Newborn Screening Protocols and Positive Predictive Value for Congenital Adrenal Hyperplasia Vary across the United States

Abstract

Newborn screening for congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is mandated throughout the US. Filter paper blood specimens are assayed for 17-hydroxyprogesterone (17OHP). Prematurity, low birth weight, or critical illness cause falsely elevated results. The purpose of this report is to highlight differences in protocols among US state laboratories. We circulated a survey to state laboratory directors requesting qualitative and quantitative information about individual screening programs. Qualitative and quantitative information provided by 17 state programs were available for analysis. Disease prevalence ranged from 1:9941 to 1:28,661 live births. Four state laboratories mandated a second screen regardless of the initial screening results; most others did so for infants in intensive care units. All but one program utilized birthweight cut-points, but cutoffs varied widely: 17OHP values of 25 to 75 ng/mL for birthweights >2250–2500 g. The positive predictive values for normal birthweight infants varied from 0.7% to 50%, with the highest predictive values based in two of the states with a mandatory second screen. Data were unavailable for negative predictive values. These data imply differences in sensitivity and specificity in CAH screening in the US. Standardization of newborn screening protocols could improve the positive predictive value.

Landscape of Congenital Adrenal Hyperplasia Newborn Screening in the United States

“…Of the information provided, in males, females and infants with unknown or unspecified biological sex, the final diagnosis was most commonly reported as Classic 21-hydroxylase deficiency (salt-wasting). This is in line with recent journal findings [ 17 ]. However, of the cases that did not provide data on biological sex, only one case had this as the final diagnosis; the remainder were identified as other adrenal disorders or data was not provided.…”

“…A recently published journal article noted the final status of CAH cases not being reported to state laboratories, and the need for quality improvement efforts to be directed at enhanced communication between clinicians and state laboratories, in addition to transparent reporting of states’ efforts on a national platform [ 17 ]. NewSTEPs data is in accordance with this finding, as NBS programs receive diagnoses back, but not necessarily detailed diagnostic level information.…”

Newborn Screening for Congenital Adrenal Hyperplasia: Review of Factors Affecting Screening Accuracy

“…17OHP is elevated in both preterm and sick newborns, and typically males have higher 17OHP concentrations than females [ 7 , 18 ]. These factors have lead laboratories to adjust cutoff values based upon the baby’s sex, birth weight and/or gestational age [ 19 , 20 , 21 , 22 , 23 , 24 ], yet in general, the positive predictive value remains low (on average less than 10%) for the first-tier immunoassay performed on specimens collected within the first two days of life [ 25 ]. Lastly, there are reports of missed cases of severe SW-CAH, because measured 17OHP concentrations were below set thresholds [ 26 ], suggesting that even lower cutoffs may be needed for the first-tier assay [ 27 ].…”

“…It has been well documented by many laboratories that the first-tier immunoassay used to measure 17OHP as an indicator of 21OHD generates a large number of false positive cases, leading to a low positive predictive value for the first-tier screen (estimated to be less than 10%) [ 25 ]. From our assessment, false positives can be attributed to five potential sources, which are outlined below.…”

“…In 2020, a nationwide US study comparing CAH screening protocols and outcomes, within a given year, was published [ 25 ]. The report included 17 states, of which 4 had a mandatory second screen.…”