Because smoking during pregnancy is a major risk factor for late fetal death and the sudden infant death syndrome, we investigated cardiorespiratory defense mechanisms to hypoxia in 7 prenatally nicotine-exposed (N) lambs (approximate maternal dose: 0.5 mg/kg/day) and 11 control (C) lambs all at an average age of 5 days. The ventilatory response to 10% oxygen (hyperpnea) was significantly attenuated during quiet sleep in N lambs compared with C lambs and in N lambs aroused from sleep later compared with C lambs (161 +/- 90 versus 75 +/- 66 seconds, p < 0.05). The ventilatory response to hypoxia was similar in the two groups during wakefulness (W), whereas the heart rate response (tachycardia) was significantly lower in N lambs compared with C lambs during both activity states. The ventilatory response to hyperoxia was significantly lower in N lambs compared with C lambs during both activity states. Transition from W to quiet sleep was associated with a significant decrease in ventilation in C lambs but not in N lambs. In conclusion, prenatal nicotine exposure, at a dose comparable with moderate smoking, blunts major elements of the cardiorespiratory defense to hypoxia, i.e., the heart rate and ventilatory and arousal responses, and abolishes the normal decrease in ventilation during sleep compared with W.