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ORIGINAL RESEARCH |
From the Pritzker School of Medicine, Biological Sciences Division, and the Section of Neonatology, Department of Pediatrics, University of Chicago, Chicago, Illinois; the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin; and the Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois.
Address reprint requests to: Robert Mittendorf, MD, DrPH Department of Obstetrics and Gynecology Loyola University Medical Center 2160 First Avenue Maywood, IL 60153 E-mail: robert{at}babies.bsd.uchicago.edu
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Abstract |
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Methods: We did a case-control study in which cases were defined as neonates or fetuses who died after being exposed to tocolytic magnesium sulfate and controls were those who survived exposure. The study included fetuses and neonates who weighed between 700 and 1249 g and whose mothers had received tocolytic magnesium sulfate at Chicago Lying-in Hospital between January 1, 1986, and March 31, 1999. We excluded women who received prophylactic magnesium sulfate for preeclampsia or preeclampsia superimposed on chronic hypertension, and fetuses or neonates with major congenital anomalies. Data were analyzed by Fisher exact test, 
2 test, Student t test, Mann–Whitney U test, multivariable logistic regression, and Cochrane–Armitage trend test.
Results: Controlling for birth weight or gestational age, year of delivery, receipt of betamethasone, acute maternal disease, and maternal race in a multivariable model, we found that exposure to total doses of tocolytic magnesium sulfate exceeding 48 g was significantly associated with increased perinatal mortality (adjusted odds ratio 4.7; 95% confidence interval 1.1, 20.0; P = .035). Using the Cochrane–Armitage trend test, we found that a significant dose response was present (P = .03), but one that was most consistent with a threshold effect.
Conclusion: Our findings support the hypothesis that high doses of tocolytic magnesium sulfate are associated with increased perinatal mortality among fetuses and neonates weighing 700–1249 g.
Magnesium sulfate is the most commonly used first-line tocolytic agent among obstetricians in the United States1 but its safety and efficacy for that indication have not been evaluated rigorously.2,3 The only randomized clinical trial that compared magnesium sulfate with saline control for treatment of preterm labor did not find evidence of tocolytic effectiveness.4 Our recent experience with unexpected fetal and infant deaths in the Magnesium and Neurologic Endpoints trial5 has raised concern about the widely accepted safety of magnesium sulfate.6
Germane to any discussion about the safety and efficacy of tocolytic magnesium sulfate is the discrimination of its other obstetric indications. The most well-studied of those is preeclampsia, for which there are clinical data documenting its safety and superiority7 compared with other anticonvulsants. A more recent and potentially very important indication that is being evaluated is as a neuroprotective agent for anticipated preterm birth. The rationale for that use is recent epidemiologic data8,9 that suggest a possible reduction of cerebral palsy and other adverse neurologic outcomes among preterm infants exposed antenatally to magnesium sulfate. For both of those indications, the cumulative dosages are generally considerably lower than those for tocolysis.
A randomized controlled trial would be ideal to further study the relationship between tocolytic magnesium sulfate and mortality in infants, but because of our experience5 such a study is deemed unethical at our institutions. The clinical trials of magnesium sulfate as a neuroprotective agent use substantially lower cumulative dosages, so they might not answer the question of high-dose magnesium and perinatal mortality. Therefore, we investigated the problem using retrospective data.
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Methods |
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A total of 40,896 infants were born at Chicago Lying-in Hospital between January 1, 1986, and March 31, 1999. Among those, 1292 weighed at least 700 g but less than 1250 g; 223 were born to women without preeclampsia or preeclampsia superimposed on chronic hypertension who had been tocolyzed. Maternal charts for 98% (218 of 223) of maternal–fetal or maternal–neonatal pairs were available for review. Eleven were subsequently excluded, ten because magnesium sulfate had actually been given for preeclampsia, and one because of a major congenital anomaly discovered during chart review. Among the remaining 207 pairs, 149 women had received tocolytic magnesium sulfate. The women from the remaining pairs had received other tocolytics only, thus were excluded. Among the 149 maternal–fetal or maternal–neonatal pairs, 22 women would have been represented twice because they gave birth to twins (n = 21) or triplets (n = 1) with two infants in the 700–1249-g weight range. When that occurred, the woman was considered the unit of observation, so 22 of 44 maternal–fetal or maternal–neonatal sibships were included. When one multifetal sibling died but the other survived (n = 4), only the sibling who died was included. When both siblings died (n = 2) or both survived (n = 16), only the sibling of lower birth weight was included. Thus, 127 children were included of whom 18 were mortal cases and 109 survived. Of the cases, four were fetal deaths and 14 were neonatal deaths.
For 
= .05, probability of death in the lower-dosage groups, P1 = 8%, and probability of death in the higher-dosage group, P2 = 24%, a sample of 126 would generate 60% power. For = .05, P1 = 8%, P2 = 32%, a sample of 126 would generate 89% power. Before chart retrieval or data collection, the research protocol was approved by the Institutional Review Board, Biological Sciences Division, University of Chicago.
To help ensure the absence of bias, data were collected by a reviewer (RS) masked to mortality outcomes. Information was recorded for numerous sociodemographic, maternal, and obstetric variables, including year of delivery, maternal age, source of medical care payment, maternal infection or other condition, maternal drug exposure including tobacco, alcohol, other illicit drugs including cocaine, antibiotics, corticosteroids, and all tocolytics, gestational age at delivery, birth weight, and several complications of pregnancy and delivery. The total dose of magnesium sulfate administered over the entire hospitalization, including the dose of magnesium given at the perinatal network hospitals before transfer, was calculated and recorded using detailed nursing notes and charts. When an intravenous infusion of magnesium sulfate was stopped then later restarted, the total amount of magnesium sulfate given in the most proximate segment of treatment also was recorded. Most proximate segment was defined as an infusion that began with a 4-g bolus of magnesium sulfate. The delay in hours between completion of the most proximate segment and delivery was recorded.
Univariate analyses were conducted on all variables to determine whether significant differences existed between cases and controls with respect to each variable. For dichotomous variables, Fisher exact test or 2 test was used. For continuous variables, either Student t test or Mann–Whitney U test was used. Our experience with the Magnesium and Neurologic Endpoints trial made us choose 48 g as the point to dichotomize total magnesium sulfate exposure. Odds ratios (ORs) were used to determined whether fetuses and infants who died were statistically significantly more likely to have mothers who were given more than 48 g of magnesium sulfate, compared with those who survived. To control for possible confounding, we used multivariable logistic regression analysis to estimate the effect of exposure to more than 48 g of tocolytic magnesium sulfate on mortality while taking into account the simultaneous effect of several other possible predictors. A Cochrane–Armitage trend test10 was done to test the hypothesis of a dose–response relationship between total magnesium sulfate given and perinatal death. Exposure categories by 24-g increments were used.
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). Nonblacks, private payers, and women with acute disease were more likely to have fetuses or infants who died (Table 1). No other demographic or maternal variable differed between groups. Univariate analyses of obstetric variables showed that mean birth weight overall and mean birth weight in the 1000–1249 g range differed significantly between those who died and survivors (Table 2). Gestational age also differed significantly between the cases and controls (Table 2). By univariate analysis, more case infants than control infants had mothers who received indomethacin or terbutaline tocolysis (Table 2). When exposure to total doses of magnesium sulfate larger than 48 g was used for the toxic dosage threshold, statistically significantly more cases (72%) than controls (45%) were born to mothers who received higher doses of magnesium sulfate (P = .03) (Table 2).
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). In particular, among infants with birth weights 700–1249 g, exposure to a total dose of magnesium sulfate larger than 48 g was associated with a more than fourfold increase in the odds of mortality (adjusted OR = 4.7; 95% confidence interval [CI] 1.1, 20.0; P = .035).
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Discussion |
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)—were 4.7 times higher for those who received cumulative dosages more than 48 g compared with those who received lower doses. Although no other studies specifically investigated perinatal effects of high-dose tocolytic magnesium, there are several clinical studies that explored questions about magnesium sulfate for preterm labor. Three randomized controlled trials of magnesium sulfate as a single-agent tocolytic compared with other tocolytics reported no excess perinatal mortality among the magnesium-exposed groups.11–13 There was no compelling reason for those studies to evaluate the exposure dosages to tocolytic magnesium and exclude neonates outside the birth weight range of interest. Two epidemiologic studies of neonatal mortality after fetal exposure to tocolytic magnesium sulfate also were reported.9,14 Neither of those reported more deaths after exposures to magnesium sulfate; however, information on fetal death could not be included, exposure dosage to tocolytic magnesium sulfate was not computed, and neonates outside the birth weight range of interest were included in both. Our findings suggest that it might be difficult to detect increased perinatal mortality in randomized controlled trials or population-based epidemiologic studies if analyses are limited to infant outcomes without evaluation of exposed pregnancies that end in stillbirth, "yes" or "no" exposure classifications without consideration of the total exposure dose to magnesium sulfate, and if birth weight groups larger than 1249 g or smaller than 700 g are analyzed with the birth weight group of interest.
This study is compatible with our previous association between tocolytic magnesium sulfate and total pediatric mortality.5 Our current data suggest that mortality might be greatest in the smaller range of preterm delivery birth weights (less than 1250 g but more than 699 g) and at high dosages of magnesium sulfate (apparently over 48 g, which is equivalent to a 1-day exposure to magnesium sulfate at the common tocolytic dose consisting of a 4-g bolus, followed by infusion of 2 g/h). Therefore, without scientific data proving tocolytic efficacy,2–4 we recommend that magnesium sulfate as a first-line tocolytic agent be reconsidered. It is prudent that cautious clinical trials be designed to re-evaluate the unproven tocolytic efficacy of magnesium sulfate and fetal and long-term infant outcomes be properly evaluated.
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Footnotes |
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Received November 3, 1999. Received in revised form March 1, 2000. Accepted March 24, 2000.
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2. Higby K, Xenakis EMJ, Pauerstein CJ. Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety. Am J Obstet Gynecol 1993;168:1247–59.[Medline]
3. Kierse MJNC, Grant A, King JF. Preterm labor. In: Enkin M, Kierse MJNC, Renfrew MJ, Neilson JP, eds. A guide to effective care in pregnancy and childbirth. Oxford, United Kingdom: Oxford University Press, 1995;161–73.
4. Cox SM, Sherman ML, Leveno KJ. Randomized investigation of magnesium sulfate for prevention of preterm birth. Am J Obstet Gynecol 1990;163:767–72.[Medline]
5. Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is tocolytic magnesium sulphate associated with increased total paediatric mortality? Lancet 1997;350:1517–8.[Medline]
6. Mittendorf R, Pryde P, Khoshnood B, Lee KS. If tocolytic magnesium sulfate is associated with excess total pediatric mortality, what is its impact? Obstet Gynecol 1998;92:308–11.[Abstract]
7. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 1995;333:201–5.
8. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995;95: 263–9.
9. Schendel DE, Berg CJ, Yeargin-Allsop M, Boyle CA, Decoufle P. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA 1996;276:1805–10.[Abstract]
10. Stata statistical software (5.0), 1997. College Station, TX: Stata Corporation.
11. Cotton DB, Strassner HT, Hill LM, Schifrin BS, Paul RH. Comparison of magnesium sulfate, terbutaline and a placebo for inhibition of preterm labor. J Reprod Med 1984;29:92–7.[Medline]
12. Glock JL, Morales WJ. Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: A randomized study. Am J Obstet Gynecol 1993;169:960–4.[Medline]
13. Morales WJ, Madhav H. Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor. A randomized study. Am J Obstet Gynecol 1993;169:97–102.[Medline]
14. Grether JK, Hoogstrate J, Selvin S, Nelson KB. Magnesium sulfate tocolysis and risk of neonatal death. Am J Obstet Gynecol 1998; 178:1–6.[Medline]
This article has been cited by other articles:
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  D. A. Grimes and K. Nanda Magnesium sulfate tocolysis: time to quit. Obstet. Gynecol., October 1, 2006; 108(4): 986 - 989. [Abstract] [Full Text] [PDF]
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S. Black, H. Yu, J. Lee, M. Sachchithananthan, and R. L. Medcalf Physiologic Concentrations of Magnesium and Placental Apoptosis: Prevention by Antioxidants Obstet. Gynecol., August 1, 2001; 98(2): 319 - 324. [Abstract] [Full Text] [PDF]
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R. Mittendorf, R. Covert, R. Elin, P. G. Pryde, B. Khoshnood, and K.-S. Lee Umbilical Cord Serum Ionized Magnesium Level and Total Pediatric Mortality Obstet. Gynecol., July 1, 2001; 98(1): 75 - 78. [Abstract] [Full Text] [PDF]
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