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Clinical Impact and Cost Efficacy of Newborn Screening for Congenital Adrenal Hyperplasia
ORIGINAL ARTICLES Clinical Impact and Cost Efficacy of Newborn Screening for Congenital Adrenal Hyperplasia Danya A. Fox, MD, FRCPC, MPH1,*, Rebecca Ronsley, MD, FRCPC1,*, Asif R. Khowaja, PhD2, Alon Haim, MD3, Hilary Vallance, MD, FRCPC, FCCMG4, Graham Sinclair, PhD, FCCMG4, and Shazhan Amed, MD, FRCPC, MScPH1 Objectives To evaluate the clinical impact of a congenital adrenal hyperplasia (CAH) newborn screening program and incremental costs relative to benefits in screened vs unscreened infants. We hypothesized that screening would lead to clinical benefits and would be cost effective. Study design This was an ambispective cohort study at British Columbia Children’s Hospital, including infants diagnosed with CAH from 1988-2008 and 2010-2018. Data were collected retrospectively (unscreened cohort) and prospectively (screened cohort). Outcome measures included hospitalization, medical transport, and resuscitation requirements. The economic analysis was performed using a public payer perspective. Results Forty unscreened and 17 screened infants were diagnosed with CAH (47% vs 53% male). Median days to positive screen was 6 and age at diagnosis was 5 days (range, 0-30 days) and 6 days (range, 0-13 days) in unscreened and screened populations, respectively. In unscreened newborns, 55% required transport to a tertiary care hospital, 85% required hospitalization, and 35% required a fluid bolus compared with 29%, 29%, and 12% in screened infants, respectively. The cost of care was $33 770 per case in unscreened vs $17 726 in screened newborns. In the screened cohort, the incremental cost-effectiveness ratio was $290 in the best case analysis and $4786 in the base case analysis, per hospital day avoided. Conclusions Compared with unscreened newborns, those screened for CAH were less likely to require medical transport and had shorter hospital stays. Screening led to a decrease in hospitalization costs. Although screening did not result in cost savings, it was assessed to be cost effective considering the clinical benefits and incremental cost-effectiveness ratio. (J Pediatr 2020;-:1-8).
C
ongenital adrenal hyperplasia (CAH) is a group of autosomal-recessive conditions caused by an enzymatic defect in the adrenal gland leading to impaired cortisol synthesis. In Canada and the US, the incidence is estimated to be 1:15 000.1 More than 90% of cases result from a deficiency of 21-hydroxylase, an enzyme required for the synthesis of cortisol and aldosterone leading to an accumulation of steroid precursors, including 17a-hydroxyprogesterone (17OHP). CAH is subdivided into the salt wasting variant, defined by insufficient aldosterone production, and the simple virilizing variant, characterized by adequate aldosterone production, with a frequency of 75% and 25%, respectively.2 CAH may present in a salt wasting crisis, marked by dehydration, hyponatremia, hyperkalemia, and potentially shock. These crises generally occur in the first month of life and may be fatal if not treated promptly.3,4 In the US, newborn screening (NBS) for CAH is currently performed in all states.5 In Canada, 5 provinces and at least some regions of all 3 territories include CAH in their NBS programs. Several large studies have corroborated that screening leads to earlier diagnosis of CAH, particularly for males who lack the genital ambiguity that is typically easily identifiable in females.6-9 Despite this evidence, certain regions have left CAH out of their NBS programs, most notably the United Kingdom.10 Reasons include the high rate of false positives in premature newborns and the limited benefits of testing for females.11,12 Determining whether screening for CAH is cost effective may help NBS programs to make informed decisions as to whether the disease should be added to their panel. However, there are few published data on the cost efficacy of this screen.13-15 From the Department of Pediatrics, and School of The recent clinical practice guidelines for CAH highlight the paucity of knowlPopulation and Public Health, University of British edge in this field.16 The 2 studies cited had strikingly different results of Columbia; Pediatric Endocrinology Unit, Department of 1
2
3
Pediatrics, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and 4BC Newborn Screening Program, Department of Pathology and Laboratory Medicine, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada
BC CAH ICER ICU NBS 17OHP
British Columbia Congenital adrenal hyperplasia Incremental cost-effectiveness ratio Intensive care unit Newborn screening 17a-hydroxyprogesterone
*Contributed equally. Funded by a Department of Pediatrics Resident Research Grant, University of British Columbia, 2011. The funders had no role in any aspect of the study nor the preparation of the manuscript. The authors declare no conflict of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.12.057
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$20 000 and $255 700 - $292 000 per quality-adjusted lifeyear, leaving it unclear as to whether screening for CAH is cost effective.13,15 In British Columbia (BC), CAH was added to the NBS program in 2010. Through this study, we sought to evaluate the clinical impact of screening for CAH and the cost effectiveness by comparing cohorts of screened and unscreened newborns. We hypothesized that screening would result in clinical benefits and would be cost effective.
Methods BC Children’s Hospital is the only tertiary care hospital in the province of BC and is located in Vancouver, Canada. The division of endocrinology at the hospital is contacted by the NBS laboratory for every positive CAH screen. The endocrinologists at BC Children’s Hospital provide care to the majority of patients with CAH, although a small number of patients are managed by community endocrinologists. NBS Program This program covers BC, as well as the Yukon Territory (<1% of births annually). This represents an area of 1 427 178 km2. Approximately 45 000 newborns are screened annually through a blood spot card, ideally collected between 24 and 48 hours of age. If newborns are discharged before 24 hours of life, testing is completed before discharge and a repeat sample is requested before 2 weeks of age. For newborns born at home under the care of a midwife, the midwife is responsible for collecting the sample at the home, or sending the family to a nearby birthing hospital for collection within the 24- to 48-hour window. All NBS samples are shipped to BC Children’s Hospital for review. Samples are requested to be shipped within 24 hours of collection, and by a shipping method that ensures receipt by the laboratory within 72 hours of collection (see http://www.perinatalservicesbc.ca/Documents/ Guidelines-Standards/Newborn/NewbornScreeningGuideline. pdf for further details). The goal is to report results before 8 days of age. For CAH, this should allow for diagnosis before a salt wasting crisis develops. Achievement of these goals is variable. Between 2015 and 2017, 83%-88% of samples were collected before 48 hours of age and samples were received within 72 hours of collection for only 56%-59% of newborns. Reports were issued by day of life 8 for 69%-70% of newborns. The NBS program uses a 2-tiered method to screen for CAH. The initial screening test measures 17OHP using the AutoDELFIA Neo17OHP immunoassay (Perkin Elmer Canada Inc, Woodbridge, Ontario). Cut-offs for advancement to the second-tier test are based on age at sample collection (<72 hours or >72 hours) and birth weight (<1500 g, 15002500 g, >2500 g). The second-tier test uses the same NBS card and measures 17OHP, cortisol, androstenedione, 11deoxycortisol, and 21-deoxycortisol via tandem mass spectrometry (modified from Janzen et al).17 Cut-off values for 2
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a positive screen over the majority of the study period were based on the algorithm suggested by Janzen et al in 2007, using absolute 17OHP levels, and the ratio of (17OHP + 21deoxycortisol)/cortisol.17 In April 2017, the ratio was changed to 17OHP/11-deoxycortisol to reduce false positives from premature infants with nonspecific low cortisol levels. When the second test is above cut-off values, the newborn screen is deemed positive, and the endocrinologist on call at BC Children’s Hospital is contacted. Subsequently, the endocrinologist contacts the patient’s primary care provider, who, in turn communicates with the family. Depending on the clinical stability and location of the newborn, the child is either brought into a local hospital for review by a pediatrician or family physician, or sent directly to BC Children’s Hospital for an endocrinology consult, typically within 24 hours of a positive NBS result. A serum 17OHP, cortisol, and electrolytes are drawn at that time. Study Methodology This was an ambispective cohort study (including both retrospective and prospective components) and was approved by BC Children & Women’s Hospital Clinical Research Ethics Boards (H10-03225). Screening for CAH began in November 2010. Data were collected retrospectively on an unscreened cohort of infants diagnosed with CAH and followed by the BC Children’s Hospital Division of Endocrinology from 1988 to 2008. From November 2010 to March 2018, a screened cohort of all newly diagnosed cases of classic CAH were recruited to the study and clinical data were collected prospectively with written, informed consent from the families. When involved in patient care, community endocrinologists also contributed to data collection. Clinical data were collected from electronic and paper records. Age at diagnosis was defined as the age at the time of the first endocrine consult or telephone call where medical advice was provided. In the screened cohort, we recorded the time from birth to reporting of the positive screen (referred to as age at time of positive screen). The recall rate was defined as true-positive plus false-positive cases, divided by the total number of newborn screens performed. Statistical and Economic Analyses The unscreened cohort and screened cohort were compared using descriptive statistics. Variables were compared using t tests and c2 tests for linear and categorical variables, respectively. Costs to the health system included the NBS, patient transfers to BC Children’s Hospital (via ambulance or plane), hospitalization, and inpatient or outpatient consultation with the endocrinologist. Specific costs related to investigation of cases (ie, imaging, further blood tests) and treatment were not included. The cost of tier 1 screening included 170HP kits, Autodelfia instrument, and personnel time, and tier 2 screening included reagents, Tandem mass spectrometry (XEVO, Bellevue, Washington) instrument and personnel time. For false-positive cases, costs included the cost of serum steroid levels from a venipuncture sample Fox et al
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Table I. Infant demographics and physical examination and investigations at presentation Variables Subject demographics Male sex Reason for suspected CAH Ambiguous genitalia Family history Salt wasting crisis Positive CAH screen Abnormal electrolytes Age at time of positive screen Age at diagnosis Age at diagnosis for males Fluid bolus Physical examination and investigations at presentation Systolic blood pressure Diastolic blood pressure 17OHP mg/L* (nmol/L) Screened Unscreened Cortisol mg/dL* (nmol/L) Screened Unscreened Sodium mEq/L* (mmol/L) Screened Unscreened Sodium <132 mEq/L (132 mmol/L) Potassium mEq/L* (mmol/L) Screened Unscreened
Screened cohort (n = 17) 8 (47)
Unscreened cohort (n = 40) 21 (53)
6 (35) 1 (6) 0 (0) 10 (59) 0 (0) 6 (0-13) 6 (0-13) 5.5 (0-13) 2 (12)
19 (48) 9 (22) 10 (25) N/A 4 (10) N/A 5 (0-30) 14 (1-30) 14 (35)
74 (65-109) 56 (29-74)
77 (47-106) 45 (27-75)
72.70 (20.95-283.87) 220.2 (63.4-859)
P value .787 .289 <.001 <.001 <.001 .299 .077 .005 .357 .047 .018
152.84 (24.52-716.79) 462.5 (74.2-2169) .695
3.62 (3.23-3.91) 100 (89-108)
3.55 (3.04-4.02) 98 (84-111)
136 (125-144) 136 (125-144) 4 (25)
136 (106-145) 136 (106-145) 17 (43)
6.2 (4.3-8.5) 6.2 (4.3-8.5)
6.9 (3.7-10.3) 6.9 (3.7-10.3)
.270 .047 .302
Data are number (%) or median (range). Bolded values are significant at the level of <0.05. *Sample size in screened and unscreened, respectively: BP (n = 13, 34); 17OHP (n = 12, 38); cortisol (n = 8, 19); sodium (n = 16, 40); potassium (n = 16, 40).
(17-OHP, cortisol, and androstenedione), second blood spot card, and the cost of an endocrine consult (some consults were conducted via telephone). The information about unit costs of transport and hospitalization were collected from the Senior Financial Analyst for the Ambulance Service of our Health Authority (personal communication, Business Planning British Columbia Emergency Health Services Provincial Health Services Authority, August 2018) and the Performance Measurement Reporting of the Provincial Health Services Authority (personal communication, May 2018), respectively. The cost of an endocrine consultation was based on physician reimbursement rates for the provincial healthcare system. The capital costs (ie, device/equipment) were annualized over the expected life of 10 years. Costs are presented in Canadian dollars as of 2018. This study used a public payer perspective; therefore, costs incurred by the patient (ie, out-of-pocket costs, time away from work) were not included. A descriptive analysis was performed to compare the financial costs of CAH cases in the screened and unscreened cohort. A decision tree analytic model was used (Figure 1 and Figure 2; available at www.jpeds.com). An analysis of lifeyears saved was not considered because no deaths from CAH were documented in this cohort. A 1-way deterministic sensitivity analysis was used to evaluate the effect of key assumptions on the results. We evaluated change in disease incidence, false-positive rate, cost of inpatient hospitalization, and transfer-related costs. These changes were applied to the
screened cohort, whereas the variables for the unscreened cohort remained fixed. For the best case, we assumed the most favorable model input values (highest incidence, sensitivity, and specificity and lowest hospitalization and screening costs), worst case the least favorable model input values, and base case the most likely values. Because of small sample sizes, a probabilistic analysis was also conducted using Monte Carlo simulations to draw values at random from 10 000 iterations. The findings were reported as the incremental cost-effectiveness ratio (ICER), defined as the difference in cost between the screening program, compared with no screening, divided by the difference in their outcome (ie, length of stay). The ICER was estimated as: ICER = (Cscreen – Cno-screen)/(Oscreen – Ono-screen).
Results Based on data from the screened cohort of 17 cases in 331 671 infants screened, the incidence of CAH in BC and Yukon Territory is 1 in 19 510 (95% CI, 1/13 224-1/37 198) (based on Mid-P Exact Test Source: OpenEpi, Version 3: www. openepi.com). From 1988 to 2008, there were 40 unscreened infants diagnosed with CAH. From November 2010 to February 2018, there were 17 screened infants diagnosed with CAH. All families consented to participate in the study. Within the screened cohort, one newborn had simple virilizing CAH, and all others had salt wasting CAH.
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Table III. Comparing financial costs of CAH cases in the screened vs the unscreened group Screened (n = 17)
Variables (resource use) Inpatient hospitalization Any hospitalization Neonatal ICU/pediatric ICU General ward Both (neonatal ICU/ pediatric ICU, and general ward)‡ Outpatient consultation Endocrine consult (all CAH cases) Mode of hospital transfers Any hospital transfer Plane/ITT Road ambulance Sum of financial costs
Total No. of days/ Frequency, consults/ Unit cost n (%) trips
Total cost
Unscreened (n = 40) Average cost Frequency, (per case)* n (%)
– $4463 $2923 –
5 (29) 2 (12) 2 (12) 1 (6)
10 11 3
$44 630 $32 153 $11 849
$17 726
$193
17 (100)
17
$3281
$193
$3532 $1247
5 (29) 4 (24) 1 (6)
4 1
$14 128 $3075 $1247 $107 288 $20 994
Total No. of days/ consults/ trips
Total cost
Average Incremental cost cost† (per case)*
34 (85) – 30 (75) 4 (10)
– $944 129 $204 042
$33 770
323 54
40 (100)
40
$7720
$193
22 (55) 10 (25) 12 (30)
10 12
$35 320 $2286 $14 964 $1 206 175 $36 248
–
–$16 044
–
$789 –$15 254
ITT, infant transport team. *Average cost of children hospitalized in the general ward, neonatal ICU/pediatric ICU, or both (neonatal ICU/pediatric ICU and the general ward). †Weighted for length of stay in the general ward and neonatal ICU/pediatric ICU. ‡Screened, minus, unscreened; cost savings per case.
Over the study’s prospective screening period, 5.2% of the initial samples screened positive and advanced to the second-tier test. The recall rate was 0.04%. Out of the 104 false-positive cases, 93 infants were premature and 8 cases had no gestational age identified. The positive predictive value of the CAH screening program was 10% using the initial second tier algorithm (November 2010 to March 2017) and improved to 60% after the change in the steroid ratio (April 2017 to March 2018).
Subject demographics, physical examination, and laboratory measures are presented in Table I. Presenting systolic blood pressure was similar between screened and unscreened subjects, and diastolic blood pressure was significantly lower in the unscreened subjects. The median serum sodium at presentation was equivalent between the 2 groups; however, a greater proportion of unscreened patients presented with a sodium <132 mEq/L (<132 mmol/L) (25% vs 43%; P = .047). The median age
Table IV. Model input variables for CAH screening Variables Epidemiologic data CAH incidence Probability of death in newborns identified with CAH Screening test characteristics Sensitivity Tier 1 screening FP Tier 2 screening FP Health facility-level resource use Inpatient hospital admission of CAH in screened Inpatient hospital admission of CAH in unscreened Average costs (in Canadian Dollars; year of costing, 2018) Direct medical care costs Cost of tier 1 screening (per 1 specimen) Cost of tier 2 screening (per 1 specimen) Cost of repeat screening and/or bloodspot card (for FP cases) Cost of ambulatory care (ie, endoconsultation) (per consult) Cost of inpatient hospitalization in screened group* Cost of inpatient hospitalization in unscreened group* Direct nonmedical care costs† Cost of hospital transfer in screened group Cost of hospital transfer in unscreened group Outcomes Mean length of stay in screened group (days) Mean length of stay in unscreened group (days)
Base case
Range ± 25%
1/19 510 0
(1/36 000-1/13 000) NA
1 5.2% 0.7%
NA (3.9%-6.5%) (0.2%-2.0%)
29% 85%
(22%-37%) (64%-99%)
$2.7 $19 $91.1 $193 $17 726 $33 770
(2.0-3.4) (14.2-23.7) (63.3-113.6) (144.6-241.3) (13 295-22 158) (25 328-42 213)
$3075 $2286
(2306-3844) (1714-2857)
4.8 11.1
(3.6-6.0) (8.3-13.9)
FP, false positive; NA, not applicable. *Average cost of children hospitalized in the general ward, neonatal ICU/pediatric ICU and both (neonatal ICU/pediatric ICU, plus the general ward). †Average cost of children transferred in plane and road ambulance.
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at diagnosis was 5 days (range, 0-30 days) in the unscreened cohort and 6 days (range, 0-13 days) in the screened cohort (Table I). For the screened cohort, the median time from birth to positive screen was 6 days. When looking solely at males, the median age of diagnosis was 14 days without screening compared with 5.5 days with screening. Table II (available at www.jpeds.com) shows the parallel analysis of Table I for male subjects only. Within the screened cohort, 2 females were diagnosed by screening; 1 female was assigned a male sex at birth owing to the extent of her virilization and the other female had mild virilization that was missed clinically. All other females were diagnosed clinically based on the presence of ambiguous genitalia. Genetic testing for CAH-causing mutations was performed as clinically indicated. Medical care and screening costs are presented in Table III and Table IV. More newborns required hospital transfers and hospitalization in the unscreened cohort (55% and 85%, respectively) compared with the screened cohort (29% and 29%, respectively). The mean length of hospital stay was 11.1 25% (range, 8.3-13.9 days) in the unscreened cohort compared with 4.8 25% (range, 3.66.0) days in the screened cohort. Among screened patients, 11 of 24 (46%) of the total hospital days were spent in the neonatal intensive care unit (ICU) or pediatric ICU (for 3 infants). In the unscreened cohort, 28 of 577 (5%) of total hospital days were in the neonatal ICU or pediatric ICU (for 4 infants). A higher proportion of subjects in the unscreened cohort required a fluid bolus (35% compared with 12%). There were no deaths in either cohort. CAH NBS test sensitivity, screen costs, and costs of hospital stay and specialist consultation are presented in Table IV. The screen false-positive rate is calculated at 5.2% for tier 1, and 0.7% for tier 2 (overall 0.03% after both tiers). The estimated cost of tier 1 and tier 2 screening was $2.70 (per specimen) and $19.00 (per specimen), respectively. The overall cost of the NBS program per detected case is $73 690.51.
The average cost of inpatient hospitalization was higher at $33 770 per case in the unscreened cohort, compared with $17 726 per case in the screened cohort (including the combined cost of general ward, neonatal ICU, and pediatric ICU admissions). The total financial costs of the management of CAH cases (inpatient hospitalization, out-patient consultation, and transfers) was $107 288 in the screened cohort (n = 17), compared with $1 206 175 in the unscreened cohort (n = 40). When evaluating this immediate medical care in isolation, the overall mean difference of –$15 254 per case suggests cost savings in the screened cohort. The cost-effectiveness analysis is provided in Table V. The best case analysis revealed an ICER of $290 per hospital day avoided for the screened cohort undergoing tier 1 and tier 2 testing. The best case ICER was much higher ($10 742 per hospital day avoided) for the hypothetical scenario using only tier 1 testing, given the high false-positive rate. In the probabilistic analysis (ie, a Bayesian approach that assumes model input values in between the minimum and maximum of the range), the ICERs were $5837, and $39 088 per hospital day avoided in tier 1 and tier 2, and tier 1 only testing, respectively. When the incidence of CAH was assumed to be 1 in 36 000, the ICER increased to $11 215 per hospital day avoided (see sensitivity analysis, Table V). The ICER substantially decreased to $1973 per hospital day avoided when the incidence was hypothetically increased to 1 in 13 000. Other scenarios varying costs of hospitalization, transfers, and false-positive rate yielded no dramatic change in results.
Discussion In this study, we found that newborns with CAH in a screened and unscreened cohort had similar biochemical profiles, aside from a higher proportion of cases with a sodium of <132 mEq/L (<132 mmol/L) in the unscreened group. However, their clinical status seemed to differ, based on a lesser need for medical transport and fluid bolus, and shorter hospital length of stay in screened infants.
Table V. Cost-effectiveness analysis for screening of classic CAH Tier 1 and tier 2 screening Scenarios Base-case analysis Best case analysis* Worst case analysis Probabilistic analysis† One-way sensitivity analysis of base-case scenario (1) Incidence of CAH (2) Tier 1 false positive (3) Tier 2 false positive (4) Cost of inpatient hospitalization (per screened case) (5) Cost of transfer to hospital (per screened case)
Range – – – – 1/36 000-1/13 000 3.9%-6.5% 0.2%-2.0% $13 295-$22 158 $2306-$3844
Only tier 1 screening
Incremental cost per hospital day avoided (in Canadian Dollars) $4786 $290 $15 834 $5837
$34 071 $10 742 $78 847 $39 088
$11 215-$1973 $4207-$5365 $4629-$5194 $4785-$4786 $4785-$4786
$63 922-$21 011 $26 125-$42 047 NA $34 063-$34 078 $34 069-$34 072
*The best case represents most favorable values such as: highest incidence, highest screening sensitivity and specificity, lowest hospitalization costs, and lowest screening costs. †Bayesian approach (to address uncertainties across all input parameters in the base case) applied using Monte Carlo simulations in the TreeAge Pro 2018 (TreeAge Software, Williamstown, Massachusetts).
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Furthermore, there were no salt wasting crises in the screened cohort (as defined by a need for resuscitation), compared with 25% of subjects in the unscreened cohort. Our data demonstrate a significant decrease in treatment costs in subjects screened for CAH compared with those who were unscreened and diagnosed with CAH. Although this cost savings is offset by the cost of running the screening program (as evidenced by the positive ICER of $290 in the best case analysis and $4786 in the base case analysis, per hospital day avoided), we do feel that overall this cost is justified by the clinical benefit of the program. Hence, although this program may not result in cost savings, in our opinion, it is cost effective. The incidence of CAH in BC and Yukon Territory (1/ 19 510; 95% CI, 1/13 224-1/37 198) is comparable with several other parts of the world, including Tokyo, Texas, and the UK.14,18,19 Although the estimated worldwide incidence (approximately 1/14 000 to 1/18 000) is lower than the incidence we have reported, it falls within our 95% CI.16 Overall, 59% of infants with CAH were diagnosed by screening, similar to the 68% reported by Pang et al who reviewed >400 cases of CAH from around the world.20 Like others, we found that approximately 20% of females (2/9) were detected by screening, highlighting the importance of screening in both males and females.11,21 Notably, of the 17 cases of CAH in the screened cohort, only one had simple virilizing CAH, much lower than the expected 25% of cases.2 All endocrinologists caring for these patients were contacted at the end of the study period to reassess the salt wasting vs simple virilizing classification of their patients, at which point the 1 aforementioned case was reclassified as simple virilizing based on clinical course and medication use. It is possible that additional cases of simple virilizing CAH were missed by the screening program, or that other cases will be reclassified as simple virilizing CAH in the future. To date, no further cases have presented at our center since screening was introduced. Our recall rate was 0.04%, lower than most other centers.22 Gidl€ of et al summarized the recall rate of 18 programs, of which only 3 were lower than 0.04%.22 In our program, nearly all false positives were in premature babies (93/104 [89%] with an additional 8 screens missing gestational age). This observation led to a change in the algorithm in April 2017 to decrease false positives from premature infants with low cortisol levels, further decreasing the recall rate to 0.02% over the subsequent 12 months. To our knowledge, no cases of salt wasting or simple virilizing CAH were missed by the NBS program, unlike other center’s experiences.23 Our data demonstrate improved patient outcomes as a result of the CAH NBS program. Within those screened for CAH, there was a decrease in hospital length of stay. This finding is similar to the results of Brosnan et al, who compared 1.6 million screened newborns with an unscreened cohort and found a 7.5-day decrease in length of hospital stay in male screened newborns with CAH compared with unscreened male newborns.24 Moreover, we saw a decrease in 6
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the need for medical transport from community hospitals to BC Children’s Hospital, and fewer infants (proportionally) requiring a fluid bolus. Together, these findings suggest that the newborns in the unscreened group were sicker at the time of diagnosis. Our program addresses the World Health Organization basic tenets of NBS, including identifying a treatable condition when the newborn is asymptomatic and employing a test with a high sensitivity.25 However, 4 of 25 screened infants had a sodium of <132 mEq/L (<132 mmol/L) on initial laboratory testing, suggesting that salt wasting was in evolution. Furthermore, although screening reduced the time spent in hospital, it did not eliminate it, as has been reported in other studies, with 5 of 17 newborns still requiring hospitalization.14,26 One possible reason for this is delays in getting the NBS card to the laboratory given the wide geographical region covered by the screening program. Other centers have reported adrenal crises as a result of delays in NBS results,27 and salt wasting by the time the positive screen is resulted is not uncommon.21,26 The age at diagnosis was similar for the screened and unscreened cohorts, with a median of 6 days (range, 0-13 days) in the screened group and 5 days (range, 0-30 days) in the unscreened group. This finding differs from other centers that have shown that screening leads to earlier diagnosis.6,26 However, when looking at males alone, there is a marked difference in age at diagnosis (8.5 days). The median age at the time of a positive screen was 6 days, lower than many other centers. In New Zealand, the median was 8 days; Sweden’s program reported a mean of 8.7 days, and Texas a median of 13 days.11,14,22 Although our laboratory requests that all samples be sent off within 24 hours of collection by a means that ensures receipt at the laboratory within 72 hours, these goals are often unmet. Evidently, this process can have significant implications and is an area that can be targeted to improve the clinical usefulness and cost effectiveness of screening. In other CAH NBS studies, the authors have described various tactics to try and circumvent delays in results. For example, one center required the NBS cards be shipped overnight, and another provide fast-post prepaid envelopes, both of which would lead to earlier results.11,28 Although the median sodium values were similar across the groups, a higher proportion of infants had a sodium of <132 mEq/L (<132 mmol/L) in the unscreened cohort. Similarly, Van der Kamp et al found a significant improvement in sodium levels, with a median sodium of 127 mEq/L (127 mmol/L) in the unscreened group, compared with 135 mEq/L (135 mmol/L) in the screened group.26 Another study compared laboratory values for males only and reported a larger difference of 113 mEq/L (113 mmol/L) in the unscreened group vs 132 mEq/L (132 mmol/L) in the screened group.29 Further evidence of the biochemical differences, our unscreened cohort had significantly higher median 17OHP values compared with screened infants ([152.84 mg/L [462.5 nmol/L] vs 72.70 mg/L [220.2 nmol/L], respectively). The absence of a difference in cortisol values across the 2 Fox et al
- 2020 groups is expected because cortisol production is impaired from birth. There was a significant decrease in treatment costs once screening for CAH was instituted, when compared with treating CAH before screening. Three studies have assessed the cost efficacy of screening for CAH.13-15 Yoo and Grosse calculated an ICER of $255 700 to $292 000 per life-year.13 Because we had no deaths in our cohort, our ICER was calculated as the cost per hospital day avoided, making it difficult to compare results. They concluded that it was doubtful that screening for CAH would be cost effective unless favorable conditions existed, differing from our conclusion. The main limitation of their study was the use of secondary data. They reported that the mortality risk in unscreened infants is unclear, yet despite this finding, mortality was the only outcome in their analyses. Brosnan et al compared a 1-test and a 2-test screening system, where the second test was completed 1-2 weeks after birth.14 The incremental costs per newborn diagnosed with CAH was $115 169 in the single screen program vs $242 865 in a 2-screen program.14 The authors did not describe the economic model used, the standard discount rate was not applied, and they failed to perform a sensitivity analysis to account for uncertainties in cost and diagnostic performance, all notable methodologic shortcomings. The increased cost for the 2-test system is not surprising, because all infants were screened twice, with abnormal results reported from either screen to improve sensitivity. This differs from our 2-tier approach, where a second test is only applied to those considered high risk on the first tier; thus, far fewer tests are required. This methodology also decreased our false-positive rate, explaining our markedly lower ICER per hospital day avoided. Finally, in a base case analysis, Carroll et al found that CAH screening, compared with no screening, yielded an ICER of $20 357 per quality-adjusted life-year gained, which is considered to be cost effective by widely used standards (ie, less than willingness-to-pay threshold of $50 000 per quality-adjusted life-year).15 Our data suggest that the CAH NBS program not only leads to improved patient outcomes, but is also cost effective when second-tier testing is used to minimize the recall rate. Although there is no threshold definition for what is considered cost effective when describing ICERs, in our opinion, the clinical benefits of screening justify the costs. Moreover, we were unable to capture the other potential financial benefits for the families when a screening program exists. These benefits may include a decrease in lost wages, child care costs for siblings, and travel costs, to name a few. Hence, the NBS program may result in cost savings, if these other unmeasured factors were to be considered. Strengths of this study include that we were able to recruit all cases of CAH after NBS implementation and collect their data prospectively. Furthermore, in our economic analysis, we were able to compare 1-tier vs 2-tier testing. The main limitation of this study is the retrospective data collection in the unscreened cohort. Available data were not always complete. For example, age at diag-
ORIGINAL ARTICLES nosis was obtained using first contact with a medical provider by telephone. This item may not have been reliably recorded in the chart. Another limitation is that the prospective cohort is smaller relative to the retrospective cohort, limiting our ability to perform detailed statistical analyses. Additionally, steroid testing changed from immunoassay to mass spectrometry in 2011, the effects of which cannot be assessed. We have reported no deaths in the unscreened cohort, although there is always the possibility that a neonatal death owing to CAH was wrongly attributed to another cause. Finally, it is possible that the unscreened cohort did not include all cases of CAH in BC and the Yukon Territory. Although almost all children with CAH are managed at BC Children’s Hospital, it is possible that some patients in the unscreened cohort may have been diagnosed and managed by community endocrinologists. However, no cases would be missed in the screened cohort, because the endocrinologist on call at BC Children’s Hospital is contacted for every positive NBS. By comparing a screened and unscreened cohort, we have shown that the CAH NBS program in BC is a cost-effective strategy when a 2-tier screen is used. In addition to decreased treatment costs, clinical benefits of screening included shortened time to diagnosis in males, a decreased need for fluid resuscitation and medical transport, and a shortened hospital length of stay at the time of diagnosis. Future studies should explore whether screening leads to long-term health benefits, which may further enhance the positive impact of screening for CAH among newborns. n We thank Dr Daniel L. Metzger, MD, FAAP, FRCPC (Department of Pediatrics, University of British Columbia) for his assistance with the retrospective data collection. Submitted for publication Sep 5, 2019; last revision received Dec 6, 2019; accepted Dec 26, 2019. Reprint requests: Danya A. Fox, MD, FRCPC, MPH, Division of Endocrinology and Diabetes, B.C. Children’s Hospital, 4480 Oak St, ACB K4-213, Vancouver, BC V6H 3V4, Canada. E-mail: [email protected]
Data Statement Data sharing statement available at www.jpeds.com.
References 1. Pang S, Shook MK. Current status of neonatal screening for congenital adrenal hyperplasia. Curr Opin Pediatr 1997;9:419-23. 2. Pang SY, Wallace MA, Hofman L, Thuline HC, Dorche C, Lyon IC, et al. Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 1988;81: 866-74. 3. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21hydroxylase deficiency. Endocr Rev 2000;21:245-91. 4. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003;349:776-88. 5. White PC. Optimizing newborn screening for congenital adrenal hyperplasia. J Pediatr 2013;163:10-2. 6. Balsamo A, Cacciari E, Piazzi S, Cassio A, Bozza D, Pirazzoli P, et al. Congenital adrenal hyperplasia: neonatal mass screening compared
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with clinical diagnosis only in the Emilia-Romagna region of Italy, 19801995. Pediatrics 1996;98:362-7. Thilen A, Nordenstr€ om A, Hagenfeldt L, D€ obeln von U, Guthenberg C, Larsson A. Benefits of neonatal screening for congenital adrenal hyperplasia (21-hydroxylase deficiency) in Sweden. Pediatrics 1998;101: E11. Therrell BL, Berenbaum SA, Manter-Kapanke V, Simmank J, Korman K, Prentice L, et al. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 1998;101:583-90. White PC. Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol 2009;5:490-8. National Health Service (NHS). Newborn blood spot test; 2018. https://www. nhs.uk/conditions/pregnancy-and-baby/newborn-blood-spot-test/. Accessed March 19, 2019. Heather NL, Seneviratne SN, Webster D, Derraik JGB, Jefferies C, Carll J, et al. Newborn screening for congenital adrenal hyperplasia in New Zealand, 1994-2013. J Clin Endocrinol Metab 2015;100: 1002-8. Coulm B, Coste J, Tardy V, Ecosse E, Roussey M, Morel Y, et al. Efficiency of neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children born in mainland France between 1996 and 2003. Arch Pediatr Adolesc Med 2012;166:113-20. Yoo BK, Grosse SD. The cost effectiveness of screening newborns for congenital adrenal hyperplasia. Public Health Genomics 2009;12:67-72. Brosnan CA, Brosnan P, Therrell BL, Slater CH, Swint JM, Annegers JF, et al. A comparative cost analysis of newborn screening for classic congenital adrenal hyperplasia in Texas. Public Health Rep 1998;113: 170-8. Carroll AE, Downs SM. Comprehensive cost-utility analysis of newborn screening strategies. Pediatrics 2006;117:S287-95. Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2018;103:4043-88. Janzen N, Peter M, Sander S, Steuerwald U, Terhardt M, Holtkamp U, et al. Newborn screening for congenital adrenal hyperplasia: additional steroid profile using liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2007;92:2581-9.
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18. Tsuji A, Konishi K, Hasegawa S, Anazawa A, Onishi T, Ono M, et al. Newborn screening for congenital adrenal hyperplasia in Tokyo, Japan from 1989 to 2013: a retrospective population-based study. BMC Pediatr 2015;15:209. 19. Khalid JM, Oerton JM, Dezateux C, Hindmarsh PC, Kelnar CJ, Knowles RL. Incidence and clinical features of congenital adrenal hyperplasia in Great Britain. Arch Dis Child 2012;97:101-6. 20. Pang S, Clark A, Camargo Neto E, Giugliani R, Dean H, Winter J, et al. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: newborn screening and its relationship to the diagnosis and treatment of the disorder. Screening 1993;2:105-39. 21. Steigert M, Schoenle EJ, Biason-Lauber A, Torresani T. High reliability of neonatal screening for congenital adrenal hyperplasia in Switzerland. J Clin Endocrinol Metab 2002;87:4106-10. 22. Gidl€ of S, Wedell A, Guthenberg C, D€ obeln von U, Nordenstrom A. Nationwide neonatal screening for congenital adrenal hyperplasia in Sweden: a 26-year longitudinal prospective population-based study. JAMA Pediatr 2014;168:567-74. 23. Sarafoglou K, Banks K, Kyllo J, Pittock S, Thomas W. Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota. JAMA 2012;307:2371-4. 24. Brosnan PG, Brosnan CA, Kemp SF, Domek DB, Jelley DH, Blackett PR, et al. Effect of newborn screening for congenital adrenal hyperplasia. Arch Pediatr Adolesc Med 1999;153:1272-8. 25. Wilson JM, Jungner G. Principles and practice of screening for disease. Public health papers. Geneva, Switzerland: World Health Organization; 1968. 26. Van der Kamp HJ, Noordam K, Elvers B, Van Baarle M, Otten BJ, Verkerk PH. Newborn screening for congenital adrenal hyperplasia in the Netherlands. Pediatrics 2001;108:1320-4. 27. Odajima H, Hosono S, Kayama K, Yoshikawa K, Takahashi S. Congenital adrenal hyperplasia and violation of newborn screening procedures. Pediatr Int 2017;59:1107-8. 28. Pearce M, DeMartino L, McMahon R, Hamel R, Maloney B, Stansfield D-M, et al. Newborn screening for congenital adrenal hyperplasia in New York State. Mol Genet Metab Rep 2016;7:1-7. 29. Gleeson HK, Wiley V, Wilcken B, Elliott E, Cowell C, Thonsett M, et al. Two-year pilot study of newborn screening for congenital adrenal hyperplasia in New South Wales compared with nationwide case surveillance in Australia. J Paediatr Child Health 2008;44:554-9.
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Figure 1. Decision tree analytic model of tier 1 screening. T1 screen, tier 1 screening; #, 1-rate/probability; pHospunscreen, probability of hospitalization in unscreened; pHospscreen, probability of hospitalization in screened.
Figure 2. Decision tree analytic model of tier 1 and tier 2 screening. T1 screen, tier 1 screening; T2 screen, tier 2 screening; #, 1rate/probability; pHospunscreen, probability of hospitalization in unscreened; pHospscreen, probability of hospitalization in screened. Clinical Impact and Cost Efficacy of Newborn Screening for Congenital Adrenal Hyperplasia
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Table II. Male infant demographics and physical examination and investigations at presentation Variables
Screened cohort (n = 8)
Unscreened cohort (n = 21)
Demographics Reason for suspected CAH Ambiguous genitalia 0 (35) 0 (0) Family history 1 (6) 6 (29) Salt wasting crisis 0 (0) 8 (38) Positive CAH screen 7 (59) N/A Abnormal 0 (0) 4 (19) electrolytes Age at time of positive 5.5 (0-13) N/A screen Age at diagnosis 5.5 (0-13) 14 (1-30) Fluid bolus 0 (0) 11 (52) Physical examination and investigations at presentation Systolic blood 73 (67-107) 77 (47-106) pressure Diastolic blood 56 (29-74) 45 (27-75) pressure 17 OHP mg/L (nmol/L) Screened 90.13 (20.95-283.87) 170.77 (24.52-716.79) Unscreened 270.4 (63.4-859) 512.3 (74.2-2169) Cortisol mg/dL (nmol/L) Screened 3.62 (3.23-3.91) 3.55 (3.04-4.02) Unscreened 100 (89-108) 98 (84-111) Sodium mEq/L (mmol/L) 136 (125-144) 136 (106-145) Screened Unscreened 136 (125-144) 136 (106-145) Sodium <132 mEq/L 4 (25) 17 (43) (132 mmol/L) Potassium mEq/L (mmol/L) Screened 6.2 (4.3-8.5) 6.9 (3.7-10.3) Unscreened 6.2 (4.3-8.5) 6.9 (3.7-10.3) Data are number (%) or median (range).
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C
ongenital adrenal hyperplasia (CAH) is a group of autosomal-recessive conditions caused by an enzymatic defect in the adrenal gland leading to impaired cortisol synthesis. In Canada and the US, the incidence is estimated to be 1:15 000.1 More than 90% of cases result from a deficiency of 21-hydroxylase, an enzyme required for the synthesis of cortisol and aldosterone leading to an accumulation of steroid precursors, including 17a-hydroxyprogesterone (17OHP). CAH is subdivided into the salt wasting variant, defined by insufficient aldosterone production, and the simple virilizing variant, characterized by adequate aldosterone production, with a frequency of 75% and 25%, respectively.2 CAH may present in a salt wasting crisis, marked by dehydration, hyponatremia, hyperkalemia, and potentially shock. These crises generally occur in the first month of life and may be fatal if not treated promptly.3,4 In the US, newborn screening (NBS) for CAH is currently performed in all states.5 In Canada, 5 provinces and at least some regions of all 3 territories include CAH in their NBS programs. Several large studies have corroborated that screening leads to earlier diagnosis of CAH, particularly for males who lack the genital ambiguity that is typically easily identifiable in females.6-9 Despite this evidence, certain regions have left CAH out of their NBS programs, most notably the United Kingdom.10 Reasons include the high rate of false positives in premature newborns and the limited benefits of testing for females.11,12 Determining whether screening for CAH is cost effective may help NBS programs to make informed decisions as to whether the disease should be added to their panel. However, there are few published data on the cost efficacy of this screen.13-15 From the Department of Pediatrics, and School of The recent clinical practice guidelines for CAH highlight the paucity of knowlPopulation and Public Health, University of British edge in this field.16 The 2 studies cited had strikingly different results of Columbia; Pediatric Endocrinology Unit, Department of 1
2
3
Pediatrics, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel; and 4BC Newborn Screening Program, Department of Pathology and Laboratory Medicine, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada
BC CAH ICER ICU NBS 17OHP
British Columbia Congenital adrenal hyperplasia Incremental cost-effectiveness ratio Intensive care unit Newborn screening 17a-hydroxyprogesterone
*Contributed equally. Funded by a Department of Pediatrics Resident Research Grant, University of British Columbia, 2011. The funders had no role in any aspect of the study nor the preparation of the manuscript. The authors declare no conflict of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.12.057
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$20 000 and $255 700 - $292 000 per quality-adjusted lifeyear, leaving it unclear as to whether screening for CAH is cost effective.13,15 In British Columbia (BC), CAH was added to the NBS program in 2010. Through this study, we sought to evaluate the clinical impact of screening for CAH and the cost effectiveness by comparing cohorts of screened and unscreened newborns. We hypothesized that screening would result in clinical benefits and would be cost effective.
Methods BC Children’s Hospital is the only tertiary care hospital in the province of BC and is located in Vancouver, Canada. The division of endocrinology at the hospital is contacted by the NBS laboratory for every positive CAH screen. The endocrinologists at BC Children’s Hospital provide care to the majority of patients with CAH, although a small number of patients are managed by community endocrinologists. NBS Program This program covers BC, as well as the Yukon Territory (<1% of births annually). This represents an area of 1 427 178 km2. Approximately 45 000 newborns are screened annually through a blood spot card, ideally collected between 24 and 48 hours of age. If newborns are discharged before 24 hours of life, testing is completed before discharge and a repeat sample is requested before 2 weeks of age. For newborns born at home under the care of a midwife, the midwife is responsible for collecting the sample at the home, or sending the family to a nearby birthing hospital for collection within the 24- to 48-hour window. All NBS samples are shipped to BC Children’s Hospital for review. Samples are requested to be shipped within 24 hours of collection, and by a shipping method that ensures receipt by the laboratory within 72 hours of collection (see http://www.perinatalservicesbc.ca/Documents/ Guidelines-Standards/Newborn/NewbornScreeningGuideline. pdf for further details). The goal is to report results before 8 days of age. For CAH, this should allow for diagnosis before a salt wasting crisis develops. Achievement of these goals is variable. Between 2015 and 2017, 83%-88% of samples were collected before 48 hours of age and samples were received within 72 hours of collection for only 56%-59% of newborns. Reports were issued by day of life 8 for 69%-70% of newborns. The NBS program uses a 2-tiered method to screen for CAH. The initial screening test measures 17OHP using the AutoDELFIA Neo17OHP immunoassay (Perkin Elmer Canada Inc, Woodbridge, Ontario). Cut-offs for advancement to the second-tier test are based on age at sample collection (<72 hours or >72 hours) and birth weight (<1500 g, 15002500 g, >2500 g). The second-tier test uses the same NBS card and measures 17OHP, cortisol, androstenedione, 11deoxycortisol, and 21-deoxycortisol via tandem mass spectrometry (modified from Janzen et al).17 Cut-off values for 2
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a positive screen over the majority of the study period were based on the algorithm suggested by Janzen et al in 2007, using absolute 17OHP levels, and the ratio of (17OHP + 21deoxycortisol)/cortisol.17 In April 2017, the ratio was changed to 17OHP/11-deoxycortisol to reduce false positives from premature infants with nonspecific low cortisol levels. When the second test is above cut-off values, the newborn screen is deemed positive, and the endocrinologist on call at BC Children’s Hospital is contacted. Subsequently, the endocrinologist contacts the patient’s primary care provider, who, in turn communicates with the family. Depending on the clinical stability and location of the newborn, the child is either brought into a local hospital for review by a pediatrician or family physician, or sent directly to BC Children’s Hospital for an endocrinology consult, typically within 24 hours of a positive NBS result. A serum 17OHP, cortisol, and electrolytes are drawn at that time. Study Methodology This was an ambispective cohort study (including both retrospective and prospective components) and was approved by BC Children & Women’s Hospital Clinical Research Ethics Boards (H10-03225). Screening for CAH began in November 2010. Data were collected retrospectively on an unscreened cohort of infants diagnosed with CAH and followed by the BC Children’s Hospital Division of Endocrinology from 1988 to 2008. From November 2010 to March 2018, a screened cohort of all newly diagnosed cases of classic CAH were recruited to the study and clinical data were collected prospectively with written, informed consent from the families. When involved in patient care, community endocrinologists also contributed to data collection. Clinical data were collected from electronic and paper records. Age at diagnosis was defined as the age at the time of the first endocrine consult or telephone call where medical advice was provided. In the screened cohort, we recorded the time from birth to reporting of the positive screen (referred to as age at time of positive screen). The recall rate was defined as true-positive plus false-positive cases, divided by the total number of newborn screens performed. Statistical and Economic Analyses The unscreened cohort and screened cohort were compared using descriptive statistics. Variables were compared using t tests and c2 tests for linear and categorical variables, respectively. Costs to the health system included the NBS, patient transfers to BC Children’s Hospital (via ambulance or plane), hospitalization, and inpatient or outpatient consultation with the endocrinologist. Specific costs related to investigation of cases (ie, imaging, further blood tests) and treatment were not included. The cost of tier 1 screening included 170HP kits, Autodelfia instrument, and personnel time, and tier 2 screening included reagents, Tandem mass spectrometry (XEVO, Bellevue, Washington) instrument and personnel time. For false-positive cases, costs included the cost of serum steroid levels from a venipuncture sample Fox et al
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Table I. Infant demographics and physical examination and investigations at presentation Variables Subject demographics Male sex Reason for suspected CAH Ambiguous genitalia Family history Salt wasting crisis Positive CAH screen Abnormal electrolytes Age at time of positive screen Age at diagnosis Age at diagnosis for males Fluid bolus Physical examination and investigations at presentation Systolic blood pressure Diastolic blood pressure 17OHP mg/L* (nmol/L) Screened Unscreened Cortisol mg/dL* (nmol/L) Screened Unscreened Sodium mEq/L* (mmol/L) Screened Unscreened Sodium <132 mEq/L (132 mmol/L) Potassium mEq/L* (mmol/L) Screened Unscreened
Screened cohort (n = 17) 8 (47)
Unscreened cohort (n = 40) 21 (53)
6 (35) 1 (6) 0 (0) 10 (59) 0 (0) 6 (0-13) 6 (0-13) 5.5 (0-13) 2 (12)
19 (48) 9 (22) 10 (25) N/A 4 (10) N/A 5 (0-30) 14 (1-30) 14 (35)
74 (65-109) 56 (29-74)
77 (47-106) 45 (27-75)
72.70 (20.95-283.87) 220.2 (63.4-859)
P value .787 .289 <.001 <.001 <.001 .299 .077 .005 .357 .047 .018
152.84 (24.52-716.79) 462.5 (74.2-2169) .695
3.62 (3.23-3.91) 100 (89-108)
3.55 (3.04-4.02) 98 (84-111)
136 (125-144) 136 (125-144) 4 (25)
136 (106-145) 136 (106-145) 17 (43)
6.2 (4.3-8.5) 6.2 (4.3-8.5)
6.9 (3.7-10.3) 6.9 (3.7-10.3)
.270 .047 .302
Data are number (%) or median (range). Bolded values are significant at the level of <0.05. *Sample size in screened and unscreened, respectively: BP (n = 13, 34); 17OHP (n = 12, 38); cortisol (n = 8, 19); sodium (n = 16, 40); potassium (n = 16, 40).
(17-OHP, cortisol, and androstenedione), second blood spot card, and the cost of an endocrine consult (some consults were conducted via telephone). The information about unit costs of transport and hospitalization were collected from the Senior Financial Analyst for the Ambulance Service of our Health Authority (personal communication, Business Planning British Columbia Emergency Health Services Provincial Health Services Authority, August 2018) and the Performance Measurement Reporting of the Provincial Health Services Authority (personal communication, May 2018), respectively. The cost of an endocrine consultation was based on physician reimbursement rates for the provincial healthcare system. The capital costs (ie, device/equipment) were annualized over the expected life of 10 years. Costs are presented in Canadian dollars as of 2018. This study used a public payer perspective; therefore, costs incurred by the patient (ie, out-of-pocket costs, time away from work) were not included. A descriptive analysis was performed to compare the financial costs of CAH cases in the screened and unscreened cohort. A decision tree analytic model was used (Figure 1 and Figure 2; available at www.jpeds.com). An analysis of lifeyears saved was not considered because no deaths from CAH were documented in this cohort. A 1-way deterministic sensitivity analysis was used to evaluate the effect of key assumptions on the results. We evaluated change in disease incidence, false-positive rate, cost of inpatient hospitalization, and transfer-related costs. These changes were applied to the
screened cohort, whereas the variables for the unscreened cohort remained fixed. For the best case, we assumed the most favorable model input values (highest incidence, sensitivity, and specificity and lowest hospitalization and screening costs), worst case the least favorable model input values, and base case the most likely values. Because of small sample sizes, a probabilistic analysis was also conducted using Monte Carlo simulations to draw values at random from 10 000 iterations. The findings were reported as the incremental cost-effectiveness ratio (ICER), defined as the difference in cost between the screening program, compared with no screening, divided by the difference in their outcome (ie, length of stay). The ICER was estimated as: ICER = (Cscreen – Cno-screen)/(Oscreen – Ono-screen).
Results Based on data from the screened cohort of 17 cases in 331 671 infants screened, the incidence of CAH in BC and Yukon Territory is 1 in 19 510 (95% CI, 1/13 224-1/37 198) (based on Mid-P Exact Test Source: OpenEpi, Version 3: www. openepi.com). From 1988 to 2008, there were 40 unscreened infants diagnosed with CAH. From November 2010 to February 2018, there were 17 screened infants diagnosed with CAH. All families consented to participate in the study. Within the screened cohort, one newborn had simple virilizing CAH, and all others had salt wasting CAH.
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Table III. Comparing financial costs of CAH cases in the screened vs the unscreened group Screened (n = 17)
Variables (resource use) Inpatient hospitalization Any hospitalization Neonatal ICU/pediatric ICU General ward Both (neonatal ICU/ pediatric ICU, and general ward)‡ Outpatient consultation Endocrine consult (all CAH cases) Mode of hospital transfers Any hospital transfer Plane/ITT Road ambulance Sum of financial costs
Total No. of days/ Frequency, consults/ Unit cost n (%) trips
Total cost
Unscreened (n = 40) Average cost Frequency, (per case)* n (%)
– $4463 $2923 –
5 (29) 2 (12) 2 (12) 1 (6)
10 11 3
$44 630 $32 153 $11 849
$17 726
$193
17 (100)
17
$3281
$193
$3532 $1247
5 (29) 4 (24) 1 (6)
4 1
$14 128 $3075 $1247 $107 288 $20 994
Total No. of days/ consults/ trips
Total cost
Average Incremental cost cost† (per case)*
34 (85) – 30 (75) 4 (10)
– $944 129 $204 042
$33 770
323 54
40 (100)
40
$7720
$193
22 (55) 10 (25) 12 (30)
10 12
$35 320 $2286 $14 964 $1 206 175 $36 248
–
–$16 044
–
$789 –$15 254
ITT, infant transport team. *Average cost of children hospitalized in the general ward, neonatal ICU/pediatric ICU, or both (neonatal ICU/pediatric ICU and the general ward). †Weighted for length of stay in the general ward and neonatal ICU/pediatric ICU. ‡Screened, minus, unscreened; cost savings per case.
Over the study’s prospective screening period, 5.2% of the initial samples screened positive and advanced to the second-tier test. The recall rate was 0.04%. Out of the 104 false-positive cases, 93 infants were premature and 8 cases had no gestational age identified. The positive predictive value of the CAH screening program was 10% using the initial second tier algorithm (November 2010 to March 2017) and improved to 60% after the change in the steroid ratio (April 2017 to March 2018).
Subject demographics, physical examination, and laboratory measures are presented in Table I. Presenting systolic blood pressure was similar between screened and unscreened subjects, and diastolic blood pressure was significantly lower in the unscreened subjects. The median serum sodium at presentation was equivalent between the 2 groups; however, a greater proportion of unscreened patients presented with a sodium <132 mEq/L (<132 mmol/L) (25% vs 43%; P = .047). The median age
Table IV. Model input variables for CAH screening Variables Epidemiologic data CAH incidence Probability of death in newborns identified with CAH Screening test characteristics Sensitivity Tier 1 screening FP Tier 2 screening FP Health facility-level resource use Inpatient hospital admission of CAH in screened Inpatient hospital admission of CAH in unscreened Average costs (in Canadian Dollars; year of costing, 2018) Direct medical care costs Cost of tier 1 screening (per 1 specimen) Cost of tier 2 screening (per 1 specimen) Cost of repeat screening and/or bloodspot card (for FP cases) Cost of ambulatory care (ie, endoconsultation) (per consult) Cost of inpatient hospitalization in screened group* Cost of inpatient hospitalization in unscreened group* Direct nonmedical care costs† Cost of hospital transfer in screened group Cost of hospital transfer in unscreened group Outcomes Mean length of stay in screened group (days) Mean length of stay in unscreened group (days)
Base case
Range ± 25%
1/19 510 0
(1/36 000-1/13 000) NA
1 5.2% 0.7%
NA (3.9%-6.5%) (0.2%-2.0%)
29% 85%
(22%-37%) (64%-99%)
$2.7 $19 $91.1 $193 $17 726 $33 770
(2.0-3.4) (14.2-23.7) (63.3-113.6) (144.6-241.3) (13 295-22 158) (25 328-42 213)
$3075 $2286
(2306-3844) (1714-2857)
4.8 11.1
(3.6-6.0) (8.3-13.9)
FP, false positive; NA, not applicable. *Average cost of children hospitalized in the general ward, neonatal ICU/pediatric ICU and both (neonatal ICU/pediatric ICU, plus the general ward). †Average cost of children transferred in plane and road ambulance.
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at diagnosis was 5 days (range, 0-30 days) in the unscreened cohort and 6 days (range, 0-13 days) in the screened cohort (Table I). For the screened cohort, the median time from birth to positive screen was 6 days. When looking solely at males, the median age of diagnosis was 14 days without screening compared with 5.5 days with screening. Table II (available at www.jpeds.com) shows the parallel analysis of Table I for male subjects only. Within the screened cohort, 2 females were diagnosed by screening; 1 female was assigned a male sex at birth owing to the extent of her virilization and the other female had mild virilization that was missed clinically. All other females were diagnosed clinically based on the presence of ambiguous genitalia. Genetic testing for CAH-causing mutations was performed as clinically indicated. Medical care and screening costs are presented in Table III and Table IV. More newborns required hospital transfers and hospitalization in the unscreened cohort (55% and 85%, respectively) compared with the screened cohort (29% and 29%, respectively). The mean length of hospital stay was 11.1 25% (range, 8.3-13.9 days) in the unscreened cohort compared with 4.8 25% (range, 3.66.0) days in the screened cohort. Among screened patients, 11 of 24 (46%) of the total hospital days were spent in the neonatal intensive care unit (ICU) or pediatric ICU (for 3 infants). In the unscreened cohort, 28 of 577 (5%) of total hospital days were in the neonatal ICU or pediatric ICU (for 4 infants). A higher proportion of subjects in the unscreened cohort required a fluid bolus (35% compared with 12%). There were no deaths in either cohort. CAH NBS test sensitivity, screen costs, and costs of hospital stay and specialist consultation are presented in Table IV. The screen false-positive rate is calculated at 5.2% for tier 1, and 0.7% for tier 2 (overall 0.03% after both tiers). The estimated cost of tier 1 and tier 2 screening was $2.70 (per specimen) and $19.00 (per specimen), respectively. The overall cost of the NBS program per detected case is $73 690.51.
The average cost of inpatient hospitalization was higher at $33 770 per case in the unscreened cohort, compared with $17 726 per case in the screened cohort (including the combined cost of general ward, neonatal ICU, and pediatric ICU admissions). The total financial costs of the management of CAH cases (inpatient hospitalization, out-patient consultation, and transfers) was $107 288 in the screened cohort (n = 17), compared with $1 206 175 in the unscreened cohort (n = 40). When evaluating this immediate medical care in isolation, the overall mean difference of –$15 254 per case suggests cost savings in the screened cohort. The cost-effectiveness analysis is provided in Table V. The best case analysis revealed an ICER of $290 per hospital day avoided for the screened cohort undergoing tier 1 and tier 2 testing. The best case ICER was much higher ($10 742 per hospital day avoided) for the hypothetical scenario using only tier 1 testing, given the high false-positive rate. In the probabilistic analysis (ie, a Bayesian approach that assumes model input values in between the minimum and maximum of the range), the ICERs were $5837, and $39 088 per hospital day avoided in tier 1 and tier 2, and tier 1 only testing, respectively. When the incidence of CAH was assumed to be 1 in 36 000, the ICER increased to $11 215 per hospital day avoided (see sensitivity analysis, Table V). The ICER substantially decreased to $1973 per hospital day avoided when the incidence was hypothetically increased to 1 in 13 000. Other scenarios varying costs of hospitalization, transfers, and false-positive rate yielded no dramatic change in results.
Discussion In this study, we found that newborns with CAH in a screened and unscreened cohort had similar biochemical profiles, aside from a higher proportion of cases with a sodium of <132 mEq/L (<132 mmol/L) in the unscreened group. However, their clinical status seemed to differ, based on a lesser need for medical transport and fluid bolus, and shorter hospital length of stay in screened infants.
Table V. Cost-effectiveness analysis for screening of classic CAH Tier 1 and tier 2 screening Scenarios Base-case analysis Best case analysis* Worst case analysis Probabilistic analysis† One-way sensitivity analysis of base-case scenario (1) Incidence of CAH (2) Tier 1 false positive (3) Tier 2 false positive (4) Cost of inpatient hospitalization (per screened case) (5) Cost of transfer to hospital (per screened case)
Range – – – – 1/36 000-1/13 000 3.9%-6.5% 0.2%-2.0% $13 295-$22 158 $2306-$3844
Only tier 1 screening
Incremental cost per hospital day avoided (in Canadian Dollars) $4786 $290 $15 834 $5837
$34 071 $10 742 $78 847 $39 088
$11 215-$1973 $4207-$5365 $4629-$5194 $4785-$4786 $4785-$4786
$63 922-$21 011 $26 125-$42 047 NA $34 063-$34 078 $34 069-$34 072
*The best case represents most favorable values such as: highest incidence, highest screening sensitivity and specificity, lowest hospitalization costs, and lowest screening costs. †Bayesian approach (to address uncertainties across all input parameters in the base case) applied using Monte Carlo simulations in the TreeAge Pro 2018 (TreeAge Software, Williamstown, Massachusetts).
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Furthermore, there were no salt wasting crises in the screened cohort (as defined by a need for resuscitation), compared with 25% of subjects in the unscreened cohort. Our data demonstrate a significant decrease in treatment costs in subjects screened for CAH compared with those who were unscreened and diagnosed with CAH. Although this cost savings is offset by the cost of running the screening program (as evidenced by the positive ICER of $290 in the best case analysis and $4786 in the base case analysis, per hospital day avoided), we do feel that overall this cost is justified by the clinical benefit of the program. Hence, although this program may not result in cost savings, in our opinion, it is cost effective. The incidence of CAH in BC and Yukon Territory (1/ 19 510; 95% CI, 1/13 224-1/37 198) is comparable with several other parts of the world, including Tokyo, Texas, and the UK.14,18,19 Although the estimated worldwide incidence (approximately 1/14 000 to 1/18 000) is lower than the incidence we have reported, it falls within our 95% CI.16 Overall, 59% of infants with CAH were diagnosed by screening, similar to the 68% reported by Pang et al who reviewed >400 cases of CAH from around the world.20 Like others, we found that approximately 20% of females (2/9) were detected by screening, highlighting the importance of screening in both males and females.11,21 Notably, of the 17 cases of CAH in the screened cohort, only one had simple virilizing CAH, much lower than the expected 25% of cases.2 All endocrinologists caring for these patients were contacted at the end of the study period to reassess the salt wasting vs simple virilizing classification of their patients, at which point the 1 aforementioned case was reclassified as simple virilizing based on clinical course and medication use. It is possible that additional cases of simple virilizing CAH were missed by the screening program, or that other cases will be reclassified as simple virilizing CAH in the future. To date, no further cases have presented at our center since screening was introduced. Our recall rate was 0.04%, lower than most other centers.22 Gidl€ of et al summarized the recall rate of 18 programs, of which only 3 were lower than 0.04%.22 In our program, nearly all false positives were in premature babies (93/104 [89%] with an additional 8 screens missing gestational age). This observation led to a change in the algorithm in April 2017 to decrease false positives from premature infants with low cortisol levels, further decreasing the recall rate to 0.02% over the subsequent 12 months. To our knowledge, no cases of salt wasting or simple virilizing CAH were missed by the NBS program, unlike other center’s experiences.23 Our data demonstrate improved patient outcomes as a result of the CAH NBS program. Within those screened for CAH, there was a decrease in hospital length of stay. This finding is similar to the results of Brosnan et al, who compared 1.6 million screened newborns with an unscreened cohort and found a 7.5-day decrease in length of hospital stay in male screened newborns with CAH compared with unscreened male newborns.24 Moreover, we saw a decrease in 6
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the need for medical transport from community hospitals to BC Children’s Hospital, and fewer infants (proportionally) requiring a fluid bolus. Together, these findings suggest that the newborns in the unscreened group were sicker at the time of diagnosis. Our program addresses the World Health Organization basic tenets of NBS, including identifying a treatable condition when the newborn is asymptomatic and employing a test with a high sensitivity.25 However, 4 of 25 screened infants had a sodium of <132 mEq/L (<132 mmol/L) on initial laboratory testing, suggesting that salt wasting was in evolution. Furthermore, although screening reduced the time spent in hospital, it did not eliminate it, as has been reported in other studies, with 5 of 17 newborns still requiring hospitalization.14,26 One possible reason for this is delays in getting the NBS card to the laboratory given the wide geographical region covered by the screening program. Other centers have reported adrenal crises as a result of delays in NBS results,27 and salt wasting by the time the positive screen is resulted is not uncommon.21,26 The age at diagnosis was similar for the screened and unscreened cohorts, with a median of 6 days (range, 0-13 days) in the screened group and 5 days (range, 0-30 days) in the unscreened group. This finding differs from other centers that have shown that screening leads to earlier diagnosis.6,26 However, when looking at males alone, there is a marked difference in age at diagnosis (8.5 days). The median age at the time of a positive screen was 6 days, lower than many other centers. In New Zealand, the median was 8 days; Sweden’s program reported a mean of 8.7 days, and Texas a median of 13 days.11,14,22 Although our laboratory requests that all samples be sent off within 24 hours of collection by a means that ensures receipt at the laboratory within 72 hours, these goals are often unmet. Evidently, this process can have significant implications and is an area that can be targeted to improve the clinical usefulness and cost effectiveness of screening. In other CAH NBS studies, the authors have described various tactics to try and circumvent delays in results. For example, one center required the NBS cards be shipped overnight, and another provide fast-post prepaid envelopes, both of which would lead to earlier results.11,28 Although the median sodium values were similar across the groups, a higher proportion of infants had a sodium of <132 mEq/L (<132 mmol/L) in the unscreened cohort. Similarly, Van der Kamp et al found a significant improvement in sodium levels, with a median sodium of 127 mEq/L (127 mmol/L) in the unscreened group, compared with 135 mEq/L (135 mmol/L) in the screened group.26 Another study compared laboratory values for males only and reported a larger difference of 113 mEq/L (113 mmol/L) in the unscreened group vs 132 mEq/L (132 mmol/L) in the screened group.29 Further evidence of the biochemical differences, our unscreened cohort had significantly higher median 17OHP values compared with screened infants ([152.84 mg/L [462.5 nmol/L] vs 72.70 mg/L [220.2 nmol/L], respectively). The absence of a difference in cortisol values across the 2 Fox et al
- 2020 groups is expected because cortisol production is impaired from birth. There was a significant decrease in treatment costs once screening for CAH was instituted, when compared with treating CAH before screening. Three studies have assessed the cost efficacy of screening for CAH.13-15 Yoo and Grosse calculated an ICER of $255 700 to $292 000 per life-year.13 Because we had no deaths in our cohort, our ICER was calculated as the cost per hospital day avoided, making it difficult to compare results. They concluded that it was doubtful that screening for CAH would be cost effective unless favorable conditions existed, differing from our conclusion. The main limitation of their study was the use of secondary data. They reported that the mortality risk in unscreened infants is unclear, yet despite this finding, mortality was the only outcome in their analyses. Brosnan et al compared a 1-test and a 2-test screening system, where the second test was completed 1-2 weeks after birth.14 The incremental costs per newborn diagnosed with CAH was $115 169 in the single screen program vs $242 865 in a 2-screen program.14 The authors did not describe the economic model used, the standard discount rate was not applied, and they failed to perform a sensitivity analysis to account for uncertainties in cost and diagnostic performance, all notable methodologic shortcomings. The increased cost for the 2-test system is not surprising, because all infants were screened twice, with abnormal results reported from either screen to improve sensitivity. This differs from our 2-tier approach, where a second test is only applied to those considered high risk on the first tier; thus, far fewer tests are required. This methodology also decreased our false-positive rate, explaining our markedly lower ICER per hospital day avoided. Finally, in a base case analysis, Carroll et al found that CAH screening, compared with no screening, yielded an ICER of $20 357 per quality-adjusted life-year gained, which is considered to be cost effective by widely used standards (ie, less than willingness-to-pay threshold of $50 000 per quality-adjusted life-year).15 Our data suggest that the CAH NBS program not only leads to improved patient outcomes, but is also cost effective when second-tier testing is used to minimize the recall rate. Although there is no threshold definition for what is considered cost effective when describing ICERs, in our opinion, the clinical benefits of screening justify the costs. Moreover, we were unable to capture the other potential financial benefits for the families when a screening program exists. These benefits may include a decrease in lost wages, child care costs for siblings, and travel costs, to name a few. Hence, the NBS program may result in cost savings, if these other unmeasured factors were to be considered. Strengths of this study include that we were able to recruit all cases of CAH after NBS implementation and collect their data prospectively. Furthermore, in our economic analysis, we were able to compare 1-tier vs 2-tier testing. The main limitation of this study is the retrospective data collection in the unscreened cohort. Available data were not always complete. For example, age at diag-
ORIGINAL ARTICLES nosis was obtained using first contact with a medical provider by telephone. This item may not have been reliably recorded in the chart. Another limitation is that the prospective cohort is smaller relative to the retrospective cohort, limiting our ability to perform detailed statistical analyses. Additionally, steroid testing changed from immunoassay to mass spectrometry in 2011, the effects of which cannot be assessed. We have reported no deaths in the unscreened cohort, although there is always the possibility that a neonatal death owing to CAH was wrongly attributed to another cause. Finally, it is possible that the unscreened cohort did not include all cases of CAH in BC and the Yukon Territory. Although almost all children with CAH are managed at BC Children’s Hospital, it is possible that some patients in the unscreened cohort may have been diagnosed and managed by community endocrinologists. However, no cases would be missed in the screened cohort, because the endocrinologist on call at BC Children’s Hospital is contacted for every positive NBS. By comparing a screened and unscreened cohort, we have shown that the CAH NBS program in BC is a cost-effective strategy when a 2-tier screen is used. In addition to decreased treatment costs, clinical benefits of screening included shortened time to diagnosis in males, a decreased need for fluid resuscitation and medical transport, and a shortened hospital length of stay at the time of diagnosis. Future studies should explore whether screening leads to long-term health benefits, which may further enhance the positive impact of screening for CAH among newborns. n We thank Dr Daniel L. Metzger, MD, FAAP, FRCPC (Department of Pediatrics, University of British Columbia) for his assistance with the retrospective data collection. Submitted for publication Sep 5, 2019; last revision received Dec 6, 2019; accepted Dec 26, 2019. Reprint requests: Danya A. Fox, MD, FRCPC, MPH, Division of Endocrinology and Diabetes, B.C. Children’s Hospital, 4480 Oak St, ACB K4-213, Vancouver, BC V6H 3V4, Canada. E-mail: [email protected]
Data Statement Data sharing statement available at www.jpeds.com.
References 1. Pang S, Shook MK. Current status of neonatal screening for congenital adrenal hyperplasia. Curr Opin Pediatr 1997;9:419-23. 2. Pang SY, Wallace MA, Hofman L, Thuline HC, Dorche C, Lyon IC, et al. Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 1988;81: 866-74. 3. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21hydroxylase deficiency. Endocr Rev 2000;21:245-91. 4. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003;349:776-88. 5. White PC. Optimizing newborn screening for congenital adrenal hyperplasia. J Pediatr 2013;163:10-2. 6. Balsamo A, Cacciari E, Piazzi S, Cassio A, Bozza D, Pirazzoli P, et al. Congenital adrenal hyperplasia: neonatal mass screening compared
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with clinical diagnosis only in the Emilia-Romagna region of Italy, 19801995. Pediatrics 1996;98:362-7. Thilen A, Nordenstr€ om A, Hagenfeldt L, D€ obeln von U, Guthenberg C, Larsson A. Benefits of neonatal screening for congenital adrenal hyperplasia (21-hydroxylase deficiency) in Sweden. Pediatrics 1998;101: E11. Therrell BL, Berenbaum SA, Manter-Kapanke V, Simmank J, Korman K, Prentice L, et al. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 1998;101:583-90. White PC. Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol 2009;5:490-8. National Health Service (NHS). Newborn blood spot test; 2018. https://www. nhs.uk/conditions/pregnancy-and-baby/newborn-blood-spot-test/. Accessed March 19, 2019. Heather NL, Seneviratne SN, Webster D, Derraik JGB, Jefferies C, Carll J, et al. Newborn screening for congenital adrenal hyperplasia in New Zealand, 1994-2013. J Clin Endocrinol Metab 2015;100: 1002-8. Coulm B, Coste J, Tardy V, Ecosse E, Roussey M, Morel Y, et al. Efficiency of neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children born in mainland France between 1996 and 2003. Arch Pediatr Adolesc Med 2012;166:113-20. Yoo BK, Grosse SD. The cost effectiveness of screening newborns for congenital adrenal hyperplasia. Public Health Genomics 2009;12:67-72. Brosnan CA, Brosnan P, Therrell BL, Slater CH, Swint JM, Annegers JF, et al. A comparative cost analysis of newborn screening for classic congenital adrenal hyperplasia in Texas. Public Health Rep 1998;113: 170-8. Carroll AE, Downs SM. Comprehensive cost-utility analysis of newborn screening strategies. Pediatrics 2006;117:S287-95. Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2018;103:4043-88. Janzen N, Peter M, Sander S, Steuerwald U, Terhardt M, Holtkamp U, et al. Newborn screening for congenital adrenal hyperplasia: additional steroid profile using liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2007;92:2581-9.
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18. Tsuji A, Konishi K, Hasegawa S, Anazawa A, Onishi T, Ono M, et al. Newborn screening for congenital adrenal hyperplasia in Tokyo, Japan from 1989 to 2013: a retrospective population-based study. BMC Pediatr 2015;15:209. 19. Khalid JM, Oerton JM, Dezateux C, Hindmarsh PC, Kelnar CJ, Knowles RL. Incidence and clinical features of congenital adrenal hyperplasia in Great Britain. Arch Dis Child 2012;97:101-6. 20. Pang S, Clark A, Camargo Neto E, Giugliani R, Dean H, Winter J, et al. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: newborn screening and its relationship to the diagnosis and treatment of the disorder. Screening 1993;2:105-39. 21. Steigert M, Schoenle EJ, Biason-Lauber A, Torresani T. High reliability of neonatal screening for congenital adrenal hyperplasia in Switzerland. J Clin Endocrinol Metab 2002;87:4106-10. 22. Gidl€ of S, Wedell A, Guthenberg C, D€ obeln von U, Nordenstrom A. Nationwide neonatal screening for congenital adrenal hyperplasia in Sweden: a 26-year longitudinal prospective population-based study. JAMA Pediatr 2014;168:567-74. 23. Sarafoglou K, Banks K, Kyllo J, Pittock S, Thomas W. Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota. JAMA 2012;307:2371-4. 24. Brosnan PG, Brosnan CA, Kemp SF, Domek DB, Jelley DH, Blackett PR, et al. Effect of newborn screening for congenital adrenal hyperplasia. Arch Pediatr Adolesc Med 1999;153:1272-8. 25. Wilson JM, Jungner G. Principles and practice of screening for disease. Public health papers. Geneva, Switzerland: World Health Organization; 1968. 26. Van der Kamp HJ, Noordam K, Elvers B, Van Baarle M, Otten BJ, Verkerk PH. Newborn screening for congenital adrenal hyperplasia in the Netherlands. Pediatrics 2001;108:1320-4. 27. Odajima H, Hosono S, Kayama K, Yoshikawa K, Takahashi S. Congenital adrenal hyperplasia and violation of newborn screening procedures. Pediatr Int 2017;59:1107-8. 28. Pearce M, DeMartino L, McMahon R, Hamel R, Maloney B, Stansfield D-M, et al. Newborn screening for congenital adrenal hyperplasia in New York State. Mol Genet Metab Rep 2016;7:1-7. 29. Gleeson HK, Wiley V, Wilcken B, Elliott E, Cowell C, Thonsett M, et al. Two-year pilot study of newborn screening for congenital adrenal hyperplasia in New South Wales compared with nationwide case surveillance in Australia. J Paediatr Child Health 2008;44:554-9.
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Figure 1. Decision tree analytic model of tier 1 screening. T1 screen, tier 1 screening; #, 1-rate/probability; pHospunscreen, probability of hospitalization in unscreened; pHospscreen, probability of hospitalization in screened.
Figure 2. Decision tree analytic model of tier 1 and tier 2 screening. T1 screen, tier 1 screening; T2 screen, tier 2 screening; #, 1rate/probability; pHospunscreen, probability of hospitalization in unscreened; pHospscreen, probability of hospitalization in screened. Clinical Impact and Cost Efficacy of Newborn Screening for Congenital Adrenal Hyperplasia
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Table II. Male infant demographics and physical examination and investigations at presentation Variables
Screened cohort (n = 8)
Unscreened cohort (n = 21)
Demographics Reason for suspected CAH Ambiguous genitalia 0 (35) 0 (0) Family history 1 (6) 6 (29) Salt wasting crisis 0 (0) 8 (38) Positive CAH screen 7 (59) N/A Abnormal 0 (0) 4 (19) electrolytes Age at time of positive 5.5 (0-13) N/A screen Age at diagnosis 5.5 (0-13) 14 (1-30) Fluid bolus 0 (0) 11 (52) Physical examination and investigations at presentation Systolic blood 73 (67-107) 77 (47-106) pressure Diastolic blood 56 (29-74) 45 (27-75) pressure 17 OHP mg/L (nmol/L) Screened 90.13 (20.95-283.87) 170.77 (24.52-716.79) Unscreened 270.4 (63.4-859) 512.3 (74.2-2169) Cortisol mg/dL (nmol/L) Screened 3.62 (3.23-3.91) 3.55 (3.04-4.02) Unscreened 100 (89-108) 98 (84-111) Sodium mEq/L (mmol/L) 136 (125-144) 136 (106-145) Screened Unscreened 136 (125-144) 136 (106-145) Sodium <132 mEq/L 4 (25) 17 (43) (132 mmol/L) Potassium mEq/L (mmol/L) Screened 6.2 (4.3-8.5) 6.9 (3.7-10.3) Unscreened 6.2 (4.3-8.5) 6.9 (3.7-10.3) Data are number (%) or median (range).
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