title: Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial.
abstract: OBJECTIVE
  To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage.
  
  
  METHODS
  A randomised double-blind placebo controlled multicentre trial.
  
  
  METHODS
  We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery.
  
  
  METHODS
  Delivery rooms of 11 Dutch hospitals.
  
  
  METHODS
  When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT).
  
  
  METHODS
  Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage.
  
  
  RESULTS
  222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64)).
  
  
  CONCLUSIONS
  Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls.
  
  
  BACKGROUND
  NCT00189007, Dutch Trial Register NTR1383.
authors.affiliation: Department of Perinatology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Joepe J
authors.initials: JJ
authors.lastname: Kaandorp
authors.affiliation: Department of Perinatology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Manon J N L
authors.initials: MJ
authors.lastname: Benders
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
authors.forename: Ewoud
authors.initials: E
authors.lastname: Schuit
authors.affiliation: Department of Clinical Pharmacy, University Medical Center, Utrecht, The Netherlands.
authors.forename: Carin M A
authors.initials: CM
authors.lastname: Rademaker
authors.affiliation: Department of Perinatology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Oudijk
authors.affiliation: Department of Perinatology, Maxima Medical Center, Veldhoven, The Netherlands.
authors.forename: Martina M
authors.initials: MM
authors.lastname: Porath
authors.affiliation: Department of Perinatology, Maxima Medical Center, Veldhoven, The Netherlands.
authors.forename: Sidarto Bambang
authors.initials: SB
authors.lastname: Oetomo
authors.affiliation: Department of Perinatology, VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Maurice G A J
authors.initials: MG
authors.lastname: Wouters
authors.affiliation: Department of Perinatology, VU Medical Center, Amsterdam, The Netherlands Danone Research, Wageningen, The Netherlands.
authors.forename: Ruurd M
authors.initials: RM
authors.lastname: van Elburg
authors.affiliation: Department of Perinatology, University Medical Center, Groningen, The Netherlands.
authors.forename: Maureen T M
authors.initials: MT
authors.lastname: Franssen
authors.affiliation: Department of Perinatology, University Medical Center, Groningen, The Netherlands.
authors.forename: Arie F
authors.initials: AF
authors.lastname: Bos
authors.affiliation: Department of Perinatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Timo R
authors.initials: TR
authors.lastname: de Haan
authors.affiliation: Department of Perinatology, Diakonessenhuis, Utrecht, The Netherlands.
authors.forename: Janine
authors.initials: J
authors.lastname: Boon
authors.affiliation: Department of Perinatology, Diakonessenhuis, Utrecht, The Netherlands.
authors.forename: Inge P
authors.initials: IP
authors.lastname: de Boer
authors.affiliation: Department of Perinatology, Jeroen Bosch Medical Center, Den Bosch, The Netherlands.
authors.forename: Robbert J P
authors.initials: RJ
authors.lastname: Rijnders
authors.affiliation: Department of Perinatology, Jeroen Bosch Medical Center, Den Bosch, The Netherlands.
authors.forename: Corrie J W F M
authors.initials: CJ
authors.lastname: Jacobs
authors.affiliation: Department of Perinatology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Liesbeth H C J
authors.initials: LH
authors.lastname: Scheepers
authors.affiliation: Department of Perinatology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Danilo A W
authors.initials: DA
authors.lastname: Gavilanes
authors.affiliation: Department of Perinatology, Leids University Medical Center, Leiden, The Netherlands.
authors.forename: Kitty W M
authors.initials: KW
authors.lastname: Bloemenkamp
authors.affiliation: Department of Perinatology, Leids University Medical Center, Leiden, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Rijken
authors.affiliation: Department of Perinatology, Groene Hart Hospital, Gouda, The Netherlands.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: van Meir
authors.affiliation: Department of Perinatology, Groene Hart Hospital, Gouda, The Netherlands.
authors.forename: Jeannette S
authors.initials: JS
authors.lastname: von Lindern
authors.affiliation: Department of Perinatology, Gelre Hospitals, Apeldoorn, The Netherlands.
authors.forename: Anjoke J M
authors.initials: AJ
authors.lastname: Huisjes
authors.affiliation: Department of Perinatology, Gelre Hospitals, Apeldoorn, The Netherlands.
authors.forename: Saskia C M J E R
authors.initials: SC
authors.lastname: Bakker
authors.affiliation: Department of Perinatology, University Medical Center, Groningen, The Netherlands.
authors.forename: Ben W J
authors.initials: BW
authors.lastname: Mol
authors.affiliation: Department of Perinatology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Gerard H A
authors.initials: GH
authors.lastname: Visser
authors.affiliation: Department of Perinatology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Van Bel
authors.affiliation: Department of Perinatology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Derks
mesh_terms: D000328:Adult; D000447:Aldehydes / Q000097:blood; D000493:Allopurinol / Q000097:blood / Q000627:therapeutic use*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D005311:Fetal Hypoxia / Q000188:drug therapy*; D006801:Humans; D007659:Ketones / Q000097:blood; D008297:Male; D008431:Maternal-Fetal Exchange; D010117:Oxypurinol / Q000097:blood; D011247:Pregnancy; D064568:S100 Calcium Binding Protein beta Subunit / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D000447:Aldehydes; D004791:Enzyme Inhibitors; D007659:Ketones; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human; C075750:8-epi-prostaglandin F2alpha; D000493:Allopurinol; D015237:Dinoprost; D014969:Xanthine Oxidase; D010117:Oxypurinol
keywords: Allopurinol; Fetal asphyxia; Gender difference; Neuroprotection; S100B