Lasting Impact of an Ephemeral Organ: The Role of the Placenta in Fetal Programming

During the winter of 1944–1945 a brutal cold snap and the World War II German occupation curtailed food shipments across the Netherlands. The Dutch plunged into severe famine, with adult food rations dwindling to just 400 calories a day in some areas. Babies conceived during the Dutch “Hunger Winter” were born shorter, thinner, and with smaller heads and placentas than babies born before or conceived afterward. Years later, the famine babies were more likely to suffer from obesity, diabetes, and heart disease than peers born in the years shortly after the famine. They tended to die younger. 1 Recent advances in molecular and imaging technologies, “omics” fields, and data sciences are offering researchers an unprecedented look at the placenta, the master regulator of the fetal environment. The Dutch famine provided early clues that environmental stressors encountered in the womb could determine disease risk in adulthood—a phenomenon known as fetal programming. Over the next several decades, evidence grew that a number of chronic conditions, including asthma, cancer, and neurodevelopmental disorders, might be traced back to environmental exposures in the womb. 2 Experts have called this emerging paradigm “developmental origins of health and disease,” or DOHaD. 2 , 3 Fetal programming is one of the most rapidly expanding areas of biomedical research. 4 Yet the mechanisms underlying this phenomenon have remained murky. Epigenetic alterations—changes that affect how genes are expressed but not the DNA itself—may underlie many of these processes. Researchers are now exploring DOHaD in relation to the structure, function, and epigenome of an often overlooked but essential organ—the placenta. Since early times humans have surmised an important, if not mystical, role for the ephemeral organ that connects the fetus, via the umbilical cord, to the mother’s blood supply and provides for the passage of nutrients and oxygen to the fetus from the mother. Ancient Egyptians revered the placenta as the “External Soul,” while Hebrew Scriptures called it the “Bundle of Life. ” The ancient Greeks settled on a more physical description for the glistening crimson sac: They named it the “placenta,” or “flat cake. ” 5 Yet for millennia, the placenta remained one of the least understood human organs. Gross placental abnormalities were known to have immediate health consequences for mother and fetus, yet no one suspected that even a seemingly normal placenta could influence the lifelong health of the child beyond the prenatal period. “Until very recently, the placenta was thought of by the scientific community as this static plug connecting the fetus to the maternal circulation,” says Graham Burton, a placentologist at the University of Cambridge, United Kingdom. That view is changing. Recent advances in molecular and imaging technologies, “omics” fields, and data sciences are offering researchers an unprecedented look at the placenta as a dynamic organ whose molecular structure and function change throughout pregnancy. 6 Scientists now know that the placenta mediates fetal interactions with the maternal immune system and exposures to compounds in the mother’s blood, in addition to its role in nutrient and waste transfer between the mother and fetus. 7 It also functions as a neuroendocrine organ that produces hormones and other important molecules to spur fetal growth and development. 7 The placenta, in essence, may be the master regulator of the fetal environment. 8