Antecedents of Cerebral
I. Univariate Analysis of Risks
Karin B. Nelson, MD, Jonas H. Ellenberg, PhD
\s=b\ A large prospective study inves-
tigated prenatal and perinatal ante-
cedents of chronic motor dysfunction
(cerebral palsy [CP]), evaluating approx-
imately 400 characteristics of the moth-
ers, pregnancies, or deliveries. In addi-
tion to confirming some, but not all, of
the classic risk factors for CP, this study
observed relatively large increases in
the CP rate in association with maternal
mental retardation, seizure disorders,
hyperthyroidism, or with the administra-
tion of thyroid hormone and estrogen in
pregnancy. Some risk factors were pre-
dictive of CP only insofar as they were
associated with low birth weight or low
Apgar scores. Among factors not signifi-
cantly related to CP rate were maternal
age, parity, socioeconomic status,
smoking history, maternal diabetes, first
trimester vaginal bleeding, kidney or
bladder infection, moderate hyperten-
sion, long cord, use of anesthetic
agents, or use of oxytoxics for initiation
or augmentation of labor. Duration of
labor, whether precipitate or prolonged,
was not a risk factor for CP.
(AJDC 1985;139:1031-1038)
rPhe Collaborative Perinatal Project
of the National Institute of Neu¬
rological and Communicative Disor¬
ders and Stroke (NCPP), a large pro¬
spective study, was undertaken to
investigate the association of maternal
and pregnancy conditions and events
of labor, delivery, and the neonatal
period, with chronic neurologic disor¬
ders of childhood. This article reports
the major results of the NCPP as they
From the Developmental Neurology Branch
(Dr Nelson), and the Biometry and Field Studies
Branch, Intramural Research Program (Dr El-
lenberg),National Institute of Neurological and
Communicative Disorders and Stroke, Bethesda,
Md.
Reprint requests to 7550 Wisconsin Ave, Room
8C-04, Bethesda, MD 20205 (Dr Nelson).
Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/21/2015
Palsy
relate to risks for cerebral palsy, as
evaluated in univariate analyses. A
companion article will consider ante¬
cedents of cerebral palsy (CP) and of
its clinical subtypes, employing multi¬
variate techniques.
SUBJECTS AND METHODS
Approximately 54,000 pregnancies were
studied at 12 cooperating university hospi¬
tals between 1959 and 1966. The study
sample was approximately 46% white and
46% black; women of Hispanic descent
made up a majority of the remaining sub¬
jects. The socioeconomic level of the NCPP
population was somewhat lower than for
the total population of the United States as
assessed by the Bureau of the Census.1
Information relating to the sample and to
study procedures is available elsewhere.z'3
At the initial prenatal visit, medical,
obstetric, and family histories were re¬
corded. At each subsequent visit, medical
and obstetric events and medication intake
were noted. Patients were examined on
admission in labor, and the course of labor
and delivery was observed.3 After delivery,
a physician reviewed all prenatal and labor
and delivery records, including documenta¬
tion of medical and surgical conditions of
the gravida before or during the pregnancy.
Ascertainment of drug exposure and its
timing was as described by Heinonen et al,4
except that we considered drug exposure
for the entire pregnancy. Neonatal infor¬
mation was derived from delivery room and
nursery records.
Examinations in the first year of life were
the basis for the recognition of congenital
malformations. A pediatric and neurologic
examination performed when children
were 7 years old provided the basis for
diagnoses of CP. Children with a CP diag¬
nosis at 1 year of age who died before 7
years of age were included. Cerebral palsy
was defined as a chronic disability charac¬
terized by aberrant control of movement or
posture that appeared early in life and that
was not the result of recognized progres¬
sive disease. Children with meningomyelo-
celes and those with motor deficits ac¬
quired through infection or injury after the
first month of life were not included. Unlike
several previous reports from the NCPP,
this report includes mild, as well as moder¬
ate and severe, CP.
The statistical test used to evaluate four¬
fold contingency table assessments of di-
chotomous antecedents for CP for signifi¬
cance was the 2 with 1 df (using a
continuity correction), except where other¬
wise indicated. Fisher's exact test was used
where cell size warranted it. Polychot-
omous antecedents were analyzed for glo¬
bal significance using the R x C contin¬
gency table format. Fourfold comparisons
of subgroups within larger contingency ta¬
bles were made only when the 2 test for the
larger table was significant at the .05 level.
Given the many 2 tests made within this
large dataset, some were likely to achieve
nominal levels of statistical significance by
chance alone. We did not adjust signifi¬
cance levels using multiple comparison
techniques, which would lessen the chance
of observing some clinically important risk
factors.5 Rather, we chose to consider the
significance values simply as indicators for
risk factors that are candidates for confir¬
mation in future studies.
Most continuous variables were exam¬
ined in both dichotomous and polychot-
omous forms. Intervals were chosen a pos¬
teriori, based on observed risk. Evaluation
of possible linear trends in the risk of CP for
polychotomous variables used weighted
least-squares regression analysis of the ob¬
served probabilities of risk, with weights
determined by the number of patients at
each observation point.
To examine whether variables signifi¬
cantly related to CP for the total population
were operative solely or chiefly through
their association with low birth weight, we
evaluated each variable significant for all
birth weights, for relationship to CP within
the 91% of the population with birth
weights over 2,500 g.

Table 1.—Risk Factors Ascertainable Prior to
Condition Prevalence, %
Demographic
Race: white
Mother working
Maternal medical
conditions before
pregnancy
Mental retardation
Seizures, recurrent,
major, active
Seizures, any active
Hyperthyroidism
Prior hospitalization
Reproductive history
Menstrual cycle
Long
Unusual
Last pregnancy
Birth weight <2,000 g
Neonatal death
No. of fetal deaths -2
History of prior siblings
Motor deficits
Sensory deficits
Mental retardation
*For each factor, the computed 2 for the comparison between the observed rate of cerebral palsy for
pregnancies with the factor as compared with those without is less than the tabled value of 2.1 The
computation of relative risk for conditions assuming prior pregnancies was computed as the rate of
cerebral palsy in the group with the factor over the rate of cerebral palsy in the group without the condition
or no prior pregnancy.
*P<.01.
*P<.05.
RESULTS
Of 51,285 pregnancies that produced
live-born singleton infants, outcome
was known at 7 years of age for 45,559
children, of whom 189 had CP.
The Mother
A higher rate of CP was observed in
white children, and a lower rate was
noted in children whose mothers were
employed outside the home (Table 1).
There was a slight and nonsignificant
increase in risk in the lowest socioeco¬
nomic status group, as defined by oc¬
cupation and education of the head of
the household and total family in¬
come.1 This group included 3% of white
grávidas and 12% of black mothers.
Grávidas 14 years of age and less, a
very low prevalence group and one
whose members were also at the low
end of the socioeconomic spectrum,
contributed a slight and nonsignificant
excess of risk. Maternal education,
marital status, parity, paternal age,
A history of maternal diabetes,
Pregnancy or at First Prenatal Visit*
length of time to become pregnant,
Relative Risk and maternal and sibling rhesus blood
Observed Rate Total
groupings were not associated with
Cerebral Palsy, % Birth Weight >2,500 g CP. Also not predictive of CP were
prior infertility, maternal sickling, age
at menarche, season of last menstrual
period, gonorrhea, syphilis, psychosis
or neurosis prior to pregnancy, mental
illness or congenital malformations in
6.5t 10.3* family members, Roentgen ray expo¬
sure of the abdominopelvic area,
0.4 2.7 6.7t 8.6* thrombotic illness or coagulation
0.8 1.4 3.5t 4.5* defect, glomerulonephritis, tuberculo¬
0.6 2.0 4.9f 4.7* sis, leiomyomata, neurologic disorders
13.5 0.6 1.6* 1.2 other than seizures or retardation,
neuromuscular or gastrointestinal
tract disease, asthma, or organic heart
3.6 0.8 1.9* 2.4* disease, including rheumatic fever
6.9 0.7 1.7* 2.2* prior to pregnancy.
None of the relative risks (RRs)
3.9 1.0 27* 0.5
1.4 1.3 3.1* 2.0
relating to social and demographic
characteristics exceeded 2, and the
0.6 1.4 3.4* 3.1 observed rate of CP associated with
any of these factors was below 1%. For
1.2 1.5 3.8* 2.7
most medical factors ascertainable be¬
1.0 1.1 2.8* 1.6
fore or very early in pregnancy, RRs
1.5 1.1 2.7* 2.9* were in the range of 2 to 10. Babies
born to mothers who were mentally
retarded or had seizures were at high¬
est risk, with absolute rates of CP
approaching 3%.
The Pregnancy
pregnancy spacing, smoking history Noneclamptic seizures during preg¬
(number of cigarettes per day and nancy, not symptomatic of acute en¬
number of years smoked), and inter¬ cephalopathy, were associated with a
course frequency were not associated relatively high RR (Table 2).
with significantly increased risk of CP, Some of the clinical elements of tox¬
nor were maternal height or prepreg¬ emia were associated with increased
nant weight. Early registration for risk if they were present in a severe
prenatal care was not associated with a degree. Severe proteinuria in the sec¬
lower rate of CP, nor was late registra¬ ond half of pregnancy, with 5 g or more
tion with increased risk. of protein present in the urine per 24
Maternal mental retardation (as rec¬ hours, was a substantial risk factor for
ognized clinically and obviously under- CP; moderate proteinuria (early or
ascertained), seizure disorders6 (espe¬ late) and severe proteinuria in the first
cially if recurrent and generalized), half of the pregnancy were not associ¬
and hyperthyroidism prior to preg¬ ated with CP. High blood pressure
nancy were significantly associated (diastolic pressure, -110 mm Hg) in
with CP in the offspring. There was an the third trimester was associated
increase in the risk of CP with an with a doubled risk of CP. High blood
increased number of confining ill¬ pressure earlier in pregnancy was un¬
nesses in the year before the last men¬ common, and was associated with a
strual period (trend significant, doubling of risk that was not statis¬
_"<.05). Menstrual cycles longer than tically significant. Moderate hyper¬
36 days, as well as unusual or irregular tension (diastolic pressure 90 to
cycles, were associated with some in¬ 110 mm Hg), whether early or late in
crease in the risk of CP. pregnancy, low blood pressure in the

Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/21/2015

 fewer visits. It appeared that it was
Table 2.—Medical Conditions and Hormone Treatment During Pregnancy the low birth weight associated with
Relative Risk* early termination of pregnancy, and
therefore lesser opportunity to keep
Observed Rate Total
Condition Prevalence, % ot Cerebral Palsy, % Birth Weight >2,500 g prenatal appointments, that might ac¬
Conditions in pregnancy count for the relationship of fewer pre¬
Seizures, noneclamptic 0.4 1.8 4.3+ 6.8+ natal visits with CP.
Tonic-clonic, Rubella and toxoplasmosis were
0.1 2.9 7.2* 11.7+
recurrent
rarely diagnosed by clinical, nonsero-
Heart disease, logic criteria in pregnancy, and the
asymptomatic 0.9 1.3 3.1* 3.0
increase in risk associated with clinical
Severe proteinuria, late 1.1 1.6 3.9* 5.1 +
Severe hypertension,
diagnosis in the mothers was not sta¬
third trimester 2.9 0.8 2.1* 2.2 tistically significant.
Incompetent cervix 0.3 2.4 5.9* 0.0
Maternal diabetes in pregnancy was
not found to be a risk factor for CP, nor
Bleeding, third
trimester 13.6 0.7 1.8+ 1.6* were hyperthermia, kidney or bladder

Polyhydramnios 1.3 1.0 2.5* 3.2* infection, asthma, leiomyoma and

Hormones
Estrogen 0.8
Progesterone 1.5
Thyroid 1.4
Thyroid and estrogen 0.1
No. of prenatal
visits -6 30.8
*For each factor, the computed 2 for the comparison between the observed rate of cerebral palsy for
pregnancies with the factor as compared with those without Is less than the tabled value of 2.'
+P-C.01.
*P<.05.
middle trimester, and edema of the
face or hands were not related to CP
rate.
Incompetent cervix in the study
pregnancy, although rare, had one of
the highest RRs of obstetric conditions
examined, with that risk limited to
infants with low birth weights. Vaginal
bleeding in the third trimester was
relatively common, and was signifi¬
cantly associated with CP. Vaginal
bleeding in the first trimester was not
associated with any increase in the
observed rate of CP, and second tri¬
mester bleeding was associated with
an RR of 1.5, a nonsignificant increase.
Maternal anemia, even if extreme
(lowest hemoglobin level, <7 g/dL),
was not significantly associated with a
risk of CP. Polyhydramnios was associ¬
ated with a trebling of the risk of CP;
neither central nervous system mal¬
formations nor anomalies preventing
swallowing were observed in affected
infants. The risk of CP was inversely
related (significant linear trend,
P<.05) to maximum maternal weight
gain in pregnancy, but this relation¬
1.4 3.3* 1.1
1.1 2.7* 2.0
0.9 2.3* 2.3
3.3 8.0* 6.2
0.6 1.7+ 1.0
term birth weight; apparently the cor¬
relation of low weight gain with low
birth weight in the child accounted for
the association.
A heightened risk of CP was ob¬
served in children of women who re¬
ceived estrogenic hormone, progester¬
one, or thyroid hormone, or thyroid
hormone and estrogen, a rare combi¬
nation, in pregnancy. This observation
was investigated in further detail (see
below).
The average number of prenatal vis¬
its per gravida was nine. Offspring of
women who made six or fewer prenatal
visits had a slightly higher rate of CP
than children of women who made
seven or more visits; this was true for
the total population, but not for
women whose babies weighed over
2,500 g. Of the infants with low birth
weights, 53% were born following
pregnancies in which there had been
six or fewer visits, and 75% of the CP in
children with low birth weights oc¬
curred in this subgroup. In contrast,
no excess of CP was seen in large
infants, 28% of whom were born after
other gynecologic tumors, psychosis
or neurosis, air travel, sick pet in the
home, Roentgen ray exposure, jaun¬
dice, vomiting including hyperemesis
gravidarum, rheumatic fever, clin¬
ically diagnosed syphilis, herpes
simplex, mumps or measles during
pregnancy, hyperthyroidism and
hypothyroidism in pregnancy, and
sulfa
treatment with antibiotics,
drugs, diuretics, anorectic agents,
vaginal contraceptives, antihyperten-
sive agents, and barbiturate and non-
barbiturate hypnotic agents and anti-
con vulsant medications.
The RRs for pregnancy characteris¬
tics were in the range of 2 to 12. The
associated absolute CP rates for most
factors ranged between 1% and 2%,
and never exceeded 3%. Except for
third trimester bleeding, pregnancy
factors significantly predictive of CP
were uncommon characteristics.
The Labor and Delivery
Vaginal bleeding present at the time
of admission to the hospital for deliv¬
ery was associated with an increased
risk of CP, as were diagnoses of ab-
ruptio placentae, placenta previa, and
marginal sinus rupture (Table 3). In
babies weighing over 2,500 g, bleeding
on admission, abruptio placentae, and
marginal sinus rupture were not sig¬
nificantly related to CP.
Rupture of membranes more than
24 hours prior to delivery was asso¬
ciated with a tripling of the risk of CP
in the total population, but was not
related to CP among babies weighing
over 2,500 g. Chorionitis, identified by

ship was not present in children of pregnancies in which there were six or marked neutrophilic infiltration of the

Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/21/2015

 Table 3.—Risk Factors in Labor and Delivery reported.8,9 For children with low birth
weights, the observed rate of CP was
Relative Risk* higher in white than in nonwhite in¬
fants (Figure).9 Gestational age, pla¬
Observed Rate Total
Condition Prevalence, % of Cerebral Palsy, % Birth Weight -2,500 g cental weight, and body length were
Vaginal bleeding at related to CP in the total population,
admission 5.6 0.8 2.2* 1.0 but all were correlated with birth
Placental complications 3.2 1.5 3.9* 2.4* weight and were not associated with
Previa 0.6 2.0 4.9* 6.2* CP in babies weighing over 2,500 g. A
Abruption 1.6 1.4 3.5* 2.0 nonsignificant association was noted
Marginal sinus between the presence of a single um¬
rupture 1.2 1.1 2.7* 0.8 bilical artery and CP rate. Short cord
Rupture of membranes (<40 cm) was a risk factor for CP.
>24 hr before
delivery 5.4 1.0 2.8* 1.0 Neither size of placental infarcts over
3 cm, nor infarct number, nor long
Chorionitis 2.3 1.8 4.8* 2.6*
umbilical cord (-80 cm) were related
Presentation
Breech 2.7 1.8 4.6+ 3.9* to CP risk.
Face, brow, Delayed onset of respiration and
transverse 0.5 2.1 5.1 + 5.3* first cry were associated with an in¬
Occiput anterior 10.2 0.4 0.4+ 0.6 creased risk of CP; for neither event
Delivery mode was a one- or two-minute delay accom¬
Breech 2.3 1.9 4.9+ 3.4+ panied by a marked increase in risk.
Vertex 92.8 0.4 0.4+ 0.5+ A series of ratios relating physical
Lowest fetal heart measurements at birth was used to
rate -60 beats/min 1.3 1.8 4.5+ 2.9
2.0 2.6
explore intrauterine growth patterns
Hemorrhagic shock 0.3 5.0+ as predictors of CP. A low weight for
*For each factor, the computed 2 for the comparison between the observed rate of cerebral palsy for
pregnancies with the factor as compared with those without is less than the tabled value of 2.1 body length at birth was associated
+P<.01. with somewhat heightened risk in the
*P<.05. total population, but not in the babies
weighing over 2,500 g. The ratio of
placental chorion on microscopie in¬ risk of CP at either the precipitate or head circumference to birth length
spection, and breech, face, brow, the prolonged ends of the distribution. demonstrated a slight increase in risk
transverse, and other presentations, Length of labor was not different in among infants whose heads were large
and breech deliveries, were related to births of children with spastic CP vs for their body length. For the total
CP risk. Delivery by emergency ce¬ controls in a previous study.7 birth weight group a high placental
sarean section was associated with an Bipartite placenta and continuous weight for birth weight was associated
RR of 1.3, which is not a statistically gas, caudal, or spinal anesthesia were with some increase in the risk of CP,
significant increase in risk. Cesarean not significantly related to CP. Also but no such relationship was observed
sections performed because of previ¬ not significantly predictive of CP were among large infants; smallness of the
ous operative deliveries and labor and cord prolapse, nuchal cord, cord placenta for birth weight was not re¬
delivery drugs were not significant around body, midforceps delivery, and lated to CP. None of the groups identi¬
predictors of CP. meconium staining of the amniotic fied through these ratios of intra-
A lowest fetal heart rate below fluid, although for all of these except uterine growth measures had a high
60 beats per minute, as recognized nuchal chord there were positive asso¬ absolute rate of CP.
by auscultation, was a predictor of ciations with CP. (In the small group of The risk of CP was increased four¬
CP, but a lowest rate between 61 and children with some of these complica¬ fold for a child with one or more major
80 beats per minute was not. Highest tions and low Apgar scores at five malformations outside the central ner¬
fetal heart rate was not significantly minutes, there were significant associ¬ vous system (as classified by Myri-
related to risk of CP. The obstetricians' ations with CP.3) anthopoulos and Chung,10 with slight
judgment of arrested progress of labor For characteristics of labor and de¬ modification). Minor malformations in
or uterine dysfunction was not a signif¬ livery, RRs ranged between 2 and 5, children free of major non-central
icant predictor of CP, and oxytocin and with absolute CP rates of 2% or less. nervous system malformations were
other medicinal agents used for initia¬ not associated with an increased rate
tion of labor or for augmentation, and DeliveryRoom Observations ofCP.
induction of labor by amniotomy, were Male infants developed CP more Characteristics of the infant once he
not. Duration of the first stage of labor often than female infants did. Birth or she could be examined directly were
to more than 40 hours, or the second weight and Apgar scores (Table 4, stronger predictors of CP than the
stage to more than 129 minutes, were Figure) were important predictors of prenatal and obstetric factors that we
not associated with differences in the CP in this population, as has been studied.

Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/21/2015

 Table 4.—Characteristics of Children at Birth
was an important risk factor for CP.
This finding is consistent with other
Relative Risk work describing the neurologic mor¬
Observed Rate Total bidity stemming from symptomatic in¬
Condition Prevalence, % of Cerebral Palsy, % Birth Weight -2,500 g fants in that majority of the newborn
Noted in delivery room population with birth weights over
Male 50.5 0.5 1.6* 1.7* 2,500 g.U12
Birth weight Respiratory problems in the nur¬
-2,500 g 9.2 1.5 4.9*
sery period in general, and those re¬
-2,000 g 2.0 4.5 13.7* lated specifically to respiratory dis¬
Placental weight tress syndrome and to aspiration,
<325 g 10.1 1.1 3.2* 1.0
were predictors of CP. The severity of
Time to cry _5 min 1.2 3.8 11.2* 10.8*
Time to breathe >3 min 0.7 3.5 9.2* 12.5*
respiratory problems, whatever the
specific diagnosis, was related to risk
Apgar score 0-3+ of CP.
1 min 4.8 1.9 6.4* 5.2*
5 min 0.9 6.5 20.8* 20.0*
Anemia in the infant with a lowest
hematocrit below 40% was a predictor
Major congenital of CP; hematocrit values over 70%
malformation, non-central
nervous system 6.8 1.3 3.8* 3.9* were not. A peak bilirubin level over
*For each factor, the computed 2 for the comparison between the observed rate of cerebral palsy for 16 mg/dL was a risk factor for CP.
pregnancies with the factor as compared with those without Is less than the tabled value of 2 at the P< .01 Infections of various sites, definite
level.1
+The computation of relative risk for children with low Apgar scores was computed by comparison with and suspect, and septicemia and men¬
a score of 7 to 10 in each time group. ingitis, both very uncommon, were
associated with CP. Maternal postpar¬
Table 5.—Characteristics of Children in Newborn Nursery tum endometritis was not related to
CP risk.
Relative Risk*
Observed Rate
An observation of interest was the
Condition Prevalence, % of Cerebral Palsy, % Total Birth Weight 2,500 g fairly high RR associated with the
In incubator _3 days+ 1.1 5.4 22.4* systemic administration of antibiotics
Newborn seizures 0.3 19.8 53.6* 63.3* in the newborn nursery. Since many
Diminished cry 1.2 5.1 14.5* 12.9* infants to whom antibiotics were given
Diminished activity 1.9 4.8 were not recorded to have definite or
14.6* 13.6*
Respiratory problems suspected sepsis or sites of infection,
(any) 1.5 3.4 9.2* 7.7* this observation was pursued, and will
Respiratory distress be discussed below.
syndrome 0.2 8.8 21.9* 49.3* Overall, the highest relative risks
Aspiration 0.2 10.3 25.7* 27.0* for CP observed in the prenatal, in¬
Lowest hematocrit <40% 2.5 3.7 10.9* 6.2* trapartum, and neonatal course ac¬
High bilirubin >16 mg/dL 2.5 2.1 5.5* 2.8§ companied very low Apgar scores, sei¬
Infection/treatment zures, and respiratory distress in large
Infection (any
definite) 1.2 2.6 6.5* 3.4 infants, all of which are characteristics
Infection (any recognized only after birth.
suspect) 1.0 3.2 8.5* 5.7*
Meningitis (definite) 0.02 12.5 30.5§ 0.0 Thyroid, Estrogen,
and Associated Factors
Meningitis (suspect) 0.02 11.1 27.1§ 0.0
Septicemia (definite) 0.06 7.1 17.4* 0.0
The observed rate of CP was in¬
Septicemia (suspect) 0.3 2.7 6.6§ 10.1§ creased in children whose mothers re¬
Antibiotics
ceived thyroid hormone or estrogen in
10.5 1.5 5.0* 3.3*
*For each factor, the computed 2 for the comparison between the observed rate of cerebral palsy for
pregnancy (Table 2). Approximately
pregnancies with the factor as compared with those without Is less than the tabled value of 2.1 two thirds of the women who received
+Term weight infants only. one or both these agents had hyper-
*P<.01. thyroidism or hypothyroidism, diabe¬
§P<.05.
tes, polyhydramnios, or a prior preg¬
The Nursery Period zures were all important risk factors nancy loss. In some women thyroid
for CP. hormone was prescribed for weight
A number of newborn signs had rela¬ A need for special nursing for in¬ reduction or as "pep pills", and in some
tively high RRs (Table 5). Evidence of fants weighing over 2,500 g, reflected women itwas included as part of a
neonatal depression, altered homeo- here by incubator care lasting for regimen intended to prevent preg¬
static mechanisms, and neonatal sei- three days or longer in large infants, nancy loss. In women who bore chil-

Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/21/2015


<1,501 1,501-2,000 2,001-2,500 >2,500
Birth Weight, g
W 54 192 1,038 19,350
NW 158 472 2,018 19,039
Birth weight groups and rate of cerebral palsy, in white and nonwhite children. At given low
birth weight, observed rate of cerebral palsy was higher in white (solid line) than in nonwhite
(broken line) children. W indicates number of white children; NW, number of nonwhite
children.
dren with CP, thyroid and/or estrogen While some of the indications for the
therapy usually was begun in the third administration of thyroid hormone and
month of pregnancy or earlier. estrogen were associated with an in¬
The CP in children exposed in utero creased risk of CP, these agents ad¬
to thyroid hormone, estrogen, or both ministered without these indications
was not homogeneous. One child had were associated with a trebling of risk.
malformed kidneys, while in the other To assess further whether it was in¬
children there were no obvious malfor¬ dications for hormone administration
mations. No child was recognized to or possible effects of the agents them¬
have abnormal thyroid function. selves that were risk factors, we ex-
Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/21/2015
amined the indications, agents, and
birth weight as predictors of CP in
stepwise logistic-regression analyses.
Variables describing thyroid disease,
prior fetal death, polyhydramnios, and
diabetes and its features (duration
longer than five years, insulin use, and
episodes of ketoacidosis, diabetic
coma, and insulin reactions) were in¬
cluded. Birth weight less than 2,500 g,
polyhydramnios, estrogen, and the
joint administration of estrogen and
thyroid hormone were identified as
significant by the logistic analyses;
diabetes and its complications were
not. None of the 206 offspring of dia¬
betic women who did not receive hor¬
mones or have polyhydramnios or thy¬
roid disease had CP. Although the
number of infants with hormone expo¬
sure and CP was small, these results
suggest that prenatal exposure to ex¬
ogenous thyroid hormone and estro¬
gen were associated with an increased
risk of CP independent of the indica¬
tions for their administration.
Thyroid hormone, estrogen, and
progesterone are all agents with im¬
portant effects on developing neuronal
systems.13"16 Estrogen administration
enhances the effects of thyroid hor¬
mone."
Antibiotics and
Related Factors
Neonatal sepsis or meningitis, re¬
corded as definitely present or only
suspect, were associated with high
RRs for CP (Table 5). However, these
conditions were very uncommon, and
these and other neonatal bacterial in¬
fections were evident in the histories
of only a small proportion of children
with CP.
More than 10% of children in the
NCPP received systemic antibiotics in
the newborn nursery, while only 2% of
the population had a definite or sus¬
pect recorded infection. Children who
received antibiotics in the nursery but
who had no recorded infection were
three times as likely to die in the first
year, and survivors were four times as
likely to have CP as were children who
had neither infection nor antibiotics.
Neonatal seizures were seven times as
common among children who received
antibiotics but had no injection; the
order of occurrence of seizures and
 antibiotic administration was not in¬
vestigated.
The antibiotics received by study
children were most frequently a com¬
bination of penicillin and strepto¬
mycin. Infants treated with antibiotics
who had no infection sometimes re¬
ceived these agents prophylactically
because of delivery in unsterile condi¬
tions, sometimes had hyperbilirubi-
nemia and exchange transfusions,
and, more often than infants who did
not receive antibiotics, were of low
birth weight and/or had low Apgar
scores. A factor associated with anti¬
biotic use without infection was the
presence of respiratory difficulty in
the newborn period, whether ascribed
to respiratory distress syndrome, ate¬
lectasis, or aspiration. Among infants
free of infection, increasing severity of
respiratory difficulty was associated
with increasing frequency of antibiotic
use, from 8.9% in children with no
respiratory problems to 74% in those
with severe respiratory difficulties.
It is probable that doctors pre¬
scribed antibiotics for an infant with¬
out infection because of a perception of
the infant as ill. Antibiotic use may
thus serve as a flag for risk. In addi¬
tion, some antibiotics are neurotoxic,
penicillin being especially associated
with seizures and streptomycin with
ototoxicity.18
Of children with CP, 37% received
antibiotics in the newborn nursery; in
24% of children with CP this was de¬
spite the absence of definite or sus¬
pected infection.
COMMENT
In a recent monograph that re¬
viewed the literature on the etiology of
CP, Alberman and Stanley19 discussed
the paucity of methodologically ade¬
quate studies on the subject. As they
remarked, "The study of the cerebral
palsies presents epidemiologists with
every possible pitfall." The NCPP was
designed to evaluate the antecedents
of CP, employing epidemiologie ap¬
proaches that aimed to avoid a few of
those pitfalls.
The prospective structure of the
NCPP allowed identification of
mother-child pairs before outcome was
known, and data were collected in the
same manner for mother-child pairs in
Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/21/2015
which CP was later the outcome as for
those subjects without CP. It was thus
possible to ascertain, with information
recorded prospectively, the frequency
of suspected antecedents of disease not
only in cases of CP but, of equal impor¬
tance, in noncases. Review of histories
of children with CP cannot provide
reliable information on cause unless
accompanied by consideration of com¬
parable events, comparably ascer¬
tained, in unaffected children.
Perhaps the foremost of the limita¬
tions of the NCPP, is its date. Ob¬
stetric and neonatal care have changed
markedly since the NCPP was begun.
Changes have been most dramatic in
the of the infant with low birth
care
weight. For this reason, we have
stressed results relating to antece¬
dents of CP in babies weighing over
2,500 g, in whom much of the CP
occurs.
As in any observational study, in the
NCPP associations between antece¬
dents and outcome could be estab¬
lished but the nature of the associa¬
tions—whether causal or not—could
not be determined; to do that would
require a differently designed study
capable of testing the effects of inter¬
ventions, necessarily a second-genera¬
tion effort. On the other hand, this
study could, because of the large num¬
ber and variety of characteristics ex¬
plored, expand the set of questions
asked relating to the etiology of CP.
This study could thus generate hy¬
potheses on etiology but not provide
definitive tests of them.
This study could rule out associa¬
tions insofar as sample size permitted.
A study that differed only by its larger
size might have found statistical signif¬
icance for some uncommon or weakly
acting factors not found to be impor¬
tant in this study. However, such ante¬
cedents could not account for a large
proportion of CP.
Some of the prenatal and perinatal
risk factors evaluated for CP were
indeed found to be fairly risky, in that
an individual possessing such charac¬
teristics was at a risk of developing CP
severalfold greater than that for indi¬
viduals without the characteristics.
However, even conditions with fairly
high relative risks were not associated
with high absolute rates of CP, and
most children with a given risk factor
did not have CP. In addition, most
conditions with high RRs were rare;
the few prelabor conditions with RRs
exceeding 3 all had prevalences less
than 1%. The conditions with the high¬
est RRs, and with highest absolute
rates of CP, were characteristics of
infants after their births.
Many factors found in the NCPP to
have high RRs have long been consid¬
ered antecedents of CP. Other condi¬
tions long assumed to be related to CP,
such as maternal diabetes, extremes of
maternal age, and low socioeconomic
status, were related only slightly, if at
all.
We have previously reported that
some risk factors, especially complica¬
tions of labor and delivery, were asso¬
ciated with increased risk of CP only in
children who also had low Apgar
scores.3 As the present report indi¬
cates, other risk factors were predic¬
tive of CP only insofar as they were
associated with low birth weight. In¬
competent cervix, low birth weight of
an older sibling, and prior neonatal
death of a sibling, for example, were
not predictors of CP in babies who
weighed over 2,500 g at birth, al¬
though they were predictive in the
total population. Thus, both low Apgar
scores and low birth weight seem to act
as pathways for the expression of cer¬
tain earlier pathogenetic factors.
A few factors or clusters of factors
identified empirically rather than by
prior hypothesis were found to have
reasonably high RRs or to occur in a
substantial proportion of cases of CP.
Of these, polyhydramnios and hor¬
mone administration in pregnancy,
and associated factors, raise tantaliz¬
ing questions. Administration of thy¬
roid hormone and estrogen in an effort
to prevent early pregnancy loss is a
regimen no longer in use. Interest in
whether these agents, given in preg¬
nancy, might have contributed to
motor disorders in the offspring de¬
rives from the more general possibility
that aspects of maternal endocrine sta¬
tus might in some cases be related to
childhood motor disorders. The find¬
ing that long or unusual menstrual
cycles were among the few maternal
characteristics predictive of CP is com¬
patible with this possibility.
 The NCPP set out to test, quantify,
and compare the risk of CP associated
with a large set of maternal, preg¬
nancy, labor and delivery, and neonatal
characteristics. In addition to confirm¬
ing some, but not all, of the classic risk
factors for CP, this study has identified
several other characteristics of the
mother or the pregnancy that seem to
be associated with a relatively high
risk of CP. If confirmed in other in¬
vestigations, these newer observa-
1. Myrianthopoulos NC, French KS: An appli-
cation of the US Bureau of the Census socioeco-
nomic index to a large, diversified patient popula-
tion. Soc Sci Med 1968;2:283-299.
2. Broman S: The Collaborative Perinatal
Project: An overview, in Mednick SA, Harway M,
Finello KM (eds): Handbook of Longitudinal
Research. New York, Praeger Publishers, 1984,
vol 2, pp 185-215.
3. Nelson KB, Ellenberg JH: Obstetric com-
plications as risk factors for cerebral palsy or
seizure disorders. JAMA 1984;251:1843-1848.
4. Heinonen OP, Slone D, Shapiro S: Birth
Defects and Drugs in Pregnancy. Littleton,
Mass, Publishing Sciences Group Inc, 1977.
5. Mantel N, Haenszel W: Statistical aspects
of the analysis of data from retrospective studies
of disease. J Natl Cancer Inst 1959;22:719-748.
6. Nelson KB, Ellenberg JH: Maternal seizure
disorder, outcome of pregnancy, and neurologic
abnormalities in the children. Neurology 1982;32:
1247-1254.
7. Dale A, Stanley FJ: An epidemiological
tions may contribute to a broadening of
our present rather limited set of hy¬
potheses regarding the etiology of CP.
The Collaborative Study of Cerebral Palsy,
Mental Retardation and Other Neurological and
Sensory Disorders of Infancy and Childhood is
supported by the National Institute of Neu¬
rological and Communicative Disorders and
Stroke. The following institutions participated:
Boston Lying-in Hospital; Brown University,
Providence, RI; Charity Hospital, New Orleans;
Children's Medical Center, Boston; Columbia
University, New York; Johns Hopkins Univer-
References
study of cerebral palsy in Western Australia
1956-1975: II. Spastic cerebral palsy and peri-
natal factors. Dev Med Child Neurol 1980;22:
13-25.
8. Ellenberg JH, Nelson KB: Birthweight and
gestational age in children with cerebral palsy or
seizure disorders. AJDC 1979;133:1044-1048.
9. Nelson KB, Ellenberg JH: Apgar scores as
predictors of chronic neurologic disability. Pedi-
atrics 1981;68:36-44.
10. Myrianthopoulos NC, Chung CS: Congeni-
tal malformations in singletons: Epidemiologic
survey. Birth Defects 1974;10:1-58.
11. Scott KG, Masi W: The outcome from and
utility of registers of risk, in Field TM (ed):
Infants Born at Risk, New York, SP Medical &
Scientific Books, 1979, pp 485-496.
12. Philips JB, Dickman HM, Resnick MB,
et al: Characteristics, mortality and outcome of
higher-birthweight infants who require intensive
care. Am J Obstet Gynecol 1984;149:875-879.
13. Sokoloff L: Biochemical mechanisms of the
action of thyroid hormones: Relationship to their
sity, Baltimore; Medical College of Virginia,
Richmond; New York Medical College; Pennsyl¬
vania Hospital, Philadelphia; University of Min¬
nesota, Minneapolis; University of Oregon, Port¬
land; University of Tennessee, Memphis; and the
Biometry and Field Studies Branch and the
Developmental Neurology Branch, National In¬
stitute of Neurological and Communicative Dis¬
orders and Stroke, Bethesda, Md.
We thank Charlotte Jackson, who did the com¬
puter programming for this study, Martha Gris-
wold, who performed computations, and Peggy
Shaw and Bea Dean, who prepared the manu¬
script.
Most of all, thanks are due to the parents and
children who participated in this study.
role in brain,
in Grave GD (ed): Thyroid Hor-
mones and Brain Development. New York,
Raven Press, 1977, pp 73-91.
14. Nunez J: Effects of thyroid hormones dur-
ing brain differentiation. Mol Cell Endocrinol
1984;27:125-132.
15. Schlumpf M, Lichtensteiger W: Drugs and
Hormones in Brain Development, Basel, Switz-
erland, S Karger AG, 1982.
16. Pfaff DW, McEwen BS: Actions of es-
trogens and progestins on nerve cells. Science
1983;219:808-814.
17. Hellman LM, Pritchard JA: Williams Ob-
stetrics, ed 14, New York, Appleton-Century\x=req-\
Crofts, 1971, p 267.
18. Snavely SR, Hodges GR: The neurotox-
icity of antibacterial agents. Ann Intern Med
1984;101:92-104.
19. Alberman E, Stanley F: Guidelines for the
epidemiologic approach, in Stanley F, Alberman
E (eds): The Epidemiology of the Cerebral Pal-
sies. Philadelphia, JB Lippincott Co, 1984, chap
14.

In Other AMA Journals

JAMA
Kawasaki Syndrome: Still a Mystery After 20 Years
D. M. Bell, MD (JAMA 1985;254:801)
Helping the Abused Child
D. A. Sargent, MD, JD (JAMA 1985;254:803)
The Accuracy of Experienced Physicians' Probability Estimates for Patients
With Sore Throats
R. M. Poses, MD; R. D. Cebul, MD; M. Collins, MD; S. S. Fager, MD (JAMA
1985;254:925-929)

Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 06/21/2015