The epigenetic jury is still out on C-sections

Thinking his wife and unborn child would die, Dr. Jesse Bennett performed the first successful reported cesarean section on American soil in 1794. Then, for good measure, he removed her ovaries so he (yes, he) “would not be subjected to such an ordeal again.”

Unbeknownst to Bennett, giving his wife a C-section might have affected their daughter’s DNA, her children’s and her grandchildren’s. People typically think about life as nature versus nurture — our genes versus our environment. But what if the environment, or our grandparents’ environments, shaped our genomes literally at the moment of birth?

Many people know the genome is not immune to environmental forces. A nuclear bomb can mutate DNA. A retrovirus like HIV can incorporate itself into genetic code. But what about subtler events? Scientists are beginning to learn how certain twists and trials, such as famine or stress, might influence which genes in our DNA are switched on or off.

Having a C-section, a group of nurses and midwives are now suggesting, could possibly be one of those twists. They are both eagerly and carefully launching studies to examine possible connections between C-sections and medical conditions. The idea is controversial, unproven and has many skeptics, but birth experts say that studying C-sections’ effects on infants and their descendents is an important question that requires experimental testing.

Every cell in the body has the same DNA. Environmental influences, however, may put chemical tags on DNA, silencing one gene or boosting another.

It’s possible Elizabeth Bennett’s C-section — a sudden environmental event — changed how her daughter’s genes were expressed. It’s also possible that her daughter passed these environmentally-influenced switches on to her descendents. The study of passing on these environmental switches is called epigenetics.

Epigenetics is beyond genetics — epi meaning ‘above’ or ‘upon.’ Cancer researchers have studied it since the 1990s, and scientists in other fields are examining the long- and short-term effects environmental markers can have on our genes. Now a group of medical professionals are comparing vaginal births to C-sections.

For many nurses and midwives, it’s about time the medical community focused on the potential environmental markers a C-section could impart on a child’s genome. In January, 11 women from the US, the UK and Australia gathered in Hawaii for a panel investigating the epigenetics of birth.

“The clinical and scientific community have paid attention to the critical time period of gestation and early life, but have not considered labor and birth as a sensitive period whereby epigenetic modulation can occur,” Aleeca Bell, one of the panel’s speakers and an assistant professor of nursing at the University of Illinois, Chicago, wrote in an email.

Since Bennett’s first daring surgery, C-sections have steadily increased. In 1997, physicians delivered about 20 percent of all births in the U.S. by C-section. In 2007, just 10 years later, C-sections accounted for 31 percent of American births.

Some C-sections are medically necessary for mothers, such as in cases of preeclampsia or gestational diabetes. But elective C-sections are increasing, according to a 2005 federal government study that took population growth into account. About 20 percent of C-sections were elective in 1994. That number rose to 28 percent in 2001, an increase of about 40 percent.

Elective C-sections could be putting the infant at unnecessary risk, says the group of midwives and nurses who held the epigenetics panel. If — and it’s still a big if — researchers do find C-sections have potentially harmful effects for the child, it could change the way families and physicians view the operation.

Hannah Dahlen, an Australian midwife, says it could increase respect and demand for vaginal birth. “We’re at the beginning of a very exciting time,” Dahlen says. “I think in 10 years we will potentially look back at what we are doing now and think, ‘What on earth did we do?’”

Dahlen helped spearhead the Epigenetic Influence and Impact on Childbirth meeting. She has practiced midwifery for 24 years, recommending vaginal birth in a country with a 30 percent C-section rate. In 2010, she convened with her colleagues at the annual Royal College of Midwives conference in England.

They were all frustrated “that despite the research, political activism and efforts they and many others were putting in to increase the rate of normal birth, intervention during childbirth kept rising and arguments about safety and outcomes all had a short term focus,” she wrote in an email.

The women were familiar with epigenetics, and wondered if it might provide a new lens they could use to study and compare vaginal birth to C-section delivery. “We thought, let’s change the track and let’s start a new song,” Dahlen says.

The difficulty with studying the effects of birth methods is that studies tend to be observational — meaning that women are allowed to choose their own method of giving birth. The gold standard of medical research is the randomized study, but it is not considered ethical or feasible to randomly assign women to have C-sections or vaginal births. This means that there will always be doubt as to whether associations are related to the birth method itself or other traits that people who choose one birth method over another share.

However, observational studies have provided clues to correlations between birth method and health risks. In recent years, they have indicated that infants born by C-section appear to have an increased risk for asthma and allergies, Type 1 diabetes, childhood leukemia and testicular cancer. In a 2011 study, researchers found that girls born via C-section may be at a higher risk for developing multiple sclerosis later in life.

The mechanism for developing these diseases is unknown, but Swedish scientist Titus Schlinzig suspects epigenetics, he co-wrote in a 2009 study.

That paper was the first to link C-sections to possible epigenetic effects. Schlinzig and his colleagues looked at 21 vaginal births and 16 elective C-sections. They took two blood samples, one from the umbilical cord after birth and a second sample three to five days following birth. Then they studied a keystone of epigenetics: DNA methylation.

DNA methylation is associated with the silencing of genes. When a methyl group — a carbon atom with three hydrogen atoms — attaches to a cytosine base, one of the four building blocks of genes, it puts the gene out of commission.

In the study, Schlinzig’s group looked at DNA methylation in white blood cells. It found that infants born by C-section had more DNA methylation in their white blood cells than babies delivered vaginally. After three to five days, methylation decreased in the C-section babies, and the two groups were no longer significantly different.

In its conclusion, Schlinzig’s group wrote that it was unknown if the effects from the high DNA methylation rate in C-section infants were long lasting, but said it highlights a new area of clinical research that could have important health implications.

Scientists can’t say for sure that DNA methylation leads to gene silencing, but it has a strong correlation, says Joyce Ohm, a professor of biochemistry and molecular biology at the University of North Dakota School of Medicine

Intrigued by the Schlinzig study, the women organized the epigenetics panel. There, they co-wrote a paper about potential issues surrounding the epigenetics of birth, began creating a website as a hub for like-minded researchers and left with research projects up their sleeves for the coming years.

Panel speaker Bell plans to study how synthetic oxytocin given to women during labor might have an epigenetic effect. “We know oxytocin promotes positive mood and social behaviors while helping to lower stress,” she wrote in an email. With so many women and infants exposed to synthetic oxytocin at birth, as well as labor pain medication, the medical field should learn if it has any effect on human epigenetics, she wrote.

Studying the epigenetics of birth is a hot topic, says Louis Muglia, the director of the Center for Prevention of Preterm Birth at Cincinnati Children’s Hospital Medical Center. It makes sense that the fetus would prime itself for life during gestation, he says. English geneticist Marcus Pembrey, the father of trans-generational epigenetics, shone light on the concept after researching the people of Overkalix, an isolated Swedish community.

In the 1800s, Overkalix’s residents depended heavily on farmers. Pembrey and his colleagues had access to records about the community’s feasts, famines and death certificates, and pieced together data for a landmark 2006 study: If a grandfather lived during a famine, his grandson was four times as likely to die of diabetes than if he lived during a time of plenty. Somehow, the grandfather’s genes were switched on or off, helping his body conserve calories — switches that were passed down to his grandson. If the grandson had access to too much food, he could get diabetes and die.

Studying the epigenetics of birth is “intriguing,” Muglia says, adding he wants to wait for the results before jumping on the bandwagon.

In context, birth is a relatively short life event. “You wouldn’t want the body to be reprogramming itself every time an event came up,” Muglia says. “To me it’s a little counterintuitive that the labor process would have as big an impact on epigenetic programming as pregnancy.”

Short window or not, Bell says birth deserves to be studied from an epigenetic standpoint, though it will take a few years to accrue preliminary data. “As midwife researchers, we view labor and birth as a time when small physiological changes can have enormous impact on the mother and infant,” she wrote in an email. “Epigenetics may be a useful tool in discovering how.”

Whatever Bell and her colleagues find, it will take a while to sort out. First, researchers will have to follow generations of babies. Historians did not follow Bennett’s daughter, so it is unknown if she developed any impairments. What is likely is this: If she had children of her own, she probably delivered them vaginally, the most common method in the early 1800s. This normal birthing process is exactly what the nurses and midwives support. But they’ll have to wait for the data before they can reveal any secrets hidden in the epigenome.