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BACKGROUND Recently the US Food and Drug Administration called for cautious use of anesthetic drugs during pregnancy. In 0.2-2% of pregnancies non-obstetric surgery is being performed. The consequences of anesthesia during pregnancy on fetal development remain unclear and preclinical studies in relevant animal models may help elucidate that. OBJECTIVE To assess the effect of maternal anesthesia and surgery during pregnancy on the developing fetal brain using a rabbit model. STUDY DESIGN This is a randomized, sham-controlled study in time-mated pregnant does at 28 days of gestation (term=31d), which corresponds to the end of the second trimester in humans. Anesthesia was induced in 14 does (155 pups) with propofol and maintained with 4 vol-% (equivalent of 1 MAC) sevoflurane for two hours and a laparotomy with minimal organ manipulation was performed (Surgery group). Maternal vital signs (blood pressure, heart rate, peripheral and cerebral oxygen saturation, temperature, end-tidal CO2, pH, lactate) were continuously monitored. Sham controls consisted of seven does (74 pups) undergoing invasive hemodynamic monitoring for 2h without sedation. At term, does were delivered by cesarean section under ketamine-medetomidine sedation and local anesthesia. Pups either underwent motor and sensory neurologic testing followed by euthanasia at day one or daily neurodevelopment testing for two weeks and extensive neurologic assessment at 5 and 7 weeks (open field and object recognition test, T- and radial arm-maze). Brains were harvested for histologic assessment of neuron density and synaptophysin expression. RESULTS Blood gases and vital parameters were stable in both groups. On postnatal day 1, surgery-pups had significant lower motor (25±1 vs 23±3; p=0.004) and sensory (16±2 vs 15±2; p=0.005) neurobehavioral scores and lower brain-to-body weight ratios (3.7%±0.6 vs 3.4%±0.6 ; p=0.001). This was accompanied by lower neuron density in multiple brain regions (e.g. hippocampus 2617±410 vs 2053±492 neurons/mm2; p=0.004) with lower proliferation rates and less synaptophysin expression. Furthermore, surgery pups had delayed motor development during the first week of life, e.g. hopping appearing later (6±5 vs 12±3 d; p=0.011). Yet, by seven weeks of age, neurobehavioral impairment was limited to a reduced digging behavior and no differences in neuron density or synaptophysin expression was seen. CONCLUSION In rabbits, two hours of maternal general anesthesia and laparotomy, with minimal organ and no fetal manipulation, have a measurable impact on neonatal neurologic function and brain morphology. Pups had a slower motoric neurodevelopment, but by seven weeks the effect became almost undetectable.