title: Potential adverse effects of antenatal melatonin as a treatment for intrauterine growth restriction: findings in pregnant sheep.
abstract: Intrauterine growth restriction is a condition in which the fetus has a birthweight and/or length <10th percentile for the gestational age. Intrauterine growth restriction can be associated with various causes, among which is low uteroplacental perfusion and chronic hypoxia during gestation. Often, intrauterine growth-restricted fetuses have increased oxidative stress; therefore, agents that decrease oxidative stress and increase utero, placental, and umbilical perfusion have been proposed as a beneficial therapeutic strategy. In this scenario, melatonin acts as an umbilical vasodilator and a potent antioxidant that has not been evaluated in pregnancies under chronic hypoxia that induce fetal growth restriction. However, this neurohormone has been proposed as a pharmacologic therapy for complicated pregnancies.
  
  
  
  The aim of this study was to determine the effects of prenatal administration of melatonin during the last trimester of pregnancy on the biometry of the growth-restricted lambs because of developmental hypoxia. Further, we aimed to determine melatonin and cortisol levels and oxidative stress markers in plasma of pregnant ewes during the treatment.
  
  
  
  High-altitude pregnant sheep received either vehicle (n = 5; 5 mL 1.4% ethanol) or melatonin (n = 7; 10 mg/kg(-1)day(-1) in 5 mL 1.4% ethanol) daily during the last one-third of gestation. Maternal plasma levels of melatonin, cortisol, antioxidant capacity, and oxidative stress were determined along treatment. At birth, neonates were examined, weighed, and measured (biparietal diameter, abdominal diameter, and crown-rump length).
  
  
  
  Antenatal treatment with melatonin markedly decreased neonatal biometry and weight at birth. Additionally, melatonin treatment increased the length of gestation by 7.5% and shifted the time of delivery. Furthermore, the prenatal treatment doubled plasma levels of melatonin and cortisol and significantly improved the antioxidant capacity of the pregnant ewes.
  
  
  
  Our findings indicate that antenatal melatonin induces further intrauterine growth restriction but improves the maternal plasma antioxidant capacity. Additional studies should address the efficiency and safety of antenatal melatonin before clinical attempts on humans.
authors.affiliation: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Alejandro
authors.initials: A
authors.lastname: González-Candia
authors.affiliation: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Marcelino
authors.initials: M
authors.lastname: Veliz
authors.affiliation: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Araya
authors.affiliation: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Quezada
authors.affiliation: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Germán
authors.initials: G
authors.lastname: Ebensperger
authors.affiliation: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: María
authors.initials: M
authors.lastname: Serón-Ferré
authors.affiliation: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Roberto V
authors.initials: RV
authors.lastname: Reyes
authors.affiliation: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile; International Center for Andean Studies (INCAS), Universidad de Chile, Putre, Chile.
authors.forename: Aníbal J
authors.initials: AJ
authors.lastname: Llanos
authors.affiliation: Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile; International Center for Andean Studies (INCAS), Universidad de Chile, Putre, Chile. Electronic address: eherrera@med.uchile.cl.
authors.forename: Emilio A
authors.initials: EA
authors.lastname: Herrera
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001724:Birth Weight / Q000187:drug effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation / Q000139:chemically induced / Q000188:drug therapy*; D005865:Gestational Age; D006854:Hydrocortisone / Q000097:blood; D008550:Melatonin / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D011256:Pregnancy Outcome; D012756:Sheep
chemical_list: D015415:Biomarkers; D008550:Melatonin; D006854:Hydrocortisone
keywords: gestation; hypoxia; intrauterine growth restriction; melatonin; neonatal biometry; oxidative stress