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Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation.

Abstract

OBJECTIVE

Intrauterine and maternal systemic infections are proposed causes of preterm labor. The resulting prematurity is associated with 75% of infant mortality and 50% of long-term neurologic handicaps. We hypothesize that free radicals generated in large quantities during an inflammatory response shift the fetomaternal redox balance to an oxidative state, compromising the fetus. Thus, if our working hypothesis is correct, selective inactivation of free radicals with N-acetylcysteine (NAC), an antioxidant and glutathione (GSH) precursor, would improve the outcome of preterm deliveries associated with inflammation. We tested aspects of this hypothesis in an animal model of preterm labor and fetal damage (death).

STUDY DESIGN

NAC (1 g/kg) was administered orally to C57Bl/6 mice injected intraperitoneally with either 10 microg lipopolysaccharide (LPS) or saline solution (CRL) on day 16 of gestation. The latency period (time from injection to delivery of the first pup) and fetal viability were recorded. To discriminate between an effect of prematurity from an effect of inflammation, and to document any improvement in survival, mice were killed at 3, 6, and 16 hours after injection. Maternal and fetal redox states were approximated by measuring hepatic GSH.

RESULTS

Each C57Bl/6 LPS-treated mouse delivered prematurely after a significantly shorter latency period (LPS: 16.8 hours [95% CI 15.9-17.6] vs CRL: 54.7 hours [95% CI 43.8-65.5]). NAC doubled the latency interval of LPS-treated animals to 35.2 hours (95% CI 21.0-49.2). LPS alone resulted in a 100% rate of stillbirth. Fifty-eight percent of fetuses were already dead 16 hours after LPS. In contrast, only 33% of fetuses were dead 16 hours after LPS (P =.001) when NAC was given. LPS was followed by a reduction in maternal (LPS: 26.3 nmol/mg [95% CI 19.9-32.8] vs CRL: 41.3 nmol/mg [95% CI 34.7-47.9, P <.01]) and fetal GSH (LPS: 19.7 nmol/mg [95% CI 11.7-27.8] vs CRL: 34.5 nmol/mg [95% CI 32.0-37.0, P <.001]). This decline was reversed by NAC (NAC/LPS maternal GSH: 37.0 nmol/mg [95% CI 22.5-51.5] and fetal GSH: 28.4 nmol/mg [95% CI 22.8-33.9]). Importantly, maternal liver GSH impacted on fetal survival. NAC/LPS mothers with living pups 16 hours after LPS had significantly higher liver GSH compared with NAC/LPS mothers whose pups died in utero. In fact, all NAC-treated mice whose hepatic GSH exceeded 20 nmol/mg had living fetuses at 16 hours.

CONCLUSION

Maternal inflammation in C57Bl/6 mice results in oxidative stress associated with maternal and fetal GSH depletion. Oxidative stress damages the fetus independent of prematurity. Restoration of maternal and fetal oxidative balance by NAC protects the fetus and reduces the rate of preterm birth.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA. ibuhimsc@med.wayne.edu

    ,

    Source

    MeSH

    Acetylcysteine
    Animals
    Female
    Fetal Death
    Gestational Age
    Glutathione
    Inflammation
    Kinetics
    Lipopolysaccharides
    Liver
    Mice
    Mice, Inbred C57BL
    Obstetric Labor, Premature
    Oxidation-Reduction
    Pregnancy
    Pregnancy Complications

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    12548218

    Citation

    Buhimschi, Irina A., et al. "Protective Effect of N-acetylcysteine Against Fetal Death and Preterm Labor Induced By Maternal Inflammation." American Journal of Obstetrics and Gynecology, vol. 188, no. 1, 2003, pp. 203-8.
    Buhimschi IA, Buhimschi CS, Weiner CP. Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation. Am J Obstet Gynecol. 2003;188(1):203-8.
    Buhimschi, I. A., Buhimschi, C. S., & Weiner, C. P. (2003). Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation. American Journal of Obstetrics and Gynecology, 188(1), pp. 203-8.
    Buhimschi IA, Buhimschi CS, Weiner CP. Protective Effect of N-acetylcysteine Against Fetal Death and Preterm Labor Induced By Maternal Inflammation. Am J Obstet Gynecol. 2003;188(1):203-8. PubMed PMID: 12548218.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation. AU - Buhimschi,Irina A, AU - Buhimschi,Catalin S, AU - Weiner,Carl P, PY - 2003/1/28/pubmed PY - 2003/2/21/medline PY - 2003/1/28/entrez SP - 203 EP - 8 JF - American journal of obstetrics and gynecology JO - Am. J. Obstet. Gynecol. VL - 188 IS - 1 N2 - OBJECTIVE: Intrauterine and maternal systemic infections are proposed causes of preterm labor. The resulting prematurity is associated with 75% of infant mortality and 50% of long-term neurologic handicaps. We hypothesize that free radicals generated in large quantities during an inflammatory response shift the fetomaternal redox balance to an oxidative state, compromising the fetus. Thus, if our working hypothesis is correct, selective inactivation of free radicals with N-acetylcysteine (NAC), an antioxidant and glutathione (GSH) precursor, would improve the outcome of preterm deliveries associated with inflammation. We tested aspects of this hypothesis in an animal model of preterm labor and fetal damage (death). STUDY DESIGN: NAC (1 g/kg) was administered orally to C57Bl/6 mice injected intraperitoneally with either 10 microg lipopolysaccharide (LPS) or saline solution (CRL) on day 16 of gestation. The latency period (time from injection to delivery of the first pup) and fetal viability were recorded. To discriminate between an effect of prematurity from an effect of inflammation, and to document any improvement in survival, mice were killed at 3, 6, and 16 hours after injection. Maternal and fetal redox states were approximated by measuring hepatic GSH. RESULTS: Each C57Bl/6 LPS-treated mouse delivered prematurely after a significantly shorter latency period (LPS: 16.8 hours [95% CI 15.9-17.6] vs CRL: 54.7 hours [95% CI 43.8-65.5]). NAC doubled the latency interval of LPS-treated animals to 35.2 hours (95% CI 21.0-49.2). LPS alone resulted in a 100% rate of stillbirth. Fifty-eight percent of fetuses were already dead 16 hours after LPS. In contrast, only 33% of fetuses were dead 16 hours after LPS (P =.001) when NAC was given. LPS was followed by a reduction in maternal (LPS: 26.3 nmol/mg [95% CI 19.9-32.8] vs CRL: 41.3 nmol/mg [95% CI 34.7-47.9, P <.01]) and fetal GSH (LPS: 19.7 nmol/mg [95% CI 11.7-27.8] vs CRL: 34.5 nmol/mg [95% CI 32.0-37.0, P <.001]). This decline was reversed by NAC (NAC/LPS maternal GSH: 37.0 nmol/mg [95% CI 22.5-51.5] and fetal GSH: 28.4 nmol/mg [95% CI 22.8-33.9]). Importantly, maternal liver GSH impacted on fetal survival. NAC/LPS mothers with living pups 16 hours after LPS had significantly higher liver GSH compared with NAC/LPS mothers whose pups died in utero. In fact, all NAC-treated mice whose hepatic GSH exceeded 20 nmol/mg had living fetuses at 16 hours. CONCLUSION: Maternal inflammation in C57Bl/6 mice results in oxidative stress associated with maternal and fetal GSH depletion. Oxidative stress damages the fetus independent of prematurity. Restoration of maternal and fetal oxidative balance by NAC protects the fetus and reduces the rate of preterm birth. SN - 0002-9378 UR - https://www.unboundmedicine.com/medline/citation/12548218/Protective_effect_of_N_acetylcysteine_against_fetal_death_and_preterm_labor_induced_by_maternal_inflammation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002937802714427 DB - PRIME DP - Unbound Medicine ER -