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Antenatal Corticosteroids and Newborn Screening for Congenital Adrenal Hyperplasia
Jennifer L. King, MS;
John M. Naber, MS, JD;
Robert J. Hopkin, MD;
David R. Repaske, MD, PhD;
Laurie Bailey, MS;
Nancy D. Leslie, MD
Arch Pediatr Adolesc Med. 2001;155:1038-1042.
ABSTRACT
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Objective To assess the effect of reported corticosteroid exposure on neonatal
levels of 17-hydroxyprogesterone (17-OHP), the cortisol precursor used in
newborn screening for congenital adrenal hyperplasia, in newborns weighing
less than 2500 g at birth.
Design A retrospective study of newborns weighing less than 2500 g at birth
and exposed to corticosteroids as reported on their newborn screening card
compared with newborns weighing less than 2500 g at birth and reported as
not exposed to corticosteroids.
Methods Birth weight, gestational age, age at screening, special care information,
and name of screening hospital were obtained from newborn screening cards
for 16 115 newborns screened in Michigan during the first 3 months of
2000. Levels of 17-OHP, measured by fluoroimmunoassay, were obtained from
Michigan's Newborn Screening Program database.
Results The mean 17-OHP level for the 69 low-birth-weight newborns in the corticosteroid-exposed
group was 52 ng/mL, which was higher than that for the 771 low-birth-weight
newborns in the unexposed group (35 ng/mL) (P<.001).
Reported corticosteroid use did not decrease the number of expected borderline
positive screening results for congenital adrenal hyperplasia (P>.05). Levels of 17-OHP varied by birth weight in corticosteroid-exposed
and unexposed newborns.
Conclusions Corticosteroid exposure may not suppress screening 17-OHP levels. Therefore,
newborn screening should not be delayed in premature newborns because of antenatal
exposure to corticosteroids.
INTRODUCTION
CONGENITAL adrenal hyperplasia (CAH) refers to a clinical spectrum of
autosomal recessive disorders defined by a deficiency in an enzyme necessary
for cortisol biosynthesis from cholesterol in the adrenal gland.1, 2
The most common of the disorders, 21-hydroxylase deficiency, occurs in approximately
1 of 15 000 live births in the United States and accounts for more than
90% of CAH cases.3, 4, 5
Boys, in particular, with classic CAH are at risk for delayed diagnosis because
there are not any specific physical signs evident immediately after birth.5, 6 Newborn screening for CAH plays a major
role in identifying these affected infants before development of symptoms
or life-threatening biochemical abnormalities.7, 8
Newborn screening for CAH is accomplished by assaying for elevated levels
of 17-hydroxyprogesterone (17-OHP) on filter paper saturated with a heel stick
capillary blood sample. The feasibility of this method was first demonstrated
by Pang et al.9 Twenty states, including Michigan,
currently screen for CAH, and several states are considering adding the test
to their screening panel.10 A major difficulty
with CAH screening is that low-birth-weight newborns typically have higher
17-OHP levels than normal-birth-weight newborns. To avoid a high false-positive
rate when screening for CAH, many states have adopted weight-adjusted cutoffs.
For those states, the less a newborn weighs, the higher his or her 17-OHP
level needs to be to have a positive screening result.11
A further complicating factor in newborn CAH screening is that all fetuses
at risk of preterm delivery between 24 and 34 weeks' gestation are considered
candidates for antenatal corticosteroid treatment for fetal lung maturation
according to a consensus statement from the National Institutes of Health.12 Long-term maternal corticosteroid treatment suppresses
fetal 17-OHP levels, as maternal treatment with dexamethasone is successful
in preventing or minimizing virilization in most prenatally treated female
fetuses affected with CAH.13 A question that
remains to be answered is whether short-term maternal corticosteroid treatment
also suppresses 17-OHP levels, possibly invalidating the results of newborn
screening. Because in many states low-birth-weight infants need to have higher
17-OHP levels to have a positive screening result, if corticosteroid treatment
suppresses 17-OHP levels, a true-positive case of CAH may be missed. The purpose
of this study was to determine whether corticosteroid treatment as reported
on the newborn screening card significantly suppresses newborn 17-OHP levels.
MATERIALS AND METHODS
Data were obtained from Michigan's Newborn Screening Program in Lansing.
A total of 16 115 newborn screening cards, collected during January,
February, and March of 2000, were examined.
Michigan mandates screening for all newborns and recommends specimen
collection at an age older than 24 hours. The Michigan newborn screening card
requests information on the newborn's name, sex, hospital of birth, medical
record number, order of birth, birth date, specimen date, newborn's age in
hours, gestational weeks, birth weight, ethnic background, and demographic
information for the mother and for the physician responsible for newborn follow-up.
The mother's hepatitis B surface antigen test result and responses to 5 special
care questions labeled "antibiotics," "transfused," "type of feeding," "neonatal
intensive care unit/special care nursery," and "steroid treatment" are also
requested.
Initial newborn screening cards marked with a birth weight of less than
2500 g were included for analysis. Age at screening, birth weight, and gestational
age were recorded. The state laboratory's unique identifying sample number
was also recorded, as were the yes/no responses to the 5 special care questions.
Special note was made if the newborn's age in hours did not agree with the
data fields for birth date and specimen date. Newborn screening cards with
unsatisfactory blood samples because of specimen age, layering of blood, insufficient
or multiple applications of blood, presence of serum rings, or contamination
were excluded from the study.
Initial screening laboratory 17-OHP values were obtained from the Michigan
Newborn Screening Program database and matched with appropriate card information
using the laboratory's unique identifying sample number. Michigan uses the
Auto DELFIA system (Perkin Elmer Life Sciences, Wellesley, Mass), a fluoroimmunoassay,
to determine the 17-OHP values of dried blood spots from heel pricks on filter
paper. This method of screening is complicated by cross-reactivity that elevates
the apparent 17-OHP level.14 In this study,
"17-OHP level" refers to the apparent or measured level on dried blood spots.
Once 17-OHP levels were paired with the matching newborn screening card information,
the sample number was deleted from the study database to ensure confidentiality.
The hospital in which the newborn screening card was completed was obtained
from the mail sorting information included with each day's processed cards.
Hospitals that submitted 1 or more newborn screening cards with the steroid
treatment "yes" box checked during this study were contacted to ascertain
how they determined whether the steroid treatment box should be checked yes
or no.
Unless otherwise indicated, data were analyzed using 2-tailed t tests and  2 tests. Results were considered
significant at P<.05.
RESULTS
Of 16 115 newborn screening cards examined for possible inclusion
in this study, 1217 (7.6%) reported that the newborn weighed less than 2500
g at birth. Twenty-seven cards (2.2%) were excluded from the study because
of an unsatisfactory blood sample. Of the remaining 1190 cards, 840 (70.6%)
had the steroid treatment question completed. According to data recorded on
the newborn screening cards, 69 of those newborns (8.2%) were exposed to corticosteroids
and 771 (91.8%) were not. The mean 17-OHP level of the corticosteroid-exposed
group was 52 ng/mL, and the mean 17-OHP level of the unexposed group was 35
ng/mL (P<.001). Mean birth weight was 1365 g for
corticosteroid-exposed newborns and 2018 g for unexposed newborns (P<.001). Based on screening card information, there was no significant
difference in mean age at screening between the 2 groups (P>.05) (Table 1).
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Table 1. Comparison of Corticosteroid-Exposed and Unexposed Groups
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Figure 1 illustrates the range
of the data. Although gestational age and birth weight correlate with 17-OHP
levels, birth weight is a more accurate and measurable variable, so it is
frequently used in formulating stratified cutoffs. A 2-factor analysis of
variance was used to determine whether mean levels of 17-OHP for newborns
exposed to corticosteroids and those not exposed were statistically significantly
different from each other. One factor in this analysis was corticosteroid
exposure, and the second factor was birth-weight class (Table 2). Because the number of newborns in each of the categories
was uneven, the analysis of variance was run using a regression approach.
Mean levels of 17-OHP were not statistically different.
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17-Hydroxyprogesterone (17-OHP) levels vs gestational age for corticosteroid-exposed
(A) or -unexposed (B) newborns. Screening 17-OHP levels were grouped by reported
gestational age (solid symbols) as well as by no reported gestational age
(open symbols). A single newborn with confirmed congenital adrenal hyperplasia
is included in the unexposed group (indicated by the star). Borderline positive
screens are 100 to 149 ng/mL, and strong positive screens are greater than
or equal to 150 ng/mL.
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Table 2. Comparison of 17-Hydroxyprogesterone (17-OHP) Levels in 69
Corticosteroid-Exposed and 771 Unexposed Infants Stratified by Birth Weight
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Fifty-seven (83%) of the 69 corticosteroid-exposed newborns were born
in hospitals that reported routinely checking the mother's prenatal history
for antenatal corticosteroid exposure, as opposed to checking only the newborn's
record for antenatal or postnatal corticosteroid exposure. The mean 17-OHP
level and birth weight of these 57 corticosteroid-exposed newborns were 50
ng/mL and 1363 g, respectively. The values for unexposed newborns (n = 244)
born at these hospitals were 34 ng/mL and 2004 g, respectively. These results
were not statistically significantly different from the results discussed
earlier for all corticosteroid-exposed and unexposed newborns.
Eight of 35 newborns whose newborn screening cards indicated that they
had been exposed to corticosteroids but weighed less than 1300 g at birth
had borderline positive or strongly positive screening results for CAH, with
none confirmed as affected. Twelve of 82 comparable unexposed newborns had
positive screening results. This result is not significantly different based
on the 2 test (P>.05).
There were 2 confirmed cases of CAH reported to the Michigan Newborn
Screening Program during this study. One newborn was not included in the study
because the birth weight was greater than 2500 g. The other newborn was included
in the unexposed group. There were no corticosteroid-exposed newborns with
CAH in our study population.
COMMENT
The primary goal of newborn CAH screening is to prevent salt-wasting
deaths before diagnosis. Additional benefits include early detection of inappropriate
sex assignment of girls and prevention of premature epiphysial closure in
children with the simple virilizing variant, as well as prevention of other
consequences associated with delayed diagnosis.1, 15
Newborn screening for classic CAH is effective in lowering morbidity and mortality
rates associated with late diagnosis, particularly in boys.
One principle of screening is that there should be minimal, preferably
zero, false-negative test results. To achieve this, a small false-positive
rate is accepted. To minimize the high false-positive rate in newborn CAH
screening, most states that screen for CAH have implemented weight-adjusted
cutoffs. This practice has been successful in decreasing the number of false-positive
findings without any reports of false-negative findings.16
However, given that premature infants may receive corticosteroids in utero
to promote fetal lung maturation and that low-birth-weight newborns require
a higher 17-OHP level to have a positive screening result, this study investigated
whether corticosteroid exposure might suppress adrenal function enough to
cause affected newborns to be missed.
The benefits of antenatal corticosteroid treatment for fetal lung maturation
include a large reduction in early neonatal death, respiratory distress syndrome,
intraventricular hemorrhage, and necrotizing enterocolitis.12
Despite these benefits, corticosteroid therapy among eligible infants remained
low throughout the 1990s. Data from multiple sources17, 18
indicate that approximately 20% to 30% of eligible preterm infants received
antenatal corticosteroid therapy, although there was great variation in use
by institution. The present study found that of 315 newborns who weighed less
than 2000 g at birth and had the corticosteroid question answered on the newborn
screening card, 54 (17%) were exposed to corticosteroids. A study19 compiling 8 multicenter data sets found that corticosteroid
therapy was used most often in infants weighing less than 1250 g and for infants
of less than 31 weeks' gestation. In the present study, 30% of newborns weighing
less than 1250 g at birth were exposed to corticosteroids. This is consistent
with the literature.
Limited data are available on the effect of maternal corticosteroid
use on fetal and neonatal endocrine systems. Plasma cortisol levels have been
reported to be lower in preterm infants exposed to antenatal glucocorticoids
compared with preterm infants not exposed or exposed at least 7 days before
testing. These differences often have not been significant, particularly after
being corrected for multiple variables.20, 21
Teramo et al22 compared the serum cortisol
levels of 24-hour-old newborns who had been treated prenatally with betamethasone
with those of newborns treated with placebo. There was no difference between
cortisol levels in the groups, indicating that use of betamethasone did not
have a sustained effect on fetal cortisol concentration.
Even after repeated antenatal corticosteroid exposure, the neonatal
adrenal gland remains capable of secreting cortisol in response to corticotropin.
Terrone et al23 administered corticotropin
to neonates whose mothers had received 3 or more courses of betamethasone
to enhance fetal lung maturity. Although the sample size was small (n = 9),
the mean cortisol concentration after corticotropin stimulation increased
significantly in these infants.
In a small but well-controlled study, Dorr et al24
found no difference in plasma cortisol and 17-OHP levels 2 hours after birth
in low-birth-weight newborns who received 2 doses of antenatal betamethasone
compared with preterm newborns with uneventful histories who were not exposed
to corticosteroids.
Based on the works of Teramo22 and Dorr24 and their colleagues, it is not surprising that this
study found that corticosteroid treatment, as reported on the newborn screening
card, did not suppress 17-OHP levels. In fact, corticosteroid-exposed newborns
were more likely than unexposed newborns to have higher 17-OHP levels. One
explanation for this finding may be that smaller, more at-risk newborns in
utero are more likely to receive the treatment, and those newborns are also
more likely to have higher 17-OHP levels. This hypothesis is consistent with
the study's finding that corticosteroid-exposed newborns had a lower mean
birth weight than did unexposed newborns. Nevertheless, even when stratified
by birth weight, there is no evidence in this study that corticosteroid exposure
suppressed 17-OHP levels.
Premature infants are at particular risk of being missed in newborn
screening programs.25 Reasons for this may
include neonatal transfer, concern about specimen validity, and concern that
severe neonatal illness precludes screening. Despite these concerns, screening
remains potentially valuable in the low-birth-weight population, especially
because medical interventions or prematurity-related illness may mask clinical
symptoms.26 Delay of screening until recovery
of the adrenal axis does not seem to be justified, and it increases the likelihood
of a missed opportunity to screen.
A limitation of this study is that the newborn screening card does not
specify whether newborns or mothers received corticosteroid treatment, although
it would be unusual for this group of newborns to receive postnatal corticosteroids
in the first 3 days of life. Of hospitals that marked the steroid treatment
"yes" box on 1 or more newborn screening cards, 60% reported routinely checking
the mother's medical record to get the information. Currently, no Michigan
Department of Community Health instructions specifically defining "steroid
treatment" have been disseminated to the nurses or technicians filling out
newborn screening cards. Therefore, although the intent was to gather data
on antenatal exposure, and most birth hospitals reported use of antenatal
corticosteroids only, a small proportion of newborns may have been exposed
postnatally.
More problematic was that the newborn screening card steroid treatment
question was more likely to be left unanswered than were other special care
questions. This suggests that individuals completing the cards might not have
understood the question, chose not to answer the question, or did not have
the proper information readily available. The response to the neonatal intensive
care unit/special care nursery question was also omitted on 23.7% of the cards.
That question does not require any special information gathering. The high
rate of omitting these answers suggests that many individuals did not understand
the importance of the information requested. Newborn screening cards provide
a means to gather health information on a population basis, but clarity and
completeness are important for many applications.
CONCLUSIONS
In this study, newborns reportedly exposed to corticosteroids had screening
17-OHP levels similar to those of unexposed newborns when corrected for birth
weight. This suggests that corticosteroid exposure may not result in significant
adrenal suppression in neonates. We recommend that newborn screening specimens
be collected from all newborns regardless of corticosteroid exposure. Because
no data are available on the effect of limited maternal corticosteroid use
on affected newborns, false-negative results remain a potential concern. A
larger prospective study including maternal dose, timing of dose, and age
of newborns at screening should be done to confirm the results of this study.
This study also documented that special care information on the newborn
screening card is frequently omitted. Information requested on the cards is
important in interpreting the results of several screening tests. Education
emphasizing the importance of the newborn screening information and clarifying
what information should be recorded may be effective in increasing proper
card completion.
AUTHOR INFORMATION
Accepted for publication April 25, 2001.
We are grateful to Harry Hawkins at the Michigan Department of Community
Health Bureau of Laboratories Newborn Screening Section for his assistance
with data collection and to Judy Bean at the Cincinnati Children's Hospital
Medical Center for her statistical expertise.
What This Study Adds
Small studies of the effect of antenatal corticosteroid use on the neonatal
adrenal axis have demonstrated small and often transient effects on cortisol
and 17-OHP levels. However, few data are available on the effect of antenatal
corticosteroid use on 17-OHP levels measured in newborn screening for CAH.
If antenatal corticosteroid use significantly alters screening test results
for CAH, changes in timing or cutoffs would improve validity.
This study showed that reported corticosteroid exposure did not change
newborn 17-OHP concentration when corrected for birth weight. In exposed and
unexposed newborns, low birth weight is associated with increased 17-OHP levels
compared with birth weights greater than 2500 g. Results of this study suggest
that newborn screening should not be delayed in newborns exposed to antenatal
corticosteroids.
From the Genetic Counseling Program, College of Allied Health Sciences,
University of Cincinnati, Cincinnati, Ohio (Ms King); Newborn Screening Program,
State of Michigan, Lansing (Mr Naber); and the Divisions of Human Genetics
(Drs Hopkin and Leslie and Ms Bailey) and Endocrinology (Dr Repaske), Children's
Hospital Research Foundation, Cincinnati.
Corresponding author and reprints: Nancy D. Leslie, MD, Division
of Human Genetics, Children's Hospital Research Foundation, 3333 Burnet Ave,
Cincinnati, OH 45229 (e-mail: lesln0{at}chmcc.org).
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