Drugs in Pregnancy and Lactation: Tenth Edition

MAGNESIUM SULFATE

Anticonvulsant/Laxative

PREGNANCY RECOMMENDATION: Compatible

BREASTFEEDING RECOMMENDATION: Compatible

PREGNANCY SUMMARY

The administration of magnesium sulfate to the mother for anticonvulsant or tocolytic effects does not usually pose a risk to the fetus or newborn. Long-term infusions of magnesium may be associated with sustained hypocalcemia in the fetus resulting in congenital rickets. Neonatal neurologic depression may occur with respiratory depression, muscle weakness, and loss of reflexes. The toxicity is not usually correlated with cord serum magnesium levels. Offspring of mothers treated with this drug close to delivery should be closely observed for signs of toxicity during the first 24–48 hours after birth. Caution is also advocated with the use of aminoglycoside antibiotics during this period.

FETAL RISK SUMMARY

Magnesium sulfate (MgSO4) is commonly used as an anticonvulsant for toxemia and as a tocolytic agent for premature labor during the last half of pregnancy. Concentrations of magnesium, a natural constituent of human serum, are readily increased in both the mother and fetus following maternal therapy with cord serum levels ranging from 70% to 100% of maternal concentrations (16). Elevated levels in the newborn may persist for up to 7 days with an elimination half-life of 43.2 hours (2). The elimination rate is the same in premature and full-term infants (2). IV magnesium sulfate did not cause lower Apgar scores in a study of women treated for pregnancy-induced hypertension, although the magnesium levels in the newborns reflected hypermagnesemia (6). The mean cord magnesium level, 5.3 mEq/dL, was equal to the mean maternal serum level.

No reports linking the use of magnesium sulfate with congenital defects have been located. The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 141 of which had exposure to magnesium sulfate during pregnancy (7). No evidence was found to suggest a relationship to congenital malformations.

In a 1987 report, 17 women, who had been successfully treated with IV magnesium sulfate for preterm labor, were given 1 g of magnesium gluconate every 4 hours after the IV magnesium had been discontinued (8). A mean serum magnesium level before any therapy was 1.44 mg/dL. Two hours after an oral dose (12–24 hours after discontinuation of IV magnesium) the mean magnesium serum level was 2.16 mg/dL, a significant increase (p <0.05). A group of 568 women was randomly assigned to receive either 15 mmol of magnesium-aspartate hydrochloride (N = 278) or 13.5 mmol of aspartic acid (N = 290) per day (9). Therapy was started as early as possible in the pregnancies, but not later than 16 weeks’ gestation. Women receiving the magnesium tablets had fewer hospitalizations (p <0.05), fewer preterm deliveries, and less frequent referral of the newborn to the neonatal intensive care unit (p <0.01) (9). In a double-blind randomized, controlled clinical study, 374 young women (mean age approximately 18 years) were treated with either 365 mg of elemental magnesium/day (provided by six tablets of magnesium-aspartate hydrochloride each containing 60.8 mg of elemental magnesium) (N = 185) or placebo tablets containing aspartic acid only (N = 189) (10). Treatment began at approximately a mean gestational age of 18 weeks (range 13–24 weeks). In addition, both groups received prenatal vitamins containing 100 mg of elemental magnesium. In contrast to the reference cited above, the magnesium therapy did not improve the outcome of the pregnancies as judged by the nonsignificant differences between the groups in incidences of preeclampsia, fetal growth restriction, preterm labor, birth weight, gestational age at delivery, or number of infants admitted to the special care unit (10).

Most studies have been unable to find a correlation between cord serum magnesium levels and newborn condition (2,5,1115). In a study of 7000 offspring of mothers treated with MgSO4for toxemia, no adverse effects from the therapy were noted in fetuses or newborns (5). Other studies have also observed a lack of toxicity (16,17). A 1983 investigation of women at term with pregnancy-induced hypertension compared newborns of magnesium-treated mothers with newborns of untreated mothers (15). No differences in neurologic behavior were observed between the two groups except that exposed infants had decreased active tone of the neck extensors on the first day after birth.

Newborn depression and hypotonia have been reported as effects of maternal magnesium therapy in some series, but intrauterine hypoxia could not always be eliminated as a potential cause or contributing factor (2,11,12,1820). In a study reporting on the effects of IV magnesium on Apgar scores, the most common negative score was assigned for color, rather than for muscle tone (6).

A 1971 report described two infants with magnesium levels >8 mg/dL who were severely depressed at birth (13). Spontaneous remission of toxic symptoms occurred after 12 hours in one infant, but the second had residual effects of anoxic encephalopathy. In a 1982 study, activities requiring sustained muscle contraction, such as head lag, ventral suspension, suck reflex, and cry response, were impaired up to 48 hours after birth in infants exposed in utero to magnesium (14). A hypertensive woman, treated with 11 g of magnesium sulfate within 3.5 hours of delivery, gave birth to a depressed infant without spontaneous respirations, movement, or reflexes (21). An exchange transfusion at 24 hours reversed the condition. In another study, decreased gastrointestinal motility, ileus, hypotonia, and patent ductus arteriosus occurring in the offspring of mothers with severe hypertension were thought to be caused by maternal drug therapy, including magnesium sulfate (22). However, the authors could not relate their findings to any particular drug or drugs and could not completely eliminate the possibility that the effects were caused by the severe maternal disease.

A mild decrease in cord calcium concentrations has been reported in mothers treated with magnesium (3,13,15). In contrast, a 1980 study reported elevated calcium levels in cord blood following magnesium therapy (4). No newborn symptoms were associated with either change in serum calcium concentrations. However, long-term maternal tocolysis with IV magnesium sulfate may cause injury to the newborn as described below.

In an investigation of five newborn infants whose mothers had been treated with IV magnesium sulfate for periods ranging from 5 to 14 weeks, radiographic bony abnormalities were noted in two of the infants (18). One of the mothers, a class C diabetic who had been insulin-dependent for 12 years, was treated with IV magnesium, beginning at 21 weeks’ gestation, for 14 weeks. A 2030-g female infant was delivered vaginally at 35 weeks’ gestation following spontaneous rupture of the mother’s membranes. The maternal histories of this and another mother treated for 6 weeks were described in 1986 (19). The infant had frank rachitic changes of the long bones and the calvaria. Serum calcium at 6 hours of age was normal. The infant was treated with IV calcium gluconate for 3 days, then given bottle feedings without additional calcium or vitamin D. Scout films for an IV pyelogram taken at 4 months of age because of a urinary tract infection showed no bony abnormalities. Growth over the first 3 years has been consistently at the 3rd percentile for height, weight, and head circumference. Dental enamel hypoplasia, especially of the central upper incisors, was the only physical abnormality noted at 3 years of age. The second infant’s mother had been treated with IV magnesium for 9 weeks beginning at 25 weeks’ gestation. The 2190-g female infant was delivered vaginally at 34 weeks because of spontaneous rupture of membranes. Hypocalcemia (5.8 mg/dL, normal 6.0–10.0 mg/dL) was measured at 6 hours of age. A chest radiograph taken on the 1st day revealed lucent bands at the distal ends of the metaphyses (18). She was treated with IV calcium for 5 days and then given bottle feedings without additional calcium or vitamin D. A scout film for an IV pyelogram at 5 months of age showed no bony abnormalities. In the remaining three cases, the mothers had been treated with IV magnesium for 4–6 weeks, and their infants were normal on examination. The authors hypothesized that the fetal hypermagnesemia produced by the long-term maternal administration of magnesium caused a depression of parathyroid hormone release that resulted in fetal hypocalcemia (18).

In another study of long-term IV magnesium tocolysis, 22 women were treated for an average of 26.3 days (maximum duration in any patient was 75 days) (20). Two infants delivered from this group were noted to have wide-spaced fontanelles and parietal bone thinning. These effects returned to normal with time. A third newborn, delivered from a mother belonging to an intermediate group treated with IV magnesium for an average of 6.3 days, suffered a parietal bone fracture during an instrumental delivery and developed spastic quadriplegia (20).

More recent studies have also described the adverse effects of prolonged magnesium therapy on fetal bone mineralization (2327). The mechanism of this reaction appears to be increased and persistent urinary calcium losses in the mother and her fetus (26,27). In one investigation, increases in 1,25-dihydroxyvitamin D and parathyroid hormone in both the mother and the fetus may have prevented more severe hypocalcemia (27).

Clinically significant drug interactions have been reported, one in a newborn and three in mothers, after maternal administration of MgSO4. In one case, an interaction between in utero acquired magnesium and gentamicin was reported in a newborn 24 hours after birth (28,29). The mother had received 24 g of MgSO4 during the 32 hours preceding birth of a neurologically depressed female infant. Gentamicin, 2.5 mg/kg IM every 12 hours, was begun at 12 hours of age for presumed sepsis. The infant developed respiratory arrest following the second dose of gentamicin, which resolved after the antibiotic was stopped. Animal experiments confirmed the interaction. The maternal cases involved an interaction between magnesium and nifedipine (30,31). One report described two women who were hospitalized at 30 and 32 weeks’ gestation, respectively, for hypertension (30). In both cases, oral methyldopa, 2 g, and IV MgSO4, 20 g, daily were ineffective in lowering the mother’s blood pressure. Oral nifedipine, 10 mg, was given and a marked hypotensive response occurred 45 minutes later. The blood pressures before nifedipine in the women were 150/110 and 140/105 mmHg, respectively, and decreased to 80/50 and 90/60 mmHg, respectively, after administration of the calcium channel blocker. Blood pressure returned to previous levels 25–30 minutes later. Both infants were delivered following the hypotensive episodes, but only one survived. In the third maternal case, a woman in premature labor at 32 weeks’ gestation was treated with oral nifedipine, 60 mg over 3 hours, then 20 mg every 8 hours (31). Because uterine contractions returned, intravenous MgSO4 was begun 12 hours later followed by the onset of pronounced muscle weakness after 500 mg had been administered. Her symptoms included jerky movements of the extremities, difficulty in swallowing, paradoxical respirations, and an inability to lift her head from the pillow. The magnesium was stopped and the symptoms resolved in the next 25 minutes. The reaction was attributed to nifedipine potentiation of the neuromuscular blocking action of magnesium.

Maternal hypothermia with maternal and fetal bradycardia apparently caused by IV magnesium sulfate has been reported (32). The 30-year-old woman, at about 31 weeks’ gestation, was being treated for premature labor. She had received a single, 12-mg IM dose of betamethasone at the same time that magnesium therapy was started. Her oral temperature fell from 99.8°F to 97°F 2 hours after the infusion had been increased from 2 to 3 g/hr. Twelve hours after admission to the hospital, her heart rate fell to 64 beats/minute (baseline 80 beats/minute), whereas the fetal heart rate decreased to 110 beats/minute (baseline 140–150 beats/minute). A rectal temperature at this time was 95.8°F and the patient complained of lethargy and diplopia. Her serum magnesium level was 6.6 mg/dL. Magnesium therapy was discontinued and all signs and symptoms returned to baseline values within 6 hours. Neither the mother nor the fetus suffered adversely from the effects attributed to magnesium.

BREASTFEEDING SUMMARY

Magnesium salts may be encountered by nursing mothers using over-the-counter laxatives. A study in which 50 mothers received an emulsion of magnesium and liquid petrolatum or mineral oil found no evidence of changes or frequency of stools in nursing infants (33). In 10 preeclamptic patients receiving magnesium sulfate 1 g/hr IV during the first 24 hours after delivery, magnesium levels in breast milk were 64 mcg/mL as compared with 48 mcg/mL in nontreated controls (34). Twenty-four hours after stopping the drug, magnesium levels in breast milk in treated and nontreated patients were 38 and 32 mcg/mL, respectively. By 48 hours, the levels were identical in the two groups. Milk:plasma ratios were 1.9 and 2.1 in treated and nontreated patients, respectively. The American Academy of Pediatrics classifies magnesium sulfate as compatible with breastfeeding (35).

References

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2.Dangman BC, Rosen TS. Magnesium levels in infants of mothers treated with MgSO4 (abstract #262). Pediatr Res 1977;11:415.

3.Cruikshank DP, Pitkin RM, Reynolds WA, Williams GA, Hargis GK. Effects of magnesium sulfate treatment on perinatal calcium metabolism. I. Maternal and fetal responses. Am J Obstet Gynecol 1979;134:243–9.

4.Donovan EF, Tsang RC, Steichen JJ, Strub RJ, Chen IW, Chen M. Neonatal hypermagnesemia: effect on parathyroid hormone and calcium homeostasis. J Pediatr 1980;96:305–10.

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7.Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:440.

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12.Lipsitz PJ. The clinical and biochemical effects of excess magnesium in the newborn. Pediatrics 1971;47:501–9.

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32.Rodis JF, Vintzileos AM, Campbell WA, Deaton JL, Nochimson DJ. Maternal hypothermia: an unusual complication of magnesium sulfate therapy. Am J Obstet Gynecol 1987;156:435–6.

33.Baldwin WF. Clinical study of senna administration to nursing mothers: assessment of effects on infant bowel habits. CMAJ 1963;89:566–8.

34.Cruikshank DP, Varner MW, Pitkin RM. Breast milk magnesium and calcium concentrations following magnesium sulfate treatment. Am J Obstet Gynecol 1982;143:685–8.

35.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.