One Study, Decades of Discoveries

A trailblazing study has influenced two generations of scientists and still generates findings today.

December 1, 2021

Toward the end of World War II, a German blockade cut off food to the Netherlands. Over the frigid Hongerwinter (“hunger winter”) of 1944–1945, 4.5 million Dutch people experienced famine; to survive, many ate tulip soup. Data from this time would lead to some of the most influential public health research of the 20th century—studies led by Columbia epidemiologists  Zena Stein, MB, BCh,  and  Mervyn Susser, MB, BCh, FRCP.

Meet the researchers

Stein and Susser took part in the war effort from their native South Africa. Stein worked in the Air Force doing aptitude testing. Among those she tested was her future husband. After the war, the couple reunited in medical school. They married in 1949 and, over the next seven years, built medical services in Alexandra Township, Johannesburg, where they emphasized the prevention of disease among the area’s poor Black residents. They were active in the struggle to end apartheid but eventually left South Africa. In 1965, Susser took a position as head of the Division of Epidemiology at what is now the Columbia Mailman School of Public Health. Stein joined as an associate professor and soon became head of the Epidemiology Research Unit at the New York State Psychiatric Institute.

A study is born

Stein and Susser were interested in the long-term effects of poor nutrition in the prenatal environment and shared the widely held notion that lack of nutrients increases a child’s risk for cognitive deficits. But evidence supporting this view was thin. Fast-forward to the late 1960s at Columbia when Stein and Susser hit on a novel way to get a definitive answer on their nutrition question: the Dutch famine. This nine-month calamity allowed them to make clean comparisons between individuals born to mothers who experienced famine and those who did not.

Working with colleagues in the Netherlands, the Columbia researchers analyzed medical exams performed on 400,000 Dutch men, as part of the country’s mandatory military service, matched to birth records from the war years and immediately after. They published their report in the journal Science in 1972 and in the 1975 book Famine and Human Development: The Dutch Hunger Winter of 1944–1945. 

Surprising findings

To their astonishment, they found that famine exposure had no effect on risk for cognitive deficits at age 18. The reaction in some quarters was hostile. Stein and Susser stuck to their guns (a sign on an office door at the time read “The Department of Negative Findings”). Subsequent research confirmed their discovery. One example was a Columbia-led study in Harlem that tested a program of nutritional supplementation during pregnancy to see if it had an effect on IQ; it didn’t. Stein and Susser worried their findings would be misinterpreted as excusing the horrors of famine; they asserted that their outcomes, from a relatively brief famine in a wealthy country, should not be universalized to other contexts.

While the famine had no effect on IQ, they did find other adverse consequences. In a 1976 paper published in the New England Journal of Medicine, they reported that famine exposure in the first half of pregnancy was associated with risk for excess weight in a mother’s offspring. The risk was twice as common at age 19 for the exposed group as for those who were not.

The paper was among the first to indicate in a rigorous way that there were fetal origins of disease. 

Making a difference for moms and babies

Stein and Susser also uncovered evidence that babies conceived during the famine’s peak had elevated rates of congenital nervous system anomalies, including neural tube defects (NTDs). These results helped lead to clinical trials to investigate the role of folate in pregnancy, and eventually to a federal recommendation that all women who could become pregnant consume 400 micrograms of folic acid daily. In 1998, the U.S. Food and Drug Administration required that enriched bread, pasta, rice, and cereal be fortified with folic acid. NTDs have decreased 35 percent since then. 

A second generation of studies

In 1995,  Ezra Susser, MD ’82, DrPH ’92 , one of Zena Stein and Mervyn Susser’s children, joined his parents on the Columbia faculty where he undertook his own studies of the Dutch famine cohort, finding an increased risk for schizophrenia in those conceived at the height of the famine. This research, first published in Archives of General Psychiatry in 1992, provided some of the first solid evidence on the fetal origins of mental illness. 

He joined an extensive group of researchers inspired by Stein and Susser’s work. For example, in the late 1970s, Dutch epidemiologist  L.H. “Bertie” Lumey, MD, MPH ’85, PhD ’88, obtained birth records from an Amsterdam hospital to shed light on the famine’s long shadow: He found that women exposed to famine in utero were more likely to have adverse reproductive outcomes when they gave birth. Today, he is a professor of Epidemiology at Columbia Mailman School, and his Dutch famine research continues. In a 2018 paper in the journal Cell Reports, he showed that naturally occurring variations in how the genome is programmed in the womb could give some babies conceived during famine a survival advantage in the form of a slower metabolism, only to later harm them in times of plenty, when their slow metabolism contributed to weight problems and diabetes. Another study found that the famine’s effect on DNA can be linked to diabetes decades later.

In a 1998 article in the American Journal of Epidemiology, Ezra Susser and co-authors reflected on how science and history were interwoven, and wrote, “The elucidation of the findings required the continuation of the study over a long period of time—something which depended upon the strength of familial and personal ties, as the study was literally passed on from the original investigators to their children and other students.” The Dutch famine research is celebrated for its rigorous design and influential findings about nutrition and the fetal origins of disease. But it is also a testament to the close relationships between investigators.

Tim Paul is editorial director of Communications and editor of the Transmission newsletter.