1. Aschenbrenner, Diane S. MS, RN

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* Magnesium sulfate's pregnancy category has been shifted from A to D (benefits of use may outweigh risks) when the drug is used off label to control preterm labor.


* The pregnancy category of valproate products has changed from D to X (risks outweigh any benefit), but only when the drug is used to treat migraine headache.



The Food and Drug Administration (FDA) has revised the labels of two drugs to reflect new information related to fetal harm. The pregnancy category of magnesium sulfate has been shifted from A (adequate and well-controlled studies have not found risk to a fetus in the first trimester of pregnancy; there's no evidence of risk in later trimesters) to D (adequate and well-controlled studies have revealed evidence of possible harm to a fetus in the first trimester, but the risk may be acceptable in certain circumstances). The pregnancy category of all valproate products has changed from D to X (there is a definite risk of injury to the fetus, and those risks outweigh any benefits), but only in certain circumstances.


Magnesium sulfate's category change is related to the off-label use of the drug to control preterm labor. When it's used for extended periods of time (more than five to seven days) to stop preterm labor, low calcium levels and bone complications, including osteopenia and fractures, can occur in the developing fetus.


Magnesium sulfate is also used to prevent or treat seizures during preeclampsia and eclampsia, potentially life-threatening complications for the mother that can lead to severe hypertension, stroke, organ failure, and death; these are labeled indications for this drug. Seizures during pregnancy also pose risks to the mother and the fetus that are related to dropping oxygen levels. The drug's label still states that controlling preterm labor remains an off-label use and that the drug's safety and efficacy for this indication are unknown. If it's used in this capacity, it shouldn't be used for more than five to seven days. High doses of magnesium sulfate lead to hypermagnesemia and hypocalcemia in the fetus.


The FDA revised the drug's -label on the basis of a review of 18 case reports of osteopenia and fractures and six epidemiologic studies. The studies found signi-f-icantly higher rates of bone and electrolyte abnormalities in neo--nates who had been exposed in utero to magnesium sulfate for five days or more than in those exposed for three days or less. Although laboratory values returned to normal shortly after birth, long-term effects on bone haven't been assessed. Despite some weaknesses related to data collection, the FDA concluded that there was enough evidence to demonstrate an association between extended mag-nesium sulfate use and neonatal hypocalcemia and bone complications. The exact length of time from the start of magnesium sulfate administration to the development of fetal bone complications hasn't been determined.


The pregnancy category change for valproate products is related only to use of the drug to treat migraine headaches. Valproate products include valproate sodium (Depacon), divalproex sodium (Depakote, Depakote CP, and Depakote ER), valproic acid (Depakene and Stavzor), and their generics. These products were originally developed as antiepileptics. The labeling change was based on data from a prospective observational study (referred to as the NEAD study) that compared the cognitive function at age six of children who had been exposed throughout gestation to one of four antiepileptic drugs: lamotrigine, phenytoin, carbamazepine, and valproate. The children who had been exposed to valproate had lower IQ scores than children exposed to any of the other anti-epileptic drugs. The FDA also reviewed other epidemiologic studies with similar findings. When valproate is used to treat epilepsy, it remains a pregnancy category D drug, and women can use it if other products aren't successful in controlling their seizures.


Nurses should provide edu-cation regarding the possible risks related to valproate products. Women of childbearing age who've taken the drug previously for migraine need to understand that the drug shouldn't be used during pregnancy. They should use birth control while taking the drug and will need to be weaned off of valproate products prior to trying to conceive.


Women taking valproate products for seizure disorders should be provided with information on the North American Antiepileptic Drug Pregnancy Registry, a national registry that collects data on the effects of antiepileptics on pregnant women and their infants. Patients must enroll in the registry on their own by calling (888) 233-2334.


To read the FDA Drug Safety Communication regarding magnesium sulfate, go to The FDA Drug Safety Communication regarding valproate products can be found at