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James Mills, M.D.

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Making His Mark on Preventing Birth Defects

Dr. James MillsWhen James Mills, M.D., was a boy, he wanted to emulate medical missionary Albert Schweitzer. He later realized that he did not have to go to a faraway land to change lives; he could make people healthier by doing research. Today, Dr. Mills, a senior investigator in the NICHD’s Division of Intramural Population Health Research (DIPHR), has changed countless lives by improving our understanding of birth defects and developing and studying ways to prevent them.

Dr. Mills has devoted his time and energy to investigating the impact of the pregnancy environment on children’s health. Although he isn’t retracing Schweitzer’s path, this research has taken Dr. Mills around the globe. He has collaborated with researchers in Ireland and Chile and with colleagues throughout the United States. His work has helped illuminate how a woman’s health during pregnancy (her nutrition, whether she has diabetes or obesity, and whether she drinks alcohol during pregnancy) can affect a developing fetus. His work has also shown that activities once thought to be harmful—such as having sex or using spermicides during pregnancy—have no adverse effects.

Most importantly, by examining the environment of the womb, Dr. Mills’ work has clarified and reinforced the concept that the pregnancy environment influences not only the health of the fetus, but also the long-term health of the child. Together these findings have had a profound impact on public health.

Read more about these topics in the sections below:

The Safety of Sex During Pregnancy
Uncontrolled Diabetes and Risk of Miscarriage
Reducing Neural Tube Defects
Obesity and Congenital Heart Defects
Drinking Alcohol During Pregnancy and Health Outcomes
More Information

The Safety of Sex During Pregnancy

When Dr. Mills arrived at the NIH, he got his first taste of how much research could affect lives. A colleague offered him access to data from a large-scale pregnancy study that he knew could hold the key to a question he wanted to answer: Is it safe to have sex during pregnancy? The conventional thinking at the time was that women should not have sex during pregnancy, because intercourse increased their risk of preterm delivery, premature rupture of membranes, and amniotic fluid infections. This is what he had been taught in medical school.

Dr. Mills and his colleagues turned to the data and examined each of these outcomes. In fact, they found that not one was associated with having sex during pregnancy. As a result of this research, conventional and clinical wisdom was revised. Now couples are told that sex during pregnancy is safe in most cases. “I think that we made a big public health contribution,” Dr. Mills said. “We certainly changed clinical practice by doing that.”

Similarly, Dr. Mills examined data on 30,000 pregnant women who used spermicidal contraceptives, to find out whether they were at greater risk of having a child with a birth defect. An earlier study had suggested spermicides could increase this risk. The analysis conducted by Dr. Mills and his research team indicated this was not the case: The data showed that women who used spermicides during pregnancy had no increased risk of having a child with a birth defect. This relieved pressure on the industry that had built up as a result of the earlier findings. “Had it not been for our research and that of other studies finding no effect, spermicides may have been removed from the market,” Dr. Mills said.

Uncontrolled Diabetes and Risk of Miscarriage

Studying birth defects led to a greater understanding of the environment of the womb and its effects on pregnancy outcomes more generally. Dr. Mills’ work with diabetes patients was particularly illuminating, and provided concrete advice for women with diabetes looking to get pregnant.

“Our first big study showed the risk of having a child with a major birth defect if you have type 1 diabetes was double or even triple the risk of a woman who did not have diabetes,” Dr. Mills said. “We also showed that the risk of having a spontaneous abortion was much higher in women with diabetes than for those who didn’t have it.”

“The most interesting finding was that you could prevent the excess risk for spontaneous abortion if you had your diabetes in really good control before you got pregnant,” Dr. Mills said. “The risk for having a baby with serious birth defects went from almost 25% in women whose diabetes was basically uncontrolled or poorly controlled down to about 5% in the women who were in good control.”

Reducing Neural Tube Defects

A major advance in preventing birth defects was made when a team of British researchers discovered that a folate deficiency during pregnancy could lead to neural tube defects.

Once researchers understood that low levels of folate very early in pregnancy led to these defects, clinicians and public health experts set out to spread the word about preventing neural tube defects by getting enough folate.

“I was one of the people who worked on this. Initially, we advised all women of childbearing age who were capable of becoming pregnant to start taking folic acid. It worked to a certain extent,” Dr. Mills said, “but about 60% of women of childbearing age did not take the supplement.” So public health experts next worked to fortify foods with folic acid. That approach worked. “If you eat anything today that says ‘fortified cereal or grain’ on the package, you’re getting folic acid,” Dr. Mills said.

“This has been a big public health success story, because we now are preventing about 50% of all the neural tube defects with fortified foods,” said Dr. Mills. “This is being done in 60 different countries around the world. It’s a great story and a great public health success.”

But it has not stopped there for Dr. Mills and his colleagues. They have eliminated about one-half of all neural tube defects—but what could they do about the other half?

Because the fortified foods did not prevent 100% of neural tube defects, researchers had to examine other possible causes to further reduce the number of these defects. Dr. Mills and his team wondered whether there was a genetic component to neural tube defects. Working with researchers in Ireland, they found one gene variant in children and one in mothers related to neural tube defect risk.

“You can overcome the effects of those variants by taking the folate supplement,” Dr. Mills said. This finding gives researchers greater insight into how neural tube defects develop and reinforces the advice that women of childbearing age should get enough folate.

Obesity and Congenital Heart Defects

More recently, working with researchers in New York State and the New York State Department of Health, Dr. Mills found a link between obesity and congenital heart defects in infants.

“New York has about a quarter of a million births every year, and they have a very good registry of all the children with birth defects,” Dr. Mills said. “We asked [the state] to identify the infants with congenital heart defects, a control group of infants without defects, and the body mass index (BMI) of the mothers, to identify who is obese.”

The study found that the higher the mother’s BMI, the greater the risk that the infant would be born with a congenital heart defect. Overweight women have a small risk, but once a woman is obese, the risk goes up—and continues to rise with greater obesity.

“The message for women who might become pregnant is that they should begin losing weight prior to becoming pregnant,” Dr. Mills said. Birth defects develop very early during pregnancy: Major heart defects occur within 6 weeks of conception. “You have to be really proactive and tell women that they have to be dealing with these things like obesity, like diabetes, before becoming pregnant. Anything you do after that is just closing the barn door after the horse is gone.”

Drinking Alcohol During Pregnancy and Health Outcomes

Dr. Mills intently investigated the causes of such structural anomalies as heart and neural tube defects, but he also had developed an abiding interest in other types of outcomes, such as when a fetus was exposed to alcohol in the womb. Much of the early research on alcohol consumption in pregnant women focused on fetal alcohol syndrome. But Dr. Mills and his colleagues wanted to know whether alcohol caused more subtle effects.

“We started doing alcohol research in the 1980s, and we had a paper showing that women who drank even one drink a day on average, their children [would] have a lower birth weight,” he recalled. “So, we started really early saying that there are a lot of problems with alcohol beyond just fetal alcohol syndrome, where much of the research was concentrated.”
Dr. Mills was able to expand his alcohol-related research when a colleague took a position at the University of Chile.

The team in Chile interviewed 9,600 women who came in for their first prenatal care, Dr. Mills said. “Out of that group, we identified 100 women who were very heavy drinkers, meaning at least four drinks of alcohol a day on average. We also identified a group of non-drinkers that we could use as a comparison group.”

Researchers counseled the women on the dangers of drinking while pregnant. The women continued to participate in the study through pregnancy and for up to seven years after.

Dr. Mills and his colleagues found that binge drinking at any point during pregnancy raised the child’s risk of having language delays, hyperactivity, attention deficits or intellectual delays. Consumption of a high total alcohol volume during pregnancy also increased the risk of these disabilities, particularly if the heavy drinking occurred early in pregnancy.

The study has continued to look at how patterns of drinking—binge drinking, the number of days per week the pregnant woman drinks, and maximum intake per day—might affect the fetus. The research is also looking at a variety of outcomes to the fetus, including neurological damage and stillbirth.

There are two lessons to be drawn from this research, Dr. Mills said:

  • Once the alcohol-related damage has occurred in the womb, it cannot be undone. Like folate and neural tube defects, prevention is key to improving outcomes.
  • There is no known safe level of alcohol that a pregnant woman can consume.

“The consensus is that we really can’t identify a safe level [of alcohol consumption during pregnancy],” Dr. Mills said. “I would be disinclined to drink at all if I were pregnant.”

More Information

For more information on Dr. Mills and his work within DESPR, select one of the following links:


Mills, J. L., Harlap S., & Harley, E. (1981). Should coitus late in pregnancy be discouraged? Lancet 2, 136-138.

Mills, J. L. (1982). Malformations in infants of diabetic mothers. Teratology 25, 385-394.

Mills, J. L., Simpson, J. L., Driscoll, S. G., Jovanovic-Peterson, L., Van Allen, M., Metzger, B., . . . the NICHD-DIEP Study. (1988). Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. New England Journal of Medicine 319, 1617-1623.

Mills, J. L., Harley, E., Reed, G., & Berendes, H. W. (1982). Are spermicides teratogenic? JAMA 248, 2148-2151.

Mills, J. L., Graubard, B. I., Harley, E. E., Rhoads, G. G., & Berendes, H. W. (1984). Maternal alcohol consumption and birth weight: How much drinking during pregnancy is safe? JAMA 252, 1875-1879.

Mills, J. L., Reed, G., Nugent, R. P., Harley, E. E., & Berendes, H. W. (1985). Are there adverse effects of periconceptional spermicide use? Fertility and Sterility 43, 442-446.

Waller, K.D., Mills, J.L., Simpson, J.L., Cunningham, G.C., Conley, M.R., Lassman, M.R., & Rhoads, G.G. (1994). Are obese women at risk for producing malformed offspring? American Journal of Obstetrics & Gynecology 1994; 170, 541-548.

Whitehead, A. S., Gallagher, P., Mills, J. L., Kirke, P. N., Burke, H., Molloy, A. M., . . . Scott, J. M. (1995). A genetic defect in 5,10 methylenetetrahydrofolate reductase in neural tube defects. QJM 88, 763-766.

Brody, L. C., Conley, M., Cox, C., Kirke, P. N., McKeever, M. P., Mills, J. L., . . . Swanson, D. A. (2002). A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase (MTHFD1) is a maternal genetic risk factor for neural tube defects. American Journal of Human Genetics 71, 1207-1215.

Parle-McDermott, A., Mills, J. L., Kirke, P. N., O’Leary, P. B., Swanson, D. A., Pangilanin, F., . . . Brody, L. C. (2003). Analysis of the MTHFR 1298 A->C and 677C->T polymorphisms as risk factors for neural tube defects. Journal of Human Genetics 48, 190-193.

Kuehn, D., Aros, S., Cassorla, F., Avaria, M., Unanue, N., Henriquez, C., . . . Mills, J. L. (2012). A prospective cohort study of the prevalence of growth, facial, and central nervous system abnormalities in children with heavy prenatal alcohol exposure. Alcoholism: Clinical and Experimental Research, 36(10), 1811–1819.

Aros, S., Mills, J. L., Torres, C., Henriquez, C., Fuentes, A., Capurro, T., . . . Cassorla, F. (2006). Prospective identification of pregnant women drinking four or more standard drinks (> or = 48 g) of alcohol per day. Substance Use & Misuse 41, 183-197.

Last Updated Date: 09/03/2013
Last Reviewed Date: 09/03/2013
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