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170 Maternal Allopurinol Administration During Term Labor is Neuroprotective in Case of Fetal Hypoxia; A Multicenter Randomized Placebo Controlled Trial
  1. JJ Kaandorp1,2,
  2. MJNL Benders1,
  3. E Schuit3,
  4. CMA Rademaker4,
  5. MA Oudijk1,
  6. MM Porath5,
  7. S Bambang Oetomo5,
  8. MGAJ Wouters6,
  9. RM van Elburg6,
  10. MTM Franssen7,
  11. AF Bos7,
  12. TR de Haan8,
  13. J Boon9,
  14. IP de Boer9,
  15. RJP Rijnders10,
  16. CJWFM Jacobs10,
  17. HCJ Scheepers11,
  18. AW Gavilanes11,
  19. KWM Bloemenkamp12,
  20. M Rijken12,
  21. CA van Meir13,
  22. J von Lindern13,
  23. AJM Huisjes14,
  24. CM Bakker14,
  25. GHA Visser1,
  26. BWJ Mol2,8,
  27. F van Bel1,
  28. JB Derks1
  1. 1Perinatology, University Medical Center Utrecht, Utrecht
  2. 2Dutch Consortium for Studies in Obstetrics, Fertility and Gynaecology, Amsterdam
  3. 3Julius Center for Health Sciences
  4. 4Clinical Pharmacy, University Medical Center Utrecht, Utrecht
  5. 5Maxima Medical Center, Veldhoven
  6. 6VU University Medical Center, Amsterdam
  7. 7University Medical Center Groningen, Groningen
  8. 8Academic Medical Center, Amsterdam
  9. 9Diakonessenhuis, Utrecht
  10. 10Jeroen Bosch Hospital, Den Bosch
  11. 11Maastricht University Medical Center, Maastricht
  12. 12Leiden University Medical Center, Leiden
  13. 13Groene Hart Hospital, Gouda
  14. 14Gelre Hospital, Apeldoorn, The Netherlands

Abstract

Background Hypoxic-ischemic encephalopathy due to perinatal hypoxia-induced free radical formation is an important cause of long-term neurodevelopmental disabilities. Allopurinol reduces the formation of free radicals, which potentially limits hypoxia-induced reperfusion damage. With this trial we aimed to assess whether maternal allopurinol treatment during fetal hypoxia would reduce the release of brain-tissue-specific biomarkers associated with neonatal brain damage.

Methods We performed a randomized double blind placebo controlled multicenter trial (NCT00189007) studying laboring women at term with imminent fetal hypoxia. Fetal distress was suspected in case of an abnormal fetal heart rate trace, ST-wave abnormalities on fetal ECG or fetal scalp pH<7.20. Women were allocated to receive allopurinol 500 mg IV or placebo immediately prior to delivery. Endpoints were S100B and neuroketal in cord blood, which are brain-tissue-specific biomarkers for brain damage. Because S100B followed a non-normal distribution, we used a poisson regression model with associated RR (95%CI). For neuroketal we report geometric mean differences.

Results We randomized 222 women to allopurinol (n=111) or placebo (n=111). S100B was significantly lower in the allopurinol-group (median 43.4; IQR 20.2–71.5) compared to the placebo-group (median 54.9; IQR 26.8–94.7), RR 0.91 (95%CI 0.88–0.94). Neuroketal did not significantly differ between groups, geometric mean difference –7.57 (95%CI –15.6; 3.57).

Post-hoc analysis showed a marked gender difference in treatment effect in favor of girls for S100B (RR 0.63 (95%CI 0.59–0.68)) and neuroketal (geometric mean difference –16.5 (95%CI –24.6; -1.83)).

Conclusion Maternal treatment with allopurinol during fetal hypoxia reduces damage to neuronal cells as indicated by brain-tissue-specific chemical biomarkers.

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