Newborn Screening for Congenital Hypothyroidism in Michigan: Past, Present, & Future Steven J. Korzeniewski, MA, MSc, Maternal & Child Health Epidemiology Section Manager Bureau of Epidemiology, Division of Genomics, Perinatal Health and Chronic Disease Epidemiology

Objective Provide a historical account of CH screening in Michigan and detail the application of epidemiology to improve outcomes. Outline: ▫Case definition ▫Screening methods over time ▫Regional efforts to improve screening outcomes ▫CH detection among LBW/Premature/NICU infants ▫Three year follow-up study preliminary findings ▫Future directions

Congenital Hypothyroidism Background No standardized case definition Defined as inadequate thyroid hormone production ▫Usually characterized by increased thyroid stimulating hormone (TSH) concentration and decreased thyroxin (T4) concentration. Insufficient thyroid hormone impacts brain development; specifically, myelination and neuronal connections are impacted

Hypothalamic-pituitary-thyroid axis T4 is stimulated by secretion of TSH by the pituitary. Low T4 (negative feedback) causes hypothalamus to secrete thyrotropin releasing hormone (TRH) which stimulates release of TSH thereby stimulating the thyroid gland to increase secretion of T4. When the thyroid does not respond to TSH stimulation (primary CH), due to dysgenesis or dyshormonogenesis, the result is low T4 and high TSH. Hypothalamus Pituitary Gland Thyroid (-) inhibition (+) stimulation TSH + T3, T4 - TRH + T3, T4 -

Etiology Dysgenesis (thyroid gland developmental defect) Dyshormongenesis (defects in thyroid hormone synthesis) Mutations in thyroid development genes or TSH receptor Defects in hypothalamus or pituitary (central or secondary/tertiary hypothyroidism) ~ rare (1/25,000 – 1/100,000) Iodine deficiency Refetoff S, Dumont JE, Vassart G 2001 Thyroid disorders. In: Scriver CR, ed. The metabolic and molecular bases of inherited diseases. Vol 3. New York: McGraw-Hill; 4029–4076 de Felice M, Di Lauro R 2004 Thyroid development and its disorders: genetics and molecular mechanisms. Endocr Rev 25:722–746 LaFranchi S. Congenital hypothyroidism: etiologies diagnosis and management. Thyroid. 1999, 7:735-40

Newborn Screening NBS for CH ▫Quebec, Canada, and Pittsburgh, Pennsylvania in 1974 ▫Michigan, 1977

Michigan CH Screening Algorithms Primary T4 Secondary TSH ▫<10 th % T4 had TSH evaluated Both T4 & TSH Initially screened ▫Increased sensitivity/specificity for primary CH  Analysis of these data is underway 2003-Present Primary TSH screen ▫T4 removed from algorithm due to extreme FPR (3-5%) and few cases of secondary CH detected ▫Fixed cut-off used (age in hours, uIU/mL): (24-36h, 31 days, <=10)

Diagnosed CH Cases (%) by Serum TSH & FT4, Michigan, 9/2003-9/2007 Serum FT4 Serum TSH >40 [N=48 (30.0%*)] >100 [N=16 (14.5%*)] Median TSHMedian FT4Median TSHMedian FT4 > *%= # with Serum FT4 >.9 / # with Serum TSH > 40, or 100 [Normal Range Serum FT4 with Significant Elevations of Serum TSH]

Disorders Identified via Newborn Screening, Michigan Residents, Type of Disorder Classification (Year Screening Began) Cases in 2007 (N) Cases Through 2007 (N) Cumulative Detection Rate* Galactosemia (1985) 81241:25,300 Biotinidase Deficiencies (1987) :17,885 Amino Acid Disorders (1965) 95991:10,177 Organic Acid Disorders (2005) 3131:29,391 Fatty Acid Oxidation Disorders (2003) 16551:11,684 Congenital Hypothyroidism (1987) 881,4821:1,931 Congenital Adrenal Hyperplasias (1993) 31061:18,744 Hemoglobinopathies (1987) 531,3891:2,060 Cystic Fibrosis (since Oct. 2007) 771:4,436 38% of all cases

CH Screening Results and Performance Metrics, Michigan, 2007 Total N** Total + N (% NICU) Strong + N Confirmed CH N Positive Detection Rate Among All Positive Screens Among Strong Positive Screens FPR % PPV % FPR % PPV % 123, (34.4) :1,

Program Evaluation

Evaluation of TSH Distributions Charles Mundt evaluated variation in initial TSH distributions; significant variation by: -gestational age -birthweight -race -month -state

Michigan TSH Variation by Selected Demographic Factors, Jan 2005-Dec 2006 FactorNMedian99.5%99.8% Sex Male126, Female120, NICU Yes26, No223, Race White162, Black42, Birthweight <2,500g23, >=2,500g226, Gestational Age < 37weeks35, >=37 weeks214, Age at Collection 1-23 Hours3, Hours212, >=37 Hours33,

Michigan Mean TSH by Month, Jan 2005-Dec 2006 ** All **Selected (Full Term, White, Female, Non-NICU, NBW, Screened hrs

TSH values, Michigan Resident Births, Jan 2005-Dec 2006, Screened < 14 Days of Life month

Implications of TSH Variation Given the variation observed, a single cut-off approach is unlikely to yield improvements in PPV/FPR. ▫Percentile based approaches to cut-off calculations appear warranted  However, stratified percentile based cut-offs would require further study and implementation would require significant changes in the NBS laboratory

NICU Screening Protocol

CH Detection in Premature Infants Maturity of the endocrine system influences initial dried blood spot TSH values. ▫Some premature infants with CH have late rising TSH and are therefore not detectable by an initial screen at 24-36hrs of life NICU/LBW screening protocol implemented (2007) to account for unreliable screens in premature newborns

NICU/LBW Screening Algorithm

CH Cases by Birth Weight & Birth Year, Michigan, 1/1/2005-5/21/2008 Birth Year Birth Weight < 1800g g> 2500g CasesScreenedRateCasesScreenedRateCasesScreenedRate : : : : : : : : :1645 1/1/08- 5/21/ : : :1868

Number of Infants Screened by Birth Weight, Michigan, 2007 Birth Weight Frequency%Cumulative Frequency Cumulative % Estimated Number of Infants Added to the NICU Protocol (Cumulative) < 1800g2, , g1, , , g1, , , g4, , ,995 >=2500g111, ,

NICU Protocol Evaluation Conclusions NICU protocol inclusion criteria currently does not consider gestational age. ▫GA is thought to be a better indicator of maturity than BW; however, concerns about data quality have led the latter to be used. ▫Adding very preterm and below (GA < 32 wks) infants would add 215 infants based on 2007 data. We are evaluating the impact of: ▫ increasing the birthweight inclusion criterion to ~2300g, ▫adding very preterm and below (GA < 32 wks) infants, and ▫eliminating 2 nd screens for infants born weighing less than ~1,000g-1,500g. Clinical Laboratory Standards Institute (CLSI) has a subcommittee working on a proposed standard for NBS of SCBU/NICU infants

CH Three-Year Follow-up Study

CH Three Year Follow-up Standard of care is to follow-up CH cases until at least age three years (AAP Guidelines) Diagnostic verification recommended (permanent vs. transient CH) ▫Thyroid function trial Rate and outcome of diagnostic verification unknown

CH Three Year Follow-up of ‘Borderline’ Cases ‘Borderline’ was initially considered as having pre- treatment serum TSH values below the 15 Th percentile. ▫We recently expanded our criteria to include cases below the 25th percentile. Survey developed and pilot tested in collaboration with PEAC endocrinologists Medical management data maintained by NBS Follow- up program used to locate cases’ physicians. ▫LTFU mitigated by use of MCIR and phone based survey

Demographics of Michigan CH Cases Detected by NBS Classified by Pre-Treatment Serum TSH/FT4 Values, 9/2003-9/2007 ClassificationN% Mean GA Mean BW White (%) Male (%) NICU (%) FT4 = % FT4 >=.9, TSH >= % FT4 <.9, TSH < % FT4 >=.9, TSH < %

Preliminary Findings of the CH Three year follow-up study Preliminary findings indicate: ▫44% (8/18) of cases with completed diagnostic re-evaluation to date appear not to have permanent CH. ▫A surprising number of patients (families) have stopped treatment of their own accord (7/22 with completed follow-up); this phenomenon requires further study.  One case (family) described miscommunication with health care provider and lack of follow-up as impetus to treatment cessation. ▫While all patients who stopped treatment on their own are thought to be transient CH (confirmation of transient CH is pending TSH value receipt- two patients have provided such confirmation to date), only 1/11 cases evaluated by an endocrinologist is considered transient.  This finding may have implications for the method of diagnostic re-evaluation.  Some cases were confirmed based on increasing treatment dosage at approximately 6 months of age; should this preclude three year thyroid challenge?  Questions remain about process and outcome of three year CH re-evaluation.

Conclusion Epidemiology is being used to improve CH screening outcomes by evaluating: ▫variations in TSH distributions and potential implications for initial CH screens ▫detection among premature/LBW infants and potential algorithm changes ▫The role of follow-up in differentiation of transient from permanent CH

Future Directions Analyze data from the tandem primary T4 & TSH screening period ( ) Evaluate impact of percentile vs. fixed initial TSH cutoffs Further analyze impact of NICU/LBW screening protocol inclusion criteria changes Follow-up with families of cases taken off of treatment Continue to collect informaiton on diagnostic re- evaluation in hopes of initiating discussion about standardization.

Acknowledgements Bill Young, Manger, Newborn Screening Follow- up Program Violanda Grigorescu, Director, Division of Genomics, Perinatal Health & Chronic Disease Epidemiology Charles Mundt, Outreach Specialist, Institute for Healthcare Studies, MSU Newborn Screening Follow-up Staff

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