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

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          Key Clinical Message

          Hypercalcemia in pregnancy is an uncommon event that can cause major maternal morbidity and/or fetal or neonatal morbidity and mortality. Management is a challenge for the clinicians, especially as regards to investigations in pregnancy, surgery, and the use of cinacalcet and bisphosphonates. We present three case reports and discuss management.

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          Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor.

          J Hunzelman, C Kovacs, H Kronenberg … (1996)
          To determine the role of PTHrP in fetal calcium metabolism, blood calcium was measured in mice homozygous (HOM) for deletion of the PTHrP gene. On day 18.5 of gestation, ionized calcium and the maternal-fetal calcium gradient were significantly reduced in HOM PTHrP-ablated fetuses compared with that of their littermates. To assess the placental contribution to the effect of PTHrP, 45Ca and 51Cr-EDTA (as a blood diffusional marker) were administered by intracardiac injection to pregnant, heterozygous dams on day 17.5 of gestation. Five minutes after the injection, whole fetal 45Ca accumulation was significantly decreased in HOM PTHrP-ablated fetuses compared with that of their littermates. Next, two fetuses from each litter were injected in utero with fragments of PTHrP, PTH, or diluent 1 h before administering 45Ca and 51Cr to the dam. PTHrP-(1-86) and PTHrP-(67-86) significantly increased relative 45Ca accumulation in HOM PTHrP-ablated fetuses, but PTHrP-(1-34), PTH-(1-84), and the diluent had no effect. Finally, similar studies were performed on fetal mice that lacked the PTH/PTHrP receptor gene. Ionized calcium was significantly reduced in HOM PTH/PTHrP receptor-ablated fetuses. However, 5 min after maternal injection of 45Ca and 51Cr, relative accumulation of 45Ca was significantly increased in these fetuses. It was concluded that PTHrP is an important regulator of fetal blood calcium and placental calcium transport. In addition, the bioactivity of PTHrP for placental calcium transport is specified by a mid-molecular region that does not use the PTH/PTHrP receptor.
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            Pregnancy outcomes in women with primary hyperparathyroidism.

            DANIA HIRSCH, Vered Kopel, Varda Nadler … (2015)
            Primary hyperparathyroidism (PHPT) during pregnancy may pose considerable risks to mother and fetus. This study examined pregnancy outcomes in women with gestational PHPT in relation to clinical and laboratory parameters.
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              Pregnancy outcome following in utero exposure to bisphosphonates.

              Shirley Levy, Ibrahim Fayez, Nobuko Taguchi … (2009)
              The safety of bisphosphonates in human pregnancy has not been well established. To characterize pregnancy outcome in women receiving bisphosphonates, we conducted a multi-centre, prospective cohort study with a comparison group. Patients were recruited through 3 teratogen information centres in Canada and South Korea. We followed 21 women exposed to bisphosphonates during or <3 months before pregnancy, and 21 matched-comparison group women without exposure to known teratogens. Pregnancy/neonatal outcome data were collected by interview. The primary endpoint was neonatal outcome including major birth defects. The secondary endpoints included other pregnancy outcomes such as spontaneous abortions. Indication of the therapy was osteoporosis in all patients. There was no difference in the maternal demographics between the 2 groups. In the bisphosphonate group, there were 18 live births, 2 spontaneous abortions and 1 therapeutic abortion, which were not significantly different from the comparison group. The mean gestational age (mean+/-SD) of the bisphosphonate group was 38.7+/-1.9 weeks (comparison group: 39.3+/-1.9 weeks; P=0.42), and the mean birth weight was 3.1+/-0.3 kg (comparison group: 3.3+/-0.5 kg; P=0.11). In the bisphosphonate group, there was a child diagnosed with Apert syndrome, an autosomal dominant acrocephalosyndactyly, with a fibroblast growth factor 2 mutation. Coupled with existing data in the literature, our findings suggest that preconceptional and first-trimester use of bisphosphonates may not pose substantial fetal risks.
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                Author and article information

                Contributors
                Evelyne Rey: evelyne_rey@ssss.gou.qc.ca
                Journal
                Journal ID (nlm-ta): Clin Case Rep
                Journal ID (iso-abbrev): Clin Case Rep
                Journal ID (doi): 10.1002/(ISSN)2050-0904
                Journal ID (publisher-id): CCR3
                Title: Clinical Case Reports
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2050-0904
                Publication date (Electronic): 17 September 2016
                Publication date Collection: October 2016
                Volume: 4
                Issue: 10 ( doiID: 10.1002/ccr3.2016.4.issue-10 )
                Pages: 1001-1008
                Affiliations
                [ 1 ]CHU Sainte‐Justine Research Center Montreal QuebecCanada
                [ 2 ] Division of Obstetric Medicine Department of Obstetrics and GynaecologyCHU Sainte‐Justine Montreal QuebecCanada
                [ 3 ] Department of MedicineUniversity of Montreal Montreal QuebecCanada
                [ 4 ] Division of Maternal‐Fetal Medicine Department of Obstetrics and GynaecologyCentre Hospitalier de l'Université de Montréal Montreal QuebecCanada
                [ 5 ] Department of MedicineMcGill University Health Centre Montreal QuebecCanada
                Author notes
                [*] [* ] Correspondence

                Evelyne Rey, Division of Obstetric Medicine, Department of Obstetrics and Gynaecology, Centre Hospitalier Universitaire Sainte‐Justine, 3175 Côte Sainte‐Catherine, H3T 1C5 Montreal, QC, Canada. Tel: 514 345 4706; Fax: 514 345 4648; E‐mail: evelyne_rey@ 123456ssss.gou.qc.ca

                Article
                Publisher ID: CCR3646
                DOI: 10.1002/ccr3.646
                PMC ID: 5054480
                PubMed ID: 27761256
                SO-VID: 4ad857ab-6fb2-450e-bf80-5f536030d959
                Copyright © © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 05 March 2016
                Date revision received : 21 June 2016
                Date accepted : 09 July 2016
                Page count
                Figures: 0, Tables: 4, Pages: 8, Words: 5236
                Categories
                Subject: Case Report
                Subject: Case Reports
                Custom metadata
                source-schema-version-number 2.0
                component-id ccr3646
                cover-date October 2016
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:07.10.2016

                Keywords: bisphosphonates,cinacalcet,fibroma,hypercalcemia,hyperparathyroidism,pregnancy
                Data availability:
                Keywords: bisphosphonates, cinacalcet, fibroma, hypercalcemia, hyperparathyroidism, pregnancy

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