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Background:
Review

Hypoparathyroidism in Pregnancy and Lactation: Current Approach to Diagnosis and Management

by
Dalal S. Ali
,
Karel Dandurand
and
Aliya A. Khan
*
Division of Endocrinology and Metabolism, McMaster University, Hamilton, ON L8S 4L8, Canada
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2021, 10(7), 1378; https://doi.org/10.3390/jcm10071378
Submission received: 26 February 2021 / Revised: 18 March 2021 / Accepted: 22 March 2021 / Published: 29 March 2021
(This article belongs to the Special Issue Primary Hyperparathyroidism and Hypoparathyroidism: Diagnosis and Management)
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Abstract

:
Background: Hypoparathyroidism is an uncommon endocrine disorder. During pregnancy, multiple changes occur in the calcium-regulating hormones, which may affect the requirements of calcium and active vitamin D during pregnancy in patients with hypoparathyroidism. Close monitoring of serum calcium during pregnancy and lactation is ideal in order to optimize maternal and fetal outcomes. In this review, we describe calcium homeostasis during pregnancy in euparathyroid individuals and also review the diagnosis and management of hypoparathyroidism during pregnancy and lactation. Methods: We searched the MEDLINE, CINAHL, EMBASE, and Google scholar databases from 1 January 1990 to 31 December 2020. Case reports, case series, book chapters, and clinical guidelines were included in this review. Conclusions: During pregnancy, rises in 1,25-dihydroxyvitamin D (1,25-(OH)2-D3) and PTH-related peptide result in suppression of PTH and enhanced calcium absorption from the bowel. In individuals with hypoparathyroidism, the requirements for calcium and active vitamin D may decrease. Close monitoring of serum calcium is advised in women with hypoparathyroidism with adjustment of the doses of calcium and active vitamin D to ensure that serum calcium is maintained in the low-normal to mid-normal reference range. Hyper- and hypocalcemia should be avoided in order to reduce the maternal and fetal complications of hypoparathyroidism during pregnancy and lactation. Standard of care therapy consisting of elemental calcium, active vitamin D, and vitamin D is safe during pregnancy.

1. Introduction

Hypoparathyroidism (HypoPT) is a rare endocrine disorder. It is characterized by low serum calcium in the presence of a low or inappropriately normal parathyroid hormone (PTH) [1]. Phosphorus may be normal or elevated [1,2,3]. The majority of cases are secondary to neck surgery with accidental removal or injury to the parathyroid glands (75% of cases) [4,5]. The remaining 25% of cases are caused by autoimmune disorders, genetic disorders, infiltrative diseases, radiation, mineral deposition, magnesium abnormalities, and other conditions (as described in Chapter 5.1) [6,7,8]. HypoPT in pregnancy is uncommon and may pose a diagnostic challenge in early gestation due to the physiological changes in calcium and phosphorus homeostasis during pregnancy [9,10]. If not managed optimally, HypoPT may cause maternal and fetal morbidity in the form of miscarriage [11], preterm delivery, fetal skeletal demineralization [12], in utero fractures [13], fetal respiratory distress, and fetal death (as described in Chapter 6) [14]. The current literature evaluating HypoPT during pregnancy is limited to case reports and case series [9,14,15,16,17,18]. In this review, we describe calcium homeostasis during euparathyroid pregnancy and present evidence-based practical guidance on the diagnosis and management of HypoPT during pregnancy and lactation.

2. Materials and Methods

We carried out a literature search on the MEDLINE, CINAHL, EMBASE, and Google scholar databases from 1 January 1990 to 31 December 2020 using the following keywords: hypoparathyroidism, pregnancy, calcium homeostasis, lactation, PTH/PTHrP, active vitamin D and calcitriol. We included review articles, clinical guidelines, book chapters, case reports, and case series written in English language. Letters to the editor were excluded from the review.

3. Calcium and Mineral Homeostasis in Euparathyroid Pregnancy and Lactation

3.1. Calcium and Phosphorus

In this section, we describe the physiology of calcium regulation in pregnancy and lactation.

3.1.1. Pregnancy

Data from longitudinal and cross-sectional studies show that serum ionized calcium and calcium corrected for albumin remain unchanged during pregnancy. As albumin levels decline due to volume expansion, it is therefore essential to evaluate calcium corrected for albumin or ionized calcium for the assessment of hyper- or hypocalcemia [19,20]. Serum phosphorus and magnesium both remain unchanged during pregnancy (Figure 1) [19,20,21].

3.1.2. Lactation

Serum ionized calcium or calcium corrected for albumin remain within the normal range, although may be slightly increased within the normal range, as observed in longitudinal studies [20]. Phosphorus may be increased, possibly in association with enhanced bone remodeling, favoring bone resorption with each remodeling cycle. During lactation, renal conservation of phosphorus appears to increase, despite the phosphaturic effect of PTH-related peptide (PTHrP) [22].

3.2. Parathyroid Hormone

3.2.1. Pregnancy

Longitudinal studies from North America, Asia, and Europe have shown that PTH is suppressed into the lower end or slightly below the normal reference range in the first trimester [21,23,24,25,26]. PTH subsequently rises to the mid-normal range in the third trimester (Figure 1) [20].

3.2.2. Lactation

PTHrP produced by the lactating breast suppresses endogenous PTH release; this may not happen in the presence of vitamin D inadequacy, as observed in longitudinal studies. Thus, in the presence of insufficient dietary calcium and vitamin D intake and absorption, PTH levels may not suppress [22]. Ethnic diversity may also affect PTH levels. In a prospective cohort study, African-Americans were noted to have higher levels of PTH during lactation when compared to Caucasians [27].

3.3. Parathyroid-Related Peptide (PTHrP)

3.3.1. Pregnancy

PTHrP rises significantly and peaks in the third trimester (Figure 1). This rise has been observed in a number of longitudinal studies [21,28,29], as well as cross-sectional studies [30]. The production of PTHrP is regulated mainly by the placenta and breast (Figure 2) [19,20].

3.3.2. Lactation

PTHrP produced by the lactating breast rises on suckling and reaches its maximum level at six weeks postpartum [19,31]. PTHrP levels rise with lactation, together with a fall in estradiol following delivery. These two hormonal changes influence calcium and phosphorus resorption from the skeleton to enrich the breast milk with minerals. Figure 3, by Kovacs et al., illustrates the breast–brain–bone circuit, which controls the process of lactation [22].

3.4. 1,25-dihydroxyvitamin D (1,25-(OH)2-D3)

3.4.1. Pregnancy

The level of the 1,25-(OH)2-D3 rises by two- to three-folds in the first trimester (Figure 1) [19,32,33,34] and plays a major role in enhancing calcium absorption from the maternal gut. Evidence suggests that the maternal kidneys are the source of the 1,25-(OH)2-D3 rise during pregnancy, as well as, to a lesser extent, the placenta [19,32,35]. The expression of Cyp27b1, also known as 1-alpha hydroxylase, is increased by 35-fold in the maternal kidneys in comparison to the placenta and is possibly influenced by PTHrP, estradiol, prolactin, or placental lactogen [19,22,35,36].

3.4.2. Lactation

The level of the 1,25-(OH)2-D3 falls postpartum and becomes normal during lactation. This is in association with the significant decline in estradiol levels and placental lactogen, which are believed to be the main stimulators for the 1,25-(OH)2-D3 rise during pregnancy with enhanced expression of Cyp27b1 in the maternal kidneys [22,36].

3.5. Calcitonin

3.5.1. Pregnancy

Calcitonin is believed to rise during pregnancy [20,37,38]. Calcitonin is a polypeptide hormone that is normally synthesized by parafollicular or C cells of the thyroid gland [39]; however, in pregnancy it can be produced by the breast tissue, as well as the placenta [20]. Rises in the calcitonin level have been observed in pregnant women post-thyroidectomy, indicating that an adaptive mechanism during pregnancy is responsible for its production and release [29,40]. Calcitonin is believed to be important in protecting the maternal skeleton from increased bone resorption during pregnancy [22].

3.5.2. Lactation

Calcitonin levels may rise in some women and may remain normal in others [22].

4. Maternal and Fetal Calcium Requirements during Euparathyroid Pregnancy and Lactation

Calcium requirements may decrease in late pregnancy, postpartum, and during lactation [41,42]. It is estimated that approximately 30 g of calcium, 20 g of phosphorus, and 0.8 g of magnesium are required by the fetus by term, with the highest rate of mineral transfer occurring in the third trimester [19,20,36,43,44]. The main sources of calcium supply to the fetus are the maternal skeleton and increased calcium absorption from the maternal gut.
The average maternal calcium deficit accrued during pregnancy and lactation is estimated to be approximately 6% of the total bone mineral content [23,45,46]. Mothers who breastfeed exclusively lose up to 10% of their bone mass [47]. Declines in bone mineral density (BMD) by 5%–10% after three to six months of lactation have been observed [20]. Data from high-resolution peripheral quantitated tomography (HR-pQCT) studies have demonstrated declines in trabecular bone thickness and cortical thickness and volume in lactating women [48,49]. Longitudinal studies involving DXA measurement in lactating women have shown recovery in BMD at 12 months postweaning [50].

5. Diagnosis of HypoPT in Pregnancy

Diagnosis of HypoPT is made in the presence of low calcium corrected for albumin and low or inappropriately normal PTH. During pregnancy, due to rises in PTHrP and 1,25-(OH)2-D3, the serum PTH may be even lower in an individual with HypoPT. HypoPT can be caused by a number of factors, with the commonest clinical scenario being pregnancy in a patient with postsurgical HypoPT following neck surgery; other causes are summarized in (Table 1). Careful evaluation is required to clarify the etiology as the management is affected by the underlying diagnosis, particularly in pregnancy.

5.1. History

A comprehensive history, including symptoms of hypocalcemia, is advised, namely, numbness or tingling in the face, hands, and feet, muscle cramping, confusion, and brain fog should be elicited. Severe symptoms of hypocalcemia may include bronchospasm, tetany, seizures, and laryngospasm, as well as congestive heart failure and arrhythmia [51]. Prior history of neck surgery and symptoms of Autoimmune Polyendocrine Syndrome type 1 (APS1), which include a history of vaginal or oral candidiasis, hypogonadism, adrenal insufficiency, type 1 diabetes, alopecia, hepatitis, and B12 deficiency, should be excluded. The presence of syndromic causes of HypoPT should be evaluated with a detailed history, including history of hearing impairment, renal impairment, or previous cardiac or oral surgeries (see Table 1 and Table 2). Other rare causes include prior exposure to ionized radiation, as well as use of certain chemotherapeutic agents such as L-asparaginase [8].

5.2. Physical Examination

The neck should be inspected for prior surgical incision scars. Additionally, an evaluation should be made for features of hypocalcemia and neuromuscular irritability by assessing the Chvostek’s sign by tapping the cheek 2 cm anterior to the earlobe (over the path of the facial nerve) and observing for twitching of the ipsilateral upper lip (sensitivity 25.6% and specificity 96.3%, estimated from a large cross-sectional study) [58]. Trousseau’s sign can be seen in 94% [59] of patients with hypocalcemia and is elicited by inflating the sphygmomanometer above the systolic blood pressure for a total of 3 min; carpopedal spasm indicates a positive test.
An evaluation should be made for adrenal insufficiency by checking for postural hypotension. Additionally, other clinical features of APS1 should be excluded, such as oral candidiasis, evidence of vitiligo, or hyperpigmentation. Features of syndromic causes of HypoPT should also be excluded, such as DiGeorge syndrome, Barakat syndrome, and pseudohypoparathyroidism (see Table 2) [51,53,54].

5.3. Laboratory Investigations

Laboratory Investigations should include measurement for serum ionized calcium, calcium corrected for albumin (Corrected calcium (mmol/L) = measured total calcium + (40-serum albumin (g/L)) × 0.02. Formula (mg/dL): Corrected calcium = measured total calcium (mg/dL) + 0.8 (4.0-serum albumin (g/dL)), intact PTH (iPTH), phosphorus, magnesium, creatinine, estimated glomerular filtration rate (eGFR), 25-hydroxyvitamin D (25-(OH)2-D3), 1,25-(OH)2-D3, 24 h urine for calcium and creatinine, TSH, free T4, free T3, full blood count, copper, ceruloplasmin, iron, total iron binding capacity (TIBC), and ferritin (Figure 4). The biochemical features of APS1 should be excluded and fasting cortisol, ACTH, renin, and fasting plasma glucose should be evaluated [51,60]. During pregnancy, total and free cortisol levels, as well as cortisol binding globulins (CBG), are elevated. The hepatic CBG levels rise in response to elevated estradiol levels during pregnancy, resulting in a transient decline in free cortisol levels and a rise in ACTH [61]. ACTH is also produced from the placenta during pregnancy [61,62,63]. Maternal gonadotrophins decrease during pregnancy and become undetectable in the second trimester in response to elevated sex steroids (estradiol and progesterone) and inhibin [64].

5.4. Assessment of Long-Term Complications

Assessment of long-term complications should be conducted for nephrocalcinosis and nephrolithiasis by renal ultrasound. Brain imaging for basal ganglia calcification can be completed post-partum [1].

6. Impact of HypoPT on Mother and Fetus during Pregnancy

In HypoPT, intestinal calcium absorption is impaired due to reduced levels of 1,25-(OH)2-D3, as conversion of 25-(OH)2-D3 to 1,25-(OH)2-D3 is decreased in the absence of PTH. In pregnancy, however, 1,25-(OH)2-D3 rises, enhancing calcium absorption from the gut irrespective of PTH activity [21,65].
This adaptive mechanism may result in improvements in the serum calcium levels in HypoPT pregnant women.
It is critically important to avoid fluctuation in maternal serum calcium levels during pregnancy, as this may cause potential adverse events in the mother and fetus (Table 3). Fetal hypocalcemia can develop in the presence of maternal hypocalcemia and stimulates the fetal parathyroid glands, causing compensatory hyperparathyroidism and subsequent demineralization of the fetal skeleton [12,66,67,68] with intrauterine rib and limb fractures [12,13,14,69]. Low birth weight and intrauterine fetal death have also been reported in women with hypocalcemia during pregnancy. Maternal hypercalcemia can lead to suppression of the fetal parathyroid glands, resulting in fetal HypoPT. Neonatal hypocalcemia as a result of neonatal HypoPT may be associated with neonatal seizures and serum calcium should be checked in infants following birth [19,70]. Unexplained polyhydramnios has been reported in a case series in association with maternal hypercalcemia [71].

7. Clinical Management of HypoPT in Pregnancy

The impact of pregnancy on the calcium and active vitamin D required during pregnancy in women with HypoPT was recently evaluated in a case series of 12 pregnant women with HypoPT from Denmark and Canada [18]. Approximately 50% of the pregnancies included in the study required an adjustment in the dose of the active vitamin D with increases in dose required more frequently than decreases in dose. The adjustments were approximately 20% between the second and third trimesters [18]. The elemental calcium requirements were unchanged, and the serum calcium level was maintained at the lower end of the normal reference range. Other case reports, however, have reported increased elemental calcium requirements during pregnancy, especially in the first trimester [20,21,31,76]. In another case report by Sweeney et al. [41], active vitamin D requirements were reduced in the third trimester and stopped. The patient remained only on elemental calcium (1200 mg) during the third trimester.
HypoPT is a rare endocrine disorder, and recently, guidance regarding its management was published by Khan et al. [19]. Evidence has been derived from case reports and case series. The standard of care therapy for HypoPT includes calcium supplements and active vitamin D (alfacalcidiol or calcitriol or other vitamin D analogues), as well as vitamin D. It is recommended that serum ionized calcium or calcium corrected for albumin be evaluated every three to four weeks, as frequent dose adjustments may be needed according to the individual’s response [19,50]. The goal of therapy is to achieve a serum ionized calcium level or calcium corrected for albumin in the lower end of the normal reference range [19]. Only one case reported the use of rhPTH (1–34) continuous infusion via pump during pregnancy in a patient with severe hypocalcemia and recurrent hospitalizations with tetany and seizures. This patient delivered at term with no maternal or fetal complications [77]. The use of PTH in pregnancy is not approved because of lack of safety data.

8. Clinical Management of HypoPT during Lactation

Close monitoring of serum calcium is recommended during lactation. Postpartum hypercalcemia has been reported in lactating women with HypoPT receiving standard of care therapy (elemental calcium and active vitamin D) [78,79,80]. In one case report of a patient with HypoPT, it was possible to stop calcium and active vitamin D during lactation for 72 weeks postpartum. This patient had significantly elevated PTHrP levels from the lactating breast and was able to stop all drug therapy during the entire lactation period [78]. Postpartum women with HypoPT should be monitored, and serum calcium should be maintained in the mid- to low-normal range. Abrupt cessation of breastfeeding can be associated with hypocalcemia [17].

9. Conclusions

In conclusion, HypoPT requires close monitoring of serum calcium (ionized or corrected) during pregnancy and lactation, maintaining the serum calcium in the mid- to low-normal reference range in order to optimize maternal and fetal outcomes. Serum phosphorus, magnesium, and 25 (OH) D should be maintained in the normal reference range. Thiazide diuretics and PTH, both (1–34) and (1–84), should be stopped during pregnancy. Elemental calcium and active vitamin D, as well as vitamin D supplements, are safe during pregnancy. We recommend the measurement of serum ionized calcium or calcium corrected for albumin every three to four weeks during pregnancy and within one week following dose adjustment, as the half-life of calcitriol is 4–6 h and steady state is reached in five days [19]. We further recommend measuring calcium level within one-week post-partum in breastfeeding mothers as hypercalcemia may potentially result, requiring adjustment to calcium and active vitamin D supplements.
To date, our recommendations have been based on low-quality evidence limited to case reports. The changes in calcium-regulating hormones may vary amongst individual women requiring close monitoring of serum calcium.
Patient education regarding symptoms of hypo- and hypercalcemia should be emphasized, and patients are advised to go for immediate blood testing should symptoms occur. An individualized approach is advised in caring for pregnant women with HypoPT. A multidisciplinary team approach involves an endocrinologist, obstetrician, pediatrician, and dietitian, as well as specialized nursing staff, is essential for the achievement of optimal maternal and fetal outcomes.

Author Contributions

D.S.A. completed the literature search and manuscript writing, K.D. completed the literature search and review; A.A.K. completed the writing and editing and is the corresponding author. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable. No new data were created or analyzed in this study.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Khan, A.A.; Koch, C.A.; Van Uum, S.; Baillargeon, J.P.; Bollerslev, J.; Brandi, M.L.; Marcocci, C.; Rejnmark, L.; Rizzoli, R.; Shrayyef, M.Z.; et al. Standards of care for hypoparathyroidism in adults: A Canadian and International Consensus. Eur. J. Endocrinol. 2019, 180, P1–P22. [Google Scholar] [CrossRef] [PubMed]
  2. Cusano, N.E.; Rubin, M.R.; Bilezikian, J.P. Parathyroid hormone therapy for hypoparathyroidism. Best Pr. Res. Clin. Endocrinol. Metab. 2015, 29, 47–55. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Rejnmark, L.; Underbjerg, L.; Sikjaer, T. Therapy of Hypoparathyroidism by Replacement with Parathyroid Hormone. Science 2014, 2014, 1–8. [Google Scholar] [CrossRef] [Green Version]
  4. Puzziello, A.; Rosato, L.; Innaro, N.; Orlando, G.; Avenia, N.; Perigli, G.; Calò, P.G.; De Palma, M. Hypocalcemia following thyroid surgery: Incidence and risk factors. A longitudinal multicenter study comprising 2,631 patients. Endocrine 2014, 47, 537–542. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Cocchiara, G.; Cajozzo, M.; Amato, G.; Mularo, A.; Agrusa, A.; Romano, G. Terminal ligature of inferior thyroid artery branches during total thyroidectomy for multinodular goiter is associated with higher postoperative calcium and PTH levels. J. Visc. Surg. 2010, 147, e329–e332. [Google Scholar] [CrossRef] [PubMed]
  6. Betterle, C.; Garelli, S.; Presotto, F. Diagnosis and classification of autoimmune parathyroid disease. Autoimmun. Rev. 2014, 13, 417–422. [Google Scholar] [CrossRef] [PubMed]
  7. Thakker, R.; Thakker, R. Genetic developments in Hypoparathyroidism. Lancet 2001, 357, 974–976. [Google Scholar] [CrossRef]
  8. Hakami, Y.; Khan, A. Hypoparathyroidism. Front. Horm. Res. 2019, 51, 109–126. [Google Scholar] [PubMed]
  9. Krysiak, R.; Kobielusz-Gembala, I.; Okopień, B. Hypoparathyroidism in pregnancy. Gynecol. Endocrinol. 2010, 27, 529–532. [Google Scholar] [CrossRef] [PubMed]
  10. Kovacs, C.S.; Fuleihan, G.E.-H. Calcium and Bone Disorders During Pregnancy and Lactation. Endocrinol. Metab. Clin. N. Am. 2006, 35, 21–51. [Google Scholar] [CrossRef]
  11. Mitchell, D.M.; Jüppner, H. Regulation of calcium homeostasis and bone metabolism in the fetus and neonate. Curr. Opin. Endocrinol. Diabetes Obes. 2010, 17, 25–30. [Google Scholar] [CrossRef] [PubMed]
  12. Aceto, T.; Batt, R.E.; Bruck, E.; Schultz, R.B.; Perez, Y.R.; Jablonski, E. Intrauterine Hyperparathyroidism: A Complication of Untreated Maternal Hypoparathyroidism1. J. Clin. Endocrinol. Metab. 1966, 26, 487–492. [Google Scholar] [CrossRef] [PubMed]
  13. Alikasifoglu, A.; Gonc, E.N.; Yalcin, E.; Dogru, D.; Yordam, N. Neonatal Hyperparathyroidism Due to Maternal Hypoparathyroidism and Vitamin D Deficiency: A Cause of Multiple Bone Fractures. Clin. Pediatr. 2005, 44, 267–269. [Google Scholar] [CrossRef] [PubMed]
  14. Demirel, N.; Aydin, M.; Zenciroglu, A.; Okumus, N.; Çetinkaya, S.; Yıldız, Y.T.; Ipek, M.S.; Yildiz, Y.T. Hyperparathyroidism secondary to maternal hypoparathyroidism and vitamin D deficiency: An uncommon cause of neonatal respiratory distress. Ann. Trop. Paediatr. 2009, 29, 149–154. [Google Scholar] [CrossRef] [PubMed]
  15. Richa, C.G.; Issa, A.I.; Echtay, A.S.; El Rawas, M.S. Idiopathic Hypoparathyroidism and Severe Hypocalcemia in Pregnancy. Case Rep. Endocrinol. 2018, 2018, 1–4. [Google Scholar] [CrossRef] [PubMed]
  16. Dixon, J.; Miller, S. Successful pregnancies and reduced treatment requirement while breast feeding in a patient with congenital hypoparathyroidism due to homozygous c.68C>A null parathyroid hormone gene mutation. BMJ Case Rep. 2018, 2018, 223811. [Google Scholar] [CrossRef] [PubMed]
  17. Hatswell, B.; Allan, C.; Teng, J.; Wong, P.; Ebeling, P.; Wallace, E.; Fuller, P.; Milat, F. Management of hypoparathyroidism in pregnancy and lactation—A report of 10 cases. Bone Rep. 2015, 3, 15–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Hartogsohn, E.A.R.; Khan, A.A.; Kjærsulf, L.U.; Sikjaer, T.; Hussain, S.; Rejnmark, L. Changes in treatment needs of hypoparathyroidism during pregnancy and lactation: A case series. Clin. Endocrinol. 2020, 93, 261–268. [Google Scholar] [CrossRef]
  19. Khan, A.A.; Clarke, B.; Rejnmark, L.; Brandi, M.L. Management of endocrine disease: Hypoparathyroidism in pregnancy: Review and evidence-based recommendations for management. Eur. J. Endocrinol. 2019, 180, R37–R44. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Kovacs, C.S. Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery. Physiol. Rev. 2016, 96, 449–547. [Google Scholar] [CrossRef] [Green Version]
  21. Ardawi, M.S.; Nasrat, H.A.; Ba’Aqueel, H.S. Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: A longitudinal study. Eur. J. Endocrinol. 1997, 137, 402–409. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Kovacs, C.S. Physiology of Calcium, Phosphorus, and Bone Metabolism During Pregnancy, Lactation, and Postweaning; Elsevier: Amsterdam, The Netherlands, 2020; pp. 61–73. [Google Scholar]
  23. Cross, N.A.; Hillman, L.S.; Allen, S.H.; Krause, G.F.; Vieira, N.E. Calcium homeostasis and bone metabolism during pregnancy, lactation, and postweaning: A longitudinal study. Am. J. Clin. Nutr. 1995, 61, 514–523. [Google Scholar] [CrossRef] [PubMed]
  24. Black, A.J.; Topping, J.; Durham, B.; Farquharson, R.G.; Fraser, W.D. A Detailed Assessment of Alterations in Bone Turnover, Calcium Homeostasis, and Bone Density in Normal Pregnancy. J. Bone Miner. Res. 2010, 15, 557–563. [Google Scholar] [CrossRef] [PubMed]
  25. Møller, U.K.; Streym, S.; Mosekilde, L.; Heickendorff, L.; Flyvbjerg, A.; Frystyk, J.; Jensen, L.T.; Rejnmark, L. Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: A controlled cohort study. Osteoporos. Int. 2013, 24, 1307–1320. [Google Scholar] [CrossRef] [PubMed]
  26. Ritchie, L.D.; Fung, E.B.; Halloran, B.P.; Turnlund, J.R.; Van Loan, M.D.; Cann, C.E.; King, J.C. A longitudinal study of calcium homeostasis during human pregnancy and lactation and after resumption of menses. Am. J. Clin. Nutr. 1998, 67, 693–701. [Google Scholar] [CrossRef] [Green Version]
  27. Carneiro, R.M.; Prebehalla, L.; Tedesco, M.B.; Sereika, S.M.; Gundberg, C.M.; Stewart, A.F.; Horwitz, M.J. Evaluation of Markers of Bone Turnover During Lactation in African-Americans: A Comparison With Caucasian Lactation. J. Clin. Endocrinol. Metab. 2013, 98, 523–532. [Google Scholar] [CrossRef] [PubMed]
  28. Bertelloni, S.; Baroncelli, G.I.; Pelletti, A.; Battini, R.; Saggese, G. Parathyroid hormone-related protein in healthy pregnant women. Calcif. Tissue Int. 1994, 54, 195–197. [Google Scholar] [CrossRef] [PubMed]
  29. Yadav, S.; Yadav, Y.S.; Goel, M.M.; Singh, U.; Natu, S.M.; Negi, M.P.S. Calcitonin gene- and parathyroid hormone-related peptides in normotensive and preeclamptic pregnancies: A nested case–control study. Arch. Gynecol. Obstet. 2014, 290, 897–903. [Google Scholar] [CrossRef] [PubMed]
  30. Glerean, M.; Furci, A.; Galich, A.M.; Fama, B.; Plantalech, L. Bone and mineral metabolism in primiparous women and its relationship with breastfeeding: A longitudinal study. Medicina 2010, 70, 227–232. [Google Scholar] [PubMed]
  31. Al Nozha, O.M.; Malakzadeh-Shirvani, P. Calcium homeostasis in a patient with hypoparathyroidism during pregnancy, lactation and menstruation. J. Taibah Univ. Med. Sci. 2013, 8, 50–53. [Google Scholar] [CrossRef] [Green Version]
  32. Alalawi, Y.; M’Hiri, I.; Alrob, H.A.; Khan, A. Hypoparathyroidism in Pregnancy, in Hypoparathyroidism: A Clinical Casebook; Cusano, N.E., Ed.; Springer International Publishing: Cham, Switzerland, 2020; pp. 143–153. [Google Scholar]
  33. Seki, K.; Makimura, N.; Mitsui, C.; Hirata, J.; Nagata, I. Calcium-regulating hormones and osteocalcin levels during pregnancy: A longitudinal study. Am. J. Obstet. Gynecol. 1991, 164, 1248–1252. [Google Scholar] [CrossRef]
  34. Seely, E.W.; Brown, E.M.; DeMaggio, D.M.; Weldon, D.K.; Graves, S.W. A prospective study of calciotropic hormones in pregnancy and post partum: Reciprocal changes in serum intact parathyroid hormone and 1,25-dihydroxyvitamin D. Am. J. Obstet. Gynecol. 1997, 176, 214–217. [Google Scholar] [CrossRef]
  35. Kirby, B.J.; Ma, Y.; Martin, H.M.; Favaro, K.L.B.; Karaplis, A.C.; Kovacs, C.S. Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone. J. Bone Miner. Res. 2013, 28, 1987–2000. [Google Scholar] [CrossRef] [PubMed]
  36. Hsu, S.C.; Levine, M.A. Perinatal calcium metabolism: Physiology and pathophysiology. Semin. Neonatol. 2004, 9, 23–36. [Google Scholar] [CrossRef]
  37. Silva, O.L.; Titus-Dillon, P.; Becker, K.L.; Snider, R.H.; Moore, C.F. Increased Serum Calcitonin in Pregnancy. J. Natl. Med. Assoc. 1981, 73, 649–652. [Google Scholar] [PubMed]
  38. Stevenson, J.; Hillyard, C.; MacIntyre, I.; Cooper, H.; Whitehead, M. A physiological role for calcitonin: Protection of the maternal skeleton. Lancet 1979, 314, 769–770. [Google Scholar] [CrossRef]
  39. DeLellis, R.A. Pathology and genetics of thyroid carcinoma. J. Surg. Oncol. 2006, 94, 662–669. [Google Scholar] [CrossRef] [PubMed]
  40. Bucht, E.; Telenius-Berg, M.; Lundell, G.; Sjöberg, H.-E. Immunoextracted calcitonin in milk and plasma from totally thyroidectomized women. Evidence of monomeric calcitonin in plasma during pregnancy and lactation. Eur. J. Endocrinol. 1986, 113, 529–535. [Google Scholar] [CrossRef] [Green Version]
  41. Sweeney, L.L.; Malabanan, A.O.; Rosen, H. Decreased Calcitriol Requirement During Pregnancy and Lactation with a Window of Increased Requirement Immediately Post Partum. Endocr. Pract. 2010, 16, 459–462. [Google Scholar] [CrossRef] [PubMed]
  42. Kovacs, C.S.; Kronenberg, H.M. Maternal-Fetal Calcium and Bone Metabolism During Pregnancy, Puerperium, and Lactation. Endocr. Rev. 1997, 18, 832–872. [Google Scholar] [CrossRef] [Green Version]
  43. Fomon, S.; Nelson, S. Calcium, phosphorus, magnesium, and sulfur. In Nutrition of Normal Infants; Fomon, S.J., Ed.; Mosby-Year Book: St. Louis, MI, USA, 1993; pp. 192–216. [Google Scholar]
  44. Ziegler, E.E.; O’Donnell, A.M.; Nelson, S.E.; Fomon, S.J. Body composition of the reference fetus. Growth 1976, 40, 329–341. [Google Scholar]
  45. Specker, B.L.; Binkley, T. High parity is associated with increased bone size and strength. Osteoporos. Int. 2005, 16, 1969–1974. [Google Scholar] [CrossRef] [PubMed]
  46. More, C.; Bettembuk, P.; Bhattoa, H.P.; Balogh, A. The Effects of Pregnancy and Lactation on Bone Mineral Density. Osteoporos. Int. 2001, 12, 732–737. [Google Scholar] [CrossRef]
  47. Carneiro, R.M.; Prebehalla, L.; Tedesco, M.B.; Sereika, S.M.; Hugo, M.; Hollis, B.W.; Gundberg, C.M.; Stewart, A.F.; Horwitz, M.J. Lactation and Bone Turnover: A Conundrum of Marked Bone Loss in the Setting of Coupled Bone Turnover. J. Clin. Endocrinol. Metab. 2010, 95, 1767–1776. [Google Scholar] [CrossRef]
  48. Brembeck, P.; Lorentzon, M.; Ohlsson, C.; Winkvist, A.; Augustin, H. Changes in Cortical Volumetric Bone Mineral Density and Thickness, and Trabecular Thickness in Lactating Women Postpartum. J. Clin. Endocrinol. Metab. 2015, 100, 535–543. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Bjørnerem, A.; Ghasem-Zadeh, A.; Wang, X.; Bui, M.; Walker, S.P.; Zebaze, R.; Seeman, E. Irreversible Deterioration of Cortical and Trabecular Microstructure Associated with Breastfeeding. J. Bone Miner. Res. 2017, 32, 681–687. [Google Scholar] [CrossRef] [PubMed]
  50. Kovacs, C.S.; Chakhtoura, M.; Fuleihan, G.E.-H. Disorders of Mineral and Bone Metabolism During Pregnancy and Lactation; Elsevier: Amsterdam, The Netherlands, 2020; pp. 329–370. [Google Scholar]
  51. Khan, A.A.; Kenshole, A.; Ezzat, S.; Goguen, J.; Gomez-Hernandez, K.; Hegele, R.A.; Houlden, R.; Joy, T.; Keely, E.; Killinger, D.; et al. Tools for Enhancement and Quality Improvement of Peer Assessment and Clinical Care in Endocrinology and Metabolism. J. Clin. Densitom. 2019, 22, 125–149. [Google Scholar] [CrossRef] [PubMed]
  52. Stremmel, W.; Merle, U.; Weiskirchen, R. Clinical features of Wilson disease. Ann. Transl. Med. 2019, 7, S61. [Google Scholar] [CrossRef]
  53. Maggadottir, S.M.; Sullivan, K.E. The Diverse Clinical Features of Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome). J. Allergy Clin. Immunol. Pract. 2013, 1, 589–594. [Google Scholar] [CrossRef] [PubMed]
  54. Mantovani, G.; Spada, A. Mutations in the Gs alpha gene causing hormone resistance. Best Pract. Res. Clin. Endocrinol. Metab. 2006, 20, 501–513. [Google Scholar] [CrossRef]
  55. Malfatti, E.; Laforêt, P.; Jardel, C.; Stojkovic, T.; Behin, A.; Eymard, B.; Lombes, A.; Benmalek, A.; Becane, H.-M.; Berber, N.; et al. High risk of severe cardiac adverse events in patients with mitochondrial m.3243A>G mutation. Neurology 2013, 80, 100–105. [Google Scholar] [CrossRef] [PubMed]
  56. Morten, K.; Cooper, J.; Brown, G.; Lake, B.; Pike, D.; Poulton, J. A new point mutation associated with mitochondrial encephalomyopathy. Hum. Mol. Genet. 1993, 2, 2081–2087. [Google Scholar] [CrossRef] [PubMed]
  57. Barakat, A.J.; Raygada, M.; Rennert, O.M. Barakat syndrome revisited. Am. J. Med. Genet. Part A 2018, 176, 1341–1348. [Google Scholar] [CrossRef] [PubMed]
  58. Hujoel, I.A. The association between serum calcium levels and Chvostek sign: A population-based study. Neurol. Clin. Pract. 2016, 6, 321–328. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Jesus, J.E.; Landry, A. Chvostek’s and Trousseau’s Signs. N. Engl. J. Med. 2012, 367, e15. [Google Scholar] [CrossRef] [PubMed]
  60. Shoback, D. Hypoparathyroidism. N. Engl. J. Med. 2008, 359, 391–403. [Google Scholar] [CrossRef] [PubMed]
  61. Karaca, Z.; Tanriverdi, F.; Unluhizarci, K.; Kelestimur, F. Pregnancy and pituitary disorders. Eur. J. Endocrinol. 2010, 162, 453–475. [Google Scholar] [CrossRef] [Green Version]
  62. Nolten, W.E.; Lindheimer, M.D.; Rueckert, P.A.; Oparil, S.; Ehrlich, E.N. Diurnal Patterns and Regulation of Cortisol Secretion in Pregnancy. J. Clin. Endocrinol. Metab. 1980, 51, 466–472. [Google Scholar] [CrossRef] [PubMed]
  63. Scott, E.M.; McGarrigle, H.H.G.; Lachelin, G.C.L. The Increase in Plasma and Saliva Cortisol Levels in Pregnancy is not due to the Increase in Corticosteroid-Binding Globulin Levels. J. Clin. Endocrinol. Metab. 1990, 71, 639–644. [Google Scholar] [CrossRef] [Green Version]
  64. Foyouzi, N.; Frisbaek, Y.; Norwitz, E.R. Pituitary gland and pregnancy. Obstet. Gynecol. Clin. N. Am. 2004, 31, 873–892. [Google Scholar] [CrossRef] [PubMed]
  65. Kohlmeier, L.; Marcus, R. Calcium Disorders of Pregnancy. Endocrinol. Metab. Clin. N. Am. 1995, 24, 15–39. [Google Scholar] [CrossRef]
  66. Glass, E.J.; Barr, D.G. Transient neonatal hyperparathyroidism secondary to maternal pseudohypoparathyroidism. Arch. Dis. Child. 1981, 56, 565–568. [Google Scholar] [CrossRef] [PubMed]
  67. Loughead, J.L.; Mughal, Z.; Mimouni, F.; Tsang, R.C.; Oestreich, A.E. Spectrum and Natural History of Congenital Hyperparathyroidism Secondary to Maternal Hypocalcemia. Am. J. Perinatol. 1990, 7, 350–355. [Google Scholar] [CrossRef] [PubMed]
  68. Stuart, C.; Aceto, T.; Kuhn, J.P.; Terplan, K. Intrauterine Hyperparathyroidism. Am. J. Dis. Child. 1979, 133, 67. [Google Scholar] [CrossRef] [PubMed]
  69. Bronsky, D.; Kiamko, R.T.; Moncada, R.; Rosenthal, I.M. Intra-uterine hyperparathyroidism secondary to maternal hypoparathyroidism. Pediatry 1968, 42, 606–613. [Google Scholar]
  70. Borkenhagen, J.F.; Connor, E.L.; Stafstrom, C.E. Neonatal Hypocalcemic Seizures Due to Excessive Maternal Calcium Ingestion. Pediatr. Neurol. 2013, 48, 469–471. [Google Scholar] [CrossRef] [PubMed]
  71. Shani, H.; Sivan, E.; Cassif, E.; Simchen, M.J. Maternal hypercalcemia as a possible cause of unexplained fetal polyhydramnion: A case series. Am. J. Obstet. Gynecol. 2008, 199, 410.e1–410.e5. [Google Scholar] [CrossRef] [PubMed]
  72. Mestman, J.H. Parathyroid Disorders of Pregnancy. Semin. Perinatol. 1998, 22, 485–496. [Google Scholar] [CrossRef]
  73. Eastell, R.; Edmonds, C.J.; De Chayal, R.C.; McFadyen, I.R. Prolonged hypoparathyroidism presenting eventually as second trimester abortion. BMJ 1985, 291, 955–956. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Almas, T.; Ullah, I.; Kaneez, M.; Ehtesham, M.; Rauf, S. Idiopathic Primary Hypoparathyroidism Presenting as Focal Seizures in a Neonate: A Rare Occurrence. Cureus 2020, 12, 10348. [Google Scholar] [CrossRef]
  75. Kaneko, N.; Kaneko, S.; Yamada, S.; Suzuki, K.; Ohyama, Y.; Nakagawa, O.; Tani, N.; Aizawa, Y. Untreated Idiopathic Hypoparathyroidism Associated with Infant Congenital Perinatal Abnormalities. Intern. Med. 1999, 38, 75. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Callies, F.; Arlt, W.; Scholz, H.J.; Reincke, M.; Allolio, B. Management of hypoparathyroidism during pregnancy--report of twelve cases. Eur. J. Endocrinol. 1998, 139, 284–289. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Ilany, J.; Vered, I.; Cohen, O. The effect of continuous subcutaneous recombinant PTH (1–34) infusion during pregnancy on calcium homeostasis—A case report. Gynecol. Endocrinol. 2013, 29, 807–810. [Google Scholar] [CrossRef] [PubMed]
  78. Mather, J.K.; Chik, C.L.; Corenblum, B. Maintenance of Serum Calcium by Parathyroid Hormone-Related Peptide During Lactation in a Hypoparathyroid Patient. J. Clin. Endocrinol. Metab. 1999, 84, 424–427. [Google Scholar] [CrossRef] [PubMed]
  79. Shomali, M.E.; Ross, D.S. Hypercalcemia in a Woman with Hypoparathyroidism Associated with Increased Parathyroid Hormone-Related Protein During Lactation. Endocr. Pract. 1999, 5, 198–200. [Google Scholar] [CrossRef]
  80. Shah, K.H.; Bhat, S.; Shetty, S.M.; Umakanth, S. Hypoparathyroidism in pregnancy. BMJ Case Rep. 2015, 2015, 2015210228. [Google Scholar] [CrossRef] [PubMed] [Green Version]
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Figure 1. Schematic depiction of the longitudinal changes in calcium, phosphorus, and calciotropic hormone levels during human pregnancy. Shaded regions depict the approximate normal ranges (reproduced with permission form Kovacs, C.S. et al.; Physiol. Rev.; 2016 [20]).
Figure 1. Schematic depiction of the longitudinal changes in calcium, phosphorus, and calciotropic hormone levels during human pregnancy. Shaded regions depict the approximate normal ranges (reproduced with permission form Kovacs, C.S. et al.; Physiol. Rev.; 2016 [20]).
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Figure 2. Schematic illustration demonstrating the role of PTHrP during pregnancy. It is produced by the placenta and breast tissue and can result in increase in serum calcium and phosphorus secondary to increased bone resorption and rise in 1,25-dihydroxyvitamin D. (reproduced with permission from Khan, A.A. et al.; Eur. J. Endocrinol.; 2019) [19].
Figure 2. Schematic illustration demonstrating the role of PTHrP during pregnancy. It is produced by the placenta and breast tissue and can result in increase in serum calcium and phosphorus secondary to increased bone resorption and rise in 1,25-dihydroxyvitamin D. (reproduced with permission from Khan, A.A. et al.; Eur. J. Endocrinol.; 2019) [19].
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Figure 3. The breast–brain–bone circuit; elevated levels of PTHrP, together with low estradiol, cause bone resorption and the release of calcium and phosphorus in the circulation, which in turn reach the breast ducts and contribute to the formation of breast milk (reproduced with permission from Kovacs, C.S.; Physiology of Calcium, Phosphorus, and Bone Metabolism During Pregnancy, Lactation, and Postweaning; published by Elsevier: Amsterdam, The Netherlands, 2020) [22].
Figure 3. The breast–brain–bone circuit; elevated levels of PTHrP, together with low estradiol, cause bone resorption and the release of calcium and phosphorus in the circulation, which in turn reach the breast ducts and contribute to the formation of breast milk (reproduced with permission from Kovacs, C.S.; Physiology of Calcium, Phosphorus, and Bone Metabolism During Pregnancy, Lactation, and Postweaning; published by Elsevier: Amsterdam, The Netherlands, 2020) [22].
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Figure 4. Evaluation and Investigations of HypoPT. Abbreviations: APS1, autoimmune polyendocrine syndrome; TIBC, total iron-binding capacity; Ca+2, calcium; eGFR, estimated glomerular filtration rate; ACTH, adrenocorticotropic hormone; CXR, chest X-ray; AIRE, autoimmune regulator of endocrine function; * please note, levels are altered during pregnancy, grey background, post-partum investigations.
Figure 4. Evaluation and Investigations of HypoPT. Abbreviations: APS1, autoimmune polyendocrine syndrome; TIBC, total iron-binding capacity; Ca+2, calcium; eGFR, estimated glomerular filtration rate; ACTH, adrenocorticotropic hormone; CXR, chest X-ray; AIRE, autoimmune regulator of endocrine function; * please note, levels are altered during pregnancy, grey background, post-partum investigations.
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Table
Table 1. Etiologies of hypoparathyroidism (HypoPT) [1,8,51,52].
Table 1. Etiologies of hypoparathyroidism (HypoPT) [1,8,51,52].
PostsurgicalAutoimmune DisordersGenetic DisordersRadiation ExposureMineral
Deposition		InfiltrationMagnesium
Abnormality		Drugs
Most common
75% of cases
post-neck surgery for thyroid cancer, laryngeal cancer, multinodular goitre, Grave’s disease, etc.
Features:
Presence of neck scar		♦APS1
Major features
Mucocutaneous candidiasis
HypoPT
Adrenal insufficiency
Minor features
keratitis, AIH, POF, enamel hypoplasia, pneumonitis, nephritis, pancreatitis, enteropathy
with chronic diarrhea or constipation, photophobia, periodic fever with rash, functional asplenia, celiac disease, type 1 diabetes, thyroiditis, retinitis, pure red cell aplasia, polyarthritis, and B12 deficiency
♦Isolated		♦DiGeorge syndrome
♦Barakat syndrome: HypoPT, deafness, renal anomaly (HDR) syndrome
♦Autosomal dominant HypoPT
♦Isolated HypoPT
♦Kenny–Caffey syndrome
- Type 1 (Sanjad Sakati syndrome)
- Type 2
♦Mitochondrial disorders
- Kearns Sayre syndrome
- MTPD
- MELAS syndrome		Exposure to ionized radiation (RAI)
Features:
Post-RAI therapy for thyroid cancer 		♦Copper deposition (e.g., Wilson’s disease) → destruction of parathyroid gland
Features:
Tremors, ataxia, jaundice, psychosis, depression, and Kayser–Fleischer corneal rings
♦Iron deposition (e.g., hemochromatosis, beta-thalassemia)
Features:
Chronic transfusion history		Rare
♦Granulomatous disease (e.g., sarcoidosis and amyloidosis)
♦Metastasis to parathyroid gland
Features:
Constitutional symptoms,
weight loss, and
night sweats		♦Magnesium deficiency
low Mg+2 → block cAMP in parathyroid cell, causing impaired PTH secretion
Mg+2 activates CaSR →
low Mg+2 → impair PTH synthesis and release
♦Hypermagnesemia
high Mg+2 → inhibit PTH release 		Chemotherapy (e.g., L asparaginase) → parathyroid necrosis
Features:
History of malignancy
Abbreviations: APS, autoimmune polyendocrine syndrome;; RAI, radioactive iodine; cAMP, cyclic adenosine monophosphate; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome; MTPDS, mitochondrial trifunctional protein deficiency; AIH, autoimmune hepatitis; POF, primary ovarian failure; ACTH, adrenocorticotropic hormone; TIBC, total iron binding capacity; LFT, liver function test; CaSR, calcium-sensing receptor; Mg+2, magnesium; →, leads to; ♦, symbol used as a bullet point.
Table
Table 2. Genetic Conditions Associated with HypoPT [51,53,54,55,56,57].
Table 2. Genetic Conditions Associated with HypoPT [51,53,54,55,56,57].
Genetic ConditionMode of
Inheritance		Clinical FeaturesGenetic Sequencing
DiGeorge syndromeADCardiac anomalies: VSD, TOF; neurocognitive abnormalities; immune deficiency: Recurrent infections; palatal defects: Cleft palat; renal anomalies; ocular; skeletal anomalies; hearing lossFluorescence in situ hybridization (FISH), TBX1 gene sequencing
AD HypoPT
♦ADH type 1 and 2
♦ADH type 1 with Barter’s
syndrome type 5		AD♦Type 1 and 2: Asymptomatic, mild hypocalcemia +/− hypocalciuria
♦Type1 with Barter’s: ↓Ca+2, ↓Mg+2, ↓K+, hypercalciuria 		♦ADH type 1—CaSR gene sequencing
♦ADH type 2—GNA11 gene sequencing
♦ADH 1/Bartter’s type 5—CaSR gene
Barakat syndrome
HypoPT, deafness, renal anomaly (HDR) syndrome		ADSensorineural deafness
Renal dysplasia, renal failure, renal agenesis
Uterine agenesis (rare)		GATA3 gene sequencing
Isolated HypoPTAR
AD
XLR		Clinical and biochemical features of HypoPT♦AR/AD: PTH or GCM2 gene sequencing
♦ XLR: SOX3 gene sequencing in (males)
Kenny–Caffey syndrome
♦Type 1 (Sanjad Sakati syndrome)
♦Type 2		AR
AD		♦Type 1: Short stature, dysmorphic features, growth retardation, cortical thickening of long bones, small hands and feet
♦Type2: Short stature, cortical thickening of the tubular bones, gracile bone dysplasia		♦Type 1: TBCE sequencing
♦Type 2: FAM111A sequencing
Mitochondrial disorders
♦Kearns Sayre syndrome
♦MTPD
♦MELAS syndrome		AR♦Kearns Sayre: Ophthalmoplegia, retinal pigmentation, cardiac conduction defects, bulbar weakness. ♦MTPD: Neuropathy, retinopathy, fatty liver. ♦MELAS: Lactic acidosis, stroke-like symptoms, external ophthalmoplegia, diabetes, hearing loss, early-onset stroke symptoms♦Kearns Sayre: MTTL1 gene mutation
♦MTPD: HADHA/HADHB gene mutation
♦MELAS: MTTL1 gene mutation (commonest)
Pseudohypoparathyroidism ADShort stature, brachydactyly
Obesity, round facies
+/– mental retardation 		GNAS gene sequencing
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; XLR, x-linked recessive; CaSR, calcium-sensing receptor; GNA11, G protein alpha subunit 11; MTTL1, mitochondrial tRNA (leucine)-1 gene; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome; MTPDS, mitochondrial trifunctional protein deficiency; Ca+2, calcium; K+, serum potassium; VSD, ventricular septal defect; TOF, tetralogy of Fallot, Mg+2, magnesium; ↓, low; +/−, with or without; ♦, symbol used as a bullet point.
Table
Table 3. Reported maternal and fetal adverse events in HypoPT [8,11,13,17,18,36,70,71,72,73,74,75].
Table 3. Reported maternal and fetal adverse events in HypoPT [8,11,13,17,18,36,70,71,72,73,74,75].
Maternal Serum Calcium FetusMother
High Maternal Ca+2Hypoparathyroidism,
polyhydramnios, and
neonatal seizures		Hypercalciuria and
kidney stones
Low Maternal Ca+2Hyperparathyroidism,
increased bone resorption,
intrauterine fragility fractures,
subperiosteal bone resorption,
osteitis fibrosa cystica, and
respiratory distress		Miscarriage, preterm labor,
seizure, and arrhythmia
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Ali, D.S.; Dandurand, K.; Khan, A.A. Hypoparathyroidism in Pregnancy and Lactation: Current Approach to Diagnosis and Management. J. Clin. Med. 2021, 10, 1378. https://doi.org/10.3390/jcm10071378

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Ali DS, Dandurand K, Khan AA. Hypoparathyroidism in Pregnancy and Lactation: Current Approach to Diagnosis and Management. Journal of Clinical Medicine. 2021; 10(7):1378. https://doi.org/10.3390/jcm10071378

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Ali, Dalal S., Karel Dandurand, and Aliya A. Khan. 2021. "Hypoparathyroidism in Pregnancy and Lactation: Current Approach to Diagnosis and Management" Journal of Clinical Medicine 10, no. 7: 1378. https://doi.org/10.3390/jcm10071378

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