New research in mice suggests that whether pups are delivered vaginally or by caesarean section (C-section) has measurable effects on the developmental process of neuronal cell death, and alters neonatal brain development and behavior. Results of the studies, by Nancy Forger, Ph.D., and colleagues at the Neuroscience Institute, Georgia State University, are published in the Proceedings of the National Academy of Sciences (PNAS), in a paper titled, “Birth delivery mode alters perinatal cell death in the mouse brain.” The authors conclude, “our results suggest that vaginal birth acutely impacts brain development, and that alterations in birth mode may have lasting consequences.”

Delivery by C-section accounts for about 30% of births in the U.S., and up to 50% of births in other countries. While the procedure can save lives, C-sections are now carried out at a rate that significantly exceeds World Health Organization recommendations, the authors write. Human epidemiological studies also indicate that C-sections may result in some health-related consequences. “For example, children born by C-section are at greater risk of developing metabolic and immune-related conditions, including type 2 diabetes, asthma, celiac disease, and obesity,” the authors write.

Prior research has reported differences in behavioral and cognitive development in children delivered either vaginally or by C-section, which suggests that birth method may also affect early brain development. However, the Georgia State University team continues, these findings have been “controversial” due to the difficulties in controlling for all potential confounding factors. And while carefully controlled work in animal models can address some of the limitations of human epidemiological research, “surprisingly few studies” have been carried out, the authors acknowledge. 

Their reported work in mice examined neuronal cell death across different brain regions, immediately before and after birth, in pups delivered either vaginally or by C-section. Cell death is a developmental process in mice that happens primarily in the first postnatal week, during which about 50% of the neurons initially generated are eliminated. The Georgia State University studies also look at whether different patterns of perinatal cell death in pups delivered vaginally or by C-section led to long-term effects on neurons in the region of the hypothalamus that regulate the brain’s stress and immune responses, and examined whether birth mode affected ultrasonic vocalizations (USV), or growth before weaning.  Mouse neonates make ultrasonic distress calls when separated from their mothers and littermates, and this is one of the few behavioral tests that can be carried out in such young animals, the authors explain.

As part of the experimental protocol female mice were all impregnated within the same 12-hour period, and for each mouse that gave birth vaginally, a C-section was performed at exactly the same time on another, randomly selected mouse, to control for any effects of gestation length and timing of birth.

The results showed that while neuronal cell death declined abruptly in many of the 13 different brain regions examined in vaginally delivered pups within 3 hours of birth, cell death increased in 9 of these brain regions in the pups delivered by C-section. “Compared with rates of cell death just before birth, vaginally-born offspring had an abrupt, transient decrease in cell death in many brain regions, suggesting that a vaginal delivery is neuroprotective,” the team states. “Remarkably, C-section–born mice never showed the decline in cell death immediately after birth, with brain regions showing either no change or increased cell death at 3 h after birth.”

C-section delivery also had longer-term effects on the paraventricular nucleus (PVN) of the hypothalamus, which controls the brain’s response to stress and immune challenges. “there was a significant 20% reduction in the number of cells immunoreactive for vasopressin in the C-section–born mice,” the researchers add.  

Further investigations found that the amplitude of USV calls was lower in neonates delivered by C-section, although there was no difference on the number, duration, or frequency of USVs. And while there was no difference in body weight at birth between vaginally and C-section-delivered mice, “C-section-born mice had gained more weight than vaginally born mice by the time of weaning.” Although the mechanism underpinning this weight gain isn’t known, the authors note that, “food intake is suppressed when vasopressin neurons in the PVN are activated, and thus a reduction in vasopressin neuron number could contribute to increased weight gain.”

The process of cell death effectively “sculpts” neural network throughout the brain, and the findings that C-section delivery has widespread effects on developmental cell death suggest that birth mode could impact on a range of neural processes, they conclude. “C-section delivery has been associated with emotional, attentional, and sleep disturbances in human infants and young children,” the team comments. “Our findings identify a mechanism that could underlie the effects of birth mode on the brain and behavior.”

 








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