Magnesium sulfate should not be used for more than 5-7 days in pregnant women in preterm labor, because in utero exposure may lead to hypocalcemia and an increased risk of osteopenia and bone fractures in newborns, the Food and Drug Administration announced May 30.
"The shortest duration of treatment that can result in harm to the baby is not known," the FDA stated.
The warning is based on epidemiologic studies that were mostly retrospective chart reviews, as well as 18 cases of newborns with skeletal anomalies whose mothers had been treated with magnesium sulfate for tocolysis. The cases had been reported to the FDA’s Adverse Event Reporting System (AERS) and were in the medical literature.
In these cases, exposure ranged from 8-12 weeks (average was almost 10 weeks), for an estimated average total maternal dose of 3,700 grams.
The newborns developed osteopenia-related skeletal anomalies, and some had multiple fractures of the ribs and long bones. The osteopenia and fractures were transient and had resolved in cases where the outcome was reported, according to the FDA.
Based on cases in the literature, "it is plausible that bone abnormalities in neonates are associated with prolonged in utero exposure to magnesium sulfate," since hypermagnesemia can cause hypocalcemia in the developing fetus, the FDA concluded.
Dr. Jeffrey Ecker, a high-risk obstetrician at Massachusetts General Hospital (MGH), Boston, said that this warning should not have an impact on practice because the length of exposure and maternal dose of magnesium sulfate cited in the FDA's statement are not recommended. The warning refers to cases of adverse outcomes in which magnesium sulfate was used for weeks at a time, which he said "would be unusual."
Magnesium sulfate is currently used to reduce the risk of cerebral palsy when premature delivery is anticipated, particularly at less than 32 weeks, and to reduce the risk of seizures in women with preeclampsia, two indications where there is good evidence that the use of magnesium sulfate improves outcomes, he noted in an interview.
There is much less evidence that it improves outcomes for the third use, as tocolysis, to delay delivery for 48 hours to allow for administration of steroids in women in preterm labor, said Dr. Ecker, also director of the maternal Fetal Medicine Fellowship at MGH and vice-chair of the American College of Obstetricians and Gynecologists' committee on obstetric practice. "But all three of those uses focus on very short term periods of exposure," he emphasized.*
The FDA is switching magnesium sulfate from a pregnancy category A (drugs for which adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester, and no evidence of risk in later trimesters) to pregnancy category D (drugs for which there is evidence of human fetal risks, but also potential benefits in pregnant women that may be acceptable in certain situations, despite the risks).
In addition to the new pregnancy category, the label for magnesium sulfate injection USP 50% will also have a new warning about these risks when administered for more than 5-7 days. There will be a new "labor and delivery" section pointing out that magnesium sulfate is not approved for treatment of preterm labor, the safety and efficacy of use for this indication "are not established," and "when used in pregnant women for conditions other than its approved indication, magnesium sulfate injection should be administered only by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities."
Magnesium sulfate is FDA approved to prevent seizures in preeclampsia.
Serious adverse events associated with this drug should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.
* Updated 6/5/2013