Cognitive outcome and cyclooxygenase-2 Gene (-765 G/C) variation in the preterm

David Harding ^1*, Steve E Humphries ², Andrew Whitelaw ³, Neil Marlow ⁴ and Hugh E Montgomery ²

¹ St. Michael's NICU, Bristol, United Kingdom
² University College London, United Kingdom
³ University of Bristol, United Kingdom
⁴ University of Nottingham, United Kingdom

^* To whom correspondence should be addressed. E-mail: david.harding{at}bristol.ac.uk.

Accepted 5 August 2006

Abstract

Objective: Cyclooxygenase (COX) inhibition (indomethacin) does not result in an improvement in long term neuro-cognitive outcome, despite reducing the frequency of both severe intraventricular haemorrhage and white matter injury visible on ultrasound. Diffuse brain injury after preterm birth may have inflammatory origins. These two points suggest that in the preterm brain COX inhibition may have a dominant pro- inflammatory or neuropathic role. The inducible form of the COX (COX2) gene is polymorphic : the -765 C (rather than G) variant of the gene being associated with reduced COX2 activity. We hypothesise, therefore, that the C allele of COX2 is associated with worse neuro- developmental outcomes after premature birth. We have tested this hypothesis.

Design: Genetic association study.

Setting: Follow up after preterm birth.

Patients: 207 infants born <33 weeks.

Interventions: None.

Outcomes: Cerebral palsy, disability, Griffiths DQ at 2 yrs and British Ability Scales-11 GCA and motor performance (ABC Movement) at 5 yrs, were compared with COX2 genotype.

Results: The C allele (GC 65 [31%], CC 3 [1%]) was independently associated with worse cognitive performance at 2 and 5 yrs: C allele mean DQ (SEM), 92.7 (1.7), vs GG 97.6 (1.5) p=0.039; C allele mean GCA (SEM), 94.3 (2.2), vs GG 100.9 (1.7) p=0.028.

Conclusion: An anti-neuropathological role for COX2 in the preterm brain may help account for the lack of impact of indomethacin therapy on improving neuro- cognitive outcomes in children born preterm despite reported reduction in apparent brain injury.

Keywords: cyclooxygenase, neurodevelopment, polymorphism, preterm infant

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