1998;102;315 Pediatrics

Avroy A. Fanaroff and Maureen Hack

Deanne Wilson-Costello, Elaine Borawski, Harriet Friedman, Raymond Redline,
Very Low Birth Weight Children
Perinatal Correlates of Cerebral Palsy and Other Neurologic Impairment Among

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Perinatal Correlates of Cerebral Palsy and Other Neurologic Impairment
Among Very Low Birth Weight Children
Deanne Wilson-Costello, MD*; Elaine Borawski, PhD; Harriet Friedman, MA*; Raymond Redline, MD;
Avroy A. Fanaroff, MB, BCh, FRCP*; and Maureen Hack, MB, ChB*
ABSTRACT. Background and Objective. The etiology
of neurologic impairments among very low birth weight
(VLBW, <1.5 kg) children is poorly understood. We
sought to investigate the perinatal predictors of major
neurologic impairment, including cerebral palsy, among
VLBW children.
Methods. Antenatal, intrapartum, and neonatal
events and therapies were compared between 72 single-
ton inborn VLBW children born between 1983 to 1991
who had neurologic impairment at 20 months corrected
age (including 50 with cerebral palsy and 22 with other
neurologic impairments) and 72 neurologically normal
VLBW children matched by birth weight, gestational age,
race, and sex via a retrospective case-control method.
Multiple logistic regression was conducted, entering
only those variables found to be significant at the biva-
riate level.
Results. There were no significant differences in the
rates of pregnancy-induced hypertension, maternal toco-
lytic use including magnesium, or antenatal steroid ther-
apy. Higher rates of clinical chorioamnionitis were found
among the mothers of the neurologically impaired chil-
dren as compared with controls (31% vs 11%), but not
among the subgroup of mothers of children with cerebral
palsy (22% vs 12%). Significant differences in neonatal
factors among the total neurologically-impaired group
(n 72) versus controls included oxygen dependence at
36 weeks (31% vs 15%), septicemia (53% vs 31%), severe
cranial ultrasound abnormality (50% vs 17%), and hypo-
thyroxinemia (43% vs 25%). In the subgroup with cere-
bral palsy (n 50), significant differences included days
on the ventilator (23 vs 14 days), septicemia (54% vs 33%),
and severe cranial ultrasound abnormality (52% vs 12%).
Multivariate analysis controlling for birth weight, gesta-
tional age, race, sex, and the birth period (before 1990
versus 1990 and after) revealed direct and independent
effects of clinical chorioamnionitis [odds ratio (OR), 3.79;
confidence interval (CI), 1.3410.78], severe cranial ultra-
sound abnormality (OR, 9.97; CI, 3.8425.87), and septi-
cemia (OR, 2.46; CI, 1.105.52) on total neurologic impair-
ment. Consideration of the 50 cases with cerebral palsy
revealed direct and independent effects of severe cranial
ultrasound abnormality only (OR, 15.01; CI, 4.3451.93).
Conclusions. Both antenatal and neonatal risk factors
contribute to the development of severe neurologic im-
pairment, including cerebral palsy among VLBW chil-
dren. Because prevention of chorioamnionitis may not be
feasible in the near future, attempts to decrease neonatal
risk factors such as severe cranial ultrasound abnormal-
ities and sepsis may be most feasible at this time.
Pediatrics 1998;102:315322; cerebral palsy, neurologic im-
pairment, perinatal correlates, very low birth weight,
magnesium.
ABBREVIATIONS. VLBW, very low birth weight; OR, odds ratio;
CI, confidence interval.
M
ore than 100 years have passed since Little
1
first suggested that cerebral palsy was as-
sociated with perinatal events; however, its
etiology is still poorly understood. Recent evidence
suggests that antenatal rather than intrapartum fac-
tors are the major determinants of cerebral palsy
among term-born children.
24
The evidence is less
clear among preterm populations. Paneth
4
and oth-
ers
59
have suggested that cerebral palsy that occurs
among preterm low birth weight children is related
to periventricular lesions. However, Stanley and En-
glish
10
found that periventricular hemorrhage alone
did not account for the majority of cases. Further-
more, Cooke
11
suggested that diplegia was associ-
ated with antenatal variables, whereas hemiplegia
and quadriplegia were associated with neonatal
complications, with cerebral ultrasound abnormality
being the most significant.
Studies of antenatal determinants of cerebral
palsy among very low birth weight [(VLBW) 1.5
kg] children suggest that maternal preeclampsia
and antenatal magnesium therapy may provide
fetal neuroprotection.
1214
Nelson and Grether
15
and Hauth et al
16
recently reported significantly
lower rates of cerebral palsy among VLBW chil-
dren born to mothers with preeclampsia, espe-
cially those with in utero exposure to magnesium
sulfate. These results have been supported by
other recent reports of a decrease in mortality,
17
periventricular hemorrhage,
18
and cerebral pal-
sy
1921
associated with antenatal magnesium sul-
fate therapy. However, others have not found
magnesium to be neuroprotective.
2226
We sought to further investigate the perinatal pre-
dictors of major neurologic impairment, including
cerebral palsy, in a cohort of singleton VLBW chil-
dren born at our center during 1983 to 1991, and to
explore the potential neuroprotective effect of ante-
natal magnesium therapy.
From the Departments of *Pediatrics, Epidemiology and Biostatistics, and
Pathology, Case Western Reserve University, Cleveland, Ohio.
Received for publication Oct 28, 1997; accepted Feb 24, 1998.
Reprint requests to (D.W.-C.) Division of Neonatology, Rainbow Babies &
Childrens Hospital, University Hospitals of Cleveland, 11100 Euclid Ave,
Cleveland, OH 441066010.
PEDIATRICS (ISSN 0031 4005). Copyright 1998 by the American Acad-
emy of Pediatrics.
PEDIATRICS Vol. 102 No. 2 August 1998 315
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POPULATION AND METHODS
The population was drawn from a cohort of 1050 singleton
VLBW children delivered at our perinatal center, University Mac-
Donald Hospital for Women, adjacent to the Neonatal Intensive
Care Unit at Rainbow Babies and Childrens Hospital, University
Hospitals, Cleveland, Ohio, between January 1, 1983, and Decem-
ber 31, 1991. Eight hundred thirty-nine children (80%) survived, of
whom 764 (91%) were examined at 20-months corrected age.
To cover the spectrum of major neurologic impairments we
included children with classically defined cerebral palsy as well as
those with other neurologic impairments such as hypertonia and
hypotonia, which may be defined as mild or nondisabling cerebral
palsy.
8,27
Children with shunt-dependent hydrocephalus who had
a normal neurologic examination were also included in the neu-
rologically impaired group, as we considered the presence of a
ventriculoperitoneal shunt an impairment according to the classi-
fication of impairment, disability, and handicap of the World
Health Organization.
28
Seventy-two children had major neuro-
logic impairments, of whom 50 had cerebral palsy (13 with spastic
quadriplegia, 22 with diplegia, 12 with hemiplegia, and 3 with
combined diplegia and hemiplegia); and 22 had other neurologic
impairments (4 with persistent hypertonia, 12 with global hypo-
tonia, and 6 with shunt-dependent hydrocephalus but a normal
neurologic exam). Shunt-dependent hydrocephalus also occurred
in 4 children with cerebral palsy (2 diplegia, 1 hemiplegia, and 1
quadriplegia) and 1 child with hypotonia.
A retrospective case control method was used to identify a
matched control population. From the list of surviving VLBW
children, a control series of neurologically normal VLBW children
was developed by selecting the next born VLBW child of similar
sex, race, birth weight within 250 g, and gestational age within 2
weeks. The mean birth weight and gestational age of the total
neurologically impaired population of 72 children was 1000 g and
27.5 weeks, and for the matched controls was 1015 g and 27.6
weeks, respectively. Mean birth weight and gestational age for the
subgroup of 50 children with cerebral palsy was 1014 g and 27.6
weeks, and for controls 1029 g and 27.7 weeks, respectively. The
study design that matched infants by both birth weight and ges-
tational age precluded examination of differences in the rates of
intrauterine growth failure. There were no significant differences
in maternal age, education, or marital status between groups.
To identify predictors of neurologic impairment, the total pop-
ulation of 72 children with neurologic impairments and the sub-
groups of children with cerebral palsy and other neurologic im-
pairments were compared with their matched controls with
respect to the maternal obstetric history, perinatal factors, and
neonatal complications. Perinatal and neonatal data had been
extracted from the hospital charts at the time of the infants
discharge home. For the purposes of the present study, additional
perinatal information specifically pertaining to chorioamnionitis,
magnesium and other tocolytic therapy, and neonatal thyroid
function were extracted from the original hospital charts by a
single examiner who was blinded to outcome (D.W.). A standard
set of definitions was used for maternal and infant variables. All
maternal hospitalizations before the infants delivery were exam-
ined.
The obstetric and neonatal risk factors considered are presented
in Table 1. Adverse pregnancy outcomes included a history of
preterm birth, stillbirth, neonatal or infant death, therapeutic and
habitual abortion, or infant anomaly. Pregnancy-induced hyper-
tension, or preeclampsia, was defined as a blood pressure
140/90 mm Hg during the second half of pregnancy in a previ-
ously normotensive mother. Antepartum hemorrhage included
bleeding from a placenta previa, abruptio placenta, or vaginal
spotting. Premature rupture of membranes was defined as rupture
of membranes that occurred more than 18 hours before delivery.
Criteria for the diagnosis of clinical chorioamnionitis included
premature rupture of membranes with a temperature of either
37.8C on two occasions, at least 1 hour apart, or 38.3C on one
occasion with no other known sources for the fever and one of the
following: maternal tachycardia (100 beats per minute), fetal
tachycardia (160 beats per minute), maternal leukocytosis
(11 000/mm white blood cells), or foul smelling amniotic fluid.
29
Information on tocolytic therapy included its indication, timing of
initiation of therapy, dosage, and duration of therapy. Fetal dis-
tress included persistent fetal tachycardia (200 beats per
minute), bradycardia (100 beats per minute), late fetal heart rate
decelerations, poor fetal heart rate variability on fetal monitoring,
or a cord pH of less than 7.20. Data regarding maternal drug abuse
by history or positive urine toxicology screen was recorded when
available. The association between placental histologic findings
and neurologic impairment will be reported separately.
Chronic lung disease was defined as an oxygen dependence at
36 weeks postconceptional age.
30
Septicemia was defined as at
least one positive blood culture accompanied by clinical signs
suggestive of infection during the hospital stay and hyperbiliru-
binemia as a maximal bilirubin level 10 mg%; necrotizing en-
terocolitis was defined according to Bells criteria,
31
and periven-
tricular hemorrhage according to Papile.
32
We furthermore
defined severe cranial ultrasound abnormality as a grade 3 or 4
periventricular hemorrhage, parenchymal infarction, periven-
tricular leukomalacia, or ventricular dilatation at discharge. Data
on neonatal thyroid function included the first thyroxine (T4)
level, lowest T4 level, normalized T4 level, the age these results
were obtained, and thyroid replacement therapy. During the years
1983 to 1991, T4 levels of 5 g/dL and greater were considered
TABLE 1. Antenatal, Intrapartum, and Neonatal Risk Factors Examined
Demographic, Obstetric and Perinatal Factors Neonatal Factors
Maternal age (35 y or 17 y) Chorioamnionitis Apgar score 6 at 1 and 5 minutes
Prior adverse pregnancy outcome Clinical Respiratory distress syndrome
Preterm birth Pathologic Days on ventilator
Stillbirth Premature rupture of membranes Oxygen therapy at 36 weeks*
Induced abortion Drug Therapy Septicemia
Habitual abortion Antibiotics Meningitis
Infant death Magnesium Hyperbilirubinemia
Infant anomaly Ritodrine Necrotizing enterocolitis
Chronic hypertension Terbutaline Periventricular hemorrhage
Diabetes Indomethacin Severe cranial ultrasound abnormality
Pulmonary dysfunction Steroids Hypothyroxinemia
Genitourinary infection Oxytocin therapy
Pregnancy induced hypertension Induction
Uterine or cervical abnormality Augmentation
Drug abuse Type of anesthesia
Oligohydramnios Fetal distress
Antepartum hemorrhage Delivery outside delivery room
Vaginal spotting Type of delivery
Placenta previa
Abruptio placenta
* Postconceptional age.
Including cocaine, alcohol, and smoking.
Including tachycardia, bradycardia, late decelerations, poor variability, cord pH 7.20.
Lowest T4 5 g/dL.
316 PERINATAL CORRELATES OF NEUROLOGIC IMPAIRMENT
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normal on state screening. We thus defined hypothyroxinemia as
the lowest T4 level 5 g/dL during the hospital stay.
Analysis of Data
The total population of children with major neurologic impair-
ments (n 72) and the subgroups with cerebral palsy (n 50) and
other neurologic impairments (n 22) were compared with their
matched controls on each of the obstetric and neonatal factors
listed in Table 1, using 2-tailed t tests and
2
analyses.
To test the independent effects of the perinatal and neonatal
factors, multiple logistic regression was conducted. However, be-
cause of the limited sample size, we were restricted in the number
of variables that could be included in the multivariate model. For
this reason, we restricted the models to include only those vari-
ables with bivariate association of P .10. Moreover, because of
the small sample size of the noncerebral palsy neurologically-
impaired cases and controls (n 22 vs 22), multivariate analyses
were not conducted for this subgroup. For both of the other
models, the period of birth (ie, before 1990 versus 1990 or later)
was entered into the model to control for the newer methods of
care introduced in the 1990s, including the introduction of sur-
factant therapy. To reduce the problem of multicollinearity, only
one variable per clinical domain was included in the model when
more than one factor was found to be significant in the bivariate
analyses. Hence oxygen dependence at 36 weeks was selected as a
measure of chronic lung disease in the larger model (72 vs 72),
excluding the days on ventilator.
To examine the effects of perinatal variables on neurologic
impairment before including the effect of severe cranial ultra-
sound abnormality in the model, these variables were entered in a
separate step. In addition to testing the independent effects of the
correlates, the secondary goal of the multivariate analysis was to
examine the role of antenatal magnesium therapy. First, we tested
the hypothesis that magnesium therapy may decrease the likeli-
hood of severe cranial ultrasound abnormality, which in turn
might reduce the risk of neurologic impairment. To determine
this, we tested whether magnesium therapy had a stronger influ-
ence on neurologic impairment directly, or indirectly, through
severe ultrasound abnormality. Alternatively, as a moderating
variable, magnesium therapy may specify the conditions (eg, hav-
ing therapy versus not having therapy) in which severe ultra-
sound abnormalities are more or less likely to lead to neurologic
impairment or cerebral palsy. To test this moderating effect, an
interaction term of magnesium therapy and severe ultrasound
abnormality was entered as a separate and final step in each
multivariate model predicting neurologic impairment and cere-
bral palsy.
RESULTS
Table 2 presents a description of selected past and
index (present) obstetric risk factors. Of note is the
high rate of previous adverse pregnancy outcomes in
the mothers of both the neurologically abnormal and
control groups of children. There were no significant
differences between groups in the rates of pregnan-
cy-induced hypertension, antepartum hemorrhage,
genitourinary tract infection, or premature rupture
of membranes. Significantly higher rates of clinical
chorioamnionitis were found in mothers of the total
group of 72 neurologically impaired children and in
the subgroup of 22 mothers of children with other
neurologic impairments, however these differences
were not significant for the 50 mothers of children
with cerebral palsy.
Table 3 presents a description of selected intrapar-
tum and delivery risk factors. There were no signif-
icant differences in the rates of antenatal steroid use,
oxytocin or antibiotic therapy, fetal distress, or mode
of delivery. Although very few mothers were
screened for cocaine, 10 of 16 (63%) mothers of chil-
dren in the total neurologically impaired group and
7 of 11 (64%) mothers of children in the cerebral
palsy subgroup, who were screened, were found to
be positive for cocaine at delivery as compared with
3 of 13 (23%) and 1 of 8 (13%) of their controls,
respectively (P .03) (results not shown in Table 3).
Table 4 presents information on maternal tocolytic
therapy. No differences in the use of magnesium,
ritodrine, or terbutaline were noted between groups.
Only 4 mothers (1 of a child with cerebral palsy and
3 of controls) received antenatal indomethacin ther-
apy. Thirty-two percent of mothers of both the total
neurologically impaired and the cerebral palsy sub-
group of children compared with 33% and 36% of
their controls, respectively, were treated with mag-
nesium before delivery. Eight of 23 (35%) mothers of
the total neurologically impaired group of children,
and 6 of the 16 (38%) mothers of children with cere-
bral palsy who received magnesium, received it for
pregnancy-induced hypertension, whereas 15 (65%)
and 10 (63%), respectively, received it as a tocolytic
for preterm labor. The total magnesium dose and
duration of therapy for mothers who received mag-
nesium for at least 4 hours within 24 hours and/or 48
hours before delivery was similar between groups.
TABLE 2. Description of Past and Index Obstetric Histories
Cerebral
Palsy
(n 50)
Controls
(n 50)
P Other
Neurologic
Impairment
(n 22)
Controls
(n 22)
P Total
Neurologic
Impairment
(n 72)
Controls
(n 72)
P
Previous obstetric history
Adverse pregnancy outcome* 25 (50%) 23 (46%) .69 10 (46%) 8 (36%) .54 35 (49%) 31 (43%) .50
Genitourinary infection 5 (10%) 5 (10%) 1.00 5 (23%) 5 (23%) 1.00 10 (14%) 10 (14%) 1.00
Chronic hypertension 3 (6%) 3 (6%) 1.00 1 (5%) 0 (0%) .31 4 (6%) 3 (4%) .70
Index obstetric history
Pregnancy induced hypertension 7 (14%) 9 (18%) .59 2 (9%) 2 (9%) 1.00 9 (13%) 11 (15%) .63
Genitourinary infection 11 (22%) 6 (12%) .18 1 (5%) 5 (23%) .08 12 (17%) 11 (15%) .82
Premature rupture of membranes 16 (32%) 19 (38%) .53 9 (41%) 10 (46%) .76 25 (35%) 29 (40%) .49
Clinical chorioamnionitis 11 (22%) 6 (12%) .18 11 (50%) 2 (9%) .00 22 (31%) 8 (11%) .00
Cervical incompetence 8 (16%) 6 (12%) .56 2 (9%) 3 (14%) .63 10 (14%) 9 (13%) .81
Abruptio placenta 9 (18%) 6 (12%) .40 2 (9%) 2 (9%) 1.00 11 (15%) 8 (11%) .46
Placenta previa 4 (8%) 3 (6%) .70 2 (9%) 1 (5%) .55 6 (8%) 4 (6%) .51
Vaginal spotting 5 (10%) 4 (8%) .73 2 (9%) 1 (5%) .55 7 (10%) 5 (7%) .55
* History of preterm birth, stillbirth, neonatal, or infant death, therapeutic and habitual abortion (3 prior abortions), or infant anomaly.
Rupture of membranes greater than 18 hours before delivery.
ARTICLES 317
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The mean maternal blood magnesium levels for 27
mothers of the neurologically-impaired children and
33 of the controls, on whom these values were avail-
able, were similar (4.4 1.4 and 4.7 1.3 mg/dL,
respectively), as were the levels for 20 of the total
neurologically impaired group of children and 17 of
their controls, respectively (2.3 0.8 and 2.1 0.5
mg/dL). There were similarly no differences be-
tween magnesium levels of mothers of the cerebral
palsy subgroup and their controls.
Table 5 presents a description of the neonatal risk
factors. When compared with their controls, children
with cerebral palsy had significantly higher rates of
periventricular hemorrhage, severe cranial ultra-
TABLE 3. Description of Selected Intrapartum and Delivery Risk Factors
Cerebral
Palsy
(n 50)
Controls
(n 50)
P Other
Neurologic
Impairment
(n 22)
Controls
(n 22)
P Total
Neurologic
Impairment
(n 72)
Controls
(n 72)
P
Antenatal steroid use 7 (14%) 8 (16%) .78 4 (18%) 3 (14%) .68 11 (15%) 11 (15%) 1.00
Complete steroid course 4 (86%) 8 (16%) .22 3 (14%) 3 (14%) 1.00 7 (10%) 11 (10%) .31
Oxytocin therapy* 12 (24%) 11 (22%) .81 7 (32%) 4 (18%) .30 19 (26%) 15 (21%) .43
Antibiotic therapy 12 (24%) 12 (24%) 1.00 8 (36%) 6 (27%) .52 20 (28%) 18 (25%) .71
Fetal Distress 18 (36%) 23 (46%) .31 11 (50%) 11 (50%) 1.00 29 (40%) 34 (47%) .40
Type of delivery
Vaginal vertex 28 (56%) 22 (44%) 7 (32%) 11 (50%) 35 (49%) 33 (46%)
Vaginal breech 2 (4%) 4 (8%) .42 4 (18%) 1 (5%) .25 6 (8%) 5 (7%) .87
Cesarean section 20 (40%) 24 (48%) 11 (50%) 10 (45%) 31 (43%) 34 (47%)
* Induction or augmentation.
Persistent fetal tachycardia (200 beats per minute), bradycardia (100 beats per minute), late fetal heart rate decelerations, poor fetal
heart rate variability on fetal monitoring, or a cord pH 7.20.
TABLE 4. Description of Magnesium, Ritodrine, and Terbutaline Tocolytic Therapy
Cerebral
Palsy
(n 50)
Matched
Controls
(n 50)
P Other
Neurologic
Impairment
(n 22)
Matched
Controls
(n 22)
P Total
Neurologic
Impairment
(n 72)
Matched
Controls
(n 72)
P
Magnesium
Used at all (n, %) 16 (32%) 18 (36%) .67 7 (32%) 6 (27%) .74 23 (32%) 24 (33%) .86
24 hours before delivery (n, %)* 11 (22%) 12 (24%) .81 5 (23%) 3 (14%) .43 16 (22%) 15 (21%) .84
Total dose 24 hours before delivery (g SD) 44 49 34 29 .48 13 8 43 28 .05 35 43 36 28 .89
Duration of therapy (hours SD) 17 20 14 16 .69 6 4 20 14 .06 13 17 16 16 .66
Ritodrine
Used at all (n, %) 12 (24%) 13 (26%) .82 3 (14%) 7 (32%) .15 15 (21%) 20 (28%) .33
24 hours before delivery (n, %) 5 (10%) 4 (8%) .73 2 (9%) 2 (9%) 1.00 7 (10%) 6 (8%) .77
Terbutaline
Used at all (n, %) 9 (18%) 12 (24%) .46 5 (23%) 7 (32%) .50 14 (19%) 19 (26%) .32
48 hours before delivery, (n, %) 6 (12%) 4 (8%) .50 0 (0%) 2 (9%) .15 6 (8%) 6 (8%) 1.00
* Received magnesium for at least 4 hours.
For those who received magnesium (cerebral palsy subgroup, n 16; controls, n 18; other neurologic impairment; n 7; controls,
n 6).
TABLE 5. Description of Neonatal Complications
Cerebral
Palsy
(n 50)
Matched
Controls
(n 50)
P Other
Neurologic
Impairment
(n 22)
Matched
Controls
(n 22)
P Total
Neurologic
Impairment
(n 72)
Matched
Controls
(n 72)
P
Respiratory distress syndrome (n, %) 46 (92%) 44 (88%) .50 22 (100%) 18 (82%) .04 68 (94%) 62 (86%) .09
Days on ventilator (n SD) 23 24 14 15 .04 41 70 20 21 .19 28 44 16 17 .03
Oxygen dependence at 36 weeks* (n, %) 11 (22%) 7 (14%) .30 11 (50%) 4 (18%) .03 22 (31%) 11 (15%) .03
Septicemia (n, %) 27 (54%) 16 (33%) .03 11 (50%) 6 (29%) .15 38 (53%) 22 (31%) .01
Hyperbilirubinemia (n, %) 14 (28%) 10 (20%) .35 10 (46%) 4 (18%) .05 24 (33%) 14 (19%) .06
Necrotizing enterocolitis (n, %) 6 (12%) 4 (8%) .53 1 (5%) 0 (0%) .32 7 (10%) 4 (6%) .37
Periventricular bleed (n, %) 32 (64%) 19 (38%) 11 (50%) 10 (45%) 43 (60%) 29 (40%)
Grade 1 10 (20%) 9 (18%) 5 (23%) 2 (9%) 15 (21%) 11 (15%)
Grade 2 2 (4%) 6 (12%) .01 0 (0%) 4 (18%) .76 2 (3%) 10 (14%) .02
Grade 3 7 (14%) 3 (6%) 5 (23%) 3 (14%) 12 (17%) 6 (8%)
Grade 4 13 (26%) 1 (2%) 1 (5%) 1 (5%) 14 (19%) 2 (3%)
Severe cranial ultrasound abnormality (n, %) 26 (52%) 6 (12%) .00 10 (45%) 6 (27%) .21 36 (50%) 12 (17%) .00
Hypothyroxinemia (n, %) 18 (36%) 11 (22%) .12 13 (59%) 7 (32%) .07 31 (43%) 18 (25%) .02
* Postconceptional age.
Total bilirubin 10 mg/dL.
Lowest neonatal thyroxine level 5 g/dL.
Grade 3 or 4 bleed, periventricular leukomalacia, ventricular dilatation at discharge.
318 PERINATAL CORRELATES OF NEUROLOGIC IMPAIRMENT
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sound abnormality, and septicemia as well as a
longer duration of ventilator dependence. The total
neurologically impaired group of children differed
significantly from their controls in the number of
days on the ventilator, rates of oxygen dependence at
36 weeks, septicemia, periventricular hemorrhage,
severe cranial ultrasound abnormality, and hypothy-
roxinemia. Overall, 5 children received thyroxine
therapy, of whom 2 developed cerebral palsy.
Table 6 presents the results of the logistic regres-
sion analyses. In each model, the results are shown in
two blocks as the variables were entered into the
model; first the perinatal and neonatal factors and
then adding the severe cranial ultrasound abnormal-
ity. In the larger model of total neurologic impair-
ment (72 vs 72), three factors were independently
associated with an increased risk of neurologic im-
pairment: septicemia, clinical chorioamnionitis, and
severe cranial ultrasound abnormality. Children
with severe cranial ultrasound abnormality were 10
times more likely to be neurologically impaired than
those without such abnormalities [odds ratio (OR),
9.97; confidence interval (CI), 3.84, 25.87]. Children
who developed septicemia were more than twice as
likely to be neurologically impaired (OR, 2.46; CI,
1.10, 5.52), with severe cranial ultrasound abnormal-
ity having little effect on the relationship between
septicemia and neurologic outcome. Children whose
mothers had clinical chorioamnionitis were at a sig-
nificantly increased risk for neurologic impairment,
with the risk increasing incrementally from 2.7 times
to nearly 4 times as likely, when severe cranial ultra-
sound abnormality was included in the model (OR,
2.77 vs 3.79; CI, 1.34, 10.78). In the model predicting
cerebral palsy cases (50 vs 50), only severe cranial
ultrasound abnormality was found to be significant,
with these children being 15 times more likely to
develop cerebral palsy than those without severe
cranial ultrasound abnormality (OR, 15.01; CI, 4.34,
51.93).
We next examined the role of magnesium therapy.
Based on the bivariate and multivariate analyses,
magnesium therapy had no direct effect on neuro-
logic impairment. Moreover, we found no relation-
ship between magnesium therapy and severe cranial
ultrasound abnormality, thus eliminating the possi-
ble mediating relationship. Similarly, we found no
evidence of a moderating effect of magnesium ther-
apy. In both models, the interaction terms were
found to be nonsignificant (results not shown).
DISCUSSION
The survival of VLBW children has improved dur-
ing the last decade but there has been no change in
the prevalence of neurologic impairment, including
cerebral palsy. In this study, we examined the ante-
natal, intrapartum, and neonatal risk factors associ-
ated with the development of neurologic impair-
ment, including cerebral palsy, among singleton
VLBW children followed to 20 months corrected age.
After controlling for confounding factors, the signif-
icant risk factors identified among the total popula-
tion of 72 children with neurologic impairment were
clinical chorioamnionitis, severe intracranial lesions
documented on neonatal ultrasound, and septicemia,
whereas among the 50 children with cerebral palsy
only severe cranial ultrasound abnormality re-
mained significant. Magnesium therapy had no di-
rect neuroprotective effect on cranial ultrasound ab-
TABLE 6. Results of Logistic Regression Analyses of Perinatal Correlates and Neurologic Impairment*
Model 1 Model 2
Beta SE Odds
Ratio
95% CI Beta SE Odds
Ratio
95% CI
Cerebral palsy versus controls
(n 50 vs 50)
Septicemia .68 .46 1.97 .81, 4.81 .83 .52 2.29 .82, 6.41
Days on ventilator .02 .01 1.02 .99, 1.04 .00 .01 1.00 .97, 1.03
Maternal magnesium therapy .01 .51 .99 .37, 2.66 .38 .60 .69 .21, 2.23
Severe cranial ultrasound abnormality 2.71 .63 15.01 4.34, 51.93*
Total neurologic impairment versus
controls (n 72 vs 72)
Septicemia .86 .37 2.36 1.14, 4.90* .90 .41 2.46 1.10, 5.52*
Oxygen dependence at 36 weeks .52 .47 1.69 .68, 4.21 .73 .52 2.08 .76, 5.72
Clinical chorioamnionitis 1.02 .48 2.77 1.07, 7.13* 1.33 .53 3.79 1.34, 10.78*
Hypothyroxinemia .42 .40 1.52 .69, 3.32 .21 .45 1.23 .51, 2.98
Hyperbilirubinemia .71 .42 2.03 .89, 4.64 .64 .46 1.89 .76, 4.70
Maternal magnesium therapy .22 .44 1.25 .52, 2.98 .06 .50 1.07 .40, 2.82
Severe cranial ultrasound abnormality 2.30 .49 9.97 3.84, 25.87*
* Correlates from the bivariate analysis which had a P .10 were included in the multivariate logistic model. Period of birth (ie, before
or after 1990) was included in each model, but was not found to be significant (results not shown).
For the comparison of cerebral palsy versus controls, model 1 includes septicemia, days on ventilator, and maternal magnesium therapy.
Model 2 includes all variables from model 1 with the addition of severe cranial ultrasound abnormality.
Includes grade III and IV periventricular hemorrhage, parenchymal infarction, periventricular leukomalacia, and ventricular dilatation.
For the comparison of total neurologic impairment versus controls, model 1 includes septicemia, oxygen dependence at 36 weeks,
clinical chorioamnionitis, hypothyroxinemia, hyperbilirubinemia, and maternal magnesium therapy. Model 2 includes all variables from
model 1 with the addition of severe cranial ultrasound abnormality.
Includes rupture of membranes, with fever of either greater than 37.8C (two occasions/one hour apart) or 38.3C (single occasion), and
one of the following maternal tachycardia (100 beats per minute), fetal tachycardia (160 beats per minute), maternal leukocytosis
(11 000/mm white blood cells), or foul smelling amniotic fluid.
T
4
5 mcg%.
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normality or on neurologic impairment. There was
furthermore no moderating effect.
Strengths of our study include the fact that this is
a single center study with the diagnosis of cerebral
palsy confirmed by a single examiner over many
years (M.H.). To cover the broader spectrum of neu-
rologic impairments among VLBW children, we in-
cluded children with classically defined cerebral
palsy in addition to those with other neurologic im-
pairments that may be defined by some as mild
cerebral palsy. We had a matched-control population
and information regarding magnesium dosage and
duration of therapy was well documented, including
magnesium use during the hospitalizations before
delivery. The weaknesses of our study include its
retrospective nature, its relatively small size with
limited power to detect subtle differences in risk
factors, the fact that we matched for birth weight and
gestational age, thus excluding the possibility of ex-
amining the effect of intrauterine growth failure, the
low rate of antenatal steroid use at the time of the
study, and the absence of maternal cocaine screening
for all participants. We are cognizant of the limita-
tions in using significance levels to select variables
for the multivariate analyses; however, because there
are no established guidelines for selecting variables
with limited samples this was our best option.
33
Based on our incidental finding of increased mater-
nal cocaine use among children with neurologic im-
pairment and cerebral palsy, it is premature to sug-
gest a causal relationship between cocaine and
cerebral palsy but this is an avenue worth further
exploration.
Many peer-reviewed manuscripts and abstracts
have recently reported on the association between
perinatal risk factors and cerebral palsy. Significant
factors identified in these reports include antenatal
magnesium therapy,
15,16,1820
chorioamnionitis,
21,34,35
intracranial pathology,
59
and neonatal hypothyrox-
inemia.
3639
Our results confirm the association be-
tween chorioamnionitis and neurologic impairment,
but fail to identify the association between pregnan-
cy-induced hypertension, hypothyroxinemia, or
magnesium therapy.
Studies supporting our findings of a lack of a
beneficial effect of magnesium therapy include those
of Leviton et al,
25
Paneth et al,
26
and others.
22,24,40,41
All
the studies on the association between antenatal
magnesium therapy and neurodevelopmental out-
comes of VLBW children have been retrospective.
They have differed in the populations from which
they were drawn with some pertaining to regional
cerebral palsy registers
15,19
and others to low birth
weight cohorts.
20,22,2426
The studies have been region-
al,
26
multicenter,
24
or single center.
16,20
Some have
used severe periventricular pathology documented
on ultrasound as a proxy for cerebral palsy.
18,23,24
The
majority have included relatively small numbers of
children with the diagnosis of cerebral palsy, con-
firmed at ages ranging from 1 year
16,20
to 3 to 5 years
of age.
15,19,26
The index populations (children with
cerebral palsy or periventricular lesions) have been
compared with all the children without the prob-
lem
24
or to randomly selected controls.
15
The rates of
magnesium therapy among studies have differed
and ranged from 17%
19
to 45%.
25
Because magnesium
therapy is not given randomly, the perinatal and
birth data of the magnesium-treated cohorts have
differed from the populations that did not receive
magnesium, which has confounded interpretation of
the results. Mothers with preeclampsia, or pregnan-
cy-induced hypertension, preferentially receive mag-
nesium therapy,
15,25,26
and preeclampsia tends to be
protective of the development of cerebral palsy, even
in countries where magnesium is rarely used.
42
This
protective effect is possibly attributable to differ-
ences associated with the mode and timing of deliv-
ery of mothers with preeclampsia.
26,42
Magnesium
therapy has also been positively correlated with an-
tenatal steroid therapy, further confounding analysis
of the outcomes.
19,25
Inflammatory cytokines, released during intrauter-
ine infection, are considered to be catalysts for the
development of periventricular leukomalacia and
subsequent cerebral palsy.
7,21,34,4346
The higher levels
of interleukin 6 found more frequently among pa-
tients with chorioamnionitis are considered to be
associated not only with increased neonatal morbid-
ity and mortality,
43
but also with the occurrence of
periventricular leukomalacia
4749
and cerebral pal-
sy.
46
Verma et al
7
found an association between clin-
ical, but not histologic, evidence of chorioamnionitis
and abnormal cranial ultrasound findings. An asso-
ciation between neonatal sepsis and neurologic im-
pairment has also previously been reported by oth-
ers.
5052
In our experience the neonatal sepsis was of
late onset with no clinical relationship to maternal
chorioamnionitis. Murphy et al
51
similarly reported
that the sequence of maternal chorioamnionitis and
neonatal septicemia rarely occurred.
The neonatal determinants of cerebral palsy usu-
ally occur together in the sickest and least mature
infants. Murphy et al
51
reported an association
between periventricular lesions, cardiovascular and
respiratory disturbances, patent ductus arteriosus,
hypotension, sepsis, and prolonged ventilator de-
pendence. She suggested that the cerebral ischemia
associated with chorioamnionitis or other antenatal
insults may not manifest itself until the neonatal
period and may occur only if the infant suffers ad-
ditional further insult during this time. Severe abnor-
mality on cranial ultrasound has uniformly been
found to be predictive of cerebral palsy and neuro-
logic impairment among VLBW children.
5,6,8,11,20,23,51
The lesions most predictive of future disability in-
clude grades 3 and 4 periventricular hemorrhage,
50,53
residual ventriculomegaly,
54
intraparenchymal peri-
ventricular echodensities, and cystic periventricular
leukomalacia.
5,55
Reports of the association between transient neo-
natal hypothyroxinemia and abnormal neurodevel-
opmental outcome of VLBW children have been con-
flicting. Although increased rates of developmental
delay,
39
neurologic dysfunction,
38
and disabling cere-
bral palsy
36,37
have been reported by some investiga-
tors, others have not found an association with de-
velopmental delay
36,56,57
or cerebral palsy.
58,59
These
studies have used varying definitions for hypothy-
320 PERINATAL CORRELATES OF NEUROLOGIC IMPAIRMENT
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roxinemia.
37,38,56,59
Furthermore, they differed in the
rates of periventricular hemorrhage, confounding in-
terpretation of the results. Trials of neonatal thyrox-
ine supplementation have not resulted in decreased
rates of neurologic impairment
60
or improved cogni-
tive function.
61
We conclude that neurologic impairments among
VLBW children including cerebral palsy are proba-
bly not caused by individual risk factors, but are
rather a final common endpoint of many factors
operating at different stages of development.
51
Fu-
ture attempts to reduce the rates of neurologic im-
pairment need to concentrate on early diagnosis of
impending preterm delivery and its prevention.
There is evidence linking bacterial vaginosis with
asymptomatic amniotic fluid infections and overt
chorioamnionitis. Antibiotic therapy for bacterial
vaginosis may prevent preterm delivery.
62
Such ther-
apy may potentially also have an effect on prevent-
ing periventricular leukomalacia and its associated
neurologic impairment. Because the prevention of
chorioamnionitis is probably not a reality in the near
future, attempts to decrease the neonatal risk factors
associated with neurologic impairment such as se-
vere cranial ultrasound abnormality and neonatal
sepsis might be most practical at this time.
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1998;102;315 Pediatrics
Avroy A. Fanaroff and Maureen Hack
Deanne Wilson-Costello, Elaine Borawski, Harriet Friedman, Raymond Redline,
Very Low Birth Weight Children
Perinatal Correlates of Cerebral Palsy and Other Neurologic Impairment Among

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