Maternal mortality, birthweight, and immunogenetics: an evolutionary framework for obstetric risk

Human childbirth is hazardous compared with other primates, where both perinatal and maternal mortality remain a major global challenge despite advances in neonatal and obstetric care. The concept of the obstetric dilemma frames the evolutionary trade-off between the requirements of bipedal locomotion, which constrains pelvic dimensions, and the need to deliver a neonate with a relatively large cranium. The limits of the maternal pelvis increase the risk of obstructed labor for larger babies, while smaller babies are vulnerable to other causes of mortality such as growth restriction or failure to thrive postnatally. This means that birthweight is subject to stabilizing selection. Contributing to the regulation of birthweight and placental function are interactions between killer immunoglobulin-like receptors (KIRs) on maternal uterine natural killer cells and fetal human leukocyte antigen-C (HLA-C) molecules expressed on invading extravillous trophoblast cells. Distinct KIR -human leukocyte antigen genetic combinations are associated with specific reproductive outcomes. Maternal inhibitory KIR with fetal HLA-C2 group allotypes are associated with impaired trophoblast invasion, defective spiral artery remodeling, and increased risk of great obstetrical syndromes, such as preeclampsia. However, these same inhibitory interactions may enhance maternal resistance to certain pathogens. In contrast, activating KIR-human leukocyte antigen interactions seem to be protective against great obstetrical syndromes but appear to confer weaker pathogen resistance. The persistence of both activating and inhibitory KIR variants binding different HLA-C groups therefore reflects stabilizing selection. This immunogenetic interplay adds another dimension to the obstetric dilemma providing a framework for understanding the evolutionary origins of childbirth by linking the evolutionary pressures of a large fetal brain, constraints on pelvic dimensions, stabilizing selection on birthweight, and responses to infection. These ideas can help understand the complex evolutionary origins of obstetric risk seen today for many conditions including preeclampsia, obstructed labor, stillbirth, fetal growth restriction, and preterm labor. We speculate how modern medical care during childbirth will affect the frequency of these conditions in future.