AIIMS- NICU protocols 2010

Hypocalcemia in the Newborn

Ashish Jain*, Ramesh Agarwal, M Jeeva Sankar, Ashok Deorari, Vino ! "a#l Division of Neonatology, Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar, New Delhi 11 !" and #Department of Pediatrics, $indu %ao $ospital, New Delhi

A ress $or correspon ence% Dr Ashok Deorari "rofessor Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar, New Delhi 11 !" &mail' sdeorari(yahoo)com Downloaded from www.newbornwhocc.org

Abstract
$ypocalcaemia is a fre*uently o+served clinical and la+oratory a+normality in neonates) Ionic calcium is crucial for many +iochemical processes including +lood coagulation, neuromuscular e,cita+ility, cell mem+rane integrity, and many of the cellular en-ymatic activities) $ealthy term infants undergo a physiological nadir in serum calcium levels +y !./.0 hours of age) 1his nadir may drop to hypocalcemic levels in high/ris2 neonates including infants of dia+etic mothers, preterm infants and infants with perinatal asphy,ia) 1he early onset hypocalcemia which presents within 3! hours re*uires treatment with calcium supplementation for at least 3! hours) In contrast, late onset hypocalcemia usually presents after 3 days and re*uires longer term therapy)

Keywords: Hypocalcemia, Newborn, Therapy

&ntro #ction During the last trimester, calcium is actively transferred from mother to the fetus as demonstrated +y concentration in a significantly high level of total calcium

cord +lood compared to maternal serum)1 Parathyroid

hormone 4P1$5 and calcitonin 4615 do not cross the placental +arrier) 1he P1$ related peptide 4P1$rP5 is the main regulator of the positive calcium +alance across the placenta) Serum calcium 4S6a5 in the fetus is 1 /11 mg7d8 at term 41/! mg higher as compared to mother5) After +irth the S6a levels in new+orns depend on the P1$ secretion, dietary calcium inta2e, renal calcium rea+sor+tion, s2eletal calcium stores, and vitamin D status) $ence, after delivery, calcium levels start decreasing 4the rate and e,tent of decrease is inversely proportional to the gestation5 and reaches a nadir of 3)9/0)9 mg7d8 in healthy term +a+ies +y day ! of life) 1his drop in postnatal S6a may +e related to hypoparathyroidism, end organ unresponsiveness to parathyroid hormone
!

, a+normalities of vitamin D

meta+olism, hyperphosphatemia, hypomagnesemia, and hypercalcitonemia : which occurs +y 1!/!. hours of age) P1$ levels increase gradually in the first .0 hours of life and normal levels of S6a are regained +y : rd day of life). 1he efficacy of the intestinal a+sorption of calcium and the renal handling matures +y ! to . wee2s) 1his transition phase is responsi+le for the increased ris2 of early onset hypocalcemia in high/ris2 neonates) 'alci#m homeostasis in newborn

4 ;ody calcium e,ists in two ma<or compartments' s2eleton 4""=5 and e,tracellular fluid 41=5) 6alcium in the e,tracellular fluid is present in three forms' 4a5 +ound to al+umin 4. =5 4+5 +ound to anions li2e phosphorus, citrate, sulfate and lactate 41 =5 and 4c5 free ioni-ed form 49 =59) Ioni-ed calcium is crucial for many +iochemical processes including +lood coagulation, neuromuscular e,cita+ility, cell mem+rane integrity and function, and cellular en-ymatic and secretory activity)

Measurement of the total serum 6a concentration alone can +e misleading +ecause the relationship +etween total and ioni-ed 6a is not always linear) 6orrelation is poor when the serum al+umin concentration is low or, to a lesser degree, with distur+ances in acid/+ase status, +oth of which occur fre*uently in premature or sic2 infants) >ith hypoal+uminemia, the total 6a concentration will +e low while the ioni-ed fraction will +e normal unless some other factor is affecting 6a meta+olism) More so, falsely low ionic calcium levels may +e recorded in al2alosis and with heparin use) In general, the plasma calcium concentration falls +y )0 mg7d8 4 )! mmol785 for every 1) g7d8 fall in the plasma al+umin concentration)

Therefore, estimation of total calcium levels is a poor substitute for measuring the ionized levels.

De$inition $ypocalcemia is defined as total serum calcium of less than 3 mg7d8 41)39 mmol785 or ioni-ed calcium less than . mg7d8 41 mmol785 in preterm infants

and less than 0 mg7d8 4! mmol78? total5 or @1)! mmol78 4ionic5 in term neonates)A 1he S6a concentration is usually reported in different ways vi-) mg7d8, me*78 and mmol78 1he relationship +etween these units is related to the following e*uations' mmol78 B Cmg7d8 , 1 D E molecular wt, me*78 B mmol78 , valency) Since the molecular weight of calcium is . and the valence is F!, 1 mg7d8 is e*uivalent to )!9 mmol78 and to )9 me*78) 1hus, values in mg7dl may +e converted to molar units 4mmol785 +y dividing +y .)

(arly onset neonatal hypocalcemia )(NH*+able ,

1his condition is fairly common and seen within the first :/. days of life in following clinical settings' "remat#rity% 1his may +e related to premature termination of trans/placental supply, e,aggeration of the postnatal drop to hypocalcemic levels, increased calcitonin and diminished target organ responsiveness to parathyroid hormone) &n$ant o$ iabetic mother 4gestational and insulin dependent5' 1his may +e

related to increased calcium demands of a macrosomic +a+y) 3 Magnesium

depletion in mothers with dia+etes mellitus causes hypomagnesemic state in the fetus) 1his hypomagnesemia induces functional hypoparathyroidism and

hypocalcemia in the infant) A high incidence of +irth asphy,ia and prematurity in infants of dia+etic mothers are also contri+uting factors)

"erinatal asphy-ia%

Delayed introduction of feeds, increased calcitonin

production, increased endogenous phosphate load, renal insufficiency, and

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diminished

parathyroid

hormone

secretion

all

may

contri+ute

to

hypocalcemia) Maternal hyperparathyroi ism% 1his causes intrauterine hypercalcemia suppressing the parathyroid activity in the fetus resulting in impaired parathyroid responsiveness to hypocalcaemia after +irth) $ypocalcaemia may +e severe and prolonged) &ntra#terine growth restriction )&./R*% Infants with IGH% may have hypocalcemia if they are +orn preterm and7or have had perinatal asphy,ia) Small for gestational age is not an independent ris factor for !NH) &atrogenic% Any condition causing al2alosis increases the +inding of the calcium with al+umin and causes decrease in ionic calcium levels Screening is recommen e in at risk neonates 1)Preterm infants +orn +efore :! w2s !) Infants of dia+etic mothers on iv fluids :)Infants +orn after severe perinatal asphy,ia defined as Apgar score @ . at 1 minute of age +ime sche #le $or screening At !. and .0 hours of age in at ris2 +a+ies

'linical presentation%
1.

"symptomatic: &N$ is usually asymptomatic unli2e the late onset variety and is incidentally detected)

2.

Symptomatic: 1he symptoms may +e of neuromuscular irrita+ility / myoclonic <er2s, <itteriness, e,aggerated startle, and sei-ures) 1hey may represent the cardiac involvement li2e/ tachycardia, heart failure, prolonged I1 interval, decreased contracti+ility) More often they are non/ specific and not related to the severity of hypocalcemia) Apnea, cyanosis, tachypnoea, vomiting and laryngospasm are other symptoms that are noted)

Diagnosis
1.

#aboratory: 1otal or ioni-ed serum calcium 4total @3 mg7d8 or ioni-ed @.) mg7d85) Ioni-ed calcium is the preferred mode for diagnosis of

hypocalcemia)
2.

!$%: Io1c J )!! seconds or I1c J ).9 seconds I1c B I1 interval in seconds %/% interval in seconds

Io1c B Io1 interval in seconds %/% interval in seconds

4I1 interval is measured from origin of * wave to end of 1 wave on &6H? Io1 is measured from origin of * wave to origin of 1 wave5)

" diagnosis of hypocalcemia based only on !$% criteria is li ely to yield a high false positive rate. "lthough these parameters have good correlation with hypocalcaemia in low birth weight infants &sensitivity of ''( and specificity of )*.'(+,, neonates suspected to have hypocalcemia by !$% criteria should have the diagnosis confirmed by

measurement of serum calcium levels.

+reatment o$ early onset hypocalcemia 41 ml of calcium gluconate 41 =5 gives " mg of elemental calcium5
1.

-atients at increased ris

of hypocalcemia& prophylactic+ :

Preterm infants 4:! wee2s5, sic2 infants of dia+etic mothers and those with severe perinatal asphy,ia should receive . mg72g7day of

elemental calcium 4. m872g7day of 1 = calcium gluconate5 for prevention of early onset hypocalcemia) $owever there is not sufficient evidence for this practice) Infants tolerating oral feeds may receive this calcium orally * A hourly) 1herapy should +e continued for : days) Kral calcium preparations have high osmolality and should +e avoided in +a+ies at higher ris2 of necroti-ing enterocolitis)
2.

-atients diagnosed to have asymptomatic hypocalcemia&on screening+' Infants detected to have hypocalcemia on screening and who are otherwise asymptomatic should receive 0 /mg72g7day

elemental calcium 40 m872g7day of 1 = calcium gluconate5 for .0 hours)

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1his may +e tapered to 9 = dose for another !. hours and then discontinued) Neonates tolerating oral feeds may +e treated with oral calcium 4IL preparation may +e used orally5)
3.

-atients diagnosed to have symptomatic hypocalcemia ' 1hese patients should receive a +olus dose of ! m872g7dose diluted 1'1 with 9= de,trose over 1 minutes under cardiac monitoring) >hen there is severe hypocalcaemia with poor cardiac function, calcium chloride ! mg72g may +e given through a central line over 1 /: minutes 4as

chloride in comparison to gluconate does not re*uire the meta+olism +y the liver for the release of free calcium5) 1his should +e followed +y a continuous IL infusion of 0 mg72g7day elemental calcium for .0 hours) 6ontinuous infusion is preferred to IL +olus doses 41 m872g7dose * A hourly5) 6alcium infusion should +e dropped to 9 = of the original dose for the ne,t !. hours and then discontinued) 1he infusion may +e replaced with oral calcium therapy on the last day) Normal calcium values should +e documented at .0 hours +efore weaning the infusion) "ll categories of hypocalcemia should be treated for at least '. hours. $ontinuous infusion is preferred to /0 bolus doses.

Symptomatic hypocalcemia should be treated with a continuous infusion for at least *, hours. &refer "lgorithm 1+

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Management o$ early neonatal hypocalcaemia Hypocalcemia

+otal ser#m 'al 01 mg2 l

Algorithm 1

"symptomatic 0 mg72g7day for .0 hrs 40 m872g7day of 1 = calcium gluconate 5 1aper to . mg72g7day for one day 1hen stop

Symptomatic ;olus of ! m872g calcium gluconate 1'1 diluted with 9 = de,trose over 1 minutes under cardiac monitoring Mollowed +y continuous infusion 0 mg72g7day for .0 hrs 40 m872g7day of 1 = calcium gluconate 5 Document normal calcium at 48 hrs 1hen taper to . mg72g7day for one day 1hen stop -rophylactic

Preterm< 32 wks, sick IDM, severe asphyxia

. mg72g7day for : days 4.ml72g7day of 1 = calcium gluconate 5 IL or oral if can tolerate per oral reatment is !or "2 hours #ontinuous in!usion is $etter than $olus %ymptomatic $a$ies treatment is 48 hrs continuous in!usion

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&n case the hypoclcemia oes not correct by the above by, 13 ho#rs than investigate $or ca#ses o$ late hypocalcemia)/ %efer 1a+le ! "reca#tions an si e e$$ects ;radycardia and arrhythmia are 2nown side effects of +olus IL calcium administration) $ence, +olus doses of calcium should +e diluted 1'1 with 9= de,trose and given slowly 4over 1 to : minutes5 under cardiac monitoring) An um+ilical venous catheter 4GL65 may +e used for administration of calcium only after ensuring that the tip is positioned in the inferior vena cava) $epatic necrosis may occur if the tip of the GL6 lies in a +ranch of the portal vein) Gm+ilical artery catheter 4GA65 should never +e used for giving calcium in<ections) Accidental in<ection into the GA6 may result in arterial spasms and intestinal necrosis) S2in and su+cutaneous tissue necrosis may occur due to e,travasation) Hence, /0 sites where calcium is being infused should be chec ed at least 2 . hourly to monitor for e3travasation and avoid subcutaneous tissue necrosis.

"rolonge or resistant hypocalcemia 1his condition should +e considered in the following situations' Symptomatic hypocalcemia unresponsive to ade*uate doses of calcium therapy Infants needing calcium supplements +eyond 3! hours of age $ypocalcemia presenting at the end of the first wee2)

1hese infants should +e investigated for causes of 8N$ 4see +elow5)

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4ate onset neonatal hypocalcemia )4NH*

1his condition is rare as compared to &N$) It usually presents at the end of the first wee2 of life) It is usually symptomatic in the form of neonatal tetany or sei-ures) 1his is usually caused +y high phosphate inta2e 4iatrogenic5) 1he causes are listed in ta+le !)

(-amination' Such +a+ies should have an e,amination with special emphasis on cataracts, hearing, and any evidence of +asal ganglia involvement 4movement disorder5) &nvestigations 1hese should +e considered in 8N$ or if the hypocalcemia does not respond to ade*uate doses of calcium) 1he wor2 up of such a case is very important to determine the etiology) 1he same can +e planned as per the ta+le :) If hypocalcemia is present with hyperphosphatemia and a normal renal function, hypoparathyroidism should +e strongly suspected +reatment o$ 4NH 1he treatment of 8N$ is specific to etiology and may in certain diseases +e life/ long)
,5

Hypomagnesemia: Symptomatic hypocalcemia unresponsive to ade*uate

doses of IL calcium therapy is usually due to hypomagnesemia) It may present either as &N$ or later as 8N$) 1he neonate should receive ! doses of )! m872g

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of 9 = MgSK. in<ection, 1! hours apart, deep IM followed +y a maintenance dose of )! m872g7day of 9 = MgSK., PK for : days) 35 High phosphate load: 1hese infants have hyperphosphatemia with near normal calcium levels) &,clusive +reast/feeding should +e encouraged and top feeding with cowNs mil2 should +e discontinued) Phosphate +inding gels should +e avoided) 6. Hypoparathyroidism) 1hese infants tend to +e hyperphosphatemic and hypocalcemic with normal renal function) &levated phosphate levels in the a+sence of e,ogenous phosphate load 4cowNs mil25 and presence of normal renal functions indicates parathormone inefficiency) It is important to reali-e that if the phosphate level is very high, then adding calcium will lead to calcium deposition and tissue damage) 1hus attempts should +e made to reduce the phosphate 4so as to 2eep the calcium and the phosphate product less than 9951 ) 1hese neonates need supplementation with calcium 49 mg72g7day in : divided doses5 and 1,!94K$5! Litamin D: 4 )9/1 g7day5) Syrups with 1!9 mg and !9 mg per 9ml of calcium are availa+le)1,!94K$5 ! vitamin D: 4calcitriol5 is availa+le as )!9 g capsules) 1herapy may +e stopped in

hypocalcemia secondary to maternal hyperparathyroidism after A wee2s) 75 0itamin 4 deficiency states: 1hese +a+ies have hypocalcemia associated with hypophosphatemia due to an intact parathormone response on the 2idneys) 1hey +enefit from Litamin D: supplementation in a dose of : /A ng72g7day Monitoring
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1he +a+y is monitored for the S6a, and phosphate, !. hour urinary calcium, and calcium creatinine ratio) 1ry to 2eep the calcium in the lower range as defective distal tu+ular a+sorption leads to hypercalciuria and

nephrocalcinosis)11 "rognosis an o#tcome Most cases of early neonatal hypocalcemia resolve within .0/3! hours without any clinically significant se*uelae) 8ate neonatal hypocalcemia secondary to e,ogenous phosphate load and magnesium deficiency also responds well to phosphate restriction and magnesium repletion) >hen caused +y hypoparathyroidism, hypocalcemia re*uires continued therapy with vitamin D meta+olites and calcium salts) 1he period of therapy depends on the nature of the hypoparathyroidism which can +e transient, last several wee2s to months, or +e permanent)

Re$erences% 1) Schau+erger 6>, Pit2in %M, Maternal/perinatal calcium relationships) K+stet Hynecol 1"3"?9:'3./A !) 8inarelli 8H, ;o+i2 O, ;o+i2 6) New+orn urinary cyclic AMP and developmental responsiveness to parathyroid harmone) Pediatrics 1"3!?9 '1./!:

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3.

$illman, %a<anasathit S, slatopols2y &, haddad OH) Serial measurements of serum calcium, magnesium, parathyroid hormone, calcitonin, and !9/ hydro,y/vitamin D in premature and term infants during the first wee2 of life) Pediatr %es 1"33?11'30"/..

4.

Salle ;8, Delvin &&, 8apillonne A, ;ishop NO, Hlorieu, M$) Perinatal meta+olism of vitamin D) Am O 6lin Nutr ! ?3149 suppl5'1:13S/!.S)

9) Singh O, Moghal N, Pearce S$, 6heetham 1) 1he investigation of hypocalcaemia and ric2ets) Arch Dis 6hild) May ! :?00495' . :/3)

A) Kden O, ;ourgeois M) Neonatal endocrinology) Indian O Pediatr ! ?A3'!13/!:

3) Schwart- %, 1eramo PA) &ffects of dia+etic pregnancy on the fetus and new+orn) Semin Perinatol !
8.

?!.'1! /:9

Ne2vasil %, Ste<s2al O, 1uma A) Detection of early onset neonatal hypocalcemia in low +irth weight infants +y I/1c and I/o1c interval measurement) Acta Paediatr Acad Sci $ung) 1"0 ?!14.5'! :/1 )

") Mar, SO) $yperparathyroid and hypoparathyroid disorders) N &ngl O Med !

10.

?:.:'10A:/39

Sharma O, ;a<pai A, Pa+ra M, Menon PSN) $ypocalcemia 6linical, +iochemical, radiological Profile and follow/up in a 1ertiary hospital in India) Indian Pediatrics ! !? :"' !3A/!0!)

11.

%igo O, 6urtis MD) Disorders of 6alcium, Phosphorus and Magnesium Meta+olism)In %ichard O Martin, Avory A Manaroff, Michele 6 >alsh 4eds5 )

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Neonatal Perinatal Medicine/ Diseases of the fetus and infant) 0th edition? &lsevier, Pihladelphia, ! A' p19 0/1.

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1a+le 1 6auses of early onset hypocalcaemia Prematurity Preeclampsia Infant of Dia+etic mother Perinatal stress7 asphy,ia Maternal inta2e of anticonvulsants 4pheno+ar+itone, phenytoin sodium5 Maternal hyperparathyroidism Iatrogenic 4al2alosis, use of +lood products, diuretics, phototherapy, lipid infusions etc5

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1a+le ! 'a#ses o$ late onset hypocalcemia /ncreased phosphate load 6ow mil2, renal insufficiency Hypomagnesemia 0itamin 4 deficiency Maternal vitamin D deficiency Mala+sorption %enal insufficiency $epato+iliary disease -TH resistence 1ransient neonatal pseudohypoparathyroidism Hypoparathyroidism Primary $ypoplasia, aplasia of parathyroid glands / 4Di HeorgeNs syndrome5, 6A16$ !! syndrome 4cardiac anomaly, a+normal facies, thymic aplasia, cleft palate, hypocalcaemia with deletion on chromosome !!5 Activating mutations of the calcium sensing receptor 46S%5 %econ&ary Maternal hyperparathyroidism 5etabolic Syndromes Penny/caffey syndrome 8ong/chain fatty acyl 6oA dehydrogenase deficiency Pearns/sayre syndrome /atrogenic 6itrated +lood products 8ipid infusions ;icr+onate therepy Diueretics 4loop diuretics5 Hlucocorticosteriods Phosphate therepy Gse of Aminoglycosides 4mainly gentamicin5 as single dose Al2alosis Phototherapy

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1a+le : &nvestigations re8#ire in in$ants with persistent 2 late onset hypocalcaemia /nvestigations re2uired
9irst line Serum phosphate Serum al2aline phosphatase 4SAP5 8iver function tests %enal function tests Q ray chest7 wrist Arterial p$ Secon line Serum magnesium Serum parathormone levels 4P1$5 Grine calcium creatinine ratio Maternal calcium, phosphate, and al2aline phosphatase :thers 61 +rain for calcification &chocardiography Litamin D levels 41,!9 D:5 $earing evaluation Serum cortisol 1hyroid function tests

S N o
1 ! : . 9 A

4isorder causing hypocalcaemia

$ypoparathyroidism Pseudo $ypoparathyroidim 6hronic renal failure $ypomagnesemia LDD%1 LDD% II

6indings
$igh ' Phosphate 8ow ' SAP, P1$, 1,!9 D: $igh ' SAP, P1$, Phosphate 8ow ' 1,!9 D: $igh ' phosphate, SAP, P1$, p$ 4acidotic5, deranged %M1 8ow ' 1,!9 D: $igh ' P1$ 8ow ' Phosphate, Mg,1,!9 D: $igh ' SAP, P1$ 8ow ' Phosphate, 1,!9 D: $igh ' SAP, 1, !9 D:, P1$ 8ow ' Phosphate

'(DD), vitamin D &epen&ent rickets*

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