Hypercalcemia during Pregnancy, Puerperium, and Lactation: Review and a Case Report of Hypercalcemic Crisis after Delivery Due to Excessive Production of PTH-related Protein (PTHrP) without Malignancy (Humoral Hypercalcemia of Pregnancy)

Abstract

Abstract. Hypercalcemia during pregnancy or after delivery is uncommon, and mostly associated with primary hyperparathyroidism (PHPT). If unrecognized, it may increase maternal and fetal morbidity. In a very few patients with PHPT, hypercalcemic crisis develops during pregnancy and particularly after delivery, since calcium transport from the mother to the fetus is abruptly disrupted. Hypercalcemia may also develop in pregnant women due to PTH-related protein (PTHrP)-producing malignant tumors (humoral hypercalcemia of malignancy). Since PTHrP is produced physiologically in fetal and maternal tissues, hypercalcemia may occasionally develop during pregnancy, puerperium, and lactation due to excessive production of PTHrP in the placenta and/or mammary glands. PTHrP may also be involved in milk-alkali syndrome that develops during pregnancy. Although non-malignant hypercalcemia is usually mild, we report a 28-yearsold pregnant woman who developed hypercalcemic crisis after normal delivery of an infant. On the first postpartum day, the corrected serum calcium concentration increased to 19.4 mg/dl with a markedly increased serum level of PTHrP (28.4 pmol/L) (normal <1.1 pmol/L). After administration of saline and pamidronate, the serum levels of calcium and PTHrP rapidly normalized. Extensive examination revealed no malignant lesion, suggesting that the placenta may have been producing an excessive amount of PTHrP (humoral hypercalcemia of pregnancy). We review case reports of nonmalignant hypercalcemic crisis associated with pregnancy indexed in PubMed in which serum levels of intact PTH and/or PTHrP were described, and stress that rapid control of hypercalcemia is mandatory to save the life of the mother and the infant.

Hypercalcemia in pregnancy – a multifaceted challenge: case reports and literature review

“…The myometrium may also synthetize PTHrP, especially under the stimulation of estrogens 14, 15. Excessive production of PTHrP by the placenta, the amnion, or the mammary glands is a rare cause of hypercalcemia in pregnancy or lactation 16, 17, 18.…”

“…The literature reports a few cases associated with the presence of dermoid cysts, pheochromocytomas, and fibromas 16, 19, 20, 21, 22, 23, 24, 25. We have identified six published cases of hypercalcemia secondary to benign uterine fibromas.…”

“…Some authors favor surgery early in the second trimester of pregnancy if calcium levels reach 2.85 mmol/L to prevent late fetal loss 9. The second trimester is the ideal time for surgery but uneventful surgeries in the third trimester have been reported as well 10, 16, 26.…”

“…There was no response to the usual treatment as well as to cinacalcet, possibly because of the humoral form of hypercalcemia. Based on the case reports previously published, both the placenta and the fibroma could have been responsible for the excess production of PTHrP and, effectively, both showed histological proof of excessive secretion 16, 17, 20, 21. As the level of PTHrP was undetectable in the early postpartum, the placenta was probably the major source of secretion.…”

Parathyroid Hormone Related Peptide (PTHrP): A Mini-Review

“…It is in the neonatal period that intestinal calcium absorption and thereby skeletal development and mineralization become dependent upon vitamin D3 and calcitriol [58]. A few cases of overproduction of PTHrP in the placenta resulting in hypercalcemia have been described [59,60].…”