Monday, February 9, 2009

Magnesium for Prevention of Cerebral Palsy

Wordle: Mag
The role of magnesium sulfate in the treatment of preterm birth continues to be investigated and advocated by some. The use of magnesium sulfate for the treatment of preterm labor has nearly been put to rest, as study after study has failed to show any prolongation of pregnancy or maternal/fetal benefit. However, evidence from some of the studies has strongly suggested the possibility that magnesium causes fetal harm/death.

At the same time, there is controversy among the studies so far regarding the possible role of magnesium for providing a neuroprotective benefit against cerebral palsy (CP). The question has been raised that even if the use of magnesium as a tocolytic is abandoned (which it should be), then perhaps we should continue giving magnesium to protect the fetus against developing cerebral palsy.

Nelson and Grether first suggested in 1995 (Pediatrics,; 95:263-9) that magnesium might serve such a role. They did a retrospective case-control study in California of 150,000 children followed to age 3. They found that 7% of very low birth weight (VLBW) babies developed CP who had been exposed to magnesium in utero compared to 36% of matched peers who had not been exposed to magnesium. These findings led to the MagNET trial.

In MagNET, women in preterm labor were randomized to magnesium vs placebo. The trial was stopped at 15 months because of the high rate of pediatric mortality noted in the magnesium group (10 deaths in the mag group vs 1 in the placebo group; p=0.02). The authors studied the data in this study and found that newborns with higher ionized magnesium levels in umbilical samples were more likely to have intraventricular hemorrhage (IVH) and the perinatal demises were 14.8x as likely to have Grade III hemorrhage (p=0.025).

Scudiero et al. (Obstet Gynec 2000;96:178-182) followed up MagNET with a case-control study which found that exposure to more than 48 grams of magnesium was associated with a 4.72 odds ratio of fetal death. This finding led advocates of magnesium to investigate low-dose magnesium protocols.

Crowther et al. (JAMA 2003;290:2669-2676), in the ACTOMgSO4 study, randomized low-dose magnesium vs placebo to 500 women and found no significant difference in the rate of cerebral palsy. All of the studies were reviewed by the Cochrane Review (Cochrane Database Syst. Rev. 2007 Jul 18[3];CD004661) and they concluded:
antenatal magnesium sulfate therapy as a neuroprotective agent for the preterm fetus is not yet established.
Now comes a study in the New England Journal of Medicine by Rouse et al. (NEJM 2008:359;9) which randomized 2241 women at risk for preterm delivery (mostly with preterm rupture of membranes) to magnesium vs placebo. The primary outcome to be studied was the incidence of moderate or severe cerebral palsy or death, and no significant difference was found between the two groups.

However, two secondary analyses were performed: death alone and moderate or severe cerebral palsy alone. For death alone, there was an excess of 10 fetal deaths in the magnesium group but this did not rise to the level of statistical significance. For moderate or severe cerebral palsy alone, there was an excess of 18 cases of CP in the placebo group and this was significant (p=0.03). However, when surviving twins (one twin died, one survived) who developed CP are excluded from each group, then the magnesium group had an excess of 12 deaths, and the placebo group had an excess of 15 cases of CP. If it can be assumed that had the excess 12 deaths lived they would have developed CP, then the whole study is a wash.

So really, this study is like the studies that have come before it: it suggests that CP may be reduced because the total number of survivors are reduced. The appropriate outcome to be studied was the combined outcome of death and CP, which again showed no significant difference. Another way of looking at the data is to think about the total number of intact survivors in each arm of the study: 88.7% of the infants in the magnesium group were intact, whereas 88.3% of the survivors in the placebo group were intact. And if we take out the 4 sets of twins with death/CP that were distributed unevenly, then those numbers change to 88.75% and 88.56% respectively. Neither set of these numbers is anywhere near statistically significant.

Many will criticize this analysis of these numbers by pointing out that the increased rate of death found in this study was not statistically significant; true - but that may be simply because the study was underpowered to study that particular outcome. The study was powered for the combined primary outcome of death + CP, and for this it showed no significant difference.

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