Epigenetic modulation at birth - altered DNA-methylation in white blood cells after Caesarean section

Swedish researchers have discovered that babies born by Caesarean section experience changes to the DNA pool in their white blood cells, which could be connected to altered stress levels during this method of delivery, according to the July issue of Acta Paediatrica.

It is thought that these genetic changes, which differ from normal vaginal deliveries, could explain why people delivered by C-section are more susceptible to immunological diseases such as diabetes and asthma in later life, when those genetic changes combine with environmental triggers.

Blood was sampled from the umbilical cords of 37 newborn infants just after delivery and then three to five days after the birth. It was analysed to see the degree of DNA-methylation in the white blood cells - a vital part of the immune system.

This showed that the 16 babies born by C-section exhibited higher DNA-methylation rates immediately after delivery than the 21 born by vaginal delivery. Three to five days after birth, DNA-methylation levels had dropped in infants delivered by C-section so that there were no longer significant differences between the two groups.

"Delivery by C-section has been associated with increased allergy, diabetes and leukaemia risks" says Professor Mikael Norman, who specialises in paediatrics at the Karolinska Institutet in Stockholm, Sweden. "Although the underlying cause is unknown, our theory is that altered birth conditions could cause a genetic imprint in the immune cells that could play a role later in life.

"That is why we were keen to look at DNA-methylation, which is an important biological mechanism in which the DNA is chemically modified to activate or shut down genes in response to changes in the external environment. As the diseases that tend to be more common in people delivered by C-section are connected with the immune system, we decided to focus our research on early DNA changes to the white blood cells."

The authors point out that the reason why DNA-methylation is higher after C-section deliveries is still unclear and further research is needed.

"Animal studies have shown that negative stress around birth affects methylation of the genes and therefore it is reasonable to believe that the differences in DNA-methylation that we found in human infants are linked to differences in birth stress.

"We know that the stress of being born is fundamentally different after planned C-section compared to normal vaginal delivery. When babies are delivered by C-section, they are unprepared for the birth and can become more stressed after delivery than before. This is different to a normal vaginal delivery, where the stress gradually builds up before the actual birth, helping the baby to start breathing and quickly adapt to the new environment outside the womb."

The authors point out that the surgical procedure itself may play a role in DNA-methylation and that factors other than the delivery method need to be explored in more detail.

"In our study, neonatal DNA-methylation did not correlate to the age of the mother, length of labour, birth weight and neonatal CPR levels - proteins that provide a key marker for inflammation" says Professor Norman. "However, although there was no relation between DNA-methylation and these factors, larger studies are needed to clarify these issues."

Professor Norman states that the Karolinska study clearly shows that gene-environment interaction through DNA-methylation is more dynamic around birth than previously known.

"The full significance of higher DNA-methylation levels after C-section is not yet understood, but it may have important clinical implications" he says.

"C-section delivery is rapidly increasing worldwide and is currently the most common surgical procedure among women of child-bearing age. Until recently, the long-term consequences of this mode of delivery had not been studied. However, reports that link C-section deliveries with increased risk for different diseases in later life are now emerging. Our results provide the first pieces of evidence that early 'epigenetic' programming of the immune system may have a role to play."

The authors feel that their discovery could make a significant contribution to the ongoing debate about the health issues around C-section deliveries.

"Although we do not know yet how specific gene expression is affected after C-section deliveries, or to what extent these genetic differences related to the mode of delivery are long-lasting, we believe that our findings open up a new area of important clinical research" concludes lead author Titus Schlinzig, a research fellow at the Karolinska Institutet.

Full bibliographic information: Epigenetic modulation at birth - altered DNA-methylation in white blood cells after Caesarean section. Schlinzig et al. Acta Paediatrica. 98, 1096-1099. (July 2009).