Fifty years of newborn screening for congenital hypothyroidism: current status in Australasia and the case for harmonisation.

OBJECTIVES: Since its implementation 50 years ago in Quebec, Canada, newborn screening for congenital hypothyroidism has become one of the most successful public health measures worldwide. Screening programmes across Australia and New Zealand are characterised by significant commonalities in screening algorithms, and a high degree of regional cooperation in harmonisation efforts. We aimed to conduct a comprehensive survey of current performance and practices related to the total testing process for congenital hypothyroidism screening and provide recommendations for harmonisation priorities within our region. METHODS: A survey was conducted involving the six newborn screening laboratories which provide complete geographic coverage across Australasia. Approximately 360,000 newborns are screened annually. Survey questions incorporated pre-analytical, analytical, and post-analytical aspects of the screening programmes and an extensive 5-year (2016-2020) retrospective analysis of individual programme performance data. Responses from individual screening programmes were collated. RESULTS: The uptake of newborn screening was over 98% for the six major jurisdictions. All programmes have adopted a single-tier thyroid stimulating hormone (TSH) strategy using the Perkin Elmer GSP instrument. Significant similarities exist between programmes for recommended age of collection and recollection protocols for low birthweight newborns. The process for the determination of TSH cutoffs varies between programmes. TSH lower cut-offs for borderline-positive and positive notifications between 12-15 and 12-25 mIU/L blood, respectively. Recall rates vary between 0.08 and 0.20%. The case definition for congenital hypothyroidism generally includes biochemical and radiological parameters in addition to the commencement of thyroxine. All programmes reported collecting biochemical and clinical data on infants with positive screening tests, and positive predictive values vary between 23.6 and 77.3%. Variation in reported incidence (1:1,300-2,000) cannot be entirely explained by cutoff or recall rate (although one programme reporting fewer cases includes only permanent disease). CONCLUSIONS: Despite similarities between newborn screening algorithms for congenital hypothyroidism across Australia and New Zealand, differences in reported programme performance provide the basis for further harmonisation. Surveillance of a large population offers the potential for the ongoing development of evidence-based screening guidelines.

Implementing steroid profiling by liquid chromatography-tandem mass spectrometry improves newborn screening for congenital adrenal hyperplasia in New Zealand.

OBJECTIVE: To evaluate the impact of a liquid chromatography-tandem mass spectrometry (LCMSMS) second-tier test on newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) in New Zealand. DESIGN: In a prospective study, a LCMSMS method to measure 17-hydroxyprogesterone (17OHP) was adapted to measure four additional steroids. Steroid concentrations were collected on all second-tier CAH screening tests while protocols remained unchanged. Steroid ratio parameters with recommended or published screening cuts-offs were evaluated for their impact on newborn screening performance. MEASUREMENTS: Precision, accuracy, linearity and recovery of the second-tier LCMSMS method were evaluated. Second-tier specimens were divided in 3 groups; newborn screening bloodspots from neonates with confirmed CAH (n = 7) and 2 groups specimens from neonates with a birthweight (BW) ≤1500 g (n = 795) and with a BW > 1500 g (n = 806) with a negative newborn screening test. Six protocols using four steroid ratio parameters were evaluated. The sensitivity, specificity, false positive rate and positive predictive value of screening was calculated for each protocol. RESULTS: The LCMSMS method was sufficiently accurate and precise to be used as a second-tier test for CAH. Screening sensitivity remained at 100% for each protocol apart from (17OHP + androstenedione)/cortisol when the highest cut-off of 3.75 was applied. The false positive rate was significantly improved when (17OHP + androstenedione)/cortisol and (17OHP + 21-deoxycortisol)/cortisol were evaluated with cut-offs of 2.5 and 1.5 respectively (P < .01) and both with a positive predictive value of 64%. CONCLUSIONS: A second-tier LCMSMS newborn screening test for CAH offers significant improvements to screening specificity without any other changes to screening protocols.

Plasma ammonia concentrations in extremely low birthweight infants in the first week after birth: secondary analysis from the ProVIDe randomized clinical trial.

BACKGROUND: Little is known about normative ammonia concentrations in extremely low birthweight (ELBW) babies and whether these vary with birth characteristics. We aimed to determine ammonia concentrations in ELBW babies in the first week after birth and relationships with neonatal characteristics and protein intake. METHODS: Arterial blood samples for the measurement of plasma ammonia concentration were collected within 7 days of birth from ProVIDe trial participants in six New Zealand neonatal intensive care units. RESULTS: Three hundred and twenty-two babies were included. Median (range) gestational age was 25.7 (22.7-31.6) weeks. Median (interquartile range (IQR)) ammonia concentration was 102 (80-131) µg/dL. There were no statistically significant associations between ammonia concentrations and birthweight or sex. Ammonia concentrations were weakly correlated with mean total (Spearman's rs = 0.11, P = 0.047) and intravenous (rs = 0.13, P = 0.02) protein intake from birth, gestational age at birth (rs = -0.13, P = 0.02) and postnatal age (rs = -0.13, P = 0.02). CONCLUSIONS: Plasma ammonia concentrations in ELBW babies are similar to those of larger and more mature babies and only weakly correlated with protein intake. Currently, recommended thresholds for investigation of hyperammonaemia are appropriate for ELBW babies. Protein intake should not be limited by concerns about potential hyperammonaemia.

Pulse oximetry screening in a midwifery-led maternity setting with high antenatal detection of congenital heart disease.

AIM: To assess local and individual factors that should be considered in the design of a pulse oximetry screening strategy in New Zealand's midwifery-led maternity setting. METHODS: An intervention study was conducted over 2 years. Three hospitals and four primary maternity units participated in the study. Post-ductal saturation levels were measured on well infants with a gestation of ≥35 weeks. Infant activity and age (hours) at the time of the test were recorded. RESULTS: Screening was performed on 16 644 of 27 172 (61%) eligible infants. The age at which the screening algorithm was initiated varied significantly among centres. The probability of achieving a pass result (saturations ≥95%) in the context of no underlying pathology ranged from .94 for an unsettled infant screened <4 hours of age to .99 (P < .001) when the test was performed after 24 hours on a settled infant. Forty-eight (0.3%) infants failed to reach saturation targets: 37 had significant pathology of which three had cardiac disease. CONCLUSION: Screening practices were influenced by the setting in which it was undertaken. Infant activity and age at the time of testing can influence saturation levels. Screening is associated with the identification of significant non-cardiac pathology.

The impact of demographic factors on newborn TSH levels and congenital hypothyroidism screening.

CONTEXT: Optimal newborn screening thyroid-stimulating hormone (TSH) cut-offs are contentious. Analysis of demographic factors that impact screen TSH levels may help explain international variance and provide guidance to screening programmes. OBJECTIVE: To determine the influence of demographic factors on newborn screening TSH levels and screening performance parameters. DESIGN AND SETTING: National, retrospective population study using blood spot TSH cards from the New Zealand newborn screening programme in 2010-2015. PATIENTS: 325 685 blood spot cards. MAIN OUTCOME MEASURES: Likelihood of exceeding specific TSH thresholds (TSH ≥5, ≥10 and ≥15 mIU/L) and group-specific screening performance parameters. RESULTS: The likelihood of high TSH levels differed between ethnic groups. Pacific Island infants were more than twice as likely to have high-normal TSH levels (≥5 and ≥10 mIU/L) and nearly twice as likely to have a positive screen (≥15 mIU/L) as New Zealand Europeans. Maori or Chinese ethnicity, male sex, younger gestational age and greater socio-economic deprivation scores were also associated with high-normal TSH levels. At a TSH threshold ≥15 mIU/L, screening sensitivity was lowest (88.89% vs 95.83% overall) and PPV greatest (88.89% vs 62.84%) amongst Asian infants. Early samples were more than three times as likely to reach the screen-positive threshold and more likely to yield a false-positive result (PPV 20.00% vs 68.87%, P = 0.004). CONCLUSIONS: Newborn TSH levels are impacted by a number of demographic variables, particularly ethnicity and age at sample collection. Screening performance may be improved through the use of targeted thresholds.

The decision to discontinue screening for carnitine uptake disorder in New Zealand.

When screening for carnitine uptake disorder (CUD), the New Zealand (NZ) newborn screening (NBS) service identified infants as screen-positive if they had initial and repeat free carnitine (C0) levels of less than 5.0 µmol/L. Since 2006, the NBS service has identified two infants with biochemical and genetic features consistent with neonatal CUD and nine mothers with features consistent with maternal CUD. A review of the literature suggests that these nine women reflect less than half the true prevalence and that CUD is relatively common. However, the NZ results (two infants) suggest a very low sensitivity and positive predictive value of NBS. While patients presenting with significant disease due to CUD are well described, the majority of adults with CUD are asymptomatic. Nonetheless, treatment with high-dose oral L-carnitine is recommended. Compliance with oral L-carnitine is likely to be poor long term. This may represent a specific risk as treatment could repress the usual compensatory mechanisms seen in CUD, such that a sudden discontinuation of treatment may be dangerous. L-carnitine is metabolized to trimethylamine-N-oxide (TMAO) and treated patients have extremely high plasma TMAO levels. TMAO is an independent risk factor for atherosclerosis and, thus, caution should be exercised regarding long-term treatment with high-dose carnitine of asymptomatic patients who may have a biochemical profile without disease. Due to these concerns, the NZ Newborn Metabolic Screening Programme (NMSP) initiated a review via a series of advisory and governance committees and decided to discontinue screening for CUD.

Evaluation of the revised New Zealand national newborn screening protocol for congenital hypothyroidism.

OBJECTIVE: The aim of this study was to assess the performance of the revised New Zealand (NZ) newborn screening TSH cut-offs for congenital hypothyroidism (CHT). METHODS: Screening data over 24 months were obtained from the NZ newborn metabolic screening programme, which utilizes a 2-tier system of direct clinical referral for infants with markedly elevated TSH, and second samples from those with mild TSH elevation. We evaluated the impact of a reduced TSH threshold (50 to 30 mIU/l blood) for direct notification and a lower cut-off (15 to 8 mIU/l blood) applied to second samples and babies older than 14 days. RESULTS: In 2013 and 2014, 117 528 infants underwent newborn screening for CHT. Fifty-two CHT cases were identified by screening (47 general newborn population, five repeat testing in low-birth-weight infants) and one case was missed. Thirty-two infants with screening TSH ≥30 mIU/l were directly referred at a median of 9 days (5-14) and 15 with TSH 15-29 mIU/l were referred after a second sample at a median of 20 days (9-52, P < 0·001). All directly referred infants were confirmed as CHT cases with no earlier referrals as a result of the reduced threshold. The lower TSH cut-off applied to second samples lead to the identification of six extra cases of CHT (15% increase) from seven extra clinical referrals. CONCLUSIONS: The NZ screening programme achieved a 15% increase in CHT case detection for minimal increase in workload or anxiety for families of healthy infants. A further decrease in the threshold for direct referral may allow earlier diagnoses.

The natural history of elevated tetradecenoyl-L-carnitine detected by newborn screening in New Zealand: implications for very long chain acyl-CoA dehydrogenase deficiency screening and treatment.

Very long chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM #201475) has been increasingly diagnosed since the advent of expanded newborn screening (NBS). Elevated levels of tetradecenoyl-L-carnitine (C14:1) in newborn screening blood spot samples are particularly common in New Zealand, however this has not translated into increased VLCADD clinical presentations. A high proportion of screen-positive cases in NZ are of Maori or Pacific ethnicity and positive for the c.1226C > T (p.Thr409Met) ACADVL gene variant. We performed a retrospective, blinded, case-control study of 255 cases, born between 2006 and 2013, with elevated NBS C14:1 levels between 0.9 and 2.4 µmol/L, below the NZ C14:1 notification cut-off of 2.5 µmol/L. Coded healthcare records were audited for cases and age- and ethnicity- matched controls. The clinical records of those with possible VLCADD-related symptoms were reviewed. The follow-up period was 6 months to 7 years. Two of 247 cases (0.8 %) had possible VLCADD-like symptoms while four of 247 controls (2 %) had VLCADD-like symptoms (p = 0.81). Maori were overrepresented (68 % of the cohort vs 15 % of population). Targeted analysis of the c.1226 locus revealed the local increase in screening C14:1 levels is associated with the c.1226C > T variant (97/152 alleles tested), found predominantly in Maori and Pacific people. There was no increase in clinically significant childhood disease, irrespective of ethnicity. The study suggests that children with elevated C14:1, between 0.9-2.4 µmol/L, on NBS are at very low risk of clinically significant childhood disease. A minimally interventional approach to managing these patients is indicated, at least in the New Zealand population.

The use of liquid chromatography-tandem mass spectrometry in newborn screening for congenital adrenal hyperplasia: improvements and future perspectives.

Newborn screening for congenital adrenal hyperplasia using 17-hydroxyprogesterone by immunoassay remains controversial despite screening been available for almost 40 years. Screening is confounded by poor immunoassay specificity, fetal adrenal physiology, stress, and illness which can result in a large number of false positive screening tests. Screening programmes apply higher screening thresholds based on co-variates such as birthweight or gestational age but the false positive rate using immunoassay remains high. Mass spectrometry was first applied to newborn screening for congenital adrenal hyperplasia over 15 years ago. Elevated 17-hydroxprogesterone by immunoassay can be retested with a specific liquid chromatography tandem mass spectrometry assay that may include additional steroid markers. Laboratories register with quality assurance programme providers to ensure accurate steroid measurements. This has led to improvements in screening but there are additional costs and added laboratory workload. The search for novel steroid markers may inform further improvements to screening. Studies have shown that 11-oxygenated androgens are elevated in untreated patients and that the adrenal steroidogenesis backdoor pathway is more active in babies with congenital adrenal hyperplasia. There is continual interest in 21-deoxycortisol, a specific marker of 21-hydroxylase deficiency. The measurement of androgenic steroids and their precursors by liquid chromatography tandem mass spectrometry in bloodspots may inform improvements for screening, diagnosis, and treatment monitoring. In this review, we describe how liquid chromatography tandem mass spectrometry has improved newborn screening for congenital adrenal hyperplasia and explore how future developments may inform further improvements to screening and diagnosis.

The risk of classical galactosaemia in newborns with borderline galactose metabolites on newborn screening.

Newborn screening (NBS) for classical galactosaemia (CG) facilitates early diagnosis and treatment to prevent life-threatening complications, but remains controversial, and screening protocols vary widely between programmes. False-negatives associated with first-tier screening of total galactose metabolites (TGAL) are infrequently reported; however, newborns with TGAL below the screening threshold have not been systematically studied. Following the diagnosis of CG in two siblings missed by NBS, a retrospective cohort study of infants with TGAL just below the cut-off (1.5 mmol/L blood) was conducted. Children born in New Zealand (NZ) from 2011 to 2019, with TGAL 1.0-1.49 mmol/L on NBS were identified from the national metabolic screening programme (NMSP) database, and clinical coding data and medical records were reviewed. GALT sequencing was performed if CG could not be excluded following review of medical records. 328 infants with TGAL 1.0-1.49 mmol/L on NBS were identified, of whom 35 had ICD-10 codes relevant to CG including vomiting, poor feeding, weight loss, failure to thrive, jaundice, hepatitis, Escherichia coli urinary tract infection, sepsis, intracranial hypertension and death. CG could be excluded in 34/35, due to documentation of clinical improvement with continued dietary galactose intake, or a clear alternative aetiology. GALT sequencing in the remaining individual confirmed Duarte-variant galactosaemia (DG). In conclusion, undiagnosed CG appears to be rare in those with TGAL 1.0-1.49 mmol/L on NBS; however, our recent experience with missed cases is nevertheless concerning. Further work is required to establish the optimum screening strategy, to maximize the early detection of CG without excess false-positives.

The impact of prolonged, maternal iodine exposure in early gestation on neonatal thyroid function.

Context: Hysterosalpingography (HSG) using oil-soluble contrast medium (OSCM) improves pregnancy rates but results in severe and persistent iodine excess, potentially impacting the fetus and neonate. Objective: To determine the incidence of thyroid dysfunction in newborns conceived within six months of OSCM HSG. Design: Offspring study of a prospective cohort of women who underwent OSCM HSG. Setting: Auckland region, New Zealand (2020-2022). Participants: Offspring from the SELFI (Safety and Efficacy of Lipiodol in Fertility Investigations) study cohort (n=57). Measurements: All newborns had a dried blood spot card for TSH measurement 48 hours after birth as part of New Zealand's Newborn Metabolic Screening Programme. Forty-one neonates also had a heel prick serum sample at one week to measure thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3). Maternal urine iodine concentration (UIC) and TSH in the six months after OSCM HSG were retrieved from the SELFI study for analyses. Primary outcome: Incidence of hypothyroidism in the neonatal period. Results: There was no evidence of primary hypothyroidism on newborn screening (TSH 2-10 mIU/L). All neonates tested at one week had normal serum TSH, FT4, and FT3 levels. However, increasing maternal peak UIC levels during pregnancy were associated with lower TSH levels (p= 0.006), although also associated with lower FT4 levels (p=0.032). Conclusions: While pre-conceptional OSCM HSG in women did not result in neonatal hypothyroidism, gestational iodine excess was associated with a paradoxical lowering of neonatal TSH levels despite lower FT4 levels. These changes likely reflect alterations in deiodinase activity in the fetal hypothalamic-pituitary axis from iodine excess. Trial registration: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000738921, identifier 12620000738921.

Missed congenital hypothyroidism in an identical twin.

Newborn screening for congenital hypothyroidism has been remarkably effective, although rare cases of false negative screening have been reported in same sex twins, presumptively due to fetal blood exchange. We report a case in which the diagnosis of congenital hypothyroidism due to thyroid ectopia in a monozygotic twin was delayed by 8 months, with a normal newborn screening TSH level of 11 mIU/L blood (normal < 15 mIU/L) at 2 days of life. This is the first such case since the national New Zealand newborn screening programme introduced screening for congenital hypothyroidism in 1981 (30 years ago). Repeating thyroid studies at 14 days of age in same-sex twins has been advocated to avoid delayed diagnosis, but given the low risk, may not be cost effective. It is important to maintain a high index of suspicion in same-sex twin pregnancies of potential congenital hypothyroidism.

Effects of syntactic cueing therapy on picture naming and connected speech in acquired aphasia.

Language therapy for word-finding difficulties in aphasia usually involves picture naming of single words with the support of cues. Most studies have addressed nouns in isolation, even though in connected speech nouns are more frequently produced with determiners. We hypothesised that improved word finding in connected speech would be most likely if intervention treated nouns in usual syntactic contexts. Six speakers with aphasia underwent language therapy using a software program developed for the purpose, which provided lexical and syntactic (determiner) cues. Exposure to determiners with nouns would potentially lead to improved picture naming of both treated and untreated nouns, and increased production of determiner plus noun combinations in connected speech. After intervention, picture naming of treated words improved for five of the six speakers, but naming of untreated words was unchanged. The number of determiner plus noun combinations in connected speech increased for four speakers. These findings attest to the close relationship between frequently co-occurring content and function words, and indicate that intervention for word-finding deficits can profitably proceed beyond single word naming, to retrieval in appropriate syntactic contexts. We also examined the relationship between effects of therapy, and amount and intensity of therapy. We found no relationship between immediate effects and amount or intensity of therapy. However, those participants whose naming maintained at follow-up completed the therapy regime in fewer sessions, of relatively longer duration. We explore the relationship between therapy regime and outcomes, and propose future considerations for research.

Introduction of a Protocol for Structured Follow-Up and Texting of Inadequate and Borderline-Positive Newborn Metabolic Screening Results.

A national protocol for structured follow-up and texting of repeat newborn bloodspot screening (NBS) sample requests was introduced. Repeat samples are needed where the initial sample is inadequate or the result borderline-positive. This protocol aimed to improve the timeliness and completeness of receipt of repeat NBS samples. Under the structured protocol, all repeat sample requests were phoned or texted to the lead maternity carer (LMC), in addition to the standard written report issued. Weekly text reminders were sent until 4 weeks or the sample was received. National data were monitored following implementation of the protocol. The proportion of repeat samples received within 10 days of request improved after the introduction of the protocol, from 35.0% in 2013 to 81.4% in 2020 (p < 0.001). The proportion of requests lost to follow-up decreased, from 4.1% in 2013 to 1.3% in 2020 (p < 0.001). A structured NBS follow-up protocol that included SMS text messaging led to an earlier and more complete receipt of repeat samples. This is likely due to practitioners receiving the request more quickly, as well as the laboratory adopting a consistent approach to repeated reminders. SMS text messages are a useful adjunctive method for screening programmes to communicate with health care providers.

Introducing Newborn Screening for Severe Combined Immunodeficiency-The New Zealand Experience.

Screening for severe combined immunodeficiency (SCID) was added to the New Zealand national newborn screening programme in December 2017. Documentation pertaining to the application to add SCID to the panel and screening results over the first three years were reviewed. Screening evaluation metrics were shown to differ according to site of collection (babies in a neonatal intensive care unit vs. the community), definition of a positive test (out-of-range result vs. result leading to a further action on baby), and screening target/case definition (primary SCID vs. non-SCID T-cell lymphopenia). Our experience demonstrates both the value of close clinical involvement during the implementation phase of SCID screening and that the use of standard definitions will facilitate international comparison.

Evaluation of a New Laboratory Protocol for Newborn Screening for Congenital Adrenal Hyperplasia in New Zealand.

Between 2005 and 2021, 49 cases of classical congenital adrenal hyperplasia were diagnosed in New Zealand, 39 were detected in newborns and 10 were not detected by screening. Currently, for every case of CAH detected by screening, 10 false-positive tests are encountered. Second-tier liquid chromatography-tandem mass spectrometry (LCMSMS) has the potential to improve screening sensitivity and specificity. A new laboratory protocol for newborn screening for CAH was evaluated. Birthweight-adjusted thresholds for first- and second-tier 17-hydroxyprogesterone, second-tier 21-deoxycortisol and a steroid ratio were applied to 4 years of newborn screening data. The study was enriched with 35 newborn screening specimens from confirmed CAH cases. Newborn screening was conducted on 232,542 babies, and 11 cases of classical CAH were detected between 2018 and 2021. There were 98 false-positive tests (specificity 99.96%, PPV = 10.1%) using the existing protocol. Applying the new protocol, the same 11 cases were detected, and there were 13 false-positive tests (sensitivity > 99.99%, PPV = 45.8%, (X2 test p < 0.0001). Incorporating the retrospective specimens, screening sensitivity for classical CAH was 78% (existing protocol), compared to 87% for the new protocol (X2 test p = 0.1338). Implementation of LCMSMS as a second-tier test will improve newborn screening for classical CAH in New Zealand.

Hysterosalpingography with Oil-Soluble Contrast Medium Does Not Increase Newborn Hypothyroidism.

OBJECTIVE: Hysterosalpingography (HSG) with oil-soluble contrast medium (OSCM) improves pregnancy rates in women with idiopathic infertility. However, OSCM has high iodine content and slow clearance resulting in potential iodine excess. If pregnancy occurs, this could impact fetal thyroid gland development and function. We aim to determine the effect of a preconceptional OSCM HSG on the thyroid function of the neonate. Design and Patients. This was a retrospective analysis of newborn TSH data for a cohort of neonates conceived within six months of an OSCM HSG in the Auckland region, New Zealand, from the years 2000 to 2019. Thyroid-stimulating hormone (TSH) levels of these newborns were obtained from newborn screening, which is routinely performed for all children at 48-72 hours of life. The primary outcome was the incidence of permanent or transient congenital hypothyroidism in this cohort. RESULTS: Of 146 babies included, all had normal TSH levels with values ranging from 1 to 7 mIU/L on the whole blood analysis of a capillary heel sample using the Perkin-Elmer AutoDelfia assay. Conception during the first 3 cycles following an OSCM HSG was 76%; however, TSH levels in this group were not higher than those conceived in later cycles. CONCLUSION: Preconceptional OSCM HSG did not increase the risk of congenital hypothyroidism in the New Zealand scenario.

Genotype-phenotype correlations in CPT1A deficiency detected by newborn screening in Pacific populations.

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a long chain fatty acid oxidation disorder, typically presenting with hypoketotic hypoglycaemia and liver dysfunction during fasting and intercurrent illness. Classical CPT1A deficiency is a rare disease, although a milder 'Arctic variant' (p.P479L) is common in the Inuit population. Since the introduction of expanded metabolic screening (EMS), the newborn screening programmes of Hawai'i and New Zealand (NZ) have detected a significant increase in the incidence of CPT1A deficiency. We report 22 individuals of Micronesian descent (12 in NZ and 10 in Hawai'i), homozygous for a CPT1A c.100T>C (p.S34P) variant detected by EMS or ascertained following diagnosis of a family member. No individuals with the Micronesian variant presented clinically with metabolic decompensation prior to diagnosis or during follow-up. Three asymptomatic homozygous adults were detected following the diagnosis of their children by EMS. CPT1A activity in cultured skin fibroblasts showed residual enzyme activity of 26% of normal controls. Secondly, we report three individuals from two unrelated Niuean families who presented clinically with symptoms of classic CPT1A deficiency, prior to the introduction of EMS. All were found to be homozygous for a CPT1A c.2122A>C (p.S708R) variant. CPT1A activity in fibroblasts of all three individuals was severely reduced at 4% of normal controls. Migration pressure, in part due to climate change may lead to increased frequency of presentation of Pacific peoples to regional metabolic services around the world. Knowledge of genotype-phenotype correlations in these populations will therefore inform counselling and treatment of those detected by newborn screening.

Birth Weight- or Gestational Age-adjusted Second-tier LCMSMS Cutoffs Improve Newborn Screening for CAH in New Zealand.

CONTEXT: The positive predictive value of newborn screening for congenital adrenal hyperplasia (CAH) in New Zealand is approximately 10%. The use of a second tier liquid chromatography-tandem mass spectrometry bloodspot steroid profile test with birth weight- or gestational age-adjusted screening cutoffs may result in further screening improvements. METHODS: Three years of newborn screening data with additional second-tier steroid metabolites was evaluated (n = 167 672 births). Data from babies with a negative screening test and confirmed CAH cases were compared. First- and second-tier steroid measurements were correlated with both birth weight and gestational age. Analysis of variance was used to determine birth weight and gestational age groups. Screening cutoffs were determined and applied retrospectively to model screening performance. RESULTS: First-tier immunoassay data correlated better with gestational age than with birth weight, but there was no difference with second-tier steroid measurements. Four distinct birth weight and gestational age groups were established for 17-hydroxyprogesterone and a steroid ratio measurement. Application of 97.5th percentile second-tier birth weight- or gestational age-adjusted cutoffs would result in 10 positive tests over the period of the study with 8 true-positive screens and 2 false-positive tests. The positive predictive value of screening would be increased from 10.8% to 80%. CONCLUSIONS: The use of either birth weight- or gestational age-adjusted cutoffs for second-tier screening tests can significantly reduce the false positive rate of newborn screening for CAH in New Zealand without loss in screening sensitivity.

It All Depends What You Count-The Importance of Definitions in Evaluation of CF Screening Performance.

Screening metrics are essential to both quality assessment and improvement, but are highly dependent on the way positive tests and cases are counted. In cystic fibrosis (CF) screening, key factors include how mild cases of late-presenting CF and CF screen positive, inconclusive diagnosis (CFSPID) are counted, whether those at prior increased risk of CF are excluded from the screened population, and which aspects of the screening pathway are considered. This paper draws on the New Zealand experience of almost forty years of newborn screening for CF. We demonstrate how different definitions impact the calculation of screening sensitivity. We suggest that, to enable meaningful comparison, CF screening reports should clarify what steps in the screening pathway are included in the assessment, as well as the algorithm used and screening target.