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DOI: 10.1542/peds.99.5.e1
1997;99;e1Pediatrics
Brain Hemorrhage Study Analysis Group
Nigel Paneth, James Jetton, Jennifer Pinto-Martin, Mervyn Susser and the Neonatal
Palsy in Low Birth Weight Infants
Magnesium Sulfate in Labor and Risk of Neonatal Brain Lesions and Cerebral
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Magnesium Sulfate in Labor and Risk of Neonatal Brain Lesions and
Cerebral Palsy in Low Birth Weight Infants
Nigel Paneth, MD, MPH*‡; James Jetton*; Jennifer Pinto-Martin, PhD§; Mervyn Susser, MB, BCh, DPHi;
and the Neonatal Brain Hemorrhage Study Analysis Group
ABSTRACT. Objectives. We tested the hypothesis
that administration of magnesium sulfate in labor pro-
tects against the development of neonatal brain lesions
and cerebral palsy (CP) in low birth weight infants.
Methods. Magnesium exposure was ascertained in a
population-based cohort of 1105 infants weighing 2000 g
or less through review of medical records of maternal
magnesium sulfate administration and, where available,
elevated maternal serum magnesium levels. Neonatal
germinal matrix/intraventricular hemorrhage and paren-
chymal brain lesions were ascertained by a prospective,
timed ultrasound scanning protocol in the first week of
life. CP was ascertained at 2 years of age by clinical
examination in 80% of survivors and by interview and
medical record review in another 6% and was classified
as disabling or nondisabling.
Results. No significant reduction in risk of nondis-
abling CP (adjusted odds ratio [OR], 1.00; 95% confi-
dence interval [CI], 0.53 to 1.88) or disabling CP [DCP]
(adjusted OR, 0.63; 95% CI, 0.32 to 1.24) CP with mag-
nesium exposure was found in a logistic regression
model that controlled for gestational age, fetal growth,
gender, multiple birth status, mode of delivery, amnio-
nitis, and hypertensive disorders. In a small subset of
infants, those with onset of parenchymal lesions at 7
days of age or later (n 5 29), magnesium exposure was
associated with a significantly reduced risk of DCP
(OR, 0.10; 95% CI, 0.02 to 0.65). Magnesium sulfate
exposure was not associated with germinal matrix/in-
traventricular hemorrhage (adjusted OR, 0.89; 95% CI,
0.64 to 1.25) or with parenchymal brain lesions (adjust-
ed OR, 0.83; 95% CI, 0.53 to 1.30).
Conclusions. The hypothesis that magnesium sulfate
use reduces the risk of neonatal brain lesions or CP in
low birth weight infants was not statistically supported
in this study, although a modest reduction in risk of DCP
cannot be excluded. The data further suggest that mag-
nesium exposure may be associated with reduction in
risk of CP in low birth weight infants who have late-
onset brain lesions, but this unpredicted observation re-
quires confirmation in another data set. Pediatrics 1997;
99(5). URL: http://www.pediatrics.org/cgi/content/full/99/
5/e1; cerebral palsy; magnesium sulfate; infant, low birth
weight; preeclampsia; cerebral hemorrhage, infant.
ABBREVIATIONS. PE, preeclampsia; CP, cerebral palsy; NBH,
Neonatal Brain Hemorrhage (cohort); DCP, disabling CP; GM/
IVH, germinal matrix or intraventricular hemorrhage; PEL/VE,
parenchymal lesion/ventricular enlargement; HYP, hypertension;
OR, odds ratio; CI, confidence interval.
Magnesium sulfate is widely used in obstetric
practice both to treat preeclampsia (PE) and to at-
tempt to arrest the progress of premature labor. A
recent case-control study in infants weighing less
than 1500 g at birth demonstrated a substantial re-
duction in cerebral palsy (CP) in children whose
mothers received magnesium sulfate in labor.
1
This observation is coherent with the multiple cat-
alytic roles of magnesium in cellular enzyme systems
and neuronal functioning
2
and particularly with ev-
idence that magnesium can block the N-methyl-d-
aspartate receptor and thus prevent excitatory amino
acids, commonly released during episodes of hyp-
oxia and ischemia, from producing neuronal dam-
age.
3
We set out to test the hypothesis suggested by this
case-control study, namely, that magnesium expo-
sure is associated with a decreased risk of CP in the
Central New Jersey Neonatal Brain Hemorrhage
(NBH) cohort. In the NBH cohort, low birth weight
infants were assessed prospectively with cranial ul-
trasound scanning in the neonatal period and exam-
ined at 2 years of age for the presence or absence of
CP. Included in this cohort of 1105 infants are 362
infants whose mothers received magnesium sulfate,
280 infants with ultrasonographically diagnosed
neonatal brain lesions, and 113 children with the
diagnosis of either disabling CP (DCP) or nondis-
abling CP. This study thus provides considerable
power to assess the relationships of magnesium sul-
fate exposure to important neurologic outcomes in
the neonatal and early childhood periods.
METHODS
Study Population
The NBH study is an investigation into the causes and conse-
quences of ultrasonographically diagnosed brain lesions in low
birth weight infants. The cohort is a geographically representative
sample of 1105 infants weighing 2000 g or less born or cared for in
three neonatal intensive care units in central New Jersey between
1984 and 1987.
4
The ultrasound screening protocol called for scans
at 4 hours, 24 hours, and 7 days of age. Such films were obtained
in more than 95% of eligible infants. Additional later scans were
obtained, usually just before discharge, in about half of the cohort.
Study films were read by two or, if needed, three radiologists to
obtain consensus on the diagnosis. In 94% of study infants, the
From the *Program in Epidemiology and ‡Department of Pediatrics and
Human Development, College of Human Medicine, Michigan State Univer-
sity, East Lansing, Michigan; §College of Nursing, University of Pennsyl-
vania, Philadelphia, Pennsylvania; and iSergievsky Center and School of
Public Health, Columbia University, New York, New York.
Received for publication Apr 10, 1996; accepted Nov 4, 1996.
Reprint requests to (N.P.) Program in Epidemiology, A 206 East Fee Hall,
College of Human Medicine, Michigan State University, East Lansing, MI
48824.
PEDIATRICS (ISSN 0031 4005). Copyright © 1997 by the American Acad-
emy of Pediatrics.
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ultrasound diagnosis was based on agreement by two indepen-
dent readers. Information on CP status was available on 86% of
surviving infants at 2 years of age, and in 80% this was based on
a standardized motor examination by a trained nurse or nurse
practitioner supplemented by medical record review and exami-
nation by study child neurologists in cases of suspected abnor-
mality.
Outcomes of Interest
Five health outcomes were selected for study: neonatal out-
comes included death in the first 28 days, sonographic diagnosis
of germinal matrix or intraventricular hemorrhage (GM/IVH) and
sonographic diagnosis of parenchymal lesion/ventricular enlarge-
ment (PEL/VE), a category that includes lesions commonly re-
ferred to as periventricular leukomalacia, porencephalic cyst, and
grades III and IV IVH. Based on pathological and outcome studies,
the above dichotomy of brain lesions distinguishes milder lesions
(GM/IVH), which do not themselves damage cortex or white
matter and are not usually associated with substantial elevation of
handicap risk, from more severe lesions (PEL/VE), which reflect
pathologic evidence of damage to white matter and predict sub-
sequent neurologic impairment. These groupings are also more
consistent with pathologic findings
5
than is the widely used clas-
sification of Papile et al.
6
When both brain lesions occurred, the
infant was categorized as having PEL/VE.
The two outcomes assessed at 2 years of age were DCP and
nondisabling CP. The term DCP was used when at least one of five
markers of disability was present in addition to specific neurologic
findings
7
:
1. Inability to walk ten steps unaided by 2 years of age;
2. Bayley motor score greater than 1 SD lower than performance
score;
3. Receipt of physical therapy for motor disability;
4. Receipt of surgical intervention for motor disorder; and
5. Use of braces or physical assistance devices.
The majority of children with DCP had Bayley motor scores of
less than 50. (Previous papers
7,20
mistakenly cited five steps rather
than ten steps as the walking criterion; no case of CP was classified
as disabled based on this criterion).
Although the stimulus for this analysis was a finding about the
relationship of magnesium sulfate to CP, we examined death
before discharge, because a reduction in CP risk might be found if
there were an increased risk of neonatal death associated with
magnesium sulfate exposure. Neonatal brain lesions were exam-
ined because of their strong relationship to risk of CP.
7
Changes in
their incidence might therefore constitute a mechanism by which
risk of CP is influenced by magnesium exposure.
Exposure Assessment
In the NBH data set, diagnoses made during pregnancy and
delivery, medications used in the 72 hours before delivery, and
blood tests obtained in the 24 hours before labor were systemati-
cally abstracted from prenatal and labor and delivery records.
Mothers were also interviewed shortly after delivery about ill-
nesses and medications taken during pregnancy. Because magne-
sium sulfate is used to treat PE, and because PE has been associ-
ated, in some studies, with reduced risk of CP,
8
control for PE is
essential for proper understanding of the relationship of magne-
sium sulfate to neurologic sequelae. Thus, we first categorized
hypertensive mothers as having either preexisting hypertension
(HYP) or PE. The presence of proteinuria during pregnancy was
not required for the diagnosis of PE, but was recorded when
noted. Figure 1 sets out the criteria for the above diagnoses and the
data sources in the NBH study used to establish them. HYP was
found in the mothers of 47 infants (4.3%), and PE was found in 212
(19.2%), which was associated with proteinuria in 136 (12.3%).
Magnesium sulfate use was ascertained in two ways: from the
recording of magnesium sulfate administration in medical records
and from the recording of elevated (.2.8 mEq/L) maternal serum
levels of magnesium sulfate. In addition, infants were presumed
exposed to magnesium sulfate if an elevated (.1.7 mEq/L) serum
magnesium level was recorded in the neonatal period.
Data Analysis
The associations between magnesium exposure of infants (de-
fined by magnesium sulfate administration, elevated serum mag-
nesium level, or both) and the five health outcomes are shown
both unadjusted and adjusted for several potentially confounding
variables. The selection of the model for adjustment was based on
known associations of the variables in the model with outcomes of
interest as well as with receipt of magnesium therapy, either in our
study or in the literature. The final model chosen included the
following variables in the analysis: gestational age, fetal growth
ratio (defined as the ratio of the infant’s birth weight to the median
birth weight for its week of gestation based on the standards of
Arbuckle et al
9
), gender, mode of delivery (vaginal, cesarean with
labor, or cesarean without labor), multiple birth status, diagnosis
of amnionitis during labor, and maternal diagnoses of PE (with or
without proteinuria) and preexisting HYP.
In addition, to replicate the findings of Nelson and Grether
1
more closely, we selected singleton infants in the NBH cohort who
weighed less than 1500 g and repeated, as best we could in our
data, the analytic model used by Nelson and Grether
1
to control
for extraneous variables.
We calculated unadjusted odds ratios (ORs) using Cornfield
95% confidence intervals (CIs) and adjusted ORs by multiple
logistic regression. Analyses included models containing all vari-
ables above and smaller models resulting from reverse-stepwise
selection. Adequacy of fit was assessed by the grouped Hosmer-
Lemeshow
x
2
test, and D
x
2
and D
b
diagnostic plots were used to
examine potential outliers.
19
All analyses were performed using
Stata (Stata Corp, College Station TX).
RESULTS
Magnesium Sulfate Exposure and HYP-Related
Diagnoses (Table 1)
A total of 362 infants were designated as exposed
to magnesium. In 173, maternal serum magnesium
was documented to be greater than 2.8 mEq/L in the
24 hours before delivery. Records of magnesium sul-
fate administration in the 72 hours before delivery
were found in the mothers of 153 of these 173 infants.
The mothers of an additional 176 infants had records
Fig 1. Criteria for the diagnoses of preexisting hypertension and
preeclampsia and the data sources in the Neonatal Brain Hemor-
rhage cohort used to establish them.
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of magnesium sulfate administration but had no
records of serum magnesium measurement (n 5 171)
or had serum magnesium levels in the normal range
(n 5 5). Additionally, 13 infants were noted to have
elevated serum magnesium levels (.1.7 mEq/L)
without other evidence of maternal receipt of mag-
nesium sulfate. These 13 infants were also catego-
rized as magnesium sulfate exposed. An additional
91 newborns with elevated serum magnesium levels
had additional evidence of maternal magnesium sul-
fate exposure and are included in the exposure cat-
egories above. In 68 infants (6.0%), insufficient infor-
mation was available about details of labor and
delivery to permit satisfactory classification of ma-
ternal exposure, and these infants were excluded
from the analysis. Most had been transferred to
study hospitals postnatally.
Magnesium sulfate use was substantially higher in
mothers with the diagnosis of PE with proteinuria
(65.4%) than in women with no HYP-related diagno-
sis (29.5%). Magnesium sulfate exposure was not
significantly higher in infants whose mothers had
HYP in pregnancy without proteinuria (33.8%) and
in infants whose mothers had preexisting HYP
(37.8%) than in women with no HYP-related diagno-
sis.
Despite the more frequent use of magnesium sul-
fate in mothers with PE, the bulk of exposure to
magnesium sulfate in this cohort, 63.8%, occurred in
infants whose mothers had no HYP-related diag-
nosis. We presume that mothers without HYP-
related diagnoses who received magnesium sulfate
received this treatment for tocolysis. The likeli-
hood of the magnesium sulfate exposure having
been determined by medication history or by
serum magnesium assessment did not differ by
maternal diagnosis.
Relationship of Magnesium Sulfate Exposure to
Neonatal Outcomes (Table 2)
No statistically significant relationship of magne-
sium sulfate exposure to either GM/IVH or PEL/VE
was detected in these data. We assessed the ORs for
this relationship in simple 2 3 2 tabulations (top row,
unadjusted), and also in models that control for the
potentially confounding variables listed in “Meth-
ods.” In adjusted and unadjusted models, ORs for
magnesium sulfate exposure and brain lesions
ranged from 0.80 to 0.97. Mortality in the neonatal
period was somewhat lower in magnesium sulfate–
exposed infants, with ORs ranging from 0.64 to 0.93
depending on the mode of exposure determination
and level of adjustment. The lack of any excess mor-
tality in magnesium-exposed infants indicates that
favorable effects of magnesium on later sequelae are
unlikely to be attributable to selection bias produced
by raised mortality in the neonatal period.
Relationship of Magnesium Sulfate Exposure to CP
(Table 3)
Analyses in Table 3 are based on the 777 infants
who were assessed at 2 years of age. Although there
was a suggestion that magnesium sulfate might be
protective against DCP, with all ORs less than 1,
ranging from 0.57 to 0.65 depending on the level of
adjustment and method of exposure determination,
none of these relationships achieved statistical signif-
icance. Nondisabling CP bore no consistent relation-
ship to magnesium sulfate exposure, with ORs vary-
ing from 0.84 to 1.11. Total CP, not surprisingly, was
TABLE 1. Magnesium Sulfate Use by Maternal Diagnosis in 1105 Infants
Magnesium Use Preeclampsia With
Proteinuria
Preeclampsia Without
Proteinuria
Preexisting
Hypertension
Healthy Total
Magnesium use based on medical
record history only
45 14 10 107 176*
Magnesium use documented by
serum Mg
11
level .2.8 mEq/L
44 10 7 112 173
Infant serum Mg
11
.1.7 mEq/L 0 1 0 12 13
Any magnesium use, n (%) 89 (65.4) 25 (33.8) 17 (37.8) 231 (29.5) 362 (34.9)
No magnesium use 47 49 28 551 675
Magnesium use uncertain 0 2 2 64 68
Total 136 76 47 846 1105
* In the mothers of 5 infants serum Mg
11
was not elevated, and in 171 no serum level was available.
TABLE 2. Odds Ratios (95% Confidence Intervals) for the Association of Magnesium Sulfate and Three Neonatal Outcomes:
Unadjusted (Top Row) and Adjusted* (Second Row) Models
Magnesium Use Germinal Matrix/
Intraventricular Hemorrhage
(n 5 238)
Parenchymal Lesions/
Ventricular Enlargement
(n 5 103)
Neonatal Death
(n 5 176)
Magnesium use based on medical 0.80 (0.53–1.20) 0.89 (0.51–1.57) 0.93 (0.57–1.52)
record history only (n 5 176) 0.85 (0.54–1.34) 0.87 (0.47–1.63) 0.90 (0.50–1.61)
Magnesium use documented by 0.97 (0.65–1.44) 0.91 (0.52–1.61) 0.75 (0.44–1.28)
serum Mg
11
level .2.8 mEq/L (n 5 173) 0.91 (0.59–1.40) 0.84 (0.45–1.55) 0.64 (0.35–1.20)
Magnesium use by either definition or 0.89 (0.65–1.20) 0.96 (0.62–1.47) 0.77 (0.54–1.10)
elevated infant serum Mg
11
(n 5 363) 0.89 (0.64–1.25) 0.94 (0.59–1.49) 0.83 (0.53–1.30)
* Adjusted for gestational age, fetal growth ratio, gender, multiple birth status, mode of delivery, labor status, amnionitis, preeclampsia,
and preexisting hypertension.
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intermediate in its relationship to magnesium sul-
fate, with ORs slightly less than 1 in all analyses,
none significant. Adjustment for covariates had only
a marginal effect on the ORs.
ORs for DCP in Relation to Neonatal Brain Lesions
Figure 2 graphs adjusted ORs and their 95% CIs
for DCP in study infants categorized by the pres-
ence or absence of neonatal brain lesions. ORs are
adjusted for the same set of variables as used in the
models presented in Tables 2 and 3. Among infants
with neither GM/IVH nor PEL/VE, magnesium
sulfate use was associated with reduced risk of
DCP but not significantly so. Among infants with
brain lesions, infants with PEL/VE without GM/
IVH had the largest reduction in risk, bordering on
significant. Thus, the presence of GM/IVH seems
to identify infants with the least reduction in risk
associated with magnesium sulfate exposure. In-
deed in all infants without GM/IVH, the OR of
0.22 is nearly significant (upper CI boundary, 1.02).
A Mantel-Haenzel test for heterogeneity indicates
that the ORs in these two strata did not differ
significantly from each other (P 5 .12). The re-
duced risk of CP in our cohort seem to be due
entirely to an association found in the 29 infants
with late-onset (ie, after days 1 and 2) of PEL/VE.
In these infants, magnesium sulfate use is associ-
ated with a large reduction in risk of CP, with an
OR of 0.10 (95% CI, 0.02 to 0.64). This subset find-
ing was not prehypothesized and must therefore
be treated with caution. The probability that the
OR for DCP does not differ between infants with
and without late PEL/VE is 0.07.
Replication of Analyses of Nelson and Grether
1
Nelson and Grether
1
reported a consistent pattern
of reduction of risk with magnesium sulfate expo-
sure in many subgroups of singleton infants weigh-
ing less than 1500 g. In Tables 4 and 5, we replicate,
to the extent possible in our data, the categories they
used to search for a possible protective effects of
magnesium sulfate in subgroups of infants. The anal-
yses in these tables are restricted to the 274 follow-up
survivors in our data set who were singleton and
weighed less than 1500 g at birth. Table 4 lists preg-
nancy and labor and delivery characteristics; Table 5
lists neonatal characteristics. Although we tabulate
both of our CP categories, Nelson and Grether
1
re-
stricted their attention to “moderate to severe” CP,
which probably corresponds most closely to our cat-
egory of DCP.
TABLE 3. Odds Ratios (95% Confidence Intervals) for the Association of Magnesium Sulfate and Cerebral Palsy Unadjusted (Top
Row) and Adjusted* (Second Row) Models
Magnesium Use Disabling Cerebral Palsy
(n 5 61)
Nondisabling Cerebral Palsy
(n 5 52)
Any Cerebral Palsy
(n 5 113)
Magnesium use based on medical record 0.62 (0.28–1.40) 0.84 (0.38–1.85) 0.72 (0.40–1.30)
history only (n 5 134) 0.64 (0.26–1.58) 0.90 (0.38–2.11) 0.72 (0.38–1.38)
Magnesium use documented by serum Mg
11
0.62 (0.28–1.40) 1.05 (0.51–2.18) 0.82 (0.47–1.44)
level .2.8 mEq/L (n 5 135) 0.57 (0.23–1.40) 1.11 (0.51–2.41) 0.81 (0.44–1.50)
Magnesium use by either definition or elevated 0.65 (0.35–1.19) 0.92 (0.51–1.67) 0.77 (0.50–1.20)
infant serum Mg
11
(n 5 276) 0.63 (0.32–1.24) 1.00 (0.53–1.88) 0.79 (0.49–1.27)
* Adjusted for gestational age, fetal growth ratio, gender, multiple birth status, mode of delivery, labor status, amnionitis, preeclampsia,
and preexisting hypertension.
Fig 2. Adjusted odds ratios and 95%
confidence limits for disabling cerebral
palsy in study infants categorized by
the presence or absence of neonatal
brain lesions.
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Just one association of statistical significance was
found in these two tables. No magnesium sulfate–
exposed infant had CP when fetal bradycardia was
present (CI, 0 to 0.85) (Table 4). This subgroup anal-
ysis was not prespecified; therefore, this OR must be
treated with caution. At the same time, there was no
suggestion of a stronger reduction in risk in infants
with low Apgar scores (Table 5).
DISCUSSION
In this cohort study, in which CP was prospec-
tively ascertained and in which magnesium sulfate
exposure was based not only on reported adminis-
tration of the medication but also on documentation
of elevated maternal serum magnesium levels in
many women, we did not find the strong protective
effect of magnesium sulfate for CP reported by Gre-
ther and Nelson
1
in their case-control study. How-
ever, our results are compatible with a more modest
protective effect of magnesium sulfate for DCP, on
the order of about a 35% reduction in risk, which
although not statistically significant in these data, is
sizable enough to encourage further investigation of
the association. There is also a suggestion in these
data that the presence of brain lesions may modify
this risk reduction, accentuating it when late-onset
lesions are present and reversing it when early hem-
orrhage occurs. It is important to note here that these
interactions, although reasonable to examine, were
not prespecified and may, therefore, have arisen by
chance.
The divergence in findings between these two
studies cannot easily be attributed to the differences
in populations. Although our study population in-
cluded multiple births and extended to 2000 g birth
weight, replication of the analyses for CP in the
subset of our infants who, as in the population of
Nelson and Grether,
1
were singleton and weighed
less than 1500 g, did not produce evidence of mag-
nesium sulfate protection against CP. We have no
evidence that the low birth weight infants in the
study by Nelson and Grether
1
differed in any impor-
tant way from those in our study.
The use of magnesium sulfate in labor is not ran-
dom. Mothers with PE (with proteinuria) were about
twice as likely to receive magnesium sulfate as were
other mothers in our study, and other investigators
have shown that PE in the mother may itself be
associated with a lower risk of CP and of neonatal
brain lesions.
10,11
One must also be concerned that
women with magnesium sulfate use might be more
likely to be delivered abdominally, a factor that has
been shown in some studies to be associated with
reduced risk of brain lesions.
12
A third factor to consider is amniotic fluid infec-
tion. Mothers with amnionitis may not be candidates
for tocolysis and will thus be less likely to receive
magnesium sulfate. If amnionitis places them at
higher risk for CP, as has also been suggested,
13,14
TABLE 4. Relation of Magnesium to Cerebral Palsy in Single-
ton Infants Weighing Less Than 1500 g by Several Pregnancy
Conditions Studied by Nelson and Grether
1
Condition Unadjusted Odds Ratios
(95% confidence intervals)
for Magnesium Use
Disabling
Cerebral Palsy
Any
Cerebral Palsy
All 0.71 (0.36–1.40) 0.92 (0.53–1.58)
Hypertension
Preeclampsia * *
Preexisting hypertension 0 (0–4.6) 0 (0–4.6)
No hypertension 0.84 (0.40–1.70) 0.99 (0.54–1.81)
Bleeding at admission
Yes 0.98 (0.26–3.8) 1.58 (0.53–4.7)
No 0.66 (0.30–1.45) 0.78 (0.41–1.47)
Abruptio or previa
Yes 0.30 (0–2.5) 0.64 (0.14–3.1)
No 0.81 (0.39–1.65) 0.98 (0.55–1.76)
Rupture of membranes .24 h
Yes 1.12 (0–8.3) 0.56 (0–3.8)
No 0.57 (0.26–1.25) 0.85 (0.45–1.61)
Breech presentation
Yes 1.74 (0.61–4.9) 2.29 (0.93–5.6)
No 0.42 (0.16–1.07) 0.56 (0.27–1.15)
Cesarean section
Yes 0.80 (0.35–1.85) 1.09 (0.55–2.1)
No 0.59 (0.19–1.89) 0.69 (0.27–1.78)
Gestational age, wk
#30 0.71 (0.34–1.46) 0.90 (0.49–1.63)
.30 0.70 (0–5.5) 1.04 (0.24–4.4)
Fetal bradycardia
Yes 0 (0–0.85)† 0.23 (0–1.01)
No 0.97 (0.47–1.99) 1.25 (0.68–2.3)
* Insufficient number of cases to compute odds ratios.
† Statistically significant findings are boldface.
TABLE 5. Relation of Magnesium to Cerebral Palsy in Single-
ton Infants Weighing Less Than 1500 g by Several Neonatal Con-
ditions Studied by Nelson and Grether
1
Condition* Unadjusted Odds Ratios
(95% confidence intervals)
for Magnesium Use
Disabling
Cerebral Palsy
Any
Cerebral Palsy
Birth weight, g
,1000 0.49 (0.15–1.64) 0.54 (0.19–1.54)
1000–1499 0.86 (0.38–1.95) 1.15 (0.60–2.2)
Gender
M 0.74 (0.27–2.0) 1.05 (0.49–2.3)
F 0.70 (0.29–1.70) 0.80 (0.37–1.72)
5-min Apgar score
,6 0.76 (0.14–4.2) 0.63 (0.12–3.4)
$6 0.75 (0.36–1.56) 0.98 (0.55–1.75)
First pH
,7.1 † †
$7.1 0.65 (0.32–1.30) 0.86 (0.50–1.50)
Respiratory distress syndrome
Yes 0.76 (0.37–1.56) 0.98 (0.55–1.75)
No 0.56 (0–4.6) 0.75 (0.14–4.0)
Intubation
Yes 0.80 (0.39–1.61) 0.90 (0.50–1.62)
No 0 (0–1.87) 1.05 (0.24–4.5)
GM/IVH
Yes 1.21 (0.51–2.9) 1.43 (0.63–3.3)
No 0.31 (0–1.33) 0.72 (0.33–1.56)
PEL/VE
Yes 0.33 (0.09–1.24) 0.43 (0.12–1.51)
No 0.78 (0.29–2.1) 0.98 (0.49–1.95)
Neonatal seizures
Yes 1.50 (0.19–11) 1.07 (0.15–7.5)
No 0.56 (0.25–1.24) 0.90 (0.50–1.63)
* GM/IVH indicates germinal matrix/intraventricular hemor-
rhage; and PEL/VE, parenchymal lesion/ventricular enlarge-
ment.
† Insufficient number of cases to compute odds ratios.
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magnesium sulfate may artifactually seem protec-
tive. In our study, these three factors, as best we
could ascertain them, were accounted for in the
analysis.
The single most important predictor of CP in the
low birth weight population is the finding of
ultrasonographically imaged brain lesions in the
neonatal period. Neither of the two major lesions,
GM/IVH or PEL/VE, was reduced with magnesium
sulfate exposure, and this might reasonably be
viewed as diminishing support for the magnesium
sulfate–CP association. However, half of the children
with DCP did not have brain lesions diagnosed;
therefore, a factor need not be associated with brain
lesions to elevate risk of CP. Magnesium sulfate ex-
posure was associated with a nonsignificant reduc-
tion of the neonatal death rate in analyses that con-
trolled for several potential confounders.
Other recent studies, some only available in ab-
stract form, have examined the relationship between
magnesium sulfate use and either CP or neonatal
brain lesions. Hauth et al
15
found a substantial reduc-
tion in CP in magnesium sulfate–treated infants
weighing less than 1 kg in Alabama, but a more
recent report from some of the same authors found,
in a different data set, no relationship of magnesium
sulfate to neonatal brain lesions.
16
Similarly, Lemons et al,
17
examining data from the
Neonatal Research Network, found no significant
protective effect of magnesium sulfate exposure in
very low birth weight infants on risk of neonatal
brain lesions. Indeed, in an analysis restricted to
singleton extremely low birth weight infants without
maternal diabetes or PE, magnesium sulfate use was
associated with a significant excess of brain lesions.
Magnesium sulfate, was, however associated with
lower mortality in that study. Leviton et al
18
have
now shown, in contrast to their findings from an
earlier data set
11
, that magnesium sulfate is not asso-
ciated with reduced risk of neonatal brain lesions.
Thus, the results of studies examining the associ-
ation of magnesium sulfate with either brain lesions
or CP in low birth weight infants produce a mixed
picture, and this inconsistency is mirrored in our
own results. Although our findings are in general
most consistent with the conclusion that magnesium
sulfate does not protect low birth weight infants
from CP, our results encourage further exploration of
this possibility. In observational studies, magnesium
sulfate exposure often co-occurs with other factors,
some of which may themselves be protective against
CP in as yet unknown ways. Thus, observational
studies of magnesium sulfate and CP in low birth
weight infants will require careful ascertainment and
control of measures of infection, PE, other routes to
preterm delivery, and modes of delivery among
other factors. A randomized treatment trial would
obviate these concerns and may, therefore, be the
preferred way to test the hypothesis that magnesium
sulfate can reduce the risk of CP in low birth weight
infants.
Note Added in Proof. Schendel et al
21
have recently
reported a reduced risk of CP in relation to prenatal
magnesium sulfate exposure in very low birth
weight children in Atlanta.
ACKNOWLEDGMENTS
This work was supported by grant RO1-NS-20713 from the
National Institute of Neurological Diseases and Stroke.
The Neonatal Brain Hemorrhage Study Analysis Group in-
cludes Colleen Clark, MPH; Joseph Gardiner, PhD; Claudia
Holzman, DVM, PhD; John M. Lorenz, MD; and M. Lynne Reuss,
MD, MPH.
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6of6 MAGNESIUM SULFATE AND RISK OF CEREBRAL PALSY
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DOI: 10.1542/peds.99.5.e1
1997;99;e1Pediatrics
Brain Hemorrhage Study Analysis Group
Nigel Paneth, James Jetton, Jennifer Pinto-Martin, Mervyn Susser and the Neonatal
Palsy in Low Birth Weight Infants
Magnesium Sulfate in Labor and Risk of Neonatal Brain Lesions and Cerebral
Services
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