEG, as clinical “seizure” activity is poorly related to aberrant electrical activity; furthermore, children with seizures can have a wide variety of clinical outcomes. Improvements in fetal monitoring are desirable, but the very low incidence of adverse events means that it will be difficult to produce a screening test with very high positive predictive value.

Paediatric treatments for asphyxia have been universally ineffective to date. However, the realisation that hypoxia-ischaemia leads to a delayed cellular injury eight to 24 hours after the initial insult, and experimental data on the mechanism of this delayed death have given new impetus to investigations of postnatal therapies for birth asphyxia A pilot study of magnesium sulphate administration within two hours of birth is being undertaken, and various other interventions, including moderate post-insult hypothermia, are being considered for clinical trials.47

HYPERBILIRUBINAEMIA

The decline of kernicterus as a result of improved management of rhesus disease has been a successful preventative intervention to reduce neurological impairment. However, hyperbilirubinaemia remains a significant cause of cerebral injury, and a recent review of 219 cases of dystonic and dyskinetic cerebral palsy still found that jaundice was involved in 57 cases.48 In preterm infants, there is a linear relation between the concentration of bilirubin and the risk of cerebral palsy.49 Non-autoimmune causes of neonatal jaundice such as glucose-6-phosphatase deficiency offer a continuing threat.

INFECTION

Infectious meningitis or encephalitis in the neonatal period or later in childhood can lead to severe neurological injury. Although there have been successful campaigns against individual pathogens—for example, the successful introduction of the Haemophilus Bvaccine, there is room for considerable progress in the treatment of bacterial sepsis to minimise the neurologically damaging effects.

TRAUMA

Recent data from Western Australia show that road traffic accidents and child abuse are emerging as significant causes of neurodevelopmental impairment, contributing an increasing proportion of the total burden of impairment (F Stanley, personal communication). Trauma is the leading cause of death of children outside the first year of life, and significant efforts are warranted to reduce this toll.

Conclusion

Epidemiological data show the association between neurological impairment and factors such as preterm birth, birth asphyxia, and interuterine growth retardation. Unfortunately, these associations may not be simple, and our understanding of biological mechanisms is often imperfect. However, several areas can be defined where intervention to prevent neurological injury could be valuable. If research into pathological mechanisms can be targeted appropriately, then successful therapies such as dexamethasone for preterm delivery and the treatment of neonatal jaundice could soon be joined by new and valuable treatments.

References

View Abstract

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.