Why reproduction has probably been very problematic in Neanderthals: The fabulous history of (pre)eclampsia

Preeclampsia and eclampsia, unique to human reproduction, represent the first disease documented in written history over 5000 years ago, yet their etiology remains elusive in 2026. These disorders, exclusive to Homo sapiens among 4300 mammal species, may have posed an even greater reproductive challenge to Neanderthals, potentially contributing to their poor fecundity. Arising from incomplete deep trophoblast invasion into maternal spiral arteries, essential for nourishing the energy-demanding fetal brain, they lead to placental insufficiency and fetal growth restriction (FGR). In humans, eclampsia (grand mal seizures) occurs naturally in ∼1 % of pregnancies, while preeclampsia affects 2-8 %, with untreated cases carrying high maternal and fetal mortality. Predominantly affecting primiparas and multiparas with a new partner ("primipaternity"), early-onset preeclampsia (EOP; delivery <34 weeks) results from failed maternal immune tolerance to paternal antigens, causing partial fetal rejection and inadequate artery remodeling. This manifests as FGR with or without maternal syndrome. Critically, humans evolved a protective mechanism decoupling maternal preeclampsia from ∼75 % of placental FGR cases, averting life-threatening complications. Without this safeguard, preeclampsia rates could soar to 10-20 %, with eclampsia at 4-5 %, severely impeding reproductive success. Neanderthals, sharing deep hemochorial placentation but possibly lacking this adaptation due to genetic divergences (e.g., imprinted genes, KIR-HLA interactions, PIEZO1 variants), likely suffered higher incidences, exacerbating demographic vulnerabilities like small populations and inbreeding. This hypothesis bridges a gap in paleoanthropology: preeclampsia, the principal human reproductive complication, is never cited by anthropologists as possible explanation of the well-known low fecundity rates in Neanderthals communities.