Published online June 29, 2009
PEDIATRICS Vol. 124 No. 1 July 2009, pp. 350-357 (doi:10.1542/peds.2008-2228)

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ARTICLE

Maternal Allopurinol During Fetal Hypoxia Lowers Cord Blood Levels of the Brain Injury Marker S-100B

Helen L. Torrance, MD, PhD^a, Manon J. Benders, MD, PhD^a, Jan B. Derks, MD, PhD^a, Carin M. A. Rademaker, PharmD, PhD^b, Arie F. Bos, MD, PhD^c, Paul Van Den Berg, MD, PhD^c, Mariangela Longini, PhD^d, Giuseppe Buonocore, MD, PhD^d, MariaElena Venegas, MD^e, Hernando Baquero, MD^e, Gerard H. A. Visser, MD, PhD^a and Frank Van Bel, MD, PhD^a

^a Perinatal Center
^b Department of Clinical Pharmacy, University Medical Center/Wilhelmina Children's Hospital, Utrecht, Netherlands
^c Departments of Obstetrics and Neonatology, University Medical Center, Groningen, Netherlands
^d Department of Obstetrics and Pediatrics, University of Siena, Siena, Italy
^e Department of Pediatrics, Universidad Del Norte, Barranquilla, Colombia

BACKGROUND: Fetal hypoxia is an important determinant of neonatal encephalopathy caused by birth asphyxia, in which hypoxia-induced free radical formation plays an important role.

HYPOTHESIS: Maternal treatment with allopurinol, will cross the placenta during fetal hypoxia (primary outcome) and reduce S-100B and free radical formation (secondary outcome).

METHODS: In a randomized, double-blind feasibility study, 53 pregnant women in labor (54 fetuses) with a gestational age of >36 weeks and fetal hypoxia, as indicated by abnormal/nonreassuring fetal heart rate tracing or fetal scalp pH of <7.20, received 500 mg of allopurinol or placebo intravenously. Severity of fetal hypoxia, brain damage and free radical formation were assessed by arterial cord blood lactate, S-100B and non-protein-bound-iron concentrations, respectively. At birth, maternal and cord blood concentrations of allopurinol and its active metabolite oxypurinol were determined.

RESULTS: Allopurinol and oxypurinol concentrations were within the therapeutic range in the mother (allopurinol > 2 mg/L and/or oxypurinol > 4 mg/L) but not always in arterial cord blood. We therefore created 3 groups: a placebo (n = 27), therapeutic allopurinol (n = 15), and subtherapeutic allopurinol group (n = 12). Cord lactate concentration did not differ, but S-100B was significantly lower in the therapeutic allopurinol group compared with the placebo and subtherapeutic allopurinol groups (P < .01). Fewer therapeutic allopurinol cord samples had measurable non–protein-bound iron concentrations compared with placebo (P < .01).

CONCLUSIONS: Maternal allopurinol/oxypurinol crosses the placenta during fetal hypoxia. In fetuses/newborns with therapeutic allopurinol/oxypurinol concentrations in cord blood, lower plasma levels of the brain injury marker protein S-100B were detected. A larger allopurinol trial in compromised fetuses at term seems warranted. The allopurinol dosage must be adjusted to achieve therapeutic fetal allopurinol/oxypurinol concentrations.

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Key Words: neuroprotection • allopurinol • fetal hypoxia • protein S-100B

Abbreviations: NPBI—non–protein-bound iron

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Accepted Jan 12, 2009.

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