Newborn Screening for Critical Congenital Heart Diseases

(CCHD)

Lazaros Kochilas, MD Associate Professor of Pediatrics University of Minnesota

Disclosures and Support

I will not discuss off label use and/or investigational use in my presentation

and

I have no conflicts of interest to disclose

Criteria for using and appraising screening • Population: - sufficiently high incidence of screened condition - likely to be compliant

• Condition: - significant mortality / morbidity - known natural history with detectable presymptomatic period - treatment makes a difference when introduced early

• Test: - suitable (simple, safe, reliable, validated) - known distribution of values in diseased and non-diseased - acceptable validation process for (+) screens - widely available and acceptable

• Treatment: - acceptable, available, effective, agreement on whom to treat

• Program: - adequate staffing/facilities - program is acceptable and effective - acceptable cost - quality management / ongoing re-evaluation

Selection Criteria for Newborn Screening Conceptual Framework

Definition - Identifiable at birth - Condition characteristics

Test characteristics – Treatment - Cost effectiveness

Concepts in screening

• All screening programs do harm; some do good as well

• Criteria for appraising screening

• Screening is a program not a test

• Assess opportunity cost

Wilson, J and Jungner, J: Principles and practice of screening for disease: WHO, 1968 Gray, MJ: New concepts in screening; BJ Gen Practice, 2004, 54, 292-298

Disease

+ - Screening adverse effects

- A B

+ C D

Particular challenges • Limitations of randomized controlled studies

• Limited evidence to assess benefit/risk ratio

• Need to calculate opportunity costs “Would you spend $$$ for screening for CHD?” vs. “If you had $$$ to spend for the field of CHD would you spend it for screening?”

• Public pressure for increasing sensitivity of the testing

• Challenge of definition

Nomination Form

HRSA Administrative

Review

SACHDNC*

Evidence Review Group

HHS Secretary

Process for addition of new conditions to the uniform panel of newborn screening

• Not adding to the NBS • Additional studies • Pilot study • Targeted screening • Add to NBS

Implementation workgroup

*Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children

The problem of CCHD

- CCHD are relatively common

- Current screening approach includes prenatal ultrasound and physical examination

-Diagnosis of newborns with CCHD remains challenging

- Newborns are discharged home with undiagnosed CCHD

- High risk for Morbidity and Mortality

- Additional screening methods are needed

oximetry screen 1st clinical reports

Larger prospective study In NY (Koppel)

Request to AHA For recommendations

AHA comment Evidence not sufficient

Proposed bill in TN to mandate screening

Several European countries adopt pulse-ox screen

as standard of care

AHA/AAP statement comment

2002 2005

Large European prospective studies (Norway, Sweden, UK, Germany, Switzerland)

Timeline of pulse oximetry screen for CCHD

2008 2011

SACHDNC recommended

adding pulse-ox screen

HHS secretary endorses addition of

pulse-ox screen

Definition of the primary target: Critical CHD (CCHD)

Requiring surgical, cath or pharmacologic intervention to avoid death or end-organ damage

- Hypoplastic left heart syndrome (HLHS)

- Tricuspid atresia

- Pulmonary atresia

-Tetralogy of Fallot (TOF)

-Total anomalous pulmonary venous return (TAPVR)

- Transposition of the great arteries (TGA)

- Truncus arteriosus

Current Uniform Screening Panel • 29 primary conditions

• 25 secondary targets

-20 metabolic detected by MS (AA, FAO, OA) -3 Hg-pathies (S/S, S/β Thal, S/C) - 6 Others (BIOT, CAH, CF, CH, GALT, HEAR*)

-22 metabolic detected by MS (AA, FAO, OA) - 1 Hg-pathies variants - 6 Others (GAL-epimerase, GAL-kinase)

* Only point-of-care type of screening

CHD: 5-10 / 1,000 live births

1.4 cyanotic CHD / 1,000 live births

2 critical CHD / 1,000 live births

25,000 cases of CHD/yr in US

25% of infantile deaths

31% of neonatal deaths

Congenital Heart Diseases: The magnitude of the problem

http://www.cdc.gov/ncbddd/features/heartdefects-keyfindings2010.html

Heron, M., et al. (2009). Deaths: Final data for 2006. National Vital Statistics Reports, 57(14). U.S. CDC and Prevention.

All together 1.55 /1,000 live births

Incidence of CHD

50% of deaths from CHD occur in 1st year and

50% of infantile deaths occur in 1st month of life

Timing of death from CHD

Boneva, R: Circulation. 2001;103:2376

Significant physiologic compromise from undiagnosed CHD

• 490 patients with undiagnosed critical CHD (2000-2003)

• 76 (15.5%) with significant physiologic compromise

• 33 (6.7%) preventable

• Incidence of potentially preventable events 1:15,000-26,000

Schultz, A: Epidemiologic features of the presentation of critical CHD: implications for screening Pediatrics 2008; 121(4):751-757

Missed Critical Congenital Heart Diseases (CCHD)

Hoffman, J. It is time for routine neonatal screening by pulse oximetry. Neonatology 2011;99:1-9

Types of frequently unrecognized CCHD

Hoffman, J. It is time for routine neonatal screening by pulse oximetry. Neonatology 2011;99:1-9

Screening for CCHD

- Fetal ultrasonography

- Physical examination

- Pulse oximetry

Pulse oximetry as screening method - pulse oximetry measures the amount of O2Hgb in the arterial blood

- based on differential absorption of O2Hgb and RHgb

- coupled with ability to separate pulsatile from non-pulsatile components

- non-invasive and painless

- accurate with newer generation oximeters

- “motion resistant” (SET) technology

- fast (<2 min) and reliable

- inexpensive

- peripheral perfusion index (PPI)

Distribution of O2 saturations in 24h newborns with newer generation pulse oximeters

de-Wahl Grannelli, A: Acta Paediatrica 2005;94:1590

Critical CHD Newborns

O2 saturation values in patients with CCHD

de-Wahl Grannelli, A: Acta Paediatrica 2005;94:1590

Reliability in wide range of O2 saturations

de-Wahl Grannelli, A: Acta Paediatrica 2005;94:1590

Pulse waveform analysis: Peripheral Perfusion Index (PPI)

PPI < 0.7 in at least one limb suggesting of critical left heart obstructive lesions

OR 23.8 [95% CI (6.4-88.7)]

de-Wahl Grannelli, A: Acta Paediatrica 2007;96:1455

Future of pulse oximetry screen for these lesions may include PPI

Mahle, W et al.: Role of Pulse Oximetry in Examining Newborns for Congenital Heart Disease A Scientific Statement From the AHA and AAP, Circulation 2009; 120:447-458

Studies examining pulse oximetry screening for CCHD

- 14 large studies ( > 240,000 newborns )

- Overall test performance >24h:

- Sensitivity 70% Specificity 99.9%

- False Positive Rate 0.035% False Negative Rate 0.01%

- Positive Predictive Value 47% Negative Predictive Value 99.9%

- overall improved detection rate vs physical exam alone

- improved outcomes?

The Swedish prospective study (2004-2007) de-Wahl Grannelli, A: BMJ 2009; 338

W. Göteland Contemporary cohort p-value

Total 46,693 108,604

Screened 39,821 -

CCHD Prenatal Dx Clinically / PE (only) Pulse Ox Undiagnosed Deaths

62 2

41 / 5 19 5 0

109 9

72 -

28 9

0.0025* 0.16

Sensitivity 62% N/A

False positives / FPR 69 (0.17%) N/A

Specificity 99.8% N/A

False negatives / FNR 11 (0.03%) N/A

• asymptomatic newborns in well baby nursery ≥ 24h of age

• newer generation pulse oximeters

• motion resistant technology measuring functional O2 saturation

• accuracy (±2% root mean square error)

• both single use and reusable probes acceptable

• two sites: right arm and a foot

• cut-off for positive screen: < 95% and │O2Sats RA- F│> 3 points (3 times)

• any value <90% is abnormal

• cut-off values for areas in high altitude not defined

• screening incorporated with nursery’s practice and other screening activities

Practical considerations

Screening Protocol in well baby nursery for asymptomatic newborns >24h or shortly before discharge

check pulse ox in right arm and foot in room air

Re-screen in 1h

90-94% in both sites or arm-foot difference > 3 points

PASSED TEST

90-94% in both sites or arm - foot difference >3 points

< 90% in either site Irrespective or difference

PCP notified (FURTHER ACTION)

≥ 95% or higher in either site and arm – foot difference ≤ 3 points

90-94 % in both sites or arm-foot difference > 3 points

Re-screen in 1h POSITIVE SCREEN

POSITIVE SCREEN

DISCHARGE

What to do for a positive pulse oximetry screen (FAIL)

1. Confirm accuracy of reading 2. If <24h consider deferring discharge and repeat test at 24h or later; otherwise,

follow same algorithm as in older infants

3. Perform additional clinical evaluation to assess for non-cardiac causes

4. Echocardiogram (in-center, transfer, telemedicine) and/or pediatric cardiology evaluation

5. Report to MDH both true and false positives

Failed Pulse ox screening: one value equal or less than 90% OR

three times <95% in both sites or absolute difference of >3 points

What to do for a negative pulse oximetry screen (PASS)

1. Negative screen does not exclude CHD 2. Continue surveillance after discharge 3. Parent and physician education for symptoms and signs of CHD

4. Clinical judgment

5. Report later diagnosed cases to MDH

≥ 95% or higher in either site and arm – foot difference ≤ 3 points

Comparative cost of screening

• CCHD: 8,000 cases per year in the US

• Screen will cause additional 8,000 ECHOs per year

• Cost: $9,000 (5.5-29K) per asymptomatic case diagnosed

• Metabolic disorders: 6,400 cases per year in the US Cost of metabolic screen $110 / infant X 4 million/year = $440M / yr or $68,750 per patient diagnosed

Expected annual activity for Minnesota

• Minnesota birth rate: 70,000

• Distribution: 60% access to pediatric cardiology services

(50% metro and 10% non-metro cities)

• Expected positive screens: 98

• Expected false positive screens: 46

• Need for transfer: 18

Estimated financial cost • Nursing time: 5-10 min / screen $200K-$400K • Pulse oximeter equipment: $100K • Pulse oximeter supplies: $200K (reusable)

$700K (single use) • Echocardiography cost: $70K-200K • Transport costs: $50K

• Estimated total cost: $620K-$950K • Additional hospital time / hidden costs: ?

* Annual Budget - Minnesota Department of Health (MDH) $500M / year ($7.5 M/ year on Newborn Screening)

Barriers in implementation • Regulatory (informed consent, reusable probes) • Cost (equipment, supplies, personnel, transfers, days in hospital) • Health care personnel: nursing staff community practitioners echo technicians

pediatric cardiologists • Equipment: pulse oximeters / ECHO machines & probes • Infrastructure & Accessibility • Medico-legal concern • Skepticism

• Newborn screening for CCHD with pulse oximetry is promising

• Physical examination still useful

• Early diagnosis of CCHD may improve outcomes

• Guidelines for implementation of screening have been defined

• Future refinements likely

Pulse Ox screening for CCHD is coming soon to a nursery close to you!

Summary