Original Article
Association between Cerebral Palsy or Death and Umbilical Cord Blood Magnesium Concentration Anna Palatnik, MD1 Dwight J. Rouse, MD, MSPH2 David M. Stamilio, MD, MSCE3 Jessica A. McPherson, MD3 William A. Grobman, MD, MBA1 1 Department of Obstetrics and Gynecology, Feinberg School of
Medicine, Northwestern University, Chicago, Illinois 2 Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, Rhode Island 3 Department of Obstetrics and Gynecology, The University of North Carolina School of Medicine, Chapel Hill, North Carolina
Address for correspondence Anna Palatnik, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Northwestern Medical Group, 250 East Superior Street, Suite 05-2175, Chicago, IL 60611 (e-mail: [email protected]).
Abstract
Keywords
► ► ► ►
cerebral palsy cord blood magnesium sulfate preterm delivery
Objective This study aims to evaluate whether magnesium sulfate (MgSO4) infusion at the time of delivery or magnesium cord blood concentration is associated with cerebral palsy (CP) or death diagnosed by the age of 2 years. Methods Secondary analysis of data from a randomized trial of MgSO4 versus placebo for prevention of CP or death among offspring of women with anticipated preterm delivery. This study cohort included singleton, nonanomalous fetuses, whose mothers received MgSO4 as neuroprophylaxis. The primary outcomes were CP or death diagnosed by the age of 2 years. Results A total of 936 neonates (93 with CP or death, 843 controls) were included in the analysis. Infants in the group with CP or death had MgSO4 infusing at delivery at a similar frequency to that of controls (49 [52.7%] vs. 463 [54.9%], p ¼ 0.68). Mean concentrations of cord blood magnesium, available for 596 neonates, also were not different between the two groups (2.7 0.9 vs. 2.6 0.9 mEq/L, p ¼ 0.66, respectively). Multivariable analyses did not alter these findings. Conclusion Among the offspring of women exposed to MgSO4, in utero, neither MgSO4 infusion at the time of delivery nor magnesium cord blood concentration is associated with CP or death.
Administration of intravenous magnesium sulfate (MgSO4) to women at risk for early preterm delivery has been shown to reduce the risk of neurodevelopmental disability in their surviving children.1 Specifically, a recent large randomized trial as well as a meta-analysis showed that children exposed as fetuses to an antenatal infusion of MgSO4 had a 45% reduced risk of moderate or severe cerebral palsy (CP) at the age of 2 years.2–4 Nevertheless, the optimal regimen of MgSO4 administration remains uncertain. Different studies have used different
loading doses (4 or 6 g), as well as different maintenance doses (none, 1 or 2 g/h) of varying durations (12 or 24 hours).2–4 Correspondingly, the American Congress of Obstetrics and Gynecology suggests that “physicians electing to use magnesium sulfate for fetal neuroprotection should develop specific guidelines regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”5 The biological plausibility for benefit of MgSO4 has been related to its inhibition of excitatory neurological pathways,
received March 17, 2015 accepted after revision April 20, 2014
Copyright © by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1554798. ISSN 0735-1631.
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Palatnik et al.
improvement of cerebral perfusion, and reduction in free radicals.6 It is plausible, therefore, that the degree of exposure to magnesium could be associated with adverse outcome. A recent study showed that there was no association between the total duration of MgSO4 infusion and the rate of CP or death.7 However, although total duration of MgSO4 may not significantly influence adverse infant outcome rate, whether magnesium infusion is ongoing at the time of delivery, or whether a certain fetal magnesium blood concentration is reached may be important factors in neuroprotective therapy efficacy. Therefore, the aims of this study were to evaluate whether MgSO4 infusion that was ongoing at the time of delivery or magnesium cord blood levels were associated with neonatal neurological outcomes.
Material and Methods This case–control study was a secondary analysis of data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network trial of MgSO4 for the prevention of CP or death among the offspring of women who were at risk of premature delivery before 32 weeks of gestation (i.e., the Beneficial Effects of Antenatal Magnesium [BEAM] study). The present analysis includes all nonanomalous singleton infants in the BEAM study whose mothers received MgSO4. By protocol, patients received a loading dose of 6 g infused for 20 to 30 minutes, followed by a maintenance infusion of 2 g/h for up to 12 hours. The infusion was discontinued if delivery was not imminent, with the intent of resuming it again for recurrent preterm labor or anticipated delivery before 34 weeks of gestation. Another loading dose was administered at resumption if at least 6 hours passed since MgSO4 discontinuation. Umbilical cord blood was collected at delivery. The samples were frozen within 12 hours of blood collection and stored at 70°C. Analysis of the level of magnesium in the cord blood was performed at a central laboratory (Olympus, Center Valley, PA), which used an analyzer with a minimum detectable magnesium concentration of 0.4 mEq/L. The primary outcomes evaluated in this study were CP or death by the age of 2 years, while CP alone was examined as a secondary outcome. The severity of CP was assessed by the Gross Motor Function Classification System by an annually certified pediatrician or pediatric neurologist.8 Univariable comparisons were performed using Pearson chi-square test for categorical data and the Student t-test for continuous measures. Multivariable analyses were performed using logistic regression for the outcomes of interest with either the presence of MgSO4 infusion at the time of delivery or the magnesium cord blood concentration forced into the equation as an independent variable. Magnesium cord concentrations were evaluated as both continuous and ordinal (by quartile) variables. Other covariates were entered into the regression equation if they differed between groups in univariable analysis at a level of p < 0.05. Adjusted odds ratios (OR) with 95% confidence intervals (CI) were estimated from the logistic regression. All analyses were performed with Stata version 12.0 (StataCorp, College Station, TX). This study American Journal of Perinatology
used publically available deidentified data and was considered exempt by the Institutional Review Board at Northwestern University.
Results A total of 936 neonates met the inclusion criteria. The maternal and neonatal characteristics for the analyzed groups, defined according to whether CP or death occurred, are summarized in ►Table 1. Mothers of neonates who subsequently had CP or death had a higher mean body mass index and higher rate of cesarean delivery. Also, the neonates with either CP or death were delivered at an earlier gestational age and were more likely to be male. In univariable analysis, infants with CP or death had a similar frequency of MgSO4 infusing at delivery as those without CP or death (49 [52.7%] vs. 463 [54.9%], p ¼ 0.68). Also, there was no difference in the frequency of MgSO4 infusion at delivery between groups when those with CP alone were compared with those without CP (11 [42.3%] vs. 476 [56.5%], p ¼ 0.15). This lack of association did not change in multivariable analysis (OR ¼ 0.87, CI 0.53–1.41 for CP or death, and OR ¼ 0.56, CI 0.23–1.33 for CP alone) (►Table 2). Magnesium cord blood concentrations were available for 596 neonates (48 neonates with CP or death and 548 neonates in the control group). The neonates without available magnesium cord blood concentration were delivered at an earlier gestational age, had a lower mean birth weight, and a higher frequency of CP or death (Supplemental Table 1). In the group with available magnesium cord blood concentration, mean levels of cord blood magnesium were not statistically different between those with and without CP or death (2.7 0.9 vs. 2.6 0.9 mEq/L, p ¼ 0.66). Similarly, quartile of magnesium cord blood level was not associated with the frequency of CP or death (1st quartile: 10/155 (6.4%); 2nd quartile: 10/150 (6.6%); 3rd quartile: 19/174 (10.9%); 4th quartile: 9/123 (7.3%); p ¼ 0.39). Multivariable analyses did not alter these findings. After adjusting for potential confounding variables, cord blood magnesium concentration, whether expressed as a continuous or categorical variable, was not associated with CP or death (OR ¼ 1.04, CI 0.78–1.52) (►Tables 3 and 4). Results were similar when CP alone was used as the outcome (OR ¼ 1.29, CI 0.57–2.87) (►Tables 3 and 4).
Comment In this secondary analysis we evaluated the association between neonatal CP and death diagnosed by 2 years of age and the degree of exposure to MgSO4 at the time of delivery. We evaluated this degree of exposure by two methods— whether or not MgSO4 was infusing at the time of delivery and the concentration of magnesium in cord blood at delivery. There was no evidence from our analysis that magnesium cord blood concentration or MgSO4 infusion at the time of delivery was associated with offspring
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Cord Magnesium Concentration and Cerebral Palsy
Cord Magnesium Concentration and Cerebral Palsy
Palatnik et al.
Table 1 Patient characteristics stratified by the presence of cerebral palsy or death Characteristic
CP/death (n ¼ 93)
p-Value
Controls (n ¼ 843)
Maternal Age (y)
26.0 5.8
26.2 6.3
0.82
Body mass index at delivery (kg/m2)
27.8 8.3
25.7 6.3
0.005
Married
48 (51.6)
419 (49.7)
0.74
Years of education
11.9 1.9
11.7 2.5
0.46
African American
49 (52.7)
363 (43.0)
Caucasian
35 (37.6)
306 (36.3)
Hispanic
8 (8.6)
154 (18.2)
Other
1 (1.1)
20 (2.4)
Nulliparous
34 (36.5)
296 (35.1)
0.78
Cigarette use during pregnancy
27 (29.0)
225 (26.7)
0.63
Alcohol use during pregnancy
5 (5.4)
78 (9.2)
0.21
Illicit drug use during pregnancy
8 (8.6)
85 (10.1)
0.65
No prenatal care
5 (5.4)
66 (7.8)
0.39
Vaginal
51 (54.8)
553 (65.6)
Cesarean
42 (45.2)
290 (34.4)
14 (15.0)
96 (11.4)
0.29
Gestational age at delivery (wk)
27.4 2.9
30.1 2.9
< 0.001
Small for gestational age
5 (5.4)
25 (2.9)
0.21
Male gender
61 (65.6)
458 (54.3)
0.04
General anesthesia
12 (12.9)
65 (7.7)
0.07
Antenatal corticosteroids
90 (96.7)
820 (97.3)
0.78
49 (52.7)
463 (54.9)
0.68
0.11
Mode of delivery
0.04
Chorioamnionitis Neonatal
Magnesium infusion at the time of delivery Abbreviations: CI, confidence interval; CP, cerebral palsy. Note: All data are presented as mean standard deviation or N (%).
outcomes among gravidas who received MgSO 4 for perinatal neuroprotection. Prior large trials found a neuroprotective effect of MgSO4 when administered to women at risk of preterm delivery (< 33 weeks).1–4 This finding led to our hypothesis that greater levels of MgSO4 exposure at the time of delivery
would be preferential in terms of risk reduction and that there may be an optimal MgSO4 cord blood concentration for the neuroprotective effect. In prior studies, neither a dose–response effect nor a threshold effect of magnesium for neuroprotection was evaluated.2–4 For example, one of the three randomized trials
Table 2 Multivariable analysis for the association of CP/death or CP alone with MgSO4 infusion at delivery Variable
CP/death
MgSO4 infusion at delivery 2
CP alone
OR
95% CI
OR
95% CI
0.87
0.53–1.41
0.56
0.23–1.33
Body mass index (kg/m )
1.03
1.00–1.06
1.04
0.99–1.11
Gestational age at delivery (wks)
0.69
0.63–0.76
0.76
0.65–0.90
Cesarean delivery
1.47
0.89–2.41
1.87
0.80–4.41
Male gender
2.01
1.20–3.36
2.96
1.12–7.80
Abbreviations: CI, confidence interval; CP, cerebral palsy; OR, odds ratio. American Journal of Perinatology
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Table 3 Results of multivariable analysis of factors associated with the risk of CP/death or CP alone, with cord blood magnesium level as a continuous variable Variable
CP/death
CP alone
OR
95% CI
OR
95% CI
Magnesium cord blood level (mEq/L)
1.04
0.78–1.52
1.29
0.57–2.87
Body mass index at delivery (kg/m2)
1.04
0.99–1.09
1.04
0.95–1.13
Gestational age at delivery (wks)
0.70
0.62–0.80
0.82
0.63–1.07
Cesarean delivery
1.35
0.68–2.67
3.91
0.90–16.91
Male gender
1.89
0.94–3.78
2.66
0.54–13.15
administered only a single 4 g loading dose with no maintenance infusion, and still showed a protective effect against severe motor dysfunction or death (OR 0.62, 95% CI 0.41– 0.93).3 An analysis of placental transfer of magnesium in the ACTOMgSO4 trial showed prompt transfer of the drug from mother to fetus after initiation of the infusion, with the neonatal magnesium levels remaining elevated for up to 24 hours.2 Finally, animal studies have shown that magnesium crosses the fetal blood–brain barrier within 2 hours of sustained maternal administration and that both single and multiple doses of MgSO4 reduced brain injury.9,10 Compounding the problem of identifying the optimal dose or timing for MgSO4 administration is that the mechanism of CP prevention by MgSO4 is not well understood. One prominent theory posits the inhibition of calcium influx through the blocking of N-methyl-D-aspartate receptors, which then prevents neuron damaging excitatory amino acid release during episodes of hypoxia and ischemia.11,12 Additional proposed mechanisms include a reduction in free radicals and proinflammatory cytokines, an increase in vasodilation in the cerebral vasculature, and prevention of large blood pressure fluctuation.11 In light of such uncertainty and likely complexity, finding a direct relationship between the regi-
men of antenatal MgSO4 administration and its neuroprotective effect, as well as identifying an optimal neonatal cord blood magnesium concentration, may be difficult. The strength of our study is that this analysis is performed within a cohort derived from a randomized trial in which intervention (exposure) was standardized and examiners evaluating the perinatal outcomes were blinded to whether there had been antenatal magnesium exposure. In addition, research staff used standardized data forms that led to the collection of detailed data. Nevertheless, it is a secondary analysis, and as such, is limited by the available sample size, with the possibility of type II error. Also, magnesium cord blood concentrations were not available for 340 neonates. This could potentially bias our results, as those neonates had a higher incidence of CP/death and CP outcomes. In conclusion, we did not find an association between magnesium cord blood concentration and MgSO4 infusion at the time of delivery and the outcome of CP/death diagnosed at the age of 2 years. This does not negate the beneficial effect of in utero exposure to MgSO4 among preterm neonates that has been demonstrated in randomized trials, but rather emphasizes our poor understanding of its neuroprotective mechanism.
Table 4 Results of multivariable analysis of factors associated with the risk of CP/death or CP alone, with cord blood magnesium level as a categorical variable Variable
CP/death
1st quartile magnesium level (n ¼ 155)
CP alone
OR
95% CI
OR
95% CI
1
Ref
1
Ref
2nd quartile magnesium level (n ¼ 150)
0.63
0.23–1.70
2.16
0.20–22.85
3rd quartile magnesium level (n ¼ 174)
1.24
0.50–3.10
3.07
0.29–32.07
4th quartile magnesium level (n ¼ 123)
0.95
0.33–2.77
3.39
0.27–42.68
2
Body mass index at delivery (kg/m )
1.04
0.99–1.10
1.04
0.95–1.14
Gestational age at delivery (wks)
0.95
0.93–0.97
0.97
0.94–1.01
Cesarean delivery
1.47
0.73–2.93
4.30
0.99–18.70
Male gender
1.85
0.92–3.72
2.76
0.55–13.67
Abbreviations: CI, confidence interval; CP, cerebral palsy; OR, odds ratio. Notes: 1st quartile: (0.2–1.7 mEq/L), 2nd quartile: (1.8–2.6 mEq/L), 3rd quartile: (2.7–3.4 mEq/L), and 4th quartile: (3.5–5.3 mEq/L). Analysis was conducted for 596 neonates who had available magnesium cord blood concentration. American Journal of Perinatology
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Abbreviations: CI, confidence interval; CP, cerebral palsy; OR, odds ratio. Note: Analysis was conducted for 596 neonates who had available magnesium cord blood concentration.
Funding None. 4
Note Poster presented at: 35th annual meeting of the Society for Maternal-Fetal Medicine; Feb 2–7, 2015; San Diego, CA.
5
Conflict of Interest The authors report no conflict of interest.
6 7
Acknowledgments We would like to acknowledge the NICHD, the MFMU Network, and the Protocol Subcommittee for making this database publically available.
References
8
9
1 Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magne-
sium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009;1(1): CD004661 2 Crowther CA, Hiller JE, Doyle LW, Haslam RR; Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003; 290(20):2669–2676 3 Marret S, Marpeau L, Zupan-Simunek V, et al; PREMAG trial group. Magnesium sulphate given before very-preterm birth to protect
10
11
12
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infant brain: the randomised controlled PREMAG trial. BJOG 2007; 114(3):310–318 Rouse DJ, Hirtz DG, Thom E, et al; Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359(9):895–905 American College of Obstetricians and Gynecologists Committee on Obstetric Practice; Society for Maternal-Fetal Medicine. Committee Opinion No. 455: Magnesium sulfate before anticipated preterm birth for neuroprotection. Obstet Gynecol 2010;115(3): 669–671 Hirtz DG, Nelson K. Magnesium sulfate and cerebral palsy in premature infants. Curr Opin Pediatr 1998;10(2):131–137 McPherson JA, Rouse DJ, Grobman WA, Palatnik A, Stamilio DM. Association of duration of neuroprotective magnesium sulfate infusion with neonatal and maternal outcomes. Obstet Gynecol 2014;124(4):749–755 Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39(4):214–223 Hallak M, Cotton DB. Transfer of maternally administered magnesium sulfate into the fetal compartment of the rat: assessment of amniotic fluid, blood, and brain concentrations. Am J Obstet Gynecol 1993;169(2 Pt 1):427–431 McDonald JW, Silverstein FS, Johnston MV. Magnesium reduces N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats. Neurosci Lett 1990;109(1-2):234–238 Marret S, Doyle LW, Crowther CA, Middleton P. Antenatal magnesium sulphate neuroprotection in the preterm infant. Semin Fetal Neonatal Med 2007;12(4):311–317 Burd I, Breen K, Friedman A, Chai J, Elovitz MA. Magnesium sulfate reduces inflammation-associated brain injury in fetal mice. Am J Obstet Gynecol 2010;202(3):292.e1–292.e9
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Cord Magnesium Concentration and Cerebral Palsy
Cord Magnesium Concentration and Cerebral Palsy
Palatnik et al.
Supplemental Table 1 Comparison of neonatal characteristics based on availability of magnesium cord blood level at the time of delivery Characteristic
Mg concentration available (n ¼ 596)
Mg concentration not available (n ¼ 340)
p-Value
Gestational age at delivery (wk)
30.2 2.9
29.4 3.4
< 0.001
Birth weight
1,501.4 538.2
1,337 608.1
< 0.001
SGA
14 (2.3)
16 (4.7)
0.049
Male gender
343 (57.5)
176 (51.8)
0.087 0.066
African American
255 (42.8)
157 (46.2)
Caucasian
233 (39.1)
108 (31.8)
Hispanic
92 (15.4)
70 (20.6)
Other
16 (2.7)
5 (1.5)
581 (97.5)
329 (96.7)
Antenatal corticosteroids Mode of delivery
0.78 0.029
Vaginal
400 (67.1)
204 (60)
Cesarean
196 (32.9)
136 (40)
General anesthesia
39 (6.5)
38 (11.2)
0.004
CP or death
48 (8.1)
45 (13.2)
0.011
CP alone
10 (1.8)
16 (4.7)
0.005
Abbreviations: CI, confidence interval; CP, cerebral palsy; Mg, magnesium. Note: All data are presented as mean standard deviation or N (%).
American Journal of Perinatology
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Race/ethnicity
Association between Cerebral Palsy or Death and Umbilical Cord Blood Magnesium Concentration Anna Palatnik, MD1 Dwight J. Rouse, MD, MSPH2 David M. Stamilio, MD, MSCE3 Jessica A. McPherson, MD3 William A. Grobman, MD, MBA1 1 Department of Obstetrics and Gynecology, Feinberg School of
Medicine, Northwestern University, Chicago, Illinois 2 Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, Rhode Island 3 Department of Obstetrics and Gynecology, The University of North Carolina School of Medicine, Chapel Hill, North Carolina
Address for correspondence Anna Palatnik, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Northwestern Medical Group, 250 East Superior Street, Suite 05-2175, Chicago, IL 60611 (e-mail: [email protected]).
Abstract
Keywords
► ► ► ►
cerebral palsy cord blood magnesium sulfate preterm delivery
Objective This study aims to evaluate whether magnesium sulfate (MgSO4) infusion at the time of delivery or magnesium cord blood concentration is associated with cerebral palsy (CP) or death diagnosed by the age of 2 years. Methods Secondary analysis of data from a randomized trial of MgSO4 versus placebo for prevention of CP or death among offspring of women with anticipated preterm delivery. This study cohort included singleton, nonanomalous fetuses, whose mothers received MgSO4 as neuroprophylaxis. The primary outcomes were CP or death diagnosed by the age of 2 years. Results A total of 936 neonates (93 with CP or death, 843 controls) were included in the analysis. Infants in the group with CP or death had MgSO4 infusing at delivery at a similar frequency to that of controls (49 [52.7%] vs. 463 [54.9%], p ¼ 0.68). Mean concentrations of cord blood magnesium, available for 596 neonates, also were not different between the two groups (2.7 0.9 vs. 2.6 0.9 mEq/L, p ¼ 0.66, respectively). Multivariable analyses did not alter these findings. Conclusion Among the offspring of women exposed to MgSO4, in utero, neither MgSO4 infusion at the time of delivery nor magnesium cord blood concentration is associated with CP or death.
Administration of intravenous magnesium sulfate (MgSO4) to women at risk for early preterm delivery has been shown to reduce the risk of neurodevelopmental disability in their surviving children.1 Specifically, a recent large randomized trial as well as a meta-analysis showed that children exposed as fetuses to an antenatal infusion of MgSO4 had a 45% reduced risk of moderate or severe cerebral palsy (CP) at the age of 2 years.2–4 Nevertheless, the optimal regimen of MgSO4 administration remains uncertain. Different studies have used different
loading doses (4 or 6 g), as well as different maintenance doses (none, 1 or 2 g/h) of varying durations (12 or 24 hours).2–4 Correspondingly, the American Congress of Obstetrics and Gynecology suggests that “physicians electing to use magnesium sulfate for fetal neuroprotection should develop specific guidelines regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”5 The biological plausibility for benefit of MgSO4 has been related to its inhibition of excitatory neurological pathways,
received March 17, 2015 accepted after revision April 20, 2014
Copyright © by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1554798. ISSN 0735-1631.
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
Am J Perinatol
Palatnik et al.
improvement of cerebral perfusion, and reduction in free radicals.6 It is plausible, therefore, that the degree of exposure to magnesium could be associated with adverse outcome. A recent study showed that there was no association between the total duration of MgSO4 infusion and the rate of CP or death.7 However, although total duration of MgSO4 may not significantly influence adverse infant outcome rate, whether magnesium infusion is ongoing at the time of delivery, or whether a certain fetal magnesium blood concentration is reached may be important factors in neuroprotective therapy efficacy. Therefore, the aims of this study were to evaluate whether MgSO4 infusion that was ongoing at the time of delivery or magnesium cord blood levels were associated with neonatal neurological outcomes.
Material and Methods This case–control study was a secondary analysis of data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network trial of MgSO4 for the prevention of CP or death among the offspring of women who were at risk of premature delivery before 32 weeks of gestation (i.e., the Beneficial Effects of Antenatal Magnesium [BEAM] study). The present analysis includes all nonanomalous singleton infants in the BEAM study whose mothers received MgSO4. By protocol, patients received a loading dose of 6 g infused for 20 to 30 minutes, followed by a maintenance infusion of 2 g/h for up to 12 hours. The infusion was discontinued if delivery was not imminent, with the intent of resuming it again for recurrent preterm labor or anticipated delivery before 34 weeks of gestation. Another loading dose was administered at resumption if at least 6 hours passed since MgSO4 discontinuation. Umbilical cord blood was collected at delivery. The samples were frozen within 12 hours of blood collection and stored at 70°C. Analysis of the level of magnesium in the cord blood was performed at a central laboratory (Olympus, Center Valley, PA), which used an analyzer with a minimum detectable magnesium concentration of 0.4 mEq/L. The primary outcomes evaluated in this study were CP or death by the age of 2 years, while CP alone was examined as a secondary outcome. The severity of CP was assessed by the Gross Motor Function Classification System by an annually certified pediatrician or pediatric neurologist.8 Univariable comparisons were performed using Pearson chi-square test for categorical data and the Student t-test for continuous measures. Multivariable analyses were performed using logistic regression for the outcomes of interest with either the presence of MgSO4 infusion at the time of delivery or the magnesium cord blood concentration forced into the equation as an independent variable. Magnesium cord concentrations were evaluated as both continuous and ordinal (by quartile) variables. Other covariates were entered into the regression equation if they differed between groups in univariable analysis at a level of p < 0.05. Adjusted odds ratios (OR) with 95% confidence intervals (CI) were estimated from the logistic regression. All analyses were performed with Stata version 12.0 (StataCorp, College Station, TX). This study American Journal of Perinatology
used publically available deidentified data and was considered exempt by the Institutional Review Board at Northwestern University.
Results A total of 936 neonates met the inclusion criteria. The maternal and neonatal characteristics for the analyzed groups, defined according to whether CP or death occurred, are summarized in ►Table 1. Mothers of neonates who subsequently had CP or death had a higher mean body mass index and higher rate of cesarean delivery. Also, the neonates with either CP or death were delivered at an earlier gestational age and were more likely to be male. In univariable analysis, infants with CP or death had a similar frequency of MgSO4 infusing at delivery as those without CP or death (49 [52.7%] vs. 463 [54.9%], p ¼ 0.68). Also, there was no difference in the frequency of MgSO4 infusion at delivery between groups when those with CP alone were compared with those without CP (11 [42.3%] vs. 476 [56.5%], p ¼ 0.15). This lack of association did not change in multivariable analysis (OR ¼ 0.87, CI 0.53–1.41 for CP or death, and OR ¼ 0.56, CI 0.23–1.33 for CP alone) (►Table 2). Magnesium cord blood concentrations were available for 596 neonates (48 neonates with CP or death and 548 neonates in the control group). The neonates without available magnesium cord blood concentration were delivered at an earlier gestational age, had a lower mean birth weight, and a higher frequency of CP or death (Supplemental Table 1). In the group with available magnesium cord blood concentration, mean levels of cord blood magnesium were not statistically different between those with and without CP or death (2.7 0.9 vs. 2.6 0.9 mEq/L, p ¼ 0.66). Similarly, quartile of magnesium cord blood level was not associated with the frequency of CP or death (1st quartile: 10/155 (6.4%); 2nd quartile: 10/150 (6.6%); 3rd quartile: 19/174 (10.9%); 4th quartile: 9/123 (7.3%); p ¼ 0.39). Multivariable analyses did not alter these findings. After adjusting for potential confounding variables, cord blood magnesium concentration, whether expressed as a continuous or categorical variable, was not associated with CP or death (OR ¼ 1.04, CI 0.78–1.52) (►Tables 3 and 4). Results were similar when CP alone was used as the outcome (OR ¼ 1.29, CI 0.57–2.87) (►Tables 3 and 4).
Comment In this secondary analysis we evaluated the association between neonatal CP and death diagnosed by 2 years of age and the degree of exposure to MgSO4 at the time of delivery. We evaluated this degree of exposure by two methods— whether or not MgSO4 was infusing at the time of delivery and the concentration of magnesium in cord blood at delivery. There was no evidence from our analysis that magnesium cord blood concentration or MgSO4 infusion at the time of delivery was associated with offspring
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Cord Magnesium Concentration and Cerebral Palsy
Cord Magnesium Concentration and Cerebral Palsy
Palatnik et al.
Table 1 Patient characteristics stratified by the presence of cerebral palsy or death Characteristic
CP/death (n ¼ 93)
p-Value
Controls (n ¼ 843)
Maternal Age (y)
26.0 5.8
26.2 6.3
0.82
Body mass index at delivery (kg/m2)
27.8 8.3
25.7 6.3
0.005
Married
48 (51.6)
419 (49.7)
0.74
Years of education
11.9 1.9
11.7 2.5
0.46
African American
49 (52.7)
363 (43.0)
Caucasian
35 (37.6)
306 (36.3)
Hispanic
8 (8.6)
154 (18.2)
Other
1 (1.1)
20 (2.4)
Nulliparous
34 (36.5)
296 (35.1)
0.78
Cigarette use during pregnancy
27 (29.0)
225 (26.7)
0.63
Alcohol use during pregnancy
5 (5.4)
78 (9.2)
0.21
Illicit drug use during pregnancy
8 (8.6)
85 (10.1)
0.65
No prenatal care
5 (5.4)
66 (7.8)
0.39
Vaginal
51 (54.8)
553 (65.6)
Cesarean
42 (45.2)
290 (34.4)
14 (15.0)
96 (11.4)
0.29
Gestational age at delivery (wk)
27.4 2.9
30.1 2.9
< 0.001
Small for gestational age
5 (5.4)
25 (2.9)
0.21
Male gender
61 (65.6)
458 (54.3)
0.04
General anesthesia
12 (12.9)
65 (7.7)
0.07
Antenatal corticosteroids
90 (96.7)
820 (97.3)
0.78
49 (52.7)
463 (54.9)
0.68
0.11
Mode of delivery
0.04
Chorioamnionitis Neonatal
Magnesium infusion at the time of delivery Abbreviations: CI, confidence interval; CP, cerebral palsy. Note: All data are presented as mean standard deviation or N (%).
outcomes among gravidas who received MgSO 4 for perinatal neuroprotection. Prior large trials found a neuroprotective effect of MgSO4 when administered to women at risk of preterm delivery (< 33 weeks).1–4 This finding led to our hypothesis that greater levels of MgSO4 exposure at the time of delivery
would be preferential in terms of risk reduction and that there may be an optimal MgSO4 cord blood concentration for the neuroprotective effect. In prior studies, neither a dose–response effect nor a threshold effect of magnesium for neuroprotection was evaluated.2–4 For example, one of the three randomized trials
Table 2 Multivariable analysis for the association of CP/death or CP alone with MgSO4 infusion at delivery Variable
CP/death
MgSO4 infusion at delivery 2
CP alone
OR
95% CI
OR
95% CI
0.87
0.53–1.41
0.56
0.23–1.33
Body mass index (kg/m )
1.03
1.00–1.06
1.04
0.99–1.11
Gestational age at delivery (wks)
0.69
0.63–0.76
0.76
0.65–0.90
Cesarean delivery
1.47
0.89–2.41
1.87
0.80–4.41
Male gender
2.01
1.20–3.36
2.96
1.12–7.80
Abbreviations: CI, confidence interval; CP, cerebral palsy; OR, odds ratio. American Journal of Perinatology
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Cord Magnesium Concentration and Cerebral Palsy
Palatnik et al.
Table 3 Results of multivariable analysis of factors associated with the risk of CP/death or CP alone, with cord blood magnesium level as a continuous variable Variable
CP/death
CP alone
OR
95% CI
OR
95% CI
Magnesium cord blood level (mEq/L)
1.04
0.78–1.52
1.29
0.57–2.87
Body mass index at delivery (kg/m2)
1.04
0.99–1.09
1.04
0.95–1.13
Gestational age at delivery (wks)
0.70
0.62–0.80
0.82
0.63–1.07
Cesarean delivery
1.35
0.68–2.67
3.91
0.90–16.91
Male gender
1.89
0.94–3.78
2.66
0.54–13.15
administered only a single 4 g loading dose with no maintenance infusion, and still showed a protective effect against severe motor dysfunction or death (OR 0.62, 95% CI 0.41– 0.93).3 An analysis of placental transfer of magnesium in the ACTOMgSO4 trial showed prompt transfer of the drug from mother to fetus after initiation of the infusion, with the neonatal magnesium levels remaining elevated for up to 24 hours.2 Finally, animal studies have shown that magnesium crosses the fetal blood–brain barrier within 2 hours of sustained maternal administration and that both single and multiple doses of MgSO4 reduced brain injury.9,10 Compounding the problem of identifying the optimal dose or timing for MgSO4 administration is that the mechanism of CP prevention by MgSO4 is not well understood. One prominent theory posits the inhibition of calcium influx through the blocking of N-methyl-D-aspartate receptors, which then prevents neuron damaging excitatory amino acid release during episodes of hypoxia and ischemia.11,12 Additional proposed mechanisms include a reduction in free radicals and proinflammatory cytokines, an increase in vasodilation in the cerebral vasculature, and prevention of large blood pressure fluctuation.11 In light of such uncertainty and likely complexity, finding a direct relationship between the regi-
men of antenatal MgSO4 administration and its neuroprotective effect, as well as identifying an optimal neonatal cord blood magnesium concentration, may be difficult. The strength of our study is that this analysis is performed within a cohort derived from a randomized trial in which intervention (exposure) was standardized and examiners evaluating the perinatal outcomes were blinded to whether there had been antenatal magnesium exposure. In addition, research staff used standardized data forms that led to the collection of detailed data. Nevertheless, it is a secondary analysis, and as such, is limited by the available sample size, with the possibility of type II error. Also, magnesium cord blood concentrations were not available for 340 neonates. This could potentially bias our results, as those neonates had a higher incidence of CP/death and CP outcomes. In conclusion, we did not find an association between magnesium cord blood concentration and MgSO4 infusion at the time of delivery and the outcome of CP/death diagnosed at the age of 2 years. This does not negate the beneficial effect of in utero exposure to MgSO4 among preterm neonates that has been demonstrated in randomized trials, but rather emphasizes our poor understanding of its neuroprotective mechanism.
Table 4 Results of multivariable analysis of factors associated with the risk of CP/death or CP alone, with cord blood magnesium level as a categorical variable Variable
CP/death
1st quartile magnesium level (n ¼ 155)
CP alone
OR
95% CI
OR
95% CI
1
Ref
1
Ref
2nd quartile magnesium level (n ¼ 150)
0.63
0.23–1.70
2.16
0.20–22.85
3rd quartile magnesium level (n ¼ 174)
1.24
0.50–3.10
3.07
0.29–32.07
4th quartile magnesium level (n ¼ 123)
0.95
0.33–2.77
3.39
0.27–42.68
2
Body mass index at delivery (kg/m )
1.04
0.99–1.10
1.04
0.95–1.14
Gestational age at delivery (wks)
0.95
0.93–0.97
0.97
0.94–1.01
Cesarean delivery
1.47
0.73–2.93
4.30
0.99–18.70
Male gender
1.85
0.92–3.72
2.76
0.55–13.67
Abbreviations: CI, confidence interval; CP, cerebral palsy; OR, odds ratio. Notes: 1st quartile: (0.2–1.7 mEq/L), 2nd quartile: (1.8–2.6 mEq/L), 3rd quartile: (2.7–3.4 mEq/L), and 4th quartile: (3.5–5.3 mEq/L). Analysis was conducted for 596 neonates who had available magnesium cord blood concentration. American Journal of Perinatology
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Abbreviations: CI, confidence interval; CP, cerebral palsy; OR, odds ratio. Note: Analysis was conducted for 596 neonates who had available magnesium cord blood concentration.
Funding None. 4
Note Poster presented at: 35th annual meeting of the Society for Maternal-Fetal Medicine; Feb 2–7, 2015; San Diego, CA.
5
Conflict of Interest The authors report no conflict of interest.
6 7
Acknowledgments We would like to acknowledge the NICHD, the MFMU Network, and the Protocol Subcommittee for making this database publically available.
References
8
9
1 Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magne-
sium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009;1(1): CD004661 2 Crowther CA, Hiller JE, Doyle LW, Haslam RR; Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003; 290(20):2669–2676 3 Marret S, Marpeau L, Zupan-Simunek V, et al; PREMAG trial group. Magnesium sulphate given before very-preterm birth to protect
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11
12
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infant brain: the randomised controlled PREMAG trial. BJOG 2007; 114(3):310–318 Rouse DJ, Hirtz DG, Thom E, et al; Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359(9):895–905 American College of Obstetricians and Gynecologists Committee on Obstetric Practice; Society for Maternal-Fetal Medicine. Committee Opinion No. 455: Magnesium sulfate before anticipated preterm birth for neuroprotection. Obstet Gynecol 2010;115(3): 669–671 Hirtz DG, Nelson K. Magnesium sulfate and cerebral palsy in premature infants. Curr Opin Pediatr 1998;10(2):131–137 McPherson JA, Rouse DJ, Grobman WA, Palatnik A, Stamilio DM. Association of duration of neuroprotective magnesium sulfate infusion with neonatal and maternal outcomes. Obstet Gynecol 2014;124(4):749–755 Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39(4):214–223 Hallak M, Cotton DB. Transfer of maternally administered magnesium sulfate into the fetal compartment of the rat: assessment of amniotic fluid, blood, and brain concentrations. Am J Obstet Gynecol 1993;169(2 Pt 1):427–431 McDonald JW, Silverstein FS, Johnston MV. Magnesium reduces N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats. Neurosci Lett 1990;109(1-2):234–238 Marret S, Doyle LW, Crowther CA, Middleton P. Antenatal magnesium sulphate neuroprotection in the preterm infant. Semin Fetal Neonatal Med 2007;12(4):311–317 Burd I, Breen K, Friedman A, Chai J, Elovitz MA. Magnesium sulfate reduces inflammation-associated brain injury in fetal mice. Am J Obstet Gynecol 2010;202(3):292.e1–292.e9
American Journal of Perinatology
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Cord Magnesium Concentration and Cerebral Palsy
Cord Magnesium Concentration and Cerebral Palsy
Palatnik et al.
Supplemental Table 1 Comparison of neonatal characteristics based on availability of magnesium cord blood level at the time of delivery Characteristic
Mg concentration available (n ¼ 596)
Mg concentration not available (n ¼ 340)
p-Value
Gestational age at delivery (wk)
30.2 2.9
29.4 3.4
< 0.001
Birth weight
1,501.4 538.2
1,337 608.1
< 0.001
SGA
14 (2.3)
16 (4.7)
0.049
Male gender
343 (57.5)
176 (51.8)
0.087 0.066
African American
255 (42.8)
157 (46.2)
Caucasian
233 (39.1)
108 (31.8)
Hispanic
92 (15.4)
70 (20.6)
Other
16 (2.7)
5 (1.5)
581 (97.5)
329 (96.7)
Antenatal corticosteroids Mode of delivery
0.78 0.029
Vaginal
400 (67.1)
204 (60)
Cesarean
196 (32.9)
136 (40)
General anesthesia
39 (6.5)
38 (11.2)
0.004
CP or death
48 (8.1)
45 (13.2)
0.011
CP alone
10 (1.8)
16 (4.7)
0.005
Abbreviations: CI, confidence interval; CP, cerebral palsy; Mg, magnesium. Note: All data are presented as mean standard deviation or N (%).
American Journal of Perinatology
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