The Ron Munger Story
The faces in the advertisements for charities Operation Smile and The Smile Train are familiar to most Americans. The photographs showing sad children whose faces are prominently marked by cleft lips, sometimes even gaping openings between their mouths and noses that reveal misshapen palates and teeth that have grown askew. The “after” pictures of surgically reconstructed smiles and beaming faces. We tend to think of them as the people who have cleft lip and cleft palate: poor and living in places like India, Guatemala, Rwanda or the Philippines.
Ron Munger ̶ who has devoted much of his career in nutritional epidemiology to deciphering the causes of cleft lip and cleft palate ̶ has spent time in several distant, developing nations. It turns out though that he has a large pool of prospective research subjects here at home. Utah has the highest recorded incidence of cleft lip and palate in the United States: two per 1,000 births, which is double the average for Caucasian Americans and equal to the numbers in the Philippines.
“It could be that rates are higher and just underreported in the Philippines, but we’re trying to understand why the numbers of recorded cases here are so similar,” Munger said. “I thought clefts were a developing world problem, a problem of poverty, and they are. But why are the numbers so high in Utah? We are in the middle nationally for rates of diabetes and obesity. We are better educated and have more resources, so we don’t understand why the rates in Utah are so high.”
People are almost certainly less aware of the birth defect in the U.S. because clefts are surgically repaired within the first weeks or months after a baby’s birth. We don’t live near children who struggle to eat, drink or talk because of cleft lips and palates, mothers who are blamed for their child’s defect because they violated some superstition during pregnancy, or people who have grown to adulthood on the fringes of their communities because of their appearance. But the defect impacts people everywhere and if Munger and his colleagues can discover the cause ̶ or causes ̶ thousands of surgeries on infants could be avoided each year.
During gestation, everyone begins with a cleft lip that typically closes between 6 and 8 weeks of fetal development. The palate follows, closing at 10 to 12 weeks. When they don’t close normally, the cleft remains. The causes of cleft lip and palate (CLP) are somewhat less mysterious than they were just a few decades ago. Scientists know maternal health and nutrition are crucial parts of the puzzle, but environment may also play a role and genes are another likely factor. Nutrition, environment, genetics: each topic is complex on its own and understanding how each may be implicated in CLP means investigating them all.
There are themes Munger’s research follows, whether he is examining data from Utah or abroad. One is focused on nutrients in mothers’ diets. Another is whether mothers of children with CLP are more prone to developing diabetes or metabolic syndrome, a collection of disorders which includes a large waistline, high triglyceride level (a type of fat in the blood), low HDL “good” cholesterol level, high blood pressure and a high fasting level of blood sugar that can lead to diabetes, heart disease and stroke. A third area of interest is the possible connection to air quality.
Three nutrients are known to be related to CLPs and neural tube defects, which are birth defects of the brain, spine or spinal cord. Folate, vitamin B6 and zinc are all important to fetal development, which led the Food and Drug Administration to mandate in 1998 that folic acid be added to flour, cornmeal, rice, pasta, enriched bread and other common grain products. The ruling was a reaction to evidence of the pronounced positive effects of folic acid on fetal development and the fact that birth defects occur so early in pregnancy that most expectant mothers are not taking prenatal vitamins during that critical stage of development. Munger said there is some indirect evidence that problems with metabolizing folate may be at play in causing CLP.
He is examining data from a study in Mexico that began in the 1970s and for 30 years tracked the health of women who had given birth to babies with and without CLP. Among the things Munger is looking for is how blood folate levels changed for women in both groups over time. He knows that within a year of delivering their babies, both groups of mothers had similar incidences of diabetes, but over the span of the study, mothers of children with CLP had lower folate metabolism and higher rates of diabetes. With funding from the Centers for Disease Control and Prevention, Munger will contact mothers in Mexico who were part of the study to gather more data. He will be looking especially for people with metabolic syndrome.
Munger also traveled to the Philippines in April to revisit and gather more samples and data from some of the people who participated in a previous study. He’ll return again this year to work alongside an Operation Smile surgical mission where mothers are given free blood pressure screening, diabetes tests and other information about their own health, while the blood samples will also provide important new data for Munger and his colleagues.
“We know maternal health matters,” Munger said. “Compared to normal weight mothers, an underweight mother’s risk of having a baby with a cleft is twenty percent higher and seventeen percent higher for obese mothers.”
Munger said based on work he and his colleagues have already done, it appears that a mother’s whole diet is far more critical to fetal development than an abundance or deficiency of any single nutrient. When asked about whether they took vitamins for the two months prior to becoming pregnant, twenty-five percent of women in the Utah sample reported planning ahead and taking them.
“About half of women don’t know they are pregnant until the second month, so at that point the number of vitamin takers jumps to about fifty percent,” Munger said. “By the third and fourth months the number jumps again. But comparing vitamin intake at different times during pregnancy between mothers of children with clefts and without, showed no difference that we can detect in the Utah sample. However, a combination of taking prenatal vitamins and eating the DASH (Dietary Approaches to Stop Hypertension) diet shows a more than fifty percent reduction of risk for clefts.”
His international work brought to Munger’s attention the possibility of links between air quality and CLP. The incidence of children born with CLP is high in Asia and women there have the world’s highest rates of lung disease, including lung cancer and chronic obstructive pulmonary disease (COPD), even if they are not tobacco smokers. It is also known that women who smoke have a forty percent increased risk of having a child with a cleft.
“Women in Asia are repeatedly exposed to cooking and heating fires in their homes,” Munger said. “Indoor air pollution is of huge interest to us, and also outdoor air pollution.”
Could Utah’s sporadically bad air quality be linked to the state’s high incidence of children born with clefts? That question prompted Munger’s current efforts to collaborate with USU Toxicology Professor Roger Coulombe who studies the adverse effects small particulate air pollution have on human cells and tissues.
In the lab, Coulombe and his associates incubate human lung cells and then expose them to PM 2.5 particles (meaning the particles are just 2.5 microns in diameter) that have been collected from polluted air. These particles are beyond tiny. To put 2.5 microns in perspective it helps to know that the diameter of a human hair is typically 50-70 microns. These particles ̶ which often become trapped for days or weeks during the winter in northern Utah’s Cache Valley and along the state’s populous Wasatch Front during the winter ̶ drastically reduce visibility and can make it painful to breathe. PM 2.5s are also small enough to pass directly into the bloodstream and cause damage. Coulombe has found lung cells react rapidly to the particles, becoming inflamed and increasing production of C-reactive protein which is associated with cardiovascular disease. Perhaps air quality alone is not a cause of CLP, but it could be an environmental factor, like maternal nutrition, that triggers some otherwise dormant genetic predisposition for clefts.
Though genes are a dominant force in human development and there are rare families with several members who were born with clefts, genes alone are not the sole determining factor. Munger wondered if Utah has some genetic “difference” that could explain the high numbers of children with clefts.
“Genetics are well studied and documented in Utah,” Munger said. “It turns out Utah has a very diverse mix of Northern European ancestry. It is not like communities that were founded by very small groups of people like the Amish or Mennonites. Utah had large influxes of immigrants and diverse groups of founders from Scandinavia, Germany and England.”
As it is with most research, a simple question like, “What causes cleft lip and cleft palate?” comes with no simple answer. What scientists learn leads to more questions and, hopefully, to more investigations of what we don’t know. Though Munger knows discovering the roots of CLP will likely consume much of his attention, and that of other researchers even after he retires, he isn’t looking for something easier to explore. He isn’t a medical doctor, his work mostly involves deciphering mountains of data, but he’s seen those faces from the Operation Smile ads in person, over and over again.
“I’m not a clinician,” he said. “I don’t do surgery. I look at data. But you can’t help but be motivated to find a way to help when you are there with these people and these problems are right in front of you. You see how important this work could be.”