2 180 A Khan and others Hypoparathyroidism in 180:2 R37–R44 Review pregnancy MANAGEMENT OF ENDOCRINE DISEASE Hypoparathyroidism in pregnancy: review and evidence-based recommendations for management Aliya A Khan1, Bart Clarke2, Lars Rejnmark3 and Maria Luisa Brandi4 1Division of Endocrinology and Metabolism, Calcium Disorders Clinic, Department of Medicine, McMaster University, Correspondence Hamilton, Ontario, Canada, 2Mayo Clinic, Endocrinology Transplant Center, Rochester, Minnesota, USA, 3Department should be addressed of Endocrinology and Internal Medicine, Aarhus University, Aarhus, Denmark, and 4Department of Surgery and to A Khan Translational Medicine, University of Florence, Florence, Italy Email [email protected] Abstract Purpose: Review calcium homeostasis in pregnancy and provide evidence-based best practice recommendations for the management of hypoparathyroidism in pregnancy. Methods: We searched MEDLINE, EMBASE and Cochrane databases from January 2000 to April 1, 2018. A total of 65 articles were included in the final review. Conclusions: During pregnancy, calcitriol levels increase by two- to—three-fold resulting in enhanced intestinal calcium absorption. The renal filtered calcium load increases leading to hypercalciuria. PTHrP production by the placenta and breasts increases by three-fold, and this may lower the doses of calcium and calcitriol required during pregnancy in mothers with hypoparathyroidism. The literature however describes a wide variation in the required doses of calcium and calcitriol during pregnancy in hypoparathyroid mothers, with some women requiring higher doses of calcitriol, whereas others require lower doses. Close monitoring is necessary as hypercalcemia in the mother may European Journal of Endocrinology suppress the fetal parathyroid gland development. Also hypocalcemia in the mother is harmful as it may result in secondary hyperparathyroidism in the fetus. This may be associated with demineralization of the fetal skeleton and the development of intrauterine fractures. Inadequate treatment of hypoparathyroidism may also result in uterine contractions and an increased risk of miscarriage. Treatment targets during pregnancy are to maintain a low normal serum calcium. Calcium, calcitriol and vitamin D supplements are safe during pregnancy. Close monitoring of the mother with a multidisciplinary team is advised for optimal care. If calcium homeostasis is well controlled during pregnancy, most women with hypoparathyroidism have an uncomplicated pregnancy and give birth to healthy babies. European Journal of Endocrinology (2019) 180, R37–R44 Introduction and methodology Hypoparathyroidism is a rare condition and when it hypoparathyroid mothers. Frequent adjustments in the occurs in pregnancy it maybe associated with significant dose of calcium and calcitriol may be required in order maternal and fetal morbidity (1, 2). Physiologic changes to avoid both hypocalcemia and hypercalcemia. Both in the calcium regulating hormones, which occur during these conditions impact fetal parathyroid development pregnancy impact calcium homeostasis and necessitate and may result in maternal and fetal morbidity. We close monitoring of serum calcium during pregnancy in reviewed the literature and provided evidence-based https://eje.bioscientifica.com © 2019 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-18-0541 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 12:47:40PM via free access -18-0541 Review A Khan and others Hypoparathyroidism in 180:2 R38 pregnancy recommendations guiding clinical practice today. levels of 25hydroxyvitamin D levels appear to be stable MEDLINE, EMBASE and CENTRAL databases were during pregnancy despite increased conversion to searched from January 1, 2000 to April 1, 2018 using calcitriol in addition to transfer of 25hydroxyvitamin D the MeSH search terms hypoparathyroidism, pregnancy, to the fetus (11). physiology, complications and management. A total Serum calcitonin rises during pregnancy and may of 1449 articles were found. These were reduced to 123 protect the maternal skeleton from demineralization articles based on abstract and title. We excluded letters during pregnancy (3, 5, 11, 21, 22). Other investigators and editorials and only included English language papers have not observed rises in serum calcitonin during dealing with humans. Case reports and case series were pregnancy (9, 13). The source of the calcitonin appears to also included due to the limited evidence available in the be the thyroid C-cells in addition the breast and placenta literature today. The final review included 65 articles. contribute to rises in serum calcitonin (23, 24). These rises in calcitonin have been observed in women who have previously had a total thyroidectomy (23, 24, 25). Impact of pregnancy on Calcitonin levels may also increase in association with calcium homeostasis the rises in estradiol, estrone and estriol in pregnancy. Rises in calcitonin have also been observed in women During pregnancy serum albumin decreases with the using oral contraceptives and this may be secondary to expansion of intravascular volume. This reduction in the rises in estrogen (11, 26). Postmenopausal women on serum albumin results in a reduction in the measured estrogen supplementation have also demonstrated rises in total albumin-bound calcium. Longitudinal studies serum calcitonin (27). have demonstrated that serum ionized calcium as well PTHrP begins to rise from the third to the thirteenth as calcium corrected for albumin remain in the normal week of gestation and increases by three-fold in comparison reference range (3, 4, 5). Serum phosphorus is unchanged to the baseline pre-pregnancy level by term as noted in during pregnancy (3, 4, 5). Parathyroid hormone (PTH) is longitudinal studies (5, 8, 25, 28, 29) The significant rise suppressed into the low normal reference range and may in PTHrP may upregulate calcitriol and suppress PTH (11). actually decline below the normal reference range in the An important source for PTHrP appears to be the 1st trimester (3, 4, 5, 6, 7, 8, 9, 10). PTH subsequently rises placenta. In a case report of a pregnant woman with into the midnormal reference range by the third trimester severe hypercalcemia and very high levels of PTHrP, as observed in longitudinal studies. PTH is affected by serum calcium normalized following cesarean section and European Journal of Endocrinology maternal dietary calcium intake as well as maternal delivery of the placenta (30). Post cesarean section the vitamin D levels (11). PTHrP levels also became undetectable (30). The breasts Calcitriol rises in the first trimester and increases by appear to be an important source of PTHrP. In a case of two- to three-fold by term as noted in longitudinal studies a pregnant woman with severe hypercalcemia and very (4, 5, 12, 13, 14, 15). This significant rise in calcitriol high levels of PTHrP in the breast tissue, serum calcium increases intestinal calcium absorption and suppresses normalized following bilateral mastectomy in the second PTH (11, 16, 17). The kidney is the main source for the trimester of pregnancy (31, 32). PTHrP also decreased post rise in calcitriol with some contribution from the placenta bilateral mastectomy and become undetectable following and the fetus. Pregnancy is associated with an increase in surgery (31, 32). High levels of estradiol may also increase renal expression of Cyp27b1 (1-alpha hydroxylase) with PTHrP. In vitro studies have demonstrated that estradiol levels of Cyp27b1 being 35-fold higher in the kidneys increases PTHrP mRNA expression in human endometrial than that found in the placenta (18). The kidney therefore cells (33). appears to be the major source of the significant rise in In conclusion, rises in calcitriol during pregnancy serum calcitriol levels. This is also supported by the fact lead to enhanced intestinal calcium absorption, which that anephric women on dialysis do not demonstrate in turn increases renal filtered calcium load and results significant rises in calcitriol during pregnancy 19( ). in increases in urine calcium (34; Fig. 1). The reductions The key stimulators of renal Cyp27b1 during in PTH (secondary to rises in calcitriol and PTHrP) pregnancy are not known and may be PTHrP. It is also also contribute to the hypercalciuria (16, 17, 34). The possible that estradiol and prolactin may be contributing hypercalciuria observed during pregnancy has been to the rise in Cyp27b1. PTHrP is known to be a weak associated with an increased risk of renal stones during stimulator of Cyp27b1 in comparison to PTH (20). The pregnancy. The rises in calcitriol and PTHrP seen in https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 09/27/2021 12:47:40PM via free access Review A Khan and others Hypoparathyroidism in 180:2 R39 pregnancy What is the impact of maternal Breast Placenta hypoparathyroidism on the developing fetus? The endochondral skeleton of the embryo gradually Bone PTHrP resorption mineralizes with approximately 80% of the mineral accruing in the third trimester (42, 43). The placenta is essential for the delivery of essential minerals namely calcium, phosphate and magnesium to the fetus from the Increases maternal circulation. Even in the presence of inadequate intestinal maternal serum calcium the placenta will extract calcium 25 (OH) D 1,25 (OH) D calcium + to meet the fetal requirements at the expense of the phosphate absorption maternal skeleton