180

European Journal of -18-0541 close monitoringofserum duringpregnancyin pregnancy impact calcium and necessitate in thecalciumregulatinghormones, whichoccurduring maternal andfetalmorbidity ( occurs inpregnancyitmaybeassociatedwithsignificant isarareconditionandwhen it Introduction andmethodology pregnancy, mostwomenwithhypoparathyroidismhaveanuncomplicatedpregnancyandgivebirthtohealthy babies. mother withamultidisciplinaryteamisadvisedforoptimalcare.Ifcalciumhomeostasiswellcontrolledduring serum calcium.Calcium,calcitriolandvitaminDsupplementsaresafeduringpregnancy.Closemonitoringofthe contractions andanincreasedriskofmiscarriage.Treatmenttargetsduringpregnancyaretomaintainalownormal the developmentofintrauterinefractures.Inadequatetreatmenthypoparathyroidismmayalsoresultinuterine secondary hyperparathyroidisminthefetus.Thismaybeassociatedwithdemineralizationoffetalskeleton and suppress thefetalparathyroidglanddevelopment.Alsohypocalcemiainmotherisharmfulasitmayresult in , whereasothersrequirelowerdoses.Closemonitoringisnecessaryashypercalcemiainthemothermay calcium andcalcitriolduringpregnancyinhypoparathyroidmothers,withsomewomenrequiringhigherdoses of in motherswithhypoparathyroidism.Theliteraturehoweverdescribesawidevariationtherequireddosesof breasts increasesbythree-fold,andthismaylowerthedosesofcalciumcalcitriolrequiredduringpregnancy absorption. Therenalfilteredcalciumloadincreasesleadingtohypercalciuria.PTHrPproductionbytheplacentaand Conclusions: articles wereincludedinthefinalreview. Methods: the managementofhypoparathyroidisminpregnancy. Purpose: Abstract Translational Medicine,UniversityofFlorence,Italy of EndocrinologyandInternalMedicine,AarhusUniversity,Aarhus,Denmark, Hamilton, Ontario,Canada, 1 Aliya A Khan management and evidence-basedrecommendationsfor Hypoparathyroidism inpregnancy:review MANAGEMENT OFENDOCRINEDISEASE Division ofEndocrinologyandMetabolism,CalciumDisordersClinic,Department ofMedicine,McMasterUniversity, https://doi.org/ https://eje.bioscientifica.com Review Reviewcalciumhomeostasisinpregnancyandprovideevidence-basedbestpracticerecommendationsfor WesearchedMEDLINE,EMBASEandCochranedatabasesfromJanuary2000toApril1,2018.Atotalof65 10.1530/EJE Duringpregnancy,calcitriollevelsincreasebytwo-to—three-foldresultinginenhancedintestinalcalcium 1 , Bart Clarke -18-0541 2 Mayo Clinic,EndocrinologyTransplantCenter,Rochester, Minnesota,USA, 2 2 , Lars Rejnmark © 2019EuropeanSociety ofEndocrinology 1 , A Khanandothers 2 ). Physiologicchanges Printed inGreatBritain 3 and Maria Luisa Brandi reviewed the literature and provided evidence-based and mayresultin maternal andfetal morbidity. We these conditions impact fetal parathyroid development to avoid both and hypercalcemia. Both dose ofcalciumandcalcitriolmayberequiredinorder hypoparathyroid mothers. Frequent adjustments in the pregnancy Hypoparathyroidism in Published byBioscientifica Ltd. 4 Department ofSurgeryand 4 3 Department Downloaded fromBioscientifica.com at09/27/202112:47:40PM (2019) Endocrinology European Journalof [email protected] Email to A Khan should be addressed Correspondence 180 180 :2 , R37–R44

R37 –R44 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com stimulator of Cyp27b1 in comparison to PTH( to theriseinCyp27b1.PTHrP isknowntobeaweak possible thatestradiolandprolactin maybecontributing pregnancy are not known andmay be PTHrP. It is also significant risesincalcitriolduringpregnancy( that anephricwomenondialysisdonotdemonstrate serum calcitriollevels.Thisisalsosupportedbythefact appears tobethemajorsource ofthesignificantrisein than thatfoundintheplacenta( levels ofCyp27b1being35-foldhigherinthekidneys renal expressionofCyp27b1(1-alphahydroxylase)with and thefetus.Pregnancyisassociatedwithanincrease in rise incalcitriolwithsomecontributionfromtheplacenta PTH ( increases intestinal calcium absorption and suppresses ( two- tothree-foldbytermasnotedinlongitudinalstudies vitamin Dlevels( calciumintakeaswellmaternal maternal dietary inlongitudinalstudies.PTHisaffectedby as observed into the midnormal reference range by the third trimester 1st trimester( actually declinebelowthenormalreferencerangein suppressed into thelow normal reference range and may during pregnancy( reference range( as calcium corrected for albumin remain in the normal have demonstratedthatserumionizedcalciumaswell total albumin-boundcalcium.Longitudinalstudies serum albuminresultsinareductionthemeasured expansion ofintravascularvolume.Thisreductionin During pregnancyserumalbumindecreaseswiththe calcium homeostasis Impact ofpregnancyon literature today. Thefinalreviewincluded65articles. also includedduetothelimitedevidenceavailablein dealing withhumans.Casereportsandcaseserieswere and editorialsonlyincludedEnglishlanguagepapers articles based on abstract and title. We excluded letters of 1449articleswerefound. These werereduced to 123 physiology, complications and management. A total the MeSHsearch termshypoparathyroidism,pregnancy, searched 1,2000toApril2018using fromJanuary MEDLINE, EMBASEandCENTRALdatabaseswere recommendations guidingclinicalpracticetoday. 4 , Review 5 The key stimulators of renal Cyp27b1 during Calcitriol risesinthefirsttrimesterandincreasesby , 11 12 , , 16 13 , , 3 17 , 14 4 ). Thekidneyisthemainsource forthe 3 , , 11 , 5 4 3 15 , ). , , 6 5 4 ). Thissignificantriseincalcitriol , ). Serumphosphorusisunchanged , 7 5 , ). Parathyroidhormone(PTH)is 8 , 9 , 10 18 ). PTHsubsequently rises A Khanandothers ). Thekidneytherefore 19 20 ). ). The estrogen supplementation have also demonstrated rises in the risesinestrogen( to using oral contraceptives and this may be secondary in women Rises in calcitonin have also been observed the risesinestradiol, estrone and estriol in pregnancy. previously hadatotalthyroidectomy( inwomenwhohave in calcitoninhavebeenobserved contribute torisesinserumcalcitonin( be thethyroidC-cellsinadditionbreastandplacenta pregnancy ( risesinserumcalcitoninduring have notobserved during pregnancy( protect thematernalskeletonfromdemineralization to thefetus( calcitriol inadditiontotransferof25hydroxyvitaminD during pregnancydespiteincreasedconversionto levels of25hydroxyvitaminDappeartobestable in PTHrPmayupregulatecalcitriolandsuppressPTH( longitudinal studies( to thebaselinepre-pregnancylevelbytermasnotedin week ofgestationandincreasesbythree-foldincomparison serum calcitonin( pregnancy. The risesincalcitriolandPTHrPseen associated withanincreased riskofrenalstonesduring during pregnancy has been observed also contribute to the hypercalciuria ( torisesincalcitriolandPTHrP) in PTH(secondary in increasesurinecalcium( in turnincreasesrenalfilteredcalciumloadandresults lead toenhancedintestinalcalciumabsorption,which cells ( increases PTHrPmRNAexpressioninhumanendometrial PTHrP. ( surgery bilateral mastectomyandbecomeundetectablefollowing trimester of pregnancy ( normalized followingbilateralmastectomyinthesecond high levelsofPTHrPinthebreasttissue,serumcalcium a pregnantwomanwithseverehypercalcemia andvery appear tobeanimportantsource ofPTHrP. Inacaseof PTHrP levels also became undetectable ( oftheplacenta( delivery serum calciumnormalizedfollowingcesareansectionand severe hypercalcemia high levels of PTHrP, and very placenta. Inacasereportofpregnantwomanwith pregnancy Hypoparathyroidism in Serum calcitonin rises during pregnancy and may Calcitonin levelsmayalsoincreaseinassociationwith An importantsource for PTHrPappearstobethe PTHrP beginstorisefromthethirdthirteenth In conclusion,risesincalcitriolduringpregnancy 33 In vitro ). 31 , 9 32 11 , 13 studieshavedemonstratedthatestradiol ). Highlevelsofestradiolmayalsoincrease ). ). Thesource ofthecalcitoninappearsto 27 3 ). , 11 5 5 , , 31 , 8 Downloaded fromBioscientifica.com at09/27/202112:47:40PM 26 11 , , 30 25 32 ). Postmenopausalwomenon , ). Postcesareansectionthe , 21 ). PTHrP also decreased post 28 34 , , 22 ; 29 Fig. 1 ). Otherinvestigators ) Thesignificantrise 180 23 23 ). Thereductions :2 16 , 30 , 24 24 , ). The breasts 17 , ). Theserises 25 , ). 34 ). The R38 11 via freeaccess ). European Journal of Endocrinology hypoparathyroidism ( calcium excretionincreases furtherwithpregnancyin calcium excretion.Thelimited datasuggestthatrenal of pregnancy in hypoparathyroid women on urinary reference range. ensure thatserumcalciumismaintainedinthenormal Close monitoringisrequiredduringpregnancy to during pregnancy in women with hypoparathyroidism. may contribute to differencesin dose requirements calcitriol fromthematernalkidneysandthesevariations from theplacentaandbreastaswellformation of Also theremaybevariationsintheproductionofPTHrP meet thecalciumrequirementsofdevelopingfetus. forthelasttrimesterinorderto mineral accrualnecessary intake inthefirsttrimestermaycontributetoinadequate calcium intake( calcium supplementsorhadinadequateunknown cases requiringhigherdosesofcalcitrioldidnotreceive calcium intake.Manyofthepatientsinreported and calcitriolmaybeareflectionofvariationsindietary pregnancy ( and calcitriolrequirementshaveactuallyincreasedduring reports ofhypoparathyroidmothersinwhomthecalcium reports. However, theliteraturealsocontainsmanycase supplements duringpregnancyasnotedinmanycase result inlowerrequirementsforcalciumandcalcitriol pregnancy inwomenwithhypoparathyroidismmay Calcium homeostasisduringpregnancy. Figure 1 Review 25 (OH)D There are very limiteddataevaluating theeffects There arevery Breast 35 ). Variations in requirements for calcium PTHrP 36 , 37 41 1,25 (OH)D , ). 38 , Placenta 39 , 40 A Khanandothers ). Inadequatecalcium resorption Bone Increases Urine phosphate absorption Increases calcium + intestinal calcium

is required with maintenance of serum calcium in the During pregnancy, careful monitoringofserumcalcium calcium duringpregnancy? What arethetreatment targetsforserum possibly fetaldeath( fractures, low birthweight,spontaneous abortion and bones, , intrauterine rib and limb with subperiostealboneresorption,bowingofthelong fetal hyperparathyroidism,withseverecasespresenting stimulationand the developmentof transfer ofcalciumisdecreasedandwillresultinfetal in the presence of maternal hypocalcemia, placental suppression ofthefetalparathyroidglands( of calciumtothefetusisincreasedandwillresultin ( contribute tooptimalskeletalcalcificationofthefetus by theplacenta( are activelytransportedagainstaconcentrationgradient to themother, andcalcium,phosphorusmagnesium maintained atahigherlevelinthefetuscomparison from theplacenta( the placenta( placenta ( calcitriol inthefetusissynthesizedfetalkidneysor Calcitriol doesnotcrosstheplacentaandcirculating demineralization ofthefetalskeleton( glands anddevelopmentofhyperparathyroidism This willresultinthestimulationoffetalparathyroid severe hypocalcemia,thefetuscandevelophypocalcemia. severely reduced.Inseverehypoparathyroidismwith does notdevelopuntilthematernalserumcalciumis maternal skeleton( to meetthefetalrequirementsatexpenseof maternal serum calcium the placenta will extract calcium maternal circulation. Even in the presence of inadequate calcium, phosphateandmagnesiumtothefetusfrom ofessentialmineralsnamely essential forthedelivery accruing inthethirdtrimester( mineralizes with approximately 80% ofthemineral gradually The endochondralskeletonoftheembryo developing fetus? hypoparathyroidism onthe What istheimpactofmaternal the fetalparathyroidglands( placenta andPTHissynthesizedinlowconcentrations pregnancy Hypoparathyroidism in 63 ). Inthepresenceofmaternalhypercalcemia, transfer Calcitonin issynthesizedinthefetalthyroidaswell 52 , 23 53 , , 59 54 63 , 61 ). MaternalPTHalsodoesnotcrossthe 60 ). Thesehighlevelsofmineralsmay 44 65 , ). CordbloodhashighlevelsofPTHrP 62 , , Downloaded fromBioscientifica.com at09/27/202112:47:40PM 66 45 ). Theserumcalciumisnormally , , 67 46 44 , , , 68 https://eje.bioscientifica.com 54 47 42 ). , ). Fetalhypocalcemia , 55 180 43 , ). Theplacentais 56 :2 48 , , 64 57 49 ). Similarly, , 58 , 50 ). R39 , 51 via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com related to serum calcium levels ( hyper-calcemia. the parathyroidglandsof newborncausinghypo-or pregnancy, asthis may have affected the development of if longperiodsofhypo-orhypercalcemia occurredduring baby if the baby is not well (e.g. does not suckle well) or clinically andcalciumlevelsshouldbeevaluatedinthe However, the newborn should be carefullymonitored thrives well,biochemicaltestsmaynotbeneeded. fairly wellcontrolledduringpregnancyandthenewborn are outofthetargetrange.Ifcalciumlevelshavebeen measurements mayofcoursebeneededifcalciumlevels range similartonon-breastfeedinglevels. More frequent levels shouldbetargetedinthelownormalreference advise measuringcalciumlevelsonceamonth.Calcium month postpartum.Inthepresenceofbreastfeedingwe followed bymeasurementonce-weeklyduringthefirst should bemeasuredwithinthefirstweekpostpartum state. Serumalbumincorrectedorionizedcalciumlevels in serumcalciumwhileadaptingtothepostpartum too frequently, asthismaycontributetowidefluctuations titrate (change)dosesofcalcitriolandcalciumsupplements calcium isadvised. However, careshouldbetakennotto postpartum arevariableandclosemonitoringofserum ( this may contribute to the reductions in calcitriol levels in pregnancyandmayhavestimulatedCyp27b1 reductions inestradiolwhichareelevatedby100-fold of the placenta. Also postpartum, following delivery calcium reabsorption ( and impactsboneresorptionaswellenhancesrenal that bothhypocalcemiaandhypercalcemia areavoided. range duringpregnancyandmonitorcloselytoensure to maintainserumcalciuminthelownormalreference an increasedriskofabortion( untreated hypoparathyroidismhasbeenassociatedwith associated with neonatal tetany ( above. Alsointrauterinehypoparathyroidismhasbeen demineralization andintrauterinefracturesasmentioned hyperparathyroidism hasbeenassociatedwithskeletal and PTH withinthe first months afterbirth, intrauterine reports havedescribednormalizationofserumcalcium hypocalcemia inthenewborn.Althoughseveralcase of thefetalparathyroidglands,whichcanresultin should also beavoided in ordertoprevent suppression of thefetalparathyroidglands( avoid hypocalcemiainordertopreventstimulation low normalreferencerange.Itisrecommendedto 11 Review ). Theeffectsofthesechangesoncalciumhomeostasis The lactating breast isasignificant source ofPTHrP As urinary calcium inhypoparathyroidismisclosely As urinary 12 , 72 ). Calcitriol levels normalize 2 ). Therefore,itisimportant A Khanandothers 34 70 , 69 73 , 71 ). Hypercalcemia ), it is advised to ). Furthermore, mother andthefetus( our understandingofcalciumhomeostasisinboththe have notreallyimproveddespiteasignificantincreasein hypoparathyroidism in pregnancy ( Since thepublicationoffirstcase in pregnancy? the managementofhypoparathyroidism What arethebesttreatmentstrategiesfor Bdrugs( are consideredFDApregnancyriskcategory diuretics should be discontinued during pregnancy and Cdrug( classified asapregnancyriskcategory has not been adequately evaluated in pregnancy and is D supplementsaresafetouseduringpregnancy. PTH renal calciumexcretion.Calcium,calcitriolandvitamin inordertoavoidfurther rises in normal referenceinterval maintain serumcalciumlevelsinthelowerpartof • low Quality ofevidence–very • Recommendations supplements aresafeduringpregnancyandlactation. maternal andfetalcomplications.Calciumcalcitriol the lownormalreferencerangeinordertoavoidpotential pregnancy toensurethatserumcalciumismaintainedin pregnancy ( and calcitriolrequirementsmayactuallyincreaseduring may notalwaysbethecaseandinsomewomencalcium calcium andcalcitriolsupplementation;however, this during pregnancymayresultinlowerrequirementsfor and PTHrPwhichoccurinhypoparathyroidwomen 81 pregnancy Hypoparathyroidism in • • , the real-worldresponsein the individualpatientas provides uswithanopportunitytoobserve 1–2 weeks and steady stateis reached in fivehalf-lives. Waiting for repeated in 1–2 weeks. The half-life of calcitriol is 4–6 with serumcalciumcorrected foralbuminshouldbe of calciumorcalcitriolareadvised,thenthelabprofile hypocalcemia donotdevelop.Ifchangesinthedose weeksduring pregnancytoensurethathyperor 3–4 We recommendmonitoringserumcalcium every toward thelowerpartofnormalreferencerange. (albumin corrected or ionized) levels shouldbetargeted avoid worseningofrenalcalciumlosses,serum and functionofthefetalparathyroidglandsto In ordertoavoidadverseeffectsonthedevelopment 82 , 83 , 84 35 , 85 , 86 ). Asnotedpreviouslytherisesincalcitriol ). Closemonitoringisrequiredduring 1 , Downloaded fromBioscientifica.com at09/27/202112:47:40PM 36 , 37 , 41 , 76 68 180 ) treatment options , 70 :2 , 77 74 , 78 ). Thiazide , 79 R40 75 , 80 via freeaccess ). h , European Journal of Endocrinology grant supportandconsultant for Shire,Inc., Data monitoring board A K – researchfunds from Shire, Amgen and Alexion, B C – Research Declaration ofinterest available today. in pregnancyordertoenhancethequalityofcare need forprospectivestudiesinhypoparathyroidism nursing staffishighlyrecommended.Thereanurgent treating endocrinologist,obstetrician,pediatricianand pregnancy. A coordinated approach to care among the within thelow-to-midnormalreferencerangethroughout healthy babiesifserumcalciumlevelsaremaintained have anuncomplicatedpregnancyandgivebirth to and caseseriesmostwomenwithhypoparathyroidism only limiteddataareavailableintheformofcasereports during pregnancy. Although 3–4 weeks monitored every are safetouseduringpregnancy. Serumcalciumshouldbe treated. Calcium,calcitriolandvitaminDsupplements severe adversepregnancy outcomes if notadequately low Quality ofevidence–very • Quality ofevidence–low • Quality ofevidence–moderate • low Quality ofevidence–very • low Quality ofevidence–very • • • • Review with appropriatemonitoringoftheserumcalcium. to ensuretheneonatecanbeimmediatelyassessed We adviseinformingthepediatricianpriortodelivery endocrinologist, obstetricianaswellthepediatrician. baby are achieved with coordinated care among the Optimal careoutcomesforboththemotherand experiencing symptomsofhypoorhypercalcemia. for albuminorionized)checkedurgentlyiftheyare advice thattheyhavetheirserumcalcium(corrected symptoms ofhypercalcemia andhypocalcemia We recommendeducatingthepatientregarding PTH (1–84)and(1–34)duringpregnancy. We recommendstoppingreplacementtherapywith during pregnancy. We recommendstoppingtreatmentwiththiazides should bemaintainedinthenormalreferencerange. 25hydroxyvitamin D and the 24-h urine for calcium We recommendserumphosphate,magnesium, andlifestylefactorssuchasexercise.including dietary serum calciumwillalsobedependentonotherfactors In conclusion, hypoparathyroidism may result in A Khanandothers completion oftheliteraturesearch. The authorsgreatlyappreciatethesupportofHajarAbu Alrob forthe Acknowledgement authors sharedindevelopingthemanuscript. candidate, HealthResearchMethodology, McMaster Universityandall Aliya KhancompletedtheliteraturesearchwithHajarAbu Alrob MSc Author contributionstatement in thepublic,commercialornot-for-profitsector. agency funding any from grants specific any receive not did research This Funding Consultant: Alexion,BrunoFarmaceutici,KyowaKirin,Servier,Shire. * SPA Shire, Servier, NPS, MSD, Kirin, Kyowa Lilly, Eli Farmaceutici, Bruno Kyowa Kirin, *Academic grants and/or speaker: Abiogen, Alexion, Amgen, from Shire,MLB–receivedhonorariaAmgen,BrunoFarmaceutici, – Speakersfeeandconsultancy from ShireandAlexion. Research funds member forAmgen, Inc., Data monitoring board member forGSK. L R References pregnancy Hypoparathyroidism in 9 8 7 6 5 4 3 2 1 Moller UK, Streym S,Mosekilde L,Heickendorff L, Flyvbjerg A, Logue FC, Gallacher SJ, Fraser WD,Owens OJ,Dryburgh FJ, Cross NA, Hillman LS,Allen SH,Krause GF&Vieira NE. Calcium Black AJ, Topping J, Durham B,Farquharson RG&Fraser WD. Ardawi M, Nasrat HA&BA’Aqueel HS. Calcium-regulatinghormones Seki K, Makimura N,Mitsui C,Hirata J&Nagata I.Calcium- Dahlman T, Sjoberg HE&Bucht E.Calciumhomeostasisin Eastell R, Edmonds CJ,DeChayal RC&McFadyen IR.Prolonged Callies F, Arlt W, Scholz HJ,Reincke M&Allolio B.Management pregnancy andpostpartum:acontrolled cohortstudy. bone markersandinsulin-likegrowth factori(IGF-I)during Jensen LTFrystyk J, &Rejnmark L.Changesincalcitropic hormones, (https://doi.org/10.1530/eje.0.1310369) pregnancy. and biochemicalmarkersofboneturnoverinnormalhuman Jenkins A, Kenndy J&Boyle IT. Changesincalciotrophic hormones Nutrition and postweaning–alongitudinal-study. homeostasis andbonemetabolismduringpregnancy, lactation, jbmr.2000.15.3.557) Bone MineralResearch homeostasis, andbonedensityinnormalpregnancy. A detailedassessmentofalterationsinboneturnover, calcium eje.0.1370402) of Endocrinology pregnancy andpostpartum:alongitudinalstudy. and parathyroidhormone-relatedpeptideinnormalhuman 164 longitudinal study. regulating hormonesandosteocalcinlevelsduringpregnancy:a org/10.3109/00016349409006250) Obstetricia GynecologicaScandinavica normal pregnancyandpuerperium.Alongitudinalstudy. bmj.291.6500.955) abortion. hypoparathyroidism presentingeventuallyassecondtrimester org/10.1530/eje.0.1390284) ofEndocrinology European Journal of hypoparathyroidismduringpregnancy–reporttwelvecases. 1248–1252. 1995 BMJ European Journal ofEndocrinology European Journal 1985 61 1997 (https://doi.org/10.1016/0002-9378(91)90694-M) 514–523. American Journal ofObstetricsandGynecology American Journal 291 2000 137 955–956. 402–409. Downloaded fromBioscientifica.com at09/27/202112:47:40PM 15 (https://doi.org/10.1093/ajcn/61.3.514) 557–563. 1998 (https://doi.org/10.1136/ 1994 (https://doi.org/10.1530/ https://eje.bioscientifica.com 139 (https://doi.org/10.1359/ American Journal ofClinical American Journal 73 284–289. 180 1994 393–398. :2 European Journal European Journal 131 (https://doi. Journal of Journal 369–374. (https://doi. Acta R41 1991 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com

24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 Review Bucht E, Telenius-Berg M, Lundell G &Sjöberg HE.Immunoextracted Balabanova S, Kruse B&Wolf AS. Calcitoninsecretionbyhuman Stevenson JC, Hillyard CJ,MacIntyre I,Cooper H&Whitehead MI. Silva OL, Titus-Dillon P, Becker KL,Snider RH&Moore CF. Increased Tedesco MB,Horwitz MJ, Sereika SM,Syed MA,Garcia-Ocaña A, Turner M, Barré P, Benjamin A,Goltzman D&Gascon-Barré M. Kirby BJ, Ma Y, Martin HM,BuckleFavaro KL,Karaplis AC& Sefa R, Cetin EH,Gurkan K&Metin K.Arechangesinurinary Smith CL, Kristensen C,Davis M&Abraham PA. Anevaluationof Wilson SG, Retallack RW, Kent JC,Worth GK &Gutteridge DH. Verhaeghe J &Bouillon R.Calciotropichormonesduring Ritchie LD, Fung EB,Halloran BP, Turnlund JR, Van Loan MD, Seely EW, Brown EM,DeMaggio DM,Weldon DK &Graves SW. A Kovacs CS. Maternalmineralandbonemetabolismduring Rasmussen N, Frolich A,Hornnes PJ&Hegedüs L.Serumionized (https://doi.org/10.1530/acta.0.1130529) pregnancy andlactation. women. Evidenceofmonomericcalcitonin inplasmaduring calcitonin inmilkandplasmafrom totally thyroidectomized 323–326. placental tissue. 6736(79)92117-2) skeleton. A physiologicroleforcalcitonin:protectionofthematernal Association serum calcitonininpregnancy. org/10.1359/JBMR.050602) of BoneandMineralResearch formation anddiscordanteffectson1,25(OH)2vitaminD. Continuous PTHandPTHrPinfusioncausessuppressionofbone Bisello A, Hollis BW, Rosen CJ,Wysolmerski JJ, Dann P and Electrolyte Metabolism 1,25-dihydroxyvitamin Dconcentrationsduringpregnancy? Does thematernalkidneycontributetoincreasedcirculating org/10.1002/jbmr.1925) of BoneandMineralResearch afterlactationdonotrequireparathyroidhormone. recovery Kovacs CS. Upregulationofcalcitriolduringpregnancyandskeletal 0051-7) Research parameters duringpregnancyclinicallysignificant? Clinical Nephrology the physicochemicalriskforrenalstonediseaseduringpregnancy. 613–622. human pregnancyandlactation. 1,25-dihydroxyvitamin Dindexduringalongitudinalstudyof Serum free1,25-dihydroxyvitaminDandthe 1992 reproduction. (https://doi.org/10.1093/ajcn/67.4.693) menses. during humanpregnancyandlactationafterresumptionof Cann CE &King JC.Alongitudinalstudyofcalciumhomeostasis 9378(97)80039-7) Gynecology and 1,25-dihydroxyvitaminD. partum: reciprocalchangesinserumintactparathyroidhormone prospective studyofcalciotropichormonesinpregnancyandpost physrev.00027.2015) Reviews pregnancy, lactation,andpost-weaningrecovery. Gynaecology and postpartum. calcium andintactparathyroidhormonelevelsduringpregnancy 012-2062-2) Internatinal 41 2016 2006 469–477. American Journal ofClinicalNutrition American Journal Lancet (https://doi.org/10.1111/j.1365-2265.1990.tb00905.x) (https://doi.org/10.3109/00016348709103646) 1997 1981 2013 1990 96 34 Journal of Steroid Biochemistry andMolecularBiology ofSteroid Biochemistry Journal 1979 449–547. Acta ObstetriciaetGynecologicaScandinavica 176 73 244–248. BJOG: An International Journal ofObstetricsand Journal BJOG: AnInternational 24 97 2001 (https://doi.org/10.1016/0960-0760(92)90372-P) 649–652. 1307–1320. 857–862. 214–217. 2 769–770. 55 1988 Acta Endocrinologica (https://doi.org/10.1152/ (https://doi.org/10.1007/s00240-006- 205–211. 2005 2013 (https://doi.org/10.1016/S0002- American Journal ofObstetricsand American Journal 14 Journal oftheNationalMedical Journal (https://doi.org/10.1007/s00198- Clinical Endocrinology (https://doi.org/10.1016/S0140- 20 28 246–52. 1792–1803. 1987–2000. A Khanandothers 1998 1986 (https://doi. (https://doi. Physiological 67 113 Urological 693–701. 1990 529–535. et al Journal Journal 1987 . 32 Mineral Journal Journal

66

pregnancy Hypoparathyroidism in 30 29 28 27 26 25 40 39 38 37 36 35 34 33 32 31 Eller-Vainicher C, Ossola MW, Beck-Peccoz P&Chiodini I.PTHrP- Rodda CP, Kubota M,Heath JA,Ebeling PR,Moseley JM,Care AD, Bertelloni S, Baroncelli GI,Pelletti A,Battini R&Saggese G. Stevenson JC, Abeyasekera G,Hillyard CJ,Phang KG,MacIntyre I, Hillyard CJ, Stevenson JC&MacIntyre I.Relativedeficiencyof Yadav S, Goel MM,Singh U,Natu SM&Negi MS.Calcitoningene- Jabbar A, Samad L,Akhter J&Khan MA. Pregnancyunmasking Bolen J. Hypoparathyroidisminpregnancy. Markestad T, Ulstein M,Bassoe HH,Aksnes L&Aarskog D.Vitamin Kobielusz-Gembala I&Okopien B.Hypoparathyroidism in Krysiak R, Turner ET &Freier AA.Hypoparathyroidismandpregnancy. Shomali ME &Ross DS.Hypercalcemia inawomanwith Mitchell DM, Regan S,Cooley MR,Lauter KB,Vrla MC, Becker CB, Casey ML, Mibe M&MacDonald PC.Regulationofparathyroid O’Brien PC&Kao PC.Parathyroid Khosla S, Johansen KL,Ory SJ, Jackson IT, Saleh J &Van-Heerden JA. hyperplasia Giganticmammary 250–251. report. associated hypercalcemia acase ofpregnancyresolvedafterdelivery: 261–271. ofmalignancy. placenta: comparisonswithasimilarproteinimplicatedinhumoral related proteininfetallambparathyroidglandsandsheep Caple IW &Martin TJ.Evidenceforanovelparathyroidhormone- org/10.1007/BF00301677) Calcified Tissue International -relatedproteininhealthypregnantwomen. 6736(81)91973-5) of estrogens. the calciumregulatinghormonesinpostmenopausalwomen:effect Campbell S, Townsend PT, Young O &Whitehead MI.Calcitoninand (https://doi.org/10.1016/S0140-6736(78)90249-0) plasma calcitonininnormalwomen. org/10.1007/s00404-014-3303-8) of GynecologyandObstetrics preeclamptic pregnancies:anestedcase–controlstudy. and parathyroidhormone-relatedpeptidesinnormotensive hypoparathyroidism. org/10.1016/0002-9378(73)90627-3) of ObstetricsandGynecology tb06774.x) 1983 lactation. Casereport. D metabolisminnormalandhypoparathyroidpregnancy org/10.3109/09513590.2010.507284) pregnancy. org/10.1016/S0002-9378(16)35361-3) ofObstetricsandGynecology Journal (https://doi.org/10.4158/EP.5.4.198) related proteinduringlactation. hypoparathyroidism associatedwithincreasedparathyroidhormone- 1808) Metabolism with hypoparathyroidism. Burnett-Bowie SA &Mannstadt M.Long-termfollow-upofpatients jcem.77.1.8325942) Metabolism stromal cellsinculture. hormone-related proteingeneexpressioninhumanendometrial S0025-6196(12)62164-8) Mayo ClinicProceedings hormone-related peptideinlactationandumbilicalcordblood. org/10.1097/00006534-198911000-00016) Surgery Plastic andReconstructive in pregnancyassociatedwithpseudohyperparathyroidism. doi.org/10.1530/EJE-11-1050) 90 European Journal ofEndocrinology European Journal 971–976. (https://doi.org/10.1677/joe.0.1170261) 2012 1993 Gynecological Endocrinology Lancet 97 77 (https://doi.org/10.1111/j.1471-0528.1983. 1981 4507–4514. 188–194. Journal ofPakistanMedicalAssociation Journal 1990 British Journal ofObstetricsandGynaecology British Journal Journal ofClinicalEndocrinologyand Journal 1 2014 1973 693–695. Downloaded fromBioscientifica.com at09/27/202112:47:40PM Journal ofClinicalEndocrinologyand Journal 1994 65 (https://doi.org/10.1210/ 1989 1408–1414. Journal ofEndocrinology Journal (https://doi.org/10.1210/jc.2012- Endocrine Practice 290 117 54 1963 195–197. 897–903. 178–179. (https://doi.org/10.1016/S0140- 84 Lancet 2011 2012 806–810. 85 133. 180 1978 American Journal American Journal 27 (https://doi.org/10.1016/ 166 (https://doi. 529–532. (https://doi. (https://doi. :2 (https://doi. 753–756. 1999 1 (https://doi. 961–962. 1988 Archives 5 (https://doi. 198–200. 1998 (https:// American 117 R42

48 via freeaccess

European Journal of Endocrinology

57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 Review Fairney A, Jackson D&Clayton BE. Measurement ofserum Rubin LP, Posillico JT, Anast CS &Brown EM.Circulating levelsof Allgrove J, Adami S,Manning RM&O’Riordan JL.Cytochemical Wieland P, Fischer JA,Trechsel U, Roth HR,Vetter K, Schneider H Steichen JJ, Tsang RC, Gratton TL,Hamstra A&DeLuca HF. Vitamin Fleischman AR, Rosen JF, Cole J,Smith CM&DeLuca HF. Maternal Vidailhet M, Monin P, Andre M,Suty Y, Marchal C &Vert P. Neonatal Stuart C, Aceto T, Kuhn JP&Terplan K. Intrauterine Loughead JL, Mughal Z,Mimouni F, Tsang RC &Oestreich AE. Glass EJ &Barr DG.Transient neonatalhyperparathyroidism Schauberger CW &Pitkin RM.Maternal-perinatalcalcium Pitkin RM, Cruikshank DP, Schauberger CW, Reynolds WA, Delivoria-Papadopoulos M, Battaglia FC,Bruns PD&Meschia G. David L &Anast CS.Calciummetabolisminnewborninfants.The Trotter M &Hixon BB.Sequentialchangesinweight,density, and Givens MH &Macy IC.Thechemicalcompositionofthehuman Graham I, Gordan Gs,Loken HF, Blum A&Halden A.Effectof (https://doi.org/10.1136/adc.48.6.419) hypocalcaemia. parathyroid hormone,withparticular referencetosomeinfantswith doi.org/10.1203/00006450-199102000-00020) in humannewborns. biologically activeandimmunoreactiveintactparathyroidhormone org/10.1136/adc.60.2.110) Archives ofDiseaseinChildhood bioassay ofparathyroidhormoneinmaternalandcordblood. ajpendo.1980.239.5.E385) and Metabolism and calcitonininman. & Huch A.Perinatalparathyroidhormone,vitaminDmetabolites, NEJM198002073020603) of Medicine D inmaternal,cord,andneonatalblood. D homeostasisintheperinatalperiod:1,25-dihydroxyvitamin 3476(80)80030-8) of Pediatrics and fetalserum1,25-dihydroxyvitaminDlevelsatterm. Archives FrancaisesDePediatrie tomaternalhypoparathyroidism. hyperparathyroidism secondary org/10.1001/archpedi.1979.02130010073013) ofDiseasesChildren Journal hyperparathyroidism. Postmortemfindingsintwocases. 1990 tomaternalhypocalcemia. secondary ofcongenitalhyperparathyroidism Spectrum andnaturalhistory adc.56.7.565) Disease inChildhood tomaternalpseudohypoparathyroidism. secondary relationships. calcium homeostasis. Williams GA &Hargis GK.Fetalcalcitropichormonesandneonatal (https://doi.org/10.1152/ajplegacy.1967.213.2.363) fetal plasmas. Total, protein-bound,andultrafilterablecalciuminmaternal doi.org/10.1172/JCI107764) newborns. and phosphorusmetabolisminnormal,sick,hypocalcemic interrelationship ofparathyroidfunctionandcalcium,magnesium, org/10.1002/ar.1091790102) through oldage. percentage ashweightofhumanskeletonsfromanearlyfetalperiod fetus. (https://doi.org/10.1210/jcem-24-6-512) ofClinicalEndocrinologyand Metabolism Journal pregnancy andofthemenstrualcycleonhypoparathyroidism. 7 Journal ofBiologicalChemistry Journal 350–355. 1980 Journal ofClinicalInvestigation Journal , 1980 Americal Journal ofPhysiology Americal Journal Obstetrics Gynecology 1980 Archives ofDiseaseinChildhood 302 Anatomical Record (https://doi.org/10.1055/s-2007-999521) 97 1981 640–642. 315–319. 239 Pediatric Research Pediatrics American Journal ofPhysiology-Endocrinology American Journal E385–E390. 56 565–568. 1979 1980 1985 1980 (https://doi.org/10.1016/S0022- (https://doi.org/10.1056/ 1979 1974 133 1933 37 60 66 A Khanandothers (https://doi.org/10.1152/ American Journal ofPerinatology American Journal 1991 305–312. 67–70. (https://doi.org/10.1136/ 110–115. 77–82. 53 1974 179 102 New England Journal New EnglandJournal 1967 74–76. 29 1–18. 7–17. 1964 1973 (https://doi. 54 201–207. 213 287–296. (https://doi. (https://doi. Archives of 24 363–366. 48 512–516. 419–424. Journal Journal American (https:// (https://

pregnancy Hypoparathyroidism in 61 59 58 63 62 65 64 69 68 67 66 73 72 71 70 60 Leroyer-Alizon E, David L & Dubois PM. Evidence for calcitonin Leroyer-Alizon E, David L&Dubois PM.Evidenceforcalcitonin Dvir R, Golander A,Jaccard N,Yedwab G, Otremski I,Spirer Z on Chan AS &Conen PE.Ultrastructuralobservations Saggese G, Baroncelli GI,Bertelloni S&Cipolloni C.Intact MacIsaac RJ, Heath JA,Rodda CP, Moseley JM,Care AD,Martin TJ Papantoniou NE, Papapetrou PD,Antsaklis AJ,Kontoleon PE, Aceto TJr, Batt RE,Bruck E,Schultz RB&Perz YR.Intrauterine Shani H, Sivan E,Cassif E&Simchen MJ.Maternalhypercalcemia as Landing BH &Kamoshita S.Congenitalhyperparathyroidism Demirel N, Aydin M, Zenciroglu A,Okumus N,Cetinkaya S, Ayfer A, Gonc EN,Ebru Y, Deniz D&Nursen Y. Neonatal Bronsky D, Kiamko RT, Moncada R&Rosenthal IM.Intra-uterine Yamamoto M, Akatsu T, Nagase T&Ogata E. Comparisonof Caplan RH &Wickus GG. Reducedcalcitriolrequirments fortreating Wright AD, Joplin GF&Dixon HG.Post-partumhypercalcaemia Mestman JH. Parathyroiddisordersofpregnancy. by amnioticfluidcells. hormone-related proteinandhormonalmodulationofitssecretion & Weisman Y. Amnioticfluidandplasmalevelsofparathyroid of thyroidextracts. immunocytological localization,radioimmunoassay, andgelfiltration in thethyroidglandofnormalandanencephalichumanfetuses: Investigation Laboratory cytodifferentiation ofparafollicularcellsinthehumanfetalthyroid. org/10.1111/j.1651-2227.1991.tb11726.x) Acta PaediatricaScandinavica term neonatesandinhypocalcemicpreterminfants. parathyroid hormonelevelsduringpregnancy, inhealthy & Caple IW. Roleofthefetalparathyroidglandsand eje.0.1340437) of Endocrinology hormone inhumanfetusesandnewborns. parathyroid hormone-relatedproteinandintact Mesogitis SA &Aravantinos D.Circulating levelsofimmunoreactive 277–282. 1980 1966 hypoparathyroidism. hyperparathyroidism: acomplicationofuntreatedmaternal (https://doi.org/10.1016/j.ajog.2008.06.092) ofObstetricsandGynecology American Journal a possiblecauseofunexplainedfetalpolyhydramnion:caseseries. RD9910447) Fertility, and Development of calcium,magnesiumandinorganicphosphate. hormone-related proteinintheregulationofplacentaltransport 77 tomaternalhypoparathyroidism. secondary 149–154. distress. of neonatalrespiratory hypoparathyroidism andvitaminDdeficiency:anuncommoncause Yildiz YT tomaternal & Ipek MS.Hyperparathyroidismsecondary org/10.1177/000992280504400312) fractures. and vitaminDdeficiency:acauseofmultiplebone hyperparathyroidism duetomaternalhypoparathyroidism Pediatrics tomaternalhypoparathyroidism. hyperparathyroidism secondary hypocalcemic hypercalciuria between patientswithidiopathic Reproductive Medicine hypoparathyroidism duringlactation. Acasereport. org/10.1136/bmj.1.5635.23) in treatedhypoparathyroidism. 0005(98)80028-1) Perinatology 842–847. 50 26 316–321. 487–492. 1968 (https://doi.org/10.1530/eje.0.1330277) (https://doi.org/10.1179/146532809X440770) Clinical Pediatrics 1998 (https://doi.org/10.1016/S0022-3476(70)80245-1) 42 1996 22 606–613. (https://doi.org/10.1210/jcem-50-2-316) (https://doi.org/10.1210/jcem-26-5-487) Journal ofClinicalEndocrinologyand Metabolism Journal 485–496. 1993 134 Journal ofClinicalEndocrinologyandMetabolism Journal 1971 European Journal ofEndocrinology European Journal 1991 437–442. 2005 38 Downloaded fromBioscientifica.com at09/27/202112:47:40PM 1991 25 914–918. (https://doi.org/10.1016/S0146- 3 249–259. Annals ofTropical Paediatrics 447–457. BMJ 44 80 267–269. 1969 (https://doi.org/10.1530/ https://eje.bioscientifica.com 36–41. 1 (https://doi.org/10.1071/ 180 European Journal European Journal 23–25. 2008 Journal ofPediatrics Journal (https://doi. (https://doi. :2 Seminars in 199 Reproduction (https://doi. Journal of Journal 410.e1–410.e5. 1995 2009 133 R43 1970

29 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com

79 78 76 75 74 77 Review Tangpricha V. Maternalhypoparathyroidismduringpregnancy Kurzel RB &Hagen GA.Useofthiazidediureticstoreduce Gerloczy F &Farkas K.Hyperparathyroidisminthenewbornofa Bulloch, MN&Carroll DG.Whenonedrugaffects2patients:a Ilany J, Vered I &Cohen O.Theeffectofcontinoussubcutaneous Salle BL, Berthezene F, Glorieux FH,Delvin E,Berland M,David L, and lactationduetoanactivatingmutationofthecalcium- org/10.1055/s-2007-999516) ofPerinatalogy American Journal the hypercalciuria ofhypoparathyroidism duringpregnancy. Metabolism treatment withcalcitriol. Varenne J &Putet G.Hypoparathyroidismduringpregnancy: Hungaricae chronic hypoparathyroidmother. org/10.1177/0897190012442070) patient. sedation, infection,andhypertensioninthehospitalizedpregnant review ofmedicationforthemanagementnonlabor-relatedpain, 2013 on calciumhemostatis-acasereport. recombinant parathyroidhormone1-34infusionduringpregnancy 4583–4591. two disorders? in thecalcium-sensingreceptor:isitpossibletodifferentiate hypoparathyroidism andthosewithgain-of-functionmutations 29 807–810. Journal of Pharmacy Practice ofPharmacy Journal 1953 1981 (https://doi.org/10.1210/jcem.85.12.7035) Journal ofClinicalEndocrinologyMetabolism Journal 4 52 73. (https://doi.org/10.3109/09513590.2013.813473) 810–813. Journal of Clinical Endocrinology and ofClinicalEndocrinologyand Journal (https://doi.org/10.1210/jcem-52-4-810) 1990 Acta Medica Academiae Scientiarum Acta MedicaAcademiaeScientiarum 2012 7 Gynecological Endocrinology A Khanandothers 333. 25 (https://doi. 352–367. (https://doi. 2000 85

Accepted 12November2018 Revised versionreceived24October2018 Received 30June2018

pregnancy Hypoparathyroidism in 86 85 84 83 82 81 80 Caplan RH &Beguin EA.Hypercalcemia inacalcitriol-treated Mahadevan S, Kumaravel V&Bharath R.Calciumandbone Cardot-Bauters C. Hypoparathyroidismandpregnancy. Hatswell BL, Allan CA,Teng J, Wong P, Ebeling P, Wallace E, Fuller P Shah KH, Bhat S,Shetty S&Umakanth S.Hypoparathyroidismin Bakas P, Chados N,Hassiakos D,Creatsa M,Liapis A&Creatsas G. Sweeney L, Malabanan A&Rosen H.decreasedcalcitriolrequirement 76 hypoparathyroid womanduringlactation. 2012 disorders inpregnancy. ando.2016.04.011) D’Endocrinologie doi.org/10.1016/j.bonr.2015.05.005) lactation –areportof10cases. & Milat F. Managementofhypoparathyroidisminpregnancyand doi.org/10.1136/bcr-2015-210228) pregnancy. Gynecology and reviewoftheliterature. hypoparathyroidismduringpregnancy–acasereport Secondary 459–462. requirement immediatelypostpartum. during pregnancyandlactationwithawindowofincreased org/10.4158/EP10056.ED) sensing receptor. (3Pt2)485–489. 16 358–363. (https://doi.org/10.4158/EP09337.CR) 2015 British Medical Journal CaseReports British MedicalJournal 2016 42 Endocrine Practice (https://doi.org/10.4103/2230-8210.95665) 825–826. 77 Indian Journal ofEndocrinologyandMetabolism Indian Journal 172–175. Downloaded fromBioscientifica.com at09/27/202112:47:40PM Clinical andExperimentalObstetrics Bone Reports 2010 (https://doi.org/10.1016/j. Endocrinology Practice 16 Obstetrics Gynecology 522–523. 180 2015 2015 :2 3 15–19. 21 (https://doi. 228. Annales (https:// (https:// 2010 R44 1990 via freeaccess 16