Mechanistic and Phylogenetic Perspectives on Pregnancy Sickness

Daniel J Stadtmauer 

Evolutionary biologists have long been fascinated by the peculiar trait of pregnancy sickness, the syndrome experienced by two-thirds of pregnant individuals which includes nausea and vomiting of pregnancy and, in 2% of cases, progresses to a pathological extreme known as hyperemesis gravidarum. With the recent discovery of the placental hormone GDF15 as the main causal factor in pregnancy sickness, it is time for a comprehensive reassessment of the field. In this Review, I synthesize current knowledge and outstanding questions in the biology of pregnancy sickness at both mechanistic and evolutionary levels of analysis. Pregnancy sickness is a heritable, stereotyped complex of behavioral and physiological traits which likely represent a pregnancy-specific homolog of its closest counterpart in normal physiology, infection-induced sickness behavior. I review four adaptive hypotheses for pregnancy sickness (prophylactic, catabolic, autocrine, and anti-rejection) and argue that knowledge of adaptive origin and mechanism are intimately linked: whether GDF15 in pregnancy acts through the canonical brainstem receptor GFRAL or additionally by local non-canonical receptors will be the deciding factor between multiple classes of adaptive hypothesis. Phylogenetic analysis reveals that placental production of GDF15 rose to prodigious amounts only in catarrhine primates and elephants, suggesting that GDF15-induced pregnancy sickness is of recent origin but is not human-specific, and may have evolved convergently. Finally, I review explanations for the persistence of pregnancy sickness in modern human populations, including mismatch, cliff edge selection, and parent-offspring conflict. With these advances, pregnancy sickness has become not just a curiosity of human evolution, but a compelling and low-hanging opportunity for the field to investigate the evolutionary mechanistic bases of complex adaptive behaviors.