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. 1999 Jan 16;318(7177):194. doi: 10.1136/bmj.318.7177.194a

Outcome of neonatal hypoglycaemia

Complete data are needed

Marvin Cornblath 1,2, Robert Schwartz 1,2
PMCID: PMC1114678  PMID: 9888932

Editor—Ten years ago Lucas et al reported a retrospective multicentre study determining whether asymptomatic neonatal hypoglycaemia results in neurological damage.1 They found that moderate hypoglycaemia (<2.6 mmol/l) may have serious neurodevelopmental consequences if present on five or more different days during the first two months of life.

Subsequently, in October 1989, a Ciba Foundation discussion meeting was held in order to clarify the data and conclusions presented by Lucas et al.1,2 Sinclair and Steere, using specific criteria, recognised that all the published follow up studies were too flawed and inadequate to provide a definite conclusion. Lucas et al had assembled a large inception cohort in their study, with objective outcome criteria and with assessments done by people who were blind to category of exposure. Follow up was almost complete. However, they had not specified a criterion for hypoglycaemia, and sampling bias was not avoided.1,3 Lucas et al’s study therefore did not provide strong evidence that neonatal hypoglycaemia impairs later development.

Despite this caveat the study by Lucas et al has received widespread attention and acceptance in both North America and Europe. Implications for the feeding and care of all neonates have been important; attempts have been made to maintain these comparatively high blood glucose concentrations as acceptable.4 In the United States these criteria have resulted in a fourfold increase in cases of medical litigation, and of awards (MC). Similar increases have occurred in England (A F Williams, personal communication).

Lucas et al have indicated to us that neurodevelopmental follow up of the 1988 cohort would clarify the importance of hypoglycaemia as stated in their preliminary report.1 The long term outcomes of all of their clinical trials of early nutrition on later health and development have been published.5 The original BMJ article1 is not mentioned, nor are any of the later follow up studies that compare glucose concentrations in the blood early in life and neurodevelopmental outcome. These data are available. We deserve to have the benefit of these observations, flawed as they may be.

References

  • 1.Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. BMJ. 1988;297:1304–1308. doi: 10.1136/bmj.297.6659.1304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Cornblath M, Schwartz R, Aynsley-Green A, Lloyd JK. Hypoglycaemia in infancy: the need for a rational definition. Pediatrics. 1990;85:834–837. [PubMed] [Google Scholar]
  • 3.Department of Clinical Epidemiology and Biostatistics; McMaster University Health Sciences Centre. How to read clinical journals. III: To learn the clinical course and prognosis of disease; IV: To determine etiology and causation. CMA Journal. 1981;124:869–872. ; 985-90. [Google Scholar]
  • 4.National Childbirth Trust. Hypoglycaemia of the breast-fed newborn. Mod Midwife 1997 Oct 7:31-3. [PubMed]
  • 5.Lucas A. Long term outcome trials of early nutrition on later health and development. In: Perman JA, Rey J, editors. Clinical trials in infant nutrition. Philadelphia, PA: Lippincott-Raven; 1998. pp. 181–201. [Google Scholar]
BMJ. 1999 Jan 16;318(7177):194.

Authors’ reply

Alan Lucas 1,2, Ruth Morley 1,2

Editor—Our study design was not “flawed”—we had intended to explore the relation between glucose concentrations in blood in neonates and neurodevelopment at 18 months, based on over 6800 blood samplings in 661 preterm infants. We did not use a definition of hypoglycaemia as our purpose was to explore what concentrations might relate to adverse outcomes. The cut off we derived (2.6 mmol/l) was the same as the glucose concentration below which acute electrophysiological changes in the brain were observed elsewhere.1-1 It is at least biologically plausible that at such a sensitive stage in brain development, hypoglycaemia occurring on three to five days (a substantial time) could influence outcome.

We do, however, entirely accept the study’s principal limitation—the difficulty of proving causation when an observational approach is used, as emphasised clearly in our paper. The BMJ publishes many articles that show worrying or provoking associations—for example, observations on small size in early life and ischaemic heart disease in later life.1-2 Such observations generate hypotheses or legitimate clinical concerns that should stimulate future studies.

The article Cornblath and Schwartz refer to, in Clinical Trials in Infant Nutrition, does not mention our hypoglycaemia study since it was not a trial. We have, however, now related neonatal hypoglycaemia, as defined and modelled previously, to overall intelligence quotient,1-3 reading and arithmetic,1-4 and motor performance1-5 at 7.5-8 years. We have found evidence of persisting associations between neonatal hypoglycaemia and lower test scores, clinically significant in two of the four outcomes (arithmetic and motor tests), with approximately 0.5 SD reduction in scores (adjusted for respiratory support, birth weight and gestation) after the neonatal concentration of blood glucose was <2.6 mmol/l on >3 days (P<0.005). Although these data share the earlier same limitation, it seems that a plausible concern remains.

Rather than express discomfort over possible medical and legal misuse of our 1988 observation, investigators might have done more definitive studies—a priority identified at the Ciba symposium cited by Cornblath and Schwartz. If better clinical studies are not done we must operate with existing data, despite misgivings about medical or legal misuse. In any case, Cornblath and Schwartz agreed with us that it would not seem prudent to let a preterm neonate sustain a blood glucose concentration <2.6 mmol/l for several days.

References

  • 1-1.Koh THHG, Aynsley-Green A, Tarbit M, Eyre JA. Neural dysfunction during hypoglycaemia. Arch Dis Child. 1998;63:1353–1358. doi: 10.1136/adc.63.11.1353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.Barker DJP, Osmond C, Golding J, Kuh D, Wadsworth MEJ. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ. 1989;298:564–567. doi: 10.1136/bmj.298.6673.564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-3.Wechsler D. Wechsler intelligence scale for children—revised. Windsor: NFER-Nelson; 1976. [Google Scholar]
  • 1-4.Elliott CD. British Ability Scales. Windsor: NFER-Nelson; 1983. [Google Scholar]
  • 1-5.Stott DH, Moyes FA, Henderson SE. Test of motor impairment. Guelph, Ontario: Brook Educational Publishing; 1972. [Google Scholar]

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