Proximate and ultimate causes of pregnancy sickness

Evolutionary biologists have long been fascinated by pregnancy sickness, the heritable, stereotyped syndrome in early pregnancy that usually consists of benign nausea and vomiting and in around 1% of cases progresses to the pathological extreme hyperemesis gravidarum. Identification of the placental hormone GDF15 as a principal causal factor justifies reassessment of its proximate and ultimate causes. This Review synthesizes knowledge of pregnancy sickness at the four levels of analysis of classical ethology-mechanism, development, phylogeny, and adaptive function. Emerging insight into GDF15's role in innate sickness behaviors suggests pregnancy sickness is a heightened state of pre-existing behavioral defenses triggered by placental production of an emetogenic hormone which may hold a different primary function. Comparison of transcriptomes reveals that placental GDF15 production rose 100- to 1000-fold to human-like levels in catarrhine primates, and is low or absent in New World monkeys, rodents, and other mammals, with the possible exception of elephants. This suggests that pregnancy sickness is phylogenetically restricted yet not human-specific, and associates with innovations in syncytiotrophoblast biology rather than diet. I re-evaluate leading adaptive hypotheses (prophylactic, metabolic rewiring, placental growth, and anti-rejection) and argue that the key to adjudicating among them hinges on whether GDF15 acts locally through non-canonical receptors and whether additional factors distinguish pregnancy sickness from sickness behavior. Finally, I evaluate explanations for the persistent risk of hyperemesis gravidarum in modern humans, including trade-offs, mismatch, and conflict. With recent advances, pregnancy sickness is not just a curiosity of human evolution, but a compelling opportunity to investigate the mechanistic bases of complex adaptive behaviors.