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org

Proximity of magnesium exposure to delivery

and neonatal outcomes
Amy L. Turitz, MD; Gloria T. Too, MD; Cynthia Gyamfi-Bannerman, MD, MSc

BACKGROUND: In infants delivered preterm, magnesium sulfate re-
duces cerebral palsy in survivors. The benefit of magnesium given remote
from delivery is unclear.
OBJECTIVE: Our objective was to evaluate the association of time from
last exposure to magnesium with cerebral palsy.
STUDY DESIGN: This was a secondary analysis of a multicenter trial
evaluating magnesium for neuroprotection. For this study, we included
women with live, nonanomalous, singleton gestations who received
magnesium. Pregnancies with missing information at the 2 year follow-up
were excluded. Women were divided into 2 groups based on exposure
timing: last infusion of magnesium <12 hours and last infusion of mag-
nesium
12 hours prior to delivery. The primary outcome was cerebral
palsy of any severity at 2 years of life. Secondary outcomes were mod-
erate/severe cerebral palsy and moderate/severe cerebral palsy or death.
A c2 test, Student t test, and Mann-Whitney U test were used for bivariate
associations. We fit a multivariable logistic regression model to adjust for
confounders.
RESULTS: A total of 906 infants were analyzed. Five hundred sixty-eight
were last exposed to magnesium <12 hours prior to delivery and 338
were last exposed
12 hours. Cerebral palsy occurred in 28 offspring
(3%), 2.3% of those last exposed <12 hours vs 4.4% last exposed
12
hours prior to delivery (P ¼ .07). On adjusted analyses, last exposure to
magnesium <12 hours prior to delivery was associated with a significant
reduction in cerebral palsy compared with last exposure
12 hours
(adjusted odds ratio, 0.41, 95% confidence interval, 0.18e0.91,
P ¼ .03). There was no difference in secondary outcomes.
CONCLUSION: Exposure to magnesium proximal to delivery
(<12 hours) is associated with a reduced odds of cerebral palsy
compared with more remote exposure. This highlights the importance of
the timing of magnesium for neuroprotection for women at risk of
preterm delivery.
Key words: cerebral palsy, magnesium sulfate, neuroprotection, pre-
term delivery, time of last exposure

C
among
erebral palsy continues to be a
common and costly problem
preterm infants.1 With
increasing survival of preterm neonates
and no curative therapy available for
cerebral palsy, efforts to prevent its
development are critical. In 2008, Rouse
et al2 demonstrated that exposure to
magnesium sulfate for women at risk of
preterm delivery reduces the risk of ce-
rebral palsy in surviving children. Both
the American College of Obstetricians
and Gynecologists and the Society for
Maternal-Fetal Medicine advocate the
use of magnesium sulfate for this pur-
pose.3 Despite this, much remains un-
known about the optimal characteristics
of magnesium sulfate administration for
neuroprotection.
Whereas other studies have looked for
the ideal magnesium sulfate dosage and
Cite this article as: Turitz AL, Too GT, Gyamfi-
Bannerman C. Proximity of magnesium exposure to
delivery and neonatal outcomes. Am J Obstet Gynecol
2016;215:508.e1-6.
0002-9378/$36.00
ª 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2016.05.004
duration required to reduce the risk of
cerebral palsy, none have looked at the
optimal timing of magnesium sulfate
exposure in relation to delivery with
regard to neonatal outcomes.2,4-7 It re-
mains unknown how exposure to mag-
nesium sulfate remote from delivery
compares with exposure closer to, or at
the time of, delivery itself in terms of
cerebral palsy risk reduction. The aim of
our study therefore was to evaluate the
association of time from last exposure to
magnesium sulfate before delivery with
cerebral palsy.
Materials and Methods
This is a secondary analysis of the
Randomized Clinical Trial of Magne-
sium Sulfate for the Prevention of
Cerebral Palsy conducted by the Eunice
Kennedy Shriver National Institute of
Child Health and Human Development
Maternal-Fetal Medicine Units Network.
The details of this study have been pre-
viously reported.2 Briefly, this was a
multicenter, randomized, placebo-
controlled study conducted at 20 in-
stitutions across the United States from
1997 to 2004 with the aim of deter-
mining whether antenatal magnesium
sulfate administration to women at high
risk for preterm delivery decreased the
rate of cerebral palsy or death.
In this study, women were exposed
to magnesium sulfate if they were at
imminent risk for delivery between 24
and 31 weeks because of the rupture of
membranes, advanced preterm labor, or
fetal indications. In this protocol,
magnesium was discontinued after 12
hours if delivery had not occurred and
was no longer considered imminent.
Magnesium was restarted when delivery
was again deemed imminent. As a
result, not all women who were exposed
to magnesium sulfate were receiving the
medication at the time of preterm
delivery.
For the current study, women with
singleton gestations were included.
Those assigned to the placebo group or
with major fetal malformations, still-
birth, or missing outcome data at 2 years
were excluded. Study groups were
defined by time interval from the last
magnesium sulfate exposure to delivery:
exposure to magnesium sulfate <12
hours prior to delivery, including at the
time of delivery, and exposure
12
hours prior to delivery. If magnesium

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FIGURE
Flow diagram of patient inclusion/exclusion
Proximity of magnesium exposure to delivery and neonatal outcomes is shown.
Turitz et al. Proximity of magnesium exposure to delivery. Am J Obstet Gynecol 2016.
sulfate was discontinued and restarted,
the time from the last exposure to
delivery was used.
The primary outcome was any type
of cerebral palsy, assessed and diag-
nosed at or beyond 2 years of age
(corrected for prematurity) by an
annually certified pediatrician or pedi-
atric neurologist if 2 or more of the
following 3 features were present: a
delay of
30% in gross motor devel-
opmental milestones; abnormality in
muscle tone,
4 or absent deep tendon
reflexes, or movement abnormality;
persistence of primitive reflexes or
absence of protective reflexes.
When cerebral palsy was diagnosed,
the Gross Motor Function Classification
System was used to assess severity (mild,
Gross Motor Function Classification
System level 1; moderate, Gross Motor
Function Classification System level 2
or 3; or severe, Gross Motor Function
Classification System level 4 or 5).2
Secondary outcomes included the
following: (1) moderate and severe ce-
rebral palsy and (2) moderate and severe
cerebral palsy or death.
Baseline characteristics among the
cohorts were compared using a Student t
test, Mann-Whitney U test, and c2 tests
as appropriate. Incidences of the pri-
mary and secondary outcomes were
compared between the 2 groups. Unad-
justed relative risks with 95% confidence
intervals were estimated. Multivariable
logistic regression models were devel-
oped to estimate the risk of each
OCTOBER 2016 American Journal of Obstetrics & Gynecology
SMFM Papers
outcome based on timing of magnesium
sulfate, adjusting for confounding fac-
tors that were identified based on his-
torical importance and in the bivariate
analyses with a value of P < .05. These
included maternal race, education level,
prenatal care, nulliparity, preeclampsia,
antibiotic exposure, total grams of
magnesium sulfate received, mode of
delivery, gestational age at delivery, and
neonatal sepsis.
Using goodness-of-fit testing, the
model that best fit the data was chosen
as the final model. This model included
magnesium sulfate as a categorical
rather than a continuous variable. All
tests were 2 tailed with P < .05
considered significant. Because our
sample size was fixed from the parent
508.e2
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TABLE 1
Patient characteristics by timing of magnesium sulfate exposurea
Last magnesium exposure <12 h Last magnesium exposure
12 h
Characteristics prior to delivery (n ¼ 568) prior to delivery (n ¼ 338) P value
Maternal age, y b
26.21  5.82 26.78  5.80 .16
Advanced maternal age (
35 y) 58 (10.21) 38 (11.24) .63
Race
African-American 251 (44.19) 152 (44.97) .79
White 203 (35.74) 125 (36.98)
Hispanic 99 (17.43) 56 (16.57)
Asian 7 (1.23) 3 (0.89)
Native American/other 8 (1.41) 2 (0.59)
Marital status
Married 281 (49.56) 171 (50.59) .94
Single 230 (40.56) 133 (39.35)
Unknown 56 (9.88) 34 (10.06)
2
Body mass index, kg/m
<18.5 98 (17.25) 46 (13.61) .24
18.5e24.9 233 (41.02) 151 (44.67)
25e29.9 116 (20.42) 59 (17.46)
>30 121 (21.30) 82 (24.26)
Education, y b
11.64  2.49 12.01  2.51 .03
Prenatal care 539 (94.89) 306 (90.53) .01
Smoking 154 (27.11) 91 (26.92) .95
Alcohol use 44 (7.75) 33 (9.76) .29
Recreational drug use 62 (10.92) 32 (9.47) .49
Nulliparous 224 (39.44) 98 (28.99) .002
Previous preterm delivery 155 (27.29) 95 (28.11) .79
Diabetes 27 (4.75) 19 (5.62) .57
Preeclampsia 3 (0.53) 7 (2.07) .03
Membranes ruptured 475 (98.75) 308 (99.04) .71
Antenatal corticosteroid exposure 23 (4.20) 15 (4.50) .83
Antibiotic exposure 502 (88.38) 314 (92.90) .03
Chorioamnionitis 67 (11.80) 36 (10.65) .60
Sepsis 100 (17.61) 53 (15.68) .45
c
Total magnesium infused, g 39.60, 29.30e51.20 29.30, 29.20e30.00 .001
c
Total magnesium infused, h 14.90, 12.10e20.50 12.00, 12.00e12.30 .001
Magnesium sulfate on at delivery 506 (89.08) 0 (0) .001
Hours since last magnesium sulfate infusion to deliveryc 0, 0e0 169.30, 66.00e516.40 .001
Turitz et al. Proximity of magnesium exposure to delivery. Am J Obstet Gynecol 2016. (continued)

trial, we evaluated the detectable effect and beta of 0.20, our study had suffi- version 9.4 (SAS Institute, Cary, NC)
size in this cohort. Based on the total cient statistical power to detect a 2-fold was used for the analysis.
sample size, rate of exposure, and rate increased risk for the primary outcome This analysis was considered exempt
of outcome, assuming an alpha of 0.05 of any cerebral palsy. SAS software, by the Institutional Review Board at

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TABLE 1
Patient characteristics by timing of magnesium sulfate exposurea (continued)
Last magnesium exposure <12 h Last magnesium exposure
12 h
Characteristics prior to delivery (n ¼ 568) prior to delivery (n ¼ 338) P value
Outcomes
Gestational age at delivery in weeksb 29.36  2.48 30.61  3.72 .001
Preterm birth (delivery <37 wks) 568 (100.00) 321 (94.97) .001
Vaginal delivery 376 (66.20) 210 (62.13) .22
Male gender 324 (57.04) 183 (54.14) .40
Birth weight, g b
1342.9  443.0 1582.6  704.4 .001
Any cerebral palsy 13 (2.29) 15 (4.44) .07
Moderate and severe cerebral palsy or death 52 (9.15) 26 (7.69) .45
a
Data are presented as percentage unless otherwise indicated; b Mean  SD; c Median (interquartile range).
Turitz et al. Proximity of magnesium exposure to delivery. Am J Obstet Gynecol 2016.

Columbia University Medical Center sequential fashion, leaving a final sample hours, and 4.4% last exposed
12
because these are publicly available, of 906 infants (Figure). hours prior to delivery.
deidentified data. A total of 568 infants (62.7%) were There were significant differences
last exposed to magnesium sulfate <12 between the groups in several charac-
Results hours prior to delivery, of which 506 teristics, including education level,
Of the 2444 infants included in the (89.1%) had magnesium sulfate prenatal care, nulliparity, preeclampsia,
original trial, 1256 were exposed to pla- infusing at the time of delivery. Three antibiotic exposure, gestational age at
cebo and thus excluded. The remaining hundred thirty-eight (37.3%) were last delivery, preterm birth, and birthweight
exclusion criteria, including multiple exposed to magnesium sulfate
12 (Table 1). There were also significant
gestation, fetal anomalies, antenatal hours prior to delivery. Overall, cere- differences in the amount of magnesium
stillbirths, and missing 2 year follow-up bral palsy occurred in 28 offspring sulfate received, hours on magnesium
information, were then applied in a (3.1%), 2.3% of those last exposed <12 sulfate, whether magnesium sulfate was
infusing at delivery, and the time interval
between last magnesium sulfate expo-
TABLE 2 sure to delivery.
Adjusted odds of any cerebral palsy Adjusting for maternal race, educa-
tion level, prenatal care, nulliparity,
Variables Adjusted OR 95% CI P value preeclampsia, antibiotic exposure, total
Interval from last magnesium to birth <12 h 0.41 0.18e0.91 .03 grams of magnesium sulfate received,
Total magnesium received, g 1.01 0.99e1.03 .60 mode of delivery, gestational age at de-
Multiparity 0.99 0.43e2.30 .98
livery, and sepsis, the last exposure to
magnesium sulfate <12 hours prior to
African American race 0.61 0.27e1.39 .36 delivery was associated with a significant
Education 0.99 0.83e1.19 .91 reduction in cerebral palsy compared
Prenatal care 0.86 0.18e4.02 .85 with women last exposed
12 hours
(adjusted odds ratio, 0.41, 95% confi-
Gestational age at birth 0.96 0.94e0.99 .001
dence interval, 0.18e0.91) (Table 2).
Antibiotic exposure 0.37 0.14e0.99 .05 The decrease in cerebral palsy was not
Preeclampsia 0.001 0.001e999.99 .99 seen when assessing the time from the
Sepsis 0.67 0.24e1.87 .44 last magnesium sulfate exposure to
delivery as a continuous variable. Total
Cesarean delivery 1.94 0.88e4.25 .10
hours on magnesium sulfate and mag-
The adjusted model controls for maternal race, education level, prenatal care, nulliparity, preeclampsia, antibiotic exposure, nesium concentrations similarly did not
total grams of magnesium sulfate received, mode of delivery, gestational age at delivery, and sepsis.
CI, confidence interval; OR, odds ratio.
alter our findings.
Turitz et al. Proximity of magnesium exposure to delivery. Am J Obstet Gynecol 2016. Although underpowered for the
secondary outcomes, there was no

OCTOBER 2016 American Journal of Obstetrics & Gynecology 508.e4

SMFM Papers
difference on adjusted analyses when
examining moderate and severe cerebral
palsy (adjusted odds ratio, 0.67, 95%
confidence interval, 0.20e2.25) and
moderate and severe cerebral palsy or
death (adjusted odds ratio, 1.09, 95%
confidence interval, 0.63e1.87) by last
exposure to magnesium sulfate <12
hours or
12 hours prior to delivery
(Table 3).
Comment
We found that last exposure to magne-
sium sulfate proximal to delivery (<12
hours) is associated with a reduced odds
of cerebral palsy compared with more
remote exposure. This highlights the
importance of timing of magnesium
sulfate for neuroprotection for women at
risk of preterm birth and underscores
the need for retreatment if delivery has
not occurred after its initial administra-
tion. A similar reduction in cerebral
palsy was not seen, however, when
looking at hours from last magnesium
sulfate exposure to delivery as a contin-
uous variable.
Multiple studies have proven the ef-
ficacy of magnesium sulfate in reducing
cerebral palsy in preterm neonates.
However, an optimal regimen has not
yet been determined, with different
studies utilizing different bolus and
maintenance regimens.2,4-6 Because
there are both maternal and fetal
concerns associated with prolonged
administration of magnesium sulfate, it
is important to determine the precise
amount of medication required to be
effective.
McPherson et al7 evaluated the asso-
ciation between the duration of magne-
sium sulfate infusion with cerebral palsy
or death and found no difference be-
tween exposure <12 hours (reference
group), between 12 and 18 hours
(adjusted odds ratio, 1.03, 95% confi-
dence interval, 0.60e1.77), or >18
hours (adjusted odds ratio, 1.08, 95%
confidence interval, 0.57e2.03) with
similar maternal adverse drug affects and
neonatal morbidities.
Although those investigators defined
their exposure groups based on total
duration in hours of magnesium sulfate
508.e5 American Journal of Obstetrics & Gynecology OCTOBER 2016
TABLE 3
Adjusted odds of selected outcomes
Variable
Interval from last magnesium to 0.41 (0.18, 0.91) 0.67 (0.20, 2.25)
delivery <12 h (aOR, 95% CI)
The adjusted model controls for maternal race, education level, prenatal care, nulliparity, preeclampsia, antibiotic exposure,
total grams of magnesium sulfate received, mode of delivery, gestational age at delivery, and sepsis.
aOR, adjusted odds ratio; CI, confidence interval; CP, cerebral palsy.
Turitz et al. Proximity of magnesium exposure to delivery. Am J Obstet Gynecol 2016.
exposure, our study utilized time
from last exposure to delivery and
controlled for other variables related to
magnesium administration. Searching
PubMed using the terms, magnesium
sulfate, interval, and cerebral palsy, fails
to yield any studies examining the effect
of time interval from last magnesium
sulfate exposure to delivery on cerebral
palsy.
Our study had several strengths,
including the prospective and rigorous
collection of data at a large number
of sites with thorough and long-term
follow-up. Information on characteris-
tics related to magnesium sulfate was
well recorded with few missing data. Our
exposure was clearly defined with an
interval of 12 hours chosen a priori to
differentiate the study groups. Although
somewhat arbitrary, we chose 12 hours
because this interval is when magnesium
sulfate was discontinued in the original
trial if delivery had not occurred and
was no longer considered imminent, and
therefore, some women may not have
been retreated after an initial exposure
to magnesium sulfate.2
Using a shorter time interval to
differentiate our study groups would
diminish our ability to detect a difference
in effect, whereas a longer interval would
have decreased our sample size. Further-
more, using a continuous outcome would
be scientifically interesting but not clini-
cally relevant. Our primary and second-
ary outcomes were also clearly defined
and were validated by blinded and certi-
fied pediatricians and pediatric neurolo-
gists at a 2 year follow-up point.
A limitation of our study was that our
sample size was fixed both by the parent
ajog.org
Moderate/severe
Any CP Moderate/severe CP CP or death
1.09 (0.63, 1.87)
study and by our exclusion criteria, and
we were able to detect only a 2-fold
difference. However, utilizing multi-
center trials of this nature is important in
the study of rare outcomes, such as ce-
rebral palsy. The variables we examined
were also limited by those collected in
the original database. Although there
were some variables with missing data,
this was a rare occurrence.
We used any cerebral palsy as our
primary outcome, whereas some might
argue that only moderate or severe ce-
rebral palsy are clinically significant. In
addition, we did not include death as
part of our primary outcome, although it
is a competing outcome. When looking
at moderate and severe cerebral palsy
with and without death, the association
was no longer significant, although we
were underpowered for these secondary
outcomes.
Finally, we used 12 hours to differ-
entiate our study groups and define a
short vs long interval between last
magnesium sulfate infusion and de-
livery. There were differences between
our 2 study groups, such as earlier
gestational age at delivery, that could
explain why last exposure to magne-
sium within 12 hours of delivery was
significant only on multivariable anal-
ysis. Because the decrease in cerebral
palsy was not seen when assessing time
from last magnesium sulfate to de-
livery as a continuous variable, the
exact time interval with which mag-
nesium sulfate confers the maximum
benefit in cerebral palsy reduction
remains unknown.
Although magnesium sulfate remains
the standard of care for women at
ajog.org
imminent risk of preterm birth for
neuroprotection, much remains un-
known about its optimal administration.
Based on our findings, the timing of
magnesium sulfate administration ap-
pears to play an important role in
reducing the risk of cerebral palsy.
Previous exposure to magnesium
sulfate >12 hours from delivery should
not negate the need to retreat women
who again appear to be at imminent risk
of delivery. Future work should further
delineate the optimal characteristics of
magnesium sulfate administration to
provide maximum benefit with minimal
medication. n protection before preterm birth: a randomized
Acknowledgment
We thank the Eunice Kennedy Shriver National
Institute of Child Health and Human Develop-
ment, the Maternal-Fetal Medicine Units
Network, and the Protocol Subcommittee for
making this database publicly available.
References
1. Centers for Disease Control and Prevention.
Data and statistics for cerebral palsy. Available
at: http://www.cdc.gov/ncbddd/cp/data.html.
Accessed June 12, 2015.
2. Rouse DJ, Hirtz DG, Thom E, et al.
A randomized, controlled trial of magnesium
sulfate for the prevention of cerebral palsy.
N Engl J Med 2008;359:895-905.
3. American College of Obstetricians and Gy-
necologists. Magnesium sulfate before antici-
pated preterm birth for neuroprotection.
Committee opinion no. 455. Obstet Gynecol
2010;116:669-71.
4. Crowther CA, Hiller JE, Doyle LW, Haslam RR.
Australasian Collaborative Trial of Magnesium
Suphate (ACTOMg SO4) Collaborative Group.
Effect of magnesium sulfate given for neuro-
controlled trial. JAMA 2003;290:2669-76.
5. Marret S, Marpeau L, Zupan-Simunek V, et al.
Magnesium sulphate given before very preterm
birth to protect infant brain: the randomized
controlled PREMAG trial. BJOG 2007;114:310-8.
6. Mittendorf R, Dambrosia J, Pryde PG, et al.
Association between the use of antenatal mag-
nesium sulfate in preterm labor and adverse
OCTOBER 2016 American Journal of Obstetrics & Gynecology
SMFM Papers
health outcomes. Am J Obstet Gynecol
2002;186:1111-8.
7. 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;124:749-55.
Author and article information
From the Division of Maternal-Fetal Medicine, Depart-
ment of Obstetrics and Gynecology, Columbia University
Medical Center, New York, NY.
Received March 3, 2016; revised April 25, 2016;
accepted May 3, 2016.
The views expressed herein are those of the authors
and do not represent the views of the Eunice Kennedy
Shriver National Institute of Child Health and Human
Development Maternal-Fetal Medicine Units Network or
the National Institutes of Health.
The authors report no conflict of interest.
Presented as a poster (number 696) entitled “The effect
of magnesium sulfate remote from delivery on cerebral
palsy” at the 34th annual meeting of the Society of
Maternal-Fetal Medicine, Atlanta, GA, Feb. 1e6, 2016.
Corresponding author: Amy L. Turitz, MD. alt2153@
cumc.columbia.edu
508.e6