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Editorials

Treating extremely low birthweight infants with prophylactic indomethacin

BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7329.60 (Published 12 January 2002) Cite this as: BMJ 2002;324:60

Evidence for short term benefits only

  1. William McGuire, senior lecturer in neonatal medicine (w.mcguire{at}dundee.ac.uk),
  2. Peter W Fowlie, honorary senior lecturer
  1. Tayside Institute of Child Health, Ninewells Hospital and Medical School, University of Dundee DD1 9SY

    A primary aim of perinatal and neonatal interventions for extremely low birthweight infants (birth weight less than 1000 g) is to increase the likelihood of survival without neurological disability.1 Although interventions, such as prophylactic antenatal steroids2 or exogenous surfactants,3 have improved certain outcomes, the overall prognosis for extremely low birthweight infants remains poor. In North America a multicentre cohort study of extremely low birthweight infants found that less than two thirds of those admitted to intensive care survived to hospital discharge. A quarter of surviving children, assessed at 18-22 months post term, had an abnormal neurological examination, and about a third had evidence of significant neurological developmental delay.4 In the United Kingdom and Eire, the EPICure Study Group evaluated the outcome for infants born before 26 weeks' gestation. The overall survival of infants admitted for intensive care was 39%.5 When assessed at a mean age of 30 months post term, about half the children had disability, and about half of these met the predefined criteria for severe disability.6

    A significant predictor of neurodevelopmental morbidity in extremely low birthweight infants is severe intraventricular haemorrhage or periventricular leucomalacia.4 Since interventions that reduce the occurrence of these conditions might improve longer term neurological outcomes these conditions have been used as a short term outcome measure in perinatal and neonatal intervention studies. One such intervention is prophylactic indomethacin. In addition to closing the patent ductus arteriosus and improving cardiovascular stability, indomethacin may have a more direct neuroprotective effect.7 A Cochrane review of the use of prophylactic indomethacin in very low birthweight babies (birth weight less than 1500 g) found evidence that indomethacin reduced the incidence of symptomatic patent ductus arteriosus and of severe intraventricular haemorrhage.8 Indomethacin, however, has potential side effects, including an increased risk of cerebral hypoxia9 that may oppose any putative neurological benefit. Therefore, the Cochrane review concluded that more data on longer term neurological outcomes were needed to clarify whether the use of prophylactic administration of indomethacin for very low birthweight babies or extremely low birthweight babies should be adopted.8

    Such data are now available. A large multicentre randomised trial of indomethacin prophylaxis assigned 1202 extremely low birthweight infants, soon after birth, to receive indomethacin (0.1 mg/kg) or placebo intravenously once daily for three days.10 The primary outcome, a composite of death, cerebral palsy, cognitive delay, deafness, and blindness at a corrected age of 18 months, was not significantly different in the intervention and placebo cohorts. However, in the indomethacin group, there was a significantly reduced incidence of patent ductus arteriosus (24% v 50% in the placebo group), and requirement for subsequent indomethacin therapy (17% v 46%), or surgical duct ligation (7% v 12%). The incidence of severe periventricular haemorrhage, but not of other evidence of intracranial abnormalities seen on cerebral ultrasound, was reduced in the indomethacin group (9% v 13%). The study did not find any evidence that prophylactic indomethacin affected other outcomes such as chronic lung disease, necrotising enterocolitis, and retinopathy.

    This major collaborative effort, involving infants from 32 centres in five countries, further shows that it is possible to do large, pragmatic trials to address clinically relevant questions in neonatology. Previous randomised controlled trials did not find any evidence for a longer term neurodevelopmental effect of prophylactic indomethacin in very low birthweight infants. These were done in the era before the frequent use of antenatal steroids and exogenous surfactant therapy,11 or were limited by small sample size and incomplete follow up.12 Now, Schmidt and colleagues have provided, with near complete follow up, an unbiased assessment of longer term neurological outcomes in a population of extremely low birthweight infants who had the opportunity to get antenatal steroids and surfactant therapy.10 This, and the fact that the cohort size was sufficient to detect a modest effect (roughly 20% difference in risk) on the primary outcome, improves confidence in using the findings in everyday practice.

    Is indomethacin prophylaxis beneficial for extremely low birthweight infants? The answer depends on which outcomes are considered most important. Prophylaxis with indomethacin reduces the incidence of severe intraventricular haemorrhage, but survival without neurological disability, the outcome of major importance to parents and carers, is not improved. However, parents and carers may value the finding that prophylactic indomethacin reduces the frequency of patent ductus arteriosus and the need for subsequent surgery to close the patent ductus arteriosus. Applying the effect size estimated by the study, for every 100 extremely low birthweight infants who get prophylactic indomethacin, patent ductus arteriosus will be prevented in about 20 and about five will not need surgical closure. The reduced need for surgery may be of particular importance in neonatal centres where infants need to be moved to specialist cardiology and thoracic surgery centre. As with many perinatal and neonatal interventions, the decision to use prophylactic indomethacin will depend on the values attached by parents and carers to these benefits.

    References

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