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Neonatal screening for congenital adrenal hyperplasia: 17-hydroxyprogesterone levels and CYP21 genotypes in preterm
A Nordenström1, A Wedell, L Hagenfeldt
1Department of Pediatrics, Karolinska Institutet, Huddinge University Hospital, Sweden. anna.nordenstrom@klinvet.ki.se
Insights
Optimizing neonatal screening for congenital adrenal hyperplasia (CAH) in preterm infants involved adjusting 17-hydroxyprogesterone (17-OHP) cutoff levels. The study found omitting the extraction step improved recall times without compromising accuracy for preterm infants.
Area of Science:
- Neonatal Medicine
- Endocrinology
- Biochemistry
Background:
- Neonatal screening for congenital adrenal hyperplasia (CAH) is challenging in preterm infants due to elevated 17-hydroxyprogesterone (17-OHP) levels.
- Standard screening methods result in high false-positive rates among preterm infants, complicating diagnosis and management.
Purpose of the Study:
- To optimize the neonatal screening procedure for CAH specifically in preterm infants.
- To reduce false-positive results and improve the efficiency of CAH detection in this vulnerable population.
Main Methods:
- Analyzed 17-hydroxyprogesterone (17-OHP) levels in relation to gestational age in 6200 preterm infants.
- Evaluated recall rates using different 17-OHP cutoff levels with and without ether extraction.
- Assessed the impact of gestational age, neonatal stress, and prenatal glucocorticoid treatment on screening results.
Main Results:
- The ether extraction step did not significantly enhance screening sensitivity or specificity for CAH.
- Extraction delayed the recall process by a median of 5 days.
- No systematic influence of stress factors or prenatal glucocorticoid treatment on 17-OHP levels was observed.
Conclusions:
- The extraction step was omitted from the Swedish CAH screening program for preterm infants.
- New gestational age-specific cutoff levels were implemented: 400 nmol/L for infants <35 weeks and 150 nmol/L for infants 35-36 weeks.
- Neonatal screening cannot detect all CAH cases; milder forms still require clinical diagnosis.
Objective:
Neonatal screening for congenital adrenal hyperplasia (CAH) among preterm infants is complicated by the fact that healthy preterm infants have higher levels of 17-hydroxyprogesterone (17-OHP) than term infants, resulting in a higher false-positive rate. Even when gestational age-related cutoff levels after ether extraction were used, the false-positive cases primarily comprised preterm infants. The aim of the study was to optimize the procedure for neonatal screening for CAH in preterm infants.
Methods:
The 17-OHP levels in 6200 preterm infants were correlated to the gestational age. We also calculated the number of recalls for different putative cutoff levels of the 17-OHP by direct assay and after extraction in 1275 preterm infants who represented the most elevated cases in a population of approximately 30 000 preterm infants. The CYP21 genotypes and screening levels were determined in the 12 preterm infants with CAH diagnosed since the start of screening. The effect of possible interfering factors such as gestational age, neonatal stress, and prenatal glucocorticoid treatment for pulmonary maturation was studied.
Results:
The extraction procedure did not significantly improve the sensitivity or specificity of the screening, whereas it delayed the day of recall from 8 to 13 days (median). We could not demonstrate any systematic influence of the studied stress factors or the prenatal glucocorticoid treatment on the 17-OHP screening levels. In the patients with CAH, the 17-OHP levels correlated better with disease severity than with the degree of prematurity.
Conclusions:
On the basis of these results, we omitted the extraction step and changed the cutoff levels in the Swedish screening program for preterm infants. We chose to use a cutoff level of 400 nmol/L plasma in infants who were born before week 35 and 150 nmol/L for infants who were born in weeks 35 and 36. For detecting more patients, the cutoff level would have to be much lower, which would result in a number of false-positive tests that we consider to be unacceptably high. It is clear that neonatal screening cannot detect all infants with CAH. Some milder forms of the disease, just like in the past, will have to be diagnosed on the basis of clinical signs and symptoms.