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

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).

METHODS

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.

CONCLUSIONS

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.