Why In Vitro Fertilization Increases Macrosomia Risk? A New Anti-Cold-Stress Theory Mirroring Bergmann's Evolutionary Adaptation Rule

In vitro fertilization revolutionized reproduction, but its association with macrosomia (overweight) remains unknown. We investigated molecular/metabolic impacts of extreme-cold-environment cryopreservation in frozen-embryo-transfer (FET), proposing new theory to explain increased macrosomia risk. Birth-weight was assessed as growth indicator; tandem mass spectrometry quantified amino-acids (AAs) and carnitine in newborn blood for metabolic profiles; and RNA sequencing analyzed gene expression in umbilical-cord vasculature, a model reflecting fetal circulatory system. Comparisons between fresh-embryo-transfer (ET) and FET revealed that extreme-cold-environment(-196°C) altered AA metabolism and transcriptional profiles linked to protein synthesis and energy metabolism. These changes were associated with higher birth-weight in FET offspring. Our findings bridge phenotypic observations (macrosomia), metabolic disturbances (AA/carnitine alterations), and molecular signatures (differential gene expression), supporting a novel anti-cold-stress mechanism. The new theory firstly suggests embryonic adaptation to cryopreservation environment may program metabolic changes increasing overweight risk, offering insights to optimize ART practices and improve long-term health outcomes of IVF-conceived children.