David E. Cantonwine

Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity, with immune dysregulation at the maternal–fetal interface central to its pathogenesis. The highly polymorphic HLA region mediates maternal immune tolerance of the semi‐allogeneic fetus, yet the contribution of HLA diversity to PE risk remains poorly defined. Whether the HLA heterozygote advantage observed in other immune disorders is relevant to PE has not been systematically evaluated. Using data from the multi‐ancestry TOPMed Boston–Colombia Collaborative for Adverse Pregnancy Outcomes ( n = 12,790; 4770 PE, 8020 controls; 10,808 maternal, 1982 fetal, including 1848 pairs), we evaluated associations between heterozygosity across eight classical HLA loci and PE and four sub‐phenotypes, adjusting for genetic ancestry. HLA heterozygosity was common across most loci (> 80%). No individual maternal HLA locus was associated with overall PE; however, heterozygosity across Class I loci showed a protective effect in preterm PE (OR = 0.81, 95% CI: 0.68–0.97), with a similar pattern for HLA‐A heterozygosity (OR = 0.78, 95% CI: 0.64–0.97). In contrast, fetal heterozygosity at HLA‐DQB1 was nominally associated with increased risk of PE (OR = 1.36, 95% CI: 1.03–1.80) and preterm PE (OR = 1.73, 95% CI: 1.13–2.74). No individual maternal or fetal HLA alleles were associated with PE. Maternal–fetal mismatch analysis demonstrated locus‐specific associations with preterm PE, including increased risk with HLA‐DQA1 mismatch and reduced risk with HLA‐C mismatch. These findings highlight distinct maternal and fetal immunogenetic contributions to PE risk and underscore the importance of considering HLA diversity—rather than individual alleles alone—in studies of PE aetiology.

Assessing and understanding the Growth and Development of animals generally, and of human fetuses specifically, provides essential information for the management of the health of the newborn and its mother. Here we show that a consideration of the formation of the body, in units of numbers of cells, N , and the change in these numbers by the binary either/or decisions of cells to divide or not, an approach we call Binary Cellular Analysis , provides new insights and new equations for quantifying the growth and development of the body and its parts. These equations include: 1) The Binary Cellular Universal Growth Equation , which captures growth from conception to adulthood, and provides a method for biologically-based, data-driven, Growth Curves ; 2) The Binary Cellular Universal Mitotic Fraction Equation , which lies within the Binary Cellular Universal Growth Equation , and captures the mechanism of growth to adult size, control of cell division; 3) The Binary Cellular Allometric Growth Equation , which captures the creation and growth of the Tissues, Organs , and Anatomical Structures of the body, and how the embryo creates each Body Part from a Single Founder Cell ; and, 4) Binary Cellular Estimated Fetal Weight Equations , derived from the Binary Cellular Allometric Growth Equation , which captures the relationship between Ultrasound Measurement and the Size of the body as a whole. These equations capture the developmental process of Cellular Selection , resulting from Differential Cellular Proliferation , which molds the formation of the body from a single fertilized ovum into a multicellular animal. The parameters of these equations both capture the differences in Size and Growth between animals across the taxonomic spectrum, and between human fetuses, as well as identify the individual mechanisms of mitosis that drive Growth and Development . From the Binary Cellular Universal Growth Equation , the Growth of human fetuses can be measured, thus providing a much-needed tool for understanding the biological forces that cause a fetus to grow to Small, Average , or Large Size at birth, for providing the basis of biologically-based, data-driven, Growth Curves , and for assisting the management of the obstetric care of the fetus and its mother.

Assessing and understanding the Size of the human fetus provides essential information for the management of the health of the newborn and its mother, a quality that is commonly measured by Fetal Ultrasound . Many equations for making such calculations have been considered, none of which have been entirely satisfactory. As we have shown in the previous paper in this series, a consideration of the formation of the body, in units of numbers of cells, N , an approach we call Binary Cellular Analysis , provides new quantitative tools for estimating the Size and Age of the fetus. These tools include a new mathematical basis for creating useful expressions, Binary Cellular Estimated Fetal Weight Equations , for calculating human Fetal Weight from Ultrasound Measurements . As we show here, the most promising of these expressions, the Abdominal Circumference Binary Cellular Estimated Fetal Weight Equation , performs better than other currently used Fetal Weight Equations , while also yielding up new methods for improving ultrasound size assessment. Web-based calculators ( https://kidzgrowth.com ) make these mathematical manipulations available for obstetric care.