Maternal calcium deficiency and offspring programming: mechanistic and translational insights

Maternal calcium deficiency during pregnancy and lactation may predispose offspring to metabolic, skeletal, and cardiovascular disorders in the context of the Developmental Origins of Health and Disease (DOHaD) paradigm. Experimental evidence from rodent models under severe or extreme calcium restriction, particularly studies by Takaya and colleagues, indicates that such conditions can induce insulin resistance, impair bone metabolism, and produce sex-specific cardiometabolic phenotypes in offspring. These effects appear to involve impaired placental calcium transport, altered expression of plasma membrane Ca-ATPase (PMCA) isoforms, and changes in parathyroid hormone, vitamin D, and calcium-sensing receptor signaling, together with persistent epigenetic modifications in hepatic 11β-hydroxysteroid dehydrogenase type 1 (Hsd11b1) and related genes. In humans, however, active placental calcium transport and maternal homeostatic adaptations generally keep fetal calcium concentrations higher than maternal concentrations, and direct evidence that modest maternal calcium deficiency alone causes fetal hypocalcemia remains limited. Nonetheless, observational studies and supplementation trials in populations with low calcium intake, including Gambian cohorts and WHO-endorsed preeclampsia-prevention studies, support the importance of adequate maternal calcium, often together with vitamin D, for maternal health and possibly for offspring growth and blood pressure regulation. This mini-review synthesizes mechanistic, epidemiological, and micronutrient-DOHaD evidence to inform preventive and research strategies.