Perinatal/Neonatal Case Presentation

Skeletal demineralization and fractures caused by fetal magnesium toxicity


Two surviving female infants, born from a triplet pregnancy at 30 weeks gestation, were noted to have severe osteopenia and multiple fractures diagnosed at 20 days of age. Their mother had been treated for preterm 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) and the two surviving infants required prolonged respiratory support. Serum calcium and phosphate levels were normal and alkaline phosphatase levels were increased. The infants were treated with supplements of calcium and phosphorous, with resultant healing of the multiple fractures without deformity. Fetal magnesium toxicity impairs bone mineralization and can lead to serious bone demineralization that may cause fractures in the newborn period that complicate recovery from respiratory disease. Early recognition and treatment may minimize complications related to osteopenia caused by fetal magnesium toxicity.


Continuous, prolonged intravenous infusion of magnesium sulfate for tocolysis was first reported by Wilkins et al. in 1986.1 Thereafter, Lamm2 reported that two infants developed bone changes after prolonged exposure to magnesium in utero. Since these first reports, approximately 25 infants with bone changes following magnesium exposure in utero have been described.1, 3, 4, 5, 6 In those reports, the severity of osteopenia was correlated with prolonged exposure5 intrauterine growth retardation,6 and multiplicity of birth.5 As magnesium crosses the placenta, perhaps competing for calcium transport or at cellular sites, skeletal abnormalities in infants are likely related to the effects of prolonged magnesium exposure on calcium homeostasis in utero. Herein, we describe the clinical course of triplets with prolonged exposure to magnesium for tocolytic therapy. The surviving infants subsequently developed multiple fractures and severe osteopenia that complicated their postnatal recovery.

Case report

Triplet infants were conceived by in vitro fertilization to a 32-year-old G2P0010 mother. The pregnancy was complicated by gestational diabetes requiring insulin. Screening for congenital viral infections was negative. Premature rupture of the membranes of triplet A occurred at 20 weeks gestation. Preterm labor began at 22 weeks gestation, and was treated with terbutaline, sulindac, indomethacin and intravenous magnesium sulfate, 2–2.5 g/h, for the duration of pregnancy (8.5 weeks) until birth at 30 weeks gestation. During this time, the mother was maintained on strict bed rest and treated with prenatal vitamins and 1.25 g 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 delivered by cesarean section for suspected chorioamnionitis and polyhydramnios. Triplet A, a male, weighed 1030 g, triplet B, a female, weighed 1450 g, and triplet C, a female, weighed 920 g. The infants were intubated in the delivery room and treated with surfactant for prevention of respiratory distress syndrome. All infants were noted to have large fontanelles, widely split sutures, and craniotabes at birth.

Triplet A died on the second day of life with Escherichia coli sepsis. The autopsy revealed a normal thymus and kidneys. Triplets B and C were extubated to continuous positive airway pressure (CPAP) in the first week of life; however, both developed chronic respiratory insufficiency and were reintubated. Enteral feedings with breast milk were begun on the third day of life, and supplemented with parenteral nutrition for the first 2 weeks of life. Chest X-ray on day of life one (Figure 1) revealed thin demineralized ribs and demineralized humeri. At 20 days of age skeletal surveys revealed fractures of the humeri, radii, ulnae and tibiae, with deformities of the femurs (Figure 2). Skeletal abnormalities were less severe in triplet C. Examination at 20 days of age of the surviving infants demonstrated widely split fontanelles, normal sclerae, and the absence of dysmorphic features. Serum calcium and phosphorous were normal at birth and at 20 days of age. Alkaline phosphatase was markedly elevated at the time of diagnosis, and decreased by the time of discharge (Table 1). Phosphoethanolamine levels were normal in both infants, ruling out congenital hypophosphatasia.

Figure 1

Day of life 1-Ribs are thin and demineralized.

Figure 2

Day of life 20-Bone in bone appearance in tibiae, Erlenmeyer flask appearance of the distal femurs, proximal metaphyseal fractures of femurs and tibiae.

Table 1 Anthropomorphic and lab data

The infants were treated with increasing concentrations of calcium and phosphorus supplements and provided with 1200 IU of 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 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.


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 clinical course of these infants with prolonged requirement for CPAP and oxygen may have been influenced by the multiple rib fractures, which potentially restricted mobility or stability of the chest during the early period of their recovery from respiratory distress syndrome.

The differential diagnosis of severe osteopenia and fractures in the early newborn period includes osteogenesis imperfecta, congenital hypophosphatasia, rickets of prematurity, and vitamin D-dependent rickets. However, these diagnoses were considered unlikely on the basis of clinical and laboratory evidence. There was no family history of osteogenesis imperfecta, fractures, hearing abnormalities or short stature, and the likelihood that three non-identical triplets shared this rare dominantly inherited disorder was considered unlikely. Congenital hypophosphatasia, an autosomal 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 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 respiratory effort at birth8 as well as radiographic bone abnormalities in the newborn.3, 4 Fetal magnesium toxicity may be associated with altered serum and urine calcium levels, and suppressed parathyroid function.9, 10 Figure 3. Hypermagnesemia is also thought to inhibit calcification of osteoid directly by competition of magnesium with calcium. It has been suggested that stress in the newborn period and prematurity result in decreased excretion of magnesium and, therefore, an extended period of hypermagnesemia.9

Figure 3

Proposed fetal response to magnesium exposure.

The more severe skeletal abnormalities which include decreased bone density, widening of the metaphyseal plates with elongated radiolucent zone but intact temporary zone of calcification, beading of the costochondral junctions and thinning of the 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 and prenatal complications such as gestational diabetes all have been shown to contribute to the severity of the bone disease.11, 12

The primary therapy for magnesium toxicity is the restoration of tissue stores of calcium and phosphorous. Even maximum supplementation of breast milk proved inadequate for the desired treatment of the fractures and for remineralization.13 Supplementation of vitamin D beyond 200 IU/day to enhance calcium absorption and retention was likely unnecessary and led to elevated levels. Time for repair of fractures and restoration of bone mineral content observed in these infants may have been further delayed by treatment with diuretics, glucocorticoid, and delays in physical therapy related to concerns for their fragility.14 The clinical course of these infants supports the need for anticipating and diagnosing fetal magnesium toxicity. Prompt recognition and treatment of fetal magnesium toxicity with appropriate nutritional support may improve bone mineralization and avoid fractures.


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Correspondence to K E Wedig.

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Wedig, K., Kogan, J., Schorry, E. et al. Skeletal demineralization and fractures caused by fetal magnesium toxicity. J Perinatol 26, 371–374 (2006).

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  • osteopenia, fractures, magnesium

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