Journal of Perinatology (2006) 26, 371–374 r 2006 Nature Publishing Group All rights reserved. 0743-8346/06 $30 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Skeletal demineralization and fractures caused by fetal magnesium toxicity

KE Wedig1, J Kogan2, EK Schorry2 and JA Whitsett3 1University of Cincinnati College of Medicine, Department of Neonatology & Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 2Department of Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA and 3Department of Neonatology & Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

clinical course of triplets with prolonged exposure to magnesium Two surviving female infants, born from a triplet pregnancy at 30 weeks for tocolytic therapy. The surviving infants subsequently developed gestation, were noted to have severe osteopenia and multiple fractures multiple fractures and severe osteopenia that complicated their diagnosed at 20 days of age. Their mother had been treated for preterm postnatal recovery. labor with intravenous magnesium sulfate from week 22 until their birth at 30 weeks gestation. At birth, the triplets exhibited craniotabes with enlarged fontanelles and sutures. All developed Respiratory Distress Syndrome (RDS) Case report and the two surviving infants required prolonged respiratory support. Serum Triplet infants were conceived by in vitro fertilization to a 32-year- calcium and phosphate levels were normal and alkaline phosphatase levels old G2P0010 mother. The pregnancy was complicated by were increased. The infants were treated with supplements of calcium and gestational diabetes requiring insulin. Screening for congenital phosphorous, with resultant healing of the multiple fractures without viral infections was negative. Premature rupture of the membranes deformity. Fetal magnesium toxicity impairs bone mineralization and can of triplet A occurred at 20 weeks gestation. Preterm labor began lead to serious bone demineralization that may cause fractures in the at 22 weeks gestation, and was treated with terbutaline, sulindac, newborn period that complicate recovery from respiratory disease. Early indomethacin and intravenous magnesium sulfate, 2–2.5 g/h, recognition and treatment may minimize complications related to for the duration of pregnancy (8.5 weeks) until birth at osteopenia caused by fetal magnesium toxicity. 30 weeks gestation. During this time, the mother was maintained Journal of Perinatology (2006) 26, 371–374. doi:10.1038/sj.jp.7211508 on strict bed rest and treated with prenatal vitamins and 1.25 g Keywords: osteopenia, fractures, magnesium of calcium carbonate daily. She was treated with a course of betamethasone at 23 weeks gestation to induce pulmonary maturation of the expected preterm infants. The infants were Introduction delivered by cesarean section for suspected chorioamnionitis and Continuous, prolonged intravenous infusion of magnesium sulfate polyhydramnios. Triplet A, a male, weighed 1030 g, triplet B, for tocolysis was first reported by Wilkins et al. in 1986.1 Thereafter, a female, weighed 1450 g, and triplet C, a female, weighed 920 g. Lamm2 reported that two infants developed bone changes after The infants were intubated in the delivery room and treated prolonged exposure to magnesium in utero. Since these first with surfactant for prevention of respiratory distress syndrome. reports, approximately 25 infants with bone changes following All infants were noted to have large fontanelles, widely split sutures, magnesium exposure in utero have been described.1,3–6 In those and craniotabes at birth. reports, the severity of osteopenia was correlated with prolonged Triplet A died on the second day of life with Escherichia coli exposure5 intrauterine growth retardation,6 and multiplicity of sepsis. The autopsy revealed a normal thymus and kidneys. Triplets birth.5 As magnesium crosses the placenta, perhaps competing for B and C were extubated to continuous positive airway pressure calcium transport or at cellular sites, skeletal abnormalities in (CPAP) in the first week of life; however, both developed chronic infants are likely related to the effects of prolonged magnesium respiratory insufficiency and were reintubated. Enteral feedings exposure on calcium homeostasis in utero. Herein, we describe the with breast milk were begun on the third day of life, and supplemented with parenteral nutrition for the first 2 weeks of life. Correspondence: Dr KE Wedig, University of Cincinnati College of Medicine, Cincinnati Chest X-ray on day of life one (Figure 1) revealed thin Children’s Hospital Medical Center, 3333 Burnet Avenue ML 7009, Cincinnati, demineralized ribs and demineralized humeri. At 20 days of age OH 45229-3039, USA. E-mail: [email protected] skeletal surveys revealed fractures of the humeri, radii, ulnae and Received 7 October 2005; revised 16 March 2006; accepted 21 March 2006 tibiae, with deformities of the femurs (Figure 2). Skeletal Fractures caused by fetal magnesium toxicity KE Wedig et al 372

Vitamin D that was reduced to 800 IU per day. They developed bronchopulmonary dysplasia (BPD) and were treated with CPAP, oxygen, and later required the addition of spironolactone and chlorothiazide and received dexamethasone for 17 and 8 days for treatment of BPD. The surviving infants recovered and were discharged to home at term adjusted age on oxygen and diuretics and breast milk supplemented with Human Milk Fortifier and NeoSure powder to give 30 cal/oz and 80 mg/kg/day calcium. Bone mineral density and bone mineral content performed on the lumbar spine with Hologic QDR-4500A, Hologic Inc., Waltham, MA, USA, near the time of discharge was low in triplet B, but normalized to weight in triplet C.7 25-Hydroxy vitamin D and 1,25 dihydroxy vitamin D were elevated and vitamin D supplementation was discontinued (Table 1). As a result of persistent decreased bone mineral density, breast milk was changed to formula, Similac Special Care with iron supplemented to 30 calorie with NeoSure powder with higher content of calcium (164 mg/kg) and Figure 1 Day of life 1-Ribs are thin and demineralized. phosphorous (84 mg/kg). (Private conversation R Tsang, MD). At 6 months of age (three months-adjusted age (3mAA)) bone mineral density had normalized and both infants were weaned from supplemental oxygen and diuretics. At 18 months of age, both infants were walking, their weights and lengths were at the 3rd percentile, and there was no evidence of bone abnormalities or deformities.

Discussion These triplet infants were chronically exposed to high concentration of magnesium sulfate for treatment of preterm labor. Prolonged duration of high doses of magnesium, maternal bed rest, diabetes and the multiplicity of gestation may have further enhanced their susceptibility to magnesium toxicity. The two surviving infants developed severe skeletal abnormalities and multiple fractures related to osteopenia. Each of the triplets had developed signs of skeletal abnormalities that were recognized at birth with large fontanelles and craniotabes. Severe osteopenia and fractures were not recognized until the third week of life. The Figure 2 Day of life 20-Bone in bone appearance in tibiae, Erlenmeyer clinical course of these infants with prolonged requirement for flask appearance of the distal femurs, proximal metaphyseal fractures of CPAP and oxygen may have been influenced by the multiple rib femurs and tibiae. fractures, which potentially restricted mobility or stability of the chest during the early period of their recovery from respiratory abnormalities were less severe in triplet C. Examination at 20 days distress syndrome. of age of the surviving infants demonstrated widely split The differential diagnosis of severe osteopenia and fractures in fontanelles, normal sclerae, and the absence of dysmorphic the early newborn period includes osteogenesis imperfecta, features. Serum calcium and phosphorous were normal at birth congenital hypophosphatasia, rickets of prematurity, and vitamin and at 20 days of age. Alkaline phosphatase was markedly elevated D-dependent rickets. However, these diagnoses were considered at the time of diagnosis, and decreased by the time of discharge unlikely on the basis of clinical and laboratory evidence. There was (Table 1). Phosphoethanolamine levels were normal in both no family history of osteogenesis imperfecta, fractures, hearing infants, ruling out congenital hypophosphatasia. abnormalities or short stature, and the likelihood that three non- The infants were treated with increasing concentrations of identical triplets shared this rare dominantly inherited disorder was calcium and phosphorus supplements and provided with 1200 IU of considered unlikely. Congenital hypophosphatasia, an autosomal

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Table 1 Anthropomorphic and lab data

BMCa BMDa Vit D 1.25 Vit D Ca P Mg Alk Phos Wt L (g) (g/cm2) (mg/ml) (pg/ml) (mg/dl) (mg/dl) (meq/l) (IU/I) (g) (cm)

Triplet ‘B’ Birth 9.3 4.2 2.9 NA 1450 40 DOL#20 9.6 2.5 1.7 1443 Term 0.89 0.167 132 88.4 10.9 7.1 NA 497 3060 46 3mAA 2.87 0.296 65 58 4380 57.5

Triplet ‘C’ Birth 9.4 4.4 4.6 NA 920 31 DOL#20 9.6 4.1 1.6 1547 Term 1.03 0.206 152.6 98.4 11 6.5 NA 573 2300 41 3mAA 2.33 0.272 NA NA 3795 52

Abbreviations: 3mAA, three months-adjusted age; NA, not applicable. aFor reference graph – Koo et al7 recessive disorder caused by mutations in the alkaline phosphatase gene, was ruled out since the phosphoethanolamine levels were normal and alkaline phosphatase levels were elevated. Rickets of prematurity and vitamin D-dependent rickets generally present considerably later than 3 weeks of age. Radiographic findings of rickets of prematurity and vitamin D-dependent rickets are distinct from those in the present infants in which provisional zones of calcification were preserved. Taken together, it is most likely that the infants’ skeletal abnormalities were caused by fetal magnesium toxicity. It is known that antenatal magnesium crosses the placenta and leads to Figure 3 Proposed fetal response to magnesium exposure. normal calcium, elevated 1,25 dihydroxy- vitamin D and a hypermagnesemic state in the newborn. Extremely high levels of magnesium can be associated with weakness and poor The primary therapy for magnesium toxicity is the restoration of respiratory effort at birth8 as well as radiographic bone tissue stores of calcium and phosphorous. Even maximum abnormalities in the newborn.3,4 Fetal magnesium toxicity may supplementation of breast milk proved inadequate for the desired be associated with altered serum and urine calcium levels, and treatment of the fractures and for remineralization.13 suppressed parathyroid function.9,10 Figure 3. Hypermagnesemia Supplementation of vitamin D beyond 200 IU/day to enhance is also thought to inhibit calcification of osteoid directly by calcium absorption and retention was likely unnecessary and led to competition of magnesium with calcium. It has been suggested elevated levels. Time for repair of fractures and restoration of bone that stress in the newborn period and prematurity result in mineral content observed in these infants may have been further decreased excretion of magnesium and, therefore, an extended delayed by treatment with diuretics, glucocorticoid, and delays in period of hypermagnesemia.9 physical therapy related to concerns for their fragility.14 The The more severe skeletal abnormalities which include decreased clinical course of these infants supports the need for anticipating bone density, widening of the metaphyseal plates with elongated and diagnosing fetal magnesium toxicity. Prompt recognition and radiolucent zone but intact temporary zone of calcification, treatment of fetal magnesium toxicity with appropriate nutritional beading of the costochondral junctions and thinning of the support may improve bone mineralization and avoid fractures. calvaria are seen more often in infants who are exposed to magnesium starting in the second trimester.1 Increased duration of magnesium exposure as well as prematurity, multiplicity References and prenatal complications such as gestational diabetes all 1 Lamm CI, Norton KI, Murphy R, Wilkins IA, Rabinowitz JG. Congenital have been shown to contribute to the severity of the bone rickets associated with magnesium sulfate infusion for tocolysis. J Pediatr 11,12 disease. 1988; 113: 1078–1082.

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2 Wilkins IA, Goldberg JD, Phillips RN, Bacall CJ, Chervenak FA, Berkowitz RL. 9 Donovan EF, Tsang RC, Steichen JJ, Strub RJ, Chen I, Chen Ml. Neonatal Long term use of magnesium sulfate as a tocolytic agent. Obstet Gynecol hypermagnesemia: effect on parathyroid hormone and calcium homeostasis. 1986; 67: 38S–40S. J Pediatr 1980; 96: 305–310. 3 Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal 10 Rantonen T, Kaapa P, Jalonen J, Ekblad U, Peltola O, Valimaki I et al. metaphyses in the neonate. AJR 1989; 152: 1071–1072. Antenatal magnesium sulphate exposure is associated with prolonged PTH 4 Holcomb WL, Shackelford GD, Petrie RH. Magnesium tocolysis and neonatal suppression in preterm neonates. Acta Paediatr 2001; 90: 278–281. bone abnormalities – a controlled study. Obstet Gynecol 1991; 78: 611–614. 11 Matsuda Y, Meeda Y. Effect of magnesium sulfate treatment on neonatal 5 Santi MD, Henry GW, Douglas GL. Magnesium sulfate treatment of preterm bone abnormalities. Gynecol Obstet Invest 1997; 44(2): 82–88. labor as a cause of abnormal bone mineralization. J Pediatr Orthop 1994; 12 Koo W, Tsang R. Calcium Magnesium, Phosphorus and Vitamin D in 14: 249–253. Nutritional Needs of the Preterm Infant. Williams & Wilkins: Baltimore, 6 Malaeb SN, Rassi AI, Haddad MC, Seoud MA, Yunis KA. Bone mineralization MD, 1993; P149. in newborns whose mothers received magnesium sulfate for tocolysis of 13 Tsukahara H, Kobata R, Tamura S, Mayumi M. Neonatal bone premature labor. Pediatr Radiol 2004; 34: 384–386. abnormalities attributable to maternal administration of magnesium sulfate. 7 Koo W, Hockman E. Physiologic predictors of lumbar spine bone mass in Pediatr Radiol 2004; 34(8): 673–674. neonates. Pediatr Res 2000; 48: 485–489. 14 Moyer-Mileur LJ, Brunstetter V, McNaught TP, Gill G, Chan GM. 8 Mittendorf R, Pryde PG, Lee KS. Association between use of antenatal Daily physical activity program increases bone mineralization and magnesium sulfate in preterm labor and adverse health outcomes in growth in preterm very low birth weight infants. Pediatrics 2000; 106: infants. Am J Obstet Gynecol 2003; 189(2): 613. 1088–1092.

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