The hedgehog signaling pathway is a mechanism that regulates cell growth and differentiation during embryonic development, called embryogenesis, in animals. The hedgehog signaling pathway works both between cells and within individual cells.

In March 1996, the National Academy of Sciences of the United States released 'Veterans and Agent Orange Update 1996: Summary and Research Highlights,' which summarized research on the health effects of Agent Orange and other herbicides used in the Vietnam War. In their 1996 report, the National Academy connects Agent Orange exposure with two health conditions: spina bifida, a birth defect that occurs when the spinal cord develops improperly, and peripheral neuropathy, a nervous system condition in which the peripheral nerves are damaged. Spina bifida was the first birth defect to linked to Agent Orange exposure. The resulting disability compensation for affected children, as a result of the conclusions in the 1996 report, marked the first time that the US Veterans Administration addressed the health outcomes of veterans' families, and not exclusively veterans themselves.

Sprayed extensively by the US military in Vietnam, Agent Orange contained a dioxin contaminant later found to be toxic to humans. Despite reports by Vietnamese citizens and Vietnam War veterans of increased rates of stillbirths and birth defects in their children, studies in the 1980s showed conflicting evidence for an association between the two. In 1996, the US National Academy of Sciences reported that there was evidence that suggested dioxin and Agent Orange exposure caused spina bifida, a birth defect in which the spinal cord develops improperly. The US Department of Veterans Affairs' subsequent provision of disability compensation for spina bifida-affected children marked the US government's first official acknowledgement of a link between Agent Orange and birth defects. By 2016, spina bifida and related neural tube defects were the only birth defects associated with Agent Orange.

Spina bifida is a birth defect that affects the spines of developing fetuses and infants, and research in the 20th century indicated that chemicals in the herbicide Agent Orange likely lead to the birth defect. People with spina bifida can have nerve damage, paralysis, and mental disabilities. During the Vietnam War in the 1960s, the US military employed Agent Orange and other herbicides to destroy enemy crops and forest cover until 1970. Though studies of the link between Agent Orange exposure and birth defects were at first inconclusive, in 1995 the US National Academy of Sciences concluded that one birth defect, spina bifida, was associated with paternal Agent Orange exposure. Spina bifida was, by the twenty-first century, the only birth defect that the US Veterans Administration connected to Agent Orange exposure.

The article Experimental Studies on Congenital Malformations was published in the Journal of Chronic Diseases in 1959. The author, James G. Wilson, studied embryos and birth defects at the University of Florida Medical School in Gainesville, Florida. In his article, Wilson reviewed experiments on birds and mammals from the previous forty years to provide general principles and guidelines in the study of birth defects and teratogens, which are things that cause birth defects. Those principles included what species are convenient for conducting teratological research, what principles act in human embryological and fetal development, and what agents impact those processes. Wilson's article was one of the first attempts in the twentieth century to synthesize basic research conducted in the field of teratology. The article helped to establish teratology as a field in medicine during the twentieth century.

Sidney Q. Cohlan studied birth defects in the US during the twentieth century. Cohlan helped to discover that if a pregnant woman ate too much vitamin A her fetus faced a higher than normal risk of teratogenic effects, such as cleft palate. A teratogen is a substance that causes malformation of a developing organism. Cohlan also identified the teratogenic effects of several other substances including a lack of normal magnesium and prenatal exposure to the antibiotic tetracycline. Cohlan's experiments with vitamins and other chemicals brought attention to how nutrition and environmental agents adversely affect human pregnancy outcomes.

In 2015, the Public Broadcasting Service, or PBS, released a three-part documentary series, Twice Born–Stories from the Special Delivery Unit, hereafter Twice Born, that follows several pregnant women and their experiences with fetal surgery. Trailblazer Studios produced the film, which predominantly features two women, although it includes the stories of many women. The two main women are pregnant with fetuses diagnosed with physical deformities. One woman’s fetus is diagnosed with spina bifida, an incomplete closure of the fetus’s spinal column. The other woman’s fetus is diagnosed with an oral teratoma, a tumor of the mouth. All the pregnant women in the series went to the Children’s Hospital of Philadelphia, or CHOP, in Philadelphia, Pennsylvania, to have in utero surgery to correct the fetus’s birth defects. Twice Born examines the benefits and risks of performing surgery on a fetus still in the pregnant woman’s uterus. Due to the popularity of PBS, the documentary reached a wide audience and brought the topic of in utero surgery to the public’s attention.

Fortunio Liceti studied natural philosophy and medicine in Italy during the first half of the seventeenth century. Liceti wrote greater than seventy works on a wide range of topics, including the human soul, reproduction, and birth defects observed in animals and human infants. In the seventeenth century, people commonly addressed birth defects using superstition and considered them as signs of evil, possibly caused by spiritual or supernatural entities. Liceti described infants with birth defects as prodigies and monsters to be admired and studied rather than feared. Liceti’s works established monsters as a possible subject of scientific inquiry and served as models for the future study of birth defects, a field later called teratology. Liceti was one of the first scholars to attempt to systematically categorize birth defects based on their causes, including multiple causes unrelated to the supernatural.

Truman William Brophy developed a cleft palate surgical repair, later called the Brophy Operation, in the late nineteenth century US. The procedure improved facial aesthetics and speech in cleft palate patients. A cleft palate occurs during development when the palatal bones in the roof of the mouth don't completely fuse, leaving an opening, or cleft, in the upper lip and mouth. Brophy's cleft repair used compression inside and outside of the mouth to push the palatal bones into normal alignment shortly after birth. Brophy advocated surgery on newborns with cleft palates as soon as possible after birth, which met with opposition in the late nineteenth and early twentieth centuries when medical professionals did not operate on infants for non-life threatening conditions. However, Brophy's successful operations convinced many doctors to adopt his technique.

In 1984, J. David Erickson and his research team published the results of a study titled 'Vietnam Veterans' Risks for Fathering Babies with Birth Defects' that indicated that Vietnam veterans were at increased risk of fathering infants with serious congenital malformations, or birth defects. Researchers at the Centers for Disease Control (CDC) in Atlanta, Georgia, conducted the study to address Though the study's results were inconclusive, the study was one of the first to document a possible association between Vietnam War service and spina bifida, a lower back birth defect in which the spinal cord does not form properly. Later research established the links between Agent Orange exposure and various birth defects and led the US Department of Veterans Affairs to offer disability compensation for Vietnam veterans and their families who were affected by Agent Orange exposure.