Changes in Treatment Needs of Hypoparathyroidism During Pregnancy and Lactation

A Case Series

Etki A. R. Hartogsohn; Aliya A. Khan; Line Underbjerg Kjærsulf; Tanja Sikjaer; Sharjil Hussain; Lars Rejnmark

Disclosures

Clin Endocrinol. 2020;93(3):261-268. 

In This Article

Abstract and Introduction

Abstract

Objective: As only sparse data are available, we aimed to investigate whether needs for activated vitamin D and calcium supplements change in women with hypoparathyroidism during pregnancy and lactation and risk of pregnancy-related complications.

Design: Retrospective review of medical records.

Patients: Twelve Danish and Canadian patients with chronic hypoparathyroidism who completed 17 pregnancies.

Measurements: Data were extracted on plasma levels of ionized calcium (P-Ca2+) and doses of active vitamin D and calcium supplements during pregnancy (N = 14) and breastfeeding (N = 10). Data on pregnancy complications were available from all 17 pregnancies.

Results: Although average doses of active vitamin D (P = .91) and calcium supplements (P = .43) did not change during pregnancies, a more than 20% increase or decrease in dose of active vitamin D was needed in more than half of the pregnancies in order to maintain normocalcemia. Five women (36%) developed hypercalcaemia by the end of pregnancy or start of lactation. Median levels of P-Ca2+ increased from 1.20 mmol/L in third trimester to 1.32 mmol/L in the post-partum period (P < .03). Accordingly, the average dose of active vitamin D was significantly reduced (P = .01) during lactation compared to 3rd trimester. One woman developed severe pre-eclampsia (6%). Further four pregnancies (24%) were complicated by polyhydramnios, dystocia and/or perinatal hypoxia. Ten pregnancies required caesarean delivery (59%) with four (24%) being performed as an emergency.

Conclusion: In chronic hypoparathyroidism, close medical monitoring of the mother with frequent adjustments in the dose of calcium and active vitamin D is required during pregnancy and lactation in order to maintain normocalcemia. Patients should be offered close obstetric care to handle potential perinatal complications. We recommend evaluating the neonate immediately after birth and notifying the paediatrician of the risks of hypocalcaemia as well as hypercalcaemia in the neonate.

Introduction

Hypoparathyroidism is a rare endocrine disease where an inadequate production of parathyroid hormone (PTH) leads to hypocalcaemia and hyperphosphatemia. The most common cause of hypoparathyroidism is anterior neck surgery which comprises 75% of the cases whereas nonsurgical causes are responsible for the remaining 25%.[1] The majority of post-surgical cases of hypoparathyroidism are transient (<6 months) while a smaller proportion of patients develop a chronic disease (≥6 months). The estimated prevalence of hypoparathyroidism in Denmark is approximately 24 per 100.000 individuals where the vast majority is due to surgery.[2,3]

The low plasma calcium levels can result in a number of symptoms ranging from mild to life-threatening depending on the severity of the hypocalcaemia. Especially neuromuscular symptoms such as muscle cramps, paraesthesia and seizures are characteristic for the condition, but also more severe complications may develop such as heart failure.[4] In order to avoid this, appropriate medical treatment and close monitoring are fundamental.

Standard treatment for hypoparathyroidism is activated vitamin D analogues such as alfacalcidol (1α-hydroxyvitamin D) or calcitriol (1,25(OH)2D) together with calcium supplements. Most oral calcium supplements contain vitamin D3 (cholecalciferol) which is the inactive form of vitamin D. In addition, it is recommended to follow the patients by regularly assessing symptoms of hypercalcaemia or hypocalcaemia as well as monitoring plasma levels of ionized calcium (P-Ca2+), phosphate, magnesium and creatinine.[2,5]

PTH is the main hormone responsible for regulating serum calcium. This is achieved by stimulating bone resorption and enhancing renal calcium reabsorption which leads to an increased level of P-Ca2+. Furthermore, PTH stimulates renal hydroxylation of 25(OH)D to 1,25(OH)2D, and this results in an increased intestinal absorption of calcium and phosphate.[6–8]

During pregnancy, it is particularly important to maintain calcium homeostasis as this mineral is vital for the mineralization of the foetal skeleton. Mineral accrual increases during pregnancy and accelerates during the third trimester.[7] Under normal circumstances, this increased demand for calcium is partly met via increases in the production of 1,25(OH)2D in the maternal kidneys. This results in enhanced intestinal absorption of calcium as well as increased mobilization of calcium from the maternal skeleton. Pregnancy is associated with an increase in the production of PTHrP from the breast and placenta, resulting in an increased formation of 1,25(OH)2D and suppression of endogenous PTH (Figure 1). During lactation, PTHrP increases further and is produced by the lactating breast.[2,5,7]

Figure 1.

Calcium homeostasis during pregnancy. Reproduced with permission from Khan et al EJE 2019.6

In the presence of hypoparathyroidism, patients may experience improvements in their symptoms due to enhanced production of both PTHrP and 1,25(OH)2D; however, these increases may not be seen universally, and patients need to be closely monitored. If the mother is hypocalcaemic, the foetal parathyroid glands may become hyperplastic, and if the mother is hypercalcaemic, the foetal parathyroid tissue may be suppressed. The neonate requires close follow-up immediately post-partum.[5]

Insufficiently managed maternal hypoparathyroidism can cause skeletal deformities, neonatal respiratory distress, preterm labour, miscarriage and stillbirth.[9–11] Additionally, maternal hypocalcaemia can result in compensatory hyperparathyroidism in the newborn while maternal hypercalcaemia can cause compensatory neonatal hypoparathyroidism.[12–14] Thus, closely following of pregnant women with hypoparathyroidism both during their pregnancy and during lactation is critical in order to reduce the risk of calcium imbalance.

We have scant knowledge about the needs for changes in medical treatment of pregnant and lactating women suffering from hypoparathyroidism. The major part of previous studies are single case reports while only a few studies include more than one case.[10,15] Most recently, Hatswell et al[16] described the topic by investigating the pregnancies of six women with hypoparathyroidism.

In this study, we aimed to investigate changes in P-Ca2+ levels together with the changes in medical treatment in women with hypoparathyroidism during their pregnancy and lactation period, as well as pregnancy complications.

Subjects and Methods

Women who had been pregnant after being diagnosed with chronic hypoparathyroidism were identified by medical records at Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark and Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

All participants gave written and verbal consent, and the study was performed in accordance with the declaration of Helsinki. The study was approved by the Central Denmark Region Committee on Biomedical Research (#M-20110074), the Danish Data Protection Agency (#2011-41-5955) and the Central Region of Denmark (#1-16-02-101-11). In Canada, the study was performed as a part of the ongoing Canadian National Hypoparathyroidism Registry Study approved by McMaster University, Ethics Review Board in Hamilton, ON, Canada.

Measurements

In Denmark, patients were asked to consent to an interview and filling in a questionnaire focusing on the presence of symptoms before, during and after the pregnancy and during lactation. In addition, questions concerning complications during pregnancies and labour were included. These answers were compared to the findings in the medical records to optimize the quality of the information. The questionnaire was not used in Canada; however, complications during pregnancy were obtained by patient interviews and from medical records.

For both Danish and Canadian patients, medical records were reviewed with specific focus on P-Ca2+ levels, changes in doses of orally administered calcium, alfacalcidol or calcitriol according to stages (trimesters) of pregnancy and breastfeeding. Other medicaments were not evaluated further in this study even though the majority of the patients are also treated with thyroid hormone. P-Ca2+ levels were analysed locally with standard equipment at hospital laboratories using ion-selective electrodes and adjusted to a pH of 7.4.

Statistics

Intake of calcium from supplements are given as mg/day of elementary calcium. As calcitriol is approximately twice as potent as alfacalcidol, doses of calcitriol were converted to equivalent alfacalcidol doses my multiplying by two.[17] Accordingly, we report doses of active vitamin D in terms of alfacalcidol equivalent. Average doses of calcium supplements, active vitamin D (alfacalcidol equivalent) as well as average P-Ca2+ levels were calculated per trimester and for women who were breastfeeding shortly after giving births as well as at follow-up during breastfeeding.

Changes in dosages and plasma levels were analysed by repeated measures of variance and by paired sample t tests or a nonparametric equivalent (Wilcoxon's signed rank test), according to the distribution of data. A P-value <.05 was considered significant. All analyses were performed using IBM SPSS Statistical version 26 (IBM, New York, USA).

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