Fetuses actively transport calcium, phosphate, and magnesium across the placenta, maintain high serum concentrations of these minerals relative to maternal and normal adult values, and accrete 80-95% of their skeletal content of mineral during the last trimester. Given the dependence of pediatric and adult mineral homeostasis on vitamin D and calcitriol, it is often assumed that vitamin D sufficiency becomes even more critical during fetal development. However, this is not the case. Calcitriol normally circulates at low levels in human and animal fetuses due to increased catabolism of calcitriol and 25OHD by 24-hydroxylase (CYP24A1). Moreover, comprehensive studies have shown that mammalian fetuses do not require vitamin D or calcitriol. The evidence comes from randomized trials of vitamin D supplementation during human pregnancy, vitamin D deficiency models in rodents, and genetic mouse models that deleted calcitriol (Cyp27b1 null) or the vitamin D receptor (Vdr null).  Despite severe vitamin D deficiency or these genetic disorders of vitamin D physiology, fetuses maintain normal serum minerals, PTH, FGF23, placental calcium and phosphate transport, and skeletal morphology and mineralization. The placenta is able to extract what it needs from the maternal circulation, even when the mother has low serum calcium or phosphate. After the placenta is gone, neonates must rely upon the intestines and kidneys for delivery of calcium and phosphate, and it is then that disordered vitamin D physiology leads to hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and rickets.

Given that calcitriol is preferentially kept at low levels in fetuses through the actions of CYP24A1, what happens if calcitriol becomes elevated in the fetal circulation? Inactivating mutations of CYP24A1 cause high postnatal levels of calcitriol and the human condition of infantile hypercalcemia type 1, but whether fetuses are disturbed by these mutations was unknown. We hypothesized that fetal loss of CYP24A1 would cause high calcitriol and hypercalcemia. Indeed, Cyp24a1 null fetuses proved to be hypercalcemic, modestly hypophosphatemic, had 3.5-fold increased calcitriol, 4-fold increased FGF23, and unchanged PTH. Placental ⁴⁵Ca and ³²P transport were normal, as were fetal ash weight and mineral content, placental weight, crown-rump length, and skeletal morphology. These results are consistent with older literature, which showed that calcitriol infusions into animal fetuses caused hypercalcemia and inconsistently decreased or increased serum phosphorus.

Overall, normal fetal mineral physiology preferentially maintains low circulating levels of calcitriol and also functions normally in extreme situations where vitamin D or calcitriol are effectively absent. Conversely, fetal physiology has less tolerance for elevated calcitriol, which overrides the fetal milieu to cause hypercalcemia.