Auditing antenatal diagnoses – what is good practice?

Auditing antenatal diagnoses – what Auditing antenatal diagnoses – what is good practice?is good practice?

Sarah Ball, Tim Hutchin, George Gray, Linda Sarah Ball, Tim Hutchin, George Gray, Linda Jenkinson, Mary Anne PreeceJenkinson, Mary Anne Preece

West Midlands Laboratory for Inherited West Midlands Laboratory for Inherited Metabolic Disorders, Birmingham Children’s Metabolic Disorders, Birmingham Children’s

HospitalHospital

SummarySummary

Purpose of antenatal auditPurpose of antenatal audit Practice at West Midlands Inherited Practice at West Midlands Inherited

Metabolic Disorders LaboratoryMetabolic Disorders Laboratory Audit outcome 1984 – 2005Audit outcome 1984 – 2005 Details of 2 inconsistent audits and resultant Details of 2 inconsistent audits and resultant

change in practicechange in practice Suggested system for adoption by other Suggested system for adoption by other

laboratorieslaboratories

Purpose of antenatal audit (1)Purpose of antenatal audit (1)

In uteroIn utero diagnosis of inherited disease: most diagnosis of inherited disease: most high risk test for genetic laboratorieshigh risk test for genetic laboratories

Misdiagnosis Misdiagnosis loss of a potentially healthy lifeloss of a potentially healthy lifebirth of a child with a painful and crippling birth of a child with a painful and crippling diseasedisease

Huge financial and social costs of misdiagnosisHuge financial and social costs of misdiagnosis


Laboratory procedures to ensure reliability of Laboratory procedures to ensure reliability of test result – minimise pre-analytical, analytical test result – minimise pre-analytical, analytical and post-analytical errorsand post-analytical errors

Potential sources of Potential sources of unexpectedunexpected risks of risks of misdiagnosis:misdiagnosis: Genetics of the disease Expression in utero (biochemical tests) Technical problems with an established test Inadequate test validation


To monitor the quality of our service To monitor the quality of our service we routinely attempt audit on we routinely attempt audit on ALLALL our antenatal diagnosesour antenatal diagnoses

Take action if there are anomaliesTake action if there are anomalies

Practice in the West Midlands Practice in the West Midlands Inherited Metabolic Disorders Inherited Metabolic Disorders

LaboratoryLaboratory West Midlands population is 5.3millionWest Midlands population is 5.3million Birth rate of 70000 per yearBirth rate of 70000 per year Since 1984 offered a regional service for co-Since 1984 offered a regional service for co-

ordinating prenatal tests for IMDsordinating prenatal tests for IMDs Test may be performed:Test may be performed:

In-house (DNA/biochemical)In-house (DNA/biochemical) UK biochemistry/molecular genetics network labUK biochemistry/molecular genetics network lab Diagnostic lab abroadDiagnostic lab abroad Research lab in UK or abroadResearch lab in UK or abroad

National/international referral centre for some National/international referral centre for some specialist biochemical and DNA testsspecialist biochemical and DNA tests

Prenatal test and audit process Prenatal test and audit process (1)(1)

At time prenatal testing arrangedAt time prenatal testing arranged letter to clarifyletter to clarify

Sample requirement and transport arrangementsSample requirement and transport arrangements Who will dissect sampleWho will dissect sample Tests to be done and by whomTests to be done and by whom Identify who will be giving results to the familyIdentify who will be giving results to the family Advise that all prenatal tests are audited and Advise that all prenatal tests are audited and

recommend early discussion of audit with the family recommend early discussion of audit with the family

All prenatal diagnoses are entered in a All prenatal diagnoses are entered in a searchable database (Access)searchable database (Access)


Analytical processAnalytical process Receive sample (CVS or AF – cultured Receive sample (CVS or AF – cultured

or uncultured)or uncultured) Perform analysisPerform analysis Results reported and authorised Results reported and authorised


Final report letter = CHASE 1Final report letter = CHASE 1 combines all results (eg MCC exclusion, combines all results (eg MCC exclusion,

uncultured and cultured CVS/AF results etc)uncultured and cultured CVS/AF results etc) Requests appropriate audit sample Requests appropriate audit sample

TOP: skin/placentaTOP: skin/placenta Continuing pregnancy: blood/biochemistry or Continuing pregnancy: blood/biochemistry or

clinical report of healthy babyclinical report of healthy baby Date of first chase letter recorded on Date of first chase letter recorded on

databasedatabase


Audit sampleAudit sample Receive audit sample for testing and enter result Receive audit sample for testing and enter result

on data baseon data base Or receive clinical report (acceptable where Or receive clinical report (acceptable where

condition manifest in neonatal period)condition manifest in neonatal period) Result of audit sample testing or clinical report Result of audit sample testing or clinical report

entered on databaseentered on database

CHASE 2CHASE 2 If no audit sample received 3 months after the edd write If no audit sample received 3 months after the edd write

to request appropriate samplesto request appropriate samples


Unaudited prenatal testUnaudited prenatal test If no response after 3 months of If no response after 3 months of

second chase letter then prenatal second chase letter then prenatal test recorded as unauditedtest recorded as unaudited

Results of antenatal auditResults of antenatal audit

Total number of auditable antenatal Total number of auditable antenatal diagnoses 1984 - 2005diagnoses 1984 - 2005

340340

Completed auditsCompleted audits 278 278 (82%)(82%)

Uncompleted auditsUncompleted audits 6262

(18%)(18%)

Completed AuditsCompleted Audits

Total completed audits 1984 – 2005Total completed audits 1984 – 2005 278278

MisdiagnosesMisdiagnoses 2 2 (0.07%)(0.07%)

Uncompleted auditsUncompleted auditsTotal uncompleted auditsTotal uncompleted audits 6262No reply to audit requestNo reply to audit request 27 27

(44%)(44%)

Parents refused testingParents refused testing 11 11 (18%)(18%)

Samples received but tests failedSamples received but tests failed 4 (6%)4 (6%)

No sample received on TOP or foetal lossNo sample received on TOP or foetal loss 20 20 (32%)(32%)

TOP when predicted affectedTOP when predicted affected 9 (45%)9 (45%)

TOP for other abnormality when predicted TOP for other abnormality when predicted unaffectedunaffected

2 (10%)2 (10%)

TOP for social reasons when predicted TOP for social reasons when predicted unaffectedunaffected

1 (5%)1 (5%)

Miscarriage subsequent to testingMiscarriage subsequent to testing 8 (40%)8 (40%)

No sample received:-No sample received:-

Inconsistent case 1Inconsistent case 1Index caseIndex case Baby boy with X-linked adrenoleukodystrophy (X-ALD) Baby boy with X-linked adrenoleukodystrophy (X-ALD)

by plasma very long chain fatty acid quantificationby plasma very long chain fatty acid quantificationPrenatal test (1995)Prenatal test (1995) VLCFA quantification in uncultured CVSVLCFA quantification in uncultured CVS Predicted unaffected male foetusPredicted unaffected male foetusAuditAudit Neonatal plasma VLCFA indicated affected statusNeonatal plasma VLCFA indicated affected status Audit trail on u-CVS – no evidence for sample swapAudit trail on u-CVS – no evidence for sample swap Reanalysis of c-CVS – variability of VLCFA levels with Reanalysis of c-CVS – variability of VLCFA levels with

passagepassageConclusionConclusion Result published and change of practice worldwide: Result published and change of practice worldwide:

VLCFA quantification AND oxidation of VLCFAsVLCFA quantification AND oxidation of VLCFAs Mutation analysis of Mutation analysis of ABCD1ABCD1 gene – now preferred gene – now preferred

procedure for X-ALD prenatal diagnoses procedure for X-ALD prenatal diagnoses
















Inconsistent test 2Inconsistent test 2Index caseIndex case Neonatal hypoglycaemia, lactic acidosisNeonatal hypoglycaemia, lactic acidosis then hypotonia, liver failure, nystagmus and diedthen hypotonia, liver failure, nystagmus and died Fibroblast phosphoenolpyruvate carboxylasekinase (PEPCK) Fibroblast phosphoenolpyruvate carboxylasekinase (PEPCK)

showed marked deficiencyshowed marked deficiencyPrenatal testPrenatal test PEPCK very rare no experience of prenatal testing worldwidePEPCK very rare no experience of prenatal testing worldwide Testing lab agreed to test c-AF cells on research basis onlyTesting lab agreed to test c-AF cells on research basis only Parents counselled that experimental procedureParents counselled that experimental procedure C-AF cell PEPCK within normal limitsC-AF cell PEPCK within normal limitsAuditAudit Baby born with same symptoms as index caseBaby born with same symptoms as index case Fibroblast PEPCK within normal limitsFibroblast PEPCK within normal limits Further studies suggested a possible mtDNA depletion disorderFurther studies suggested a possible mtDNA depletion disorderConclusionConclusion Involvement of PEPCK remains unknownInvolvement of PEPCK remains unknown Availability of information on reliability of test crucial for informed Availability of information on reliability of test crucial for informed

genetic counsellinggenetic counselling










A system for antenatal auditA system for antenatal audit

Database in place for auditDatabase in place for audit Facilitates running work lists regularly Facilitates running work lists regularly

to chase audit gapsto chase audit gaps Add data:Add data:

Before prenatal testBefore prenatal test Final result of prenatal test: date of first Final result of prenatal test: date of first

chasechase Date of second chase (if necessary)Date of second chase (if necessary) Result of audit Result of audit

Minimum data required for Minimum data required for audit databaseaudit database

Before prenatal testBefore prenatal test Mother’s nameMother’s name DiseaseDisease Date of sampling procedureDate of sampling procedure Sample typeSample type


After prenatal testAfter prenatal test Result of diagnostic testResult of diagnostic test Date of first chase (i.e. final report Date of first chase (i.e. final report

letter)letter) Pregnancy continuing or termination Pregnancy continuing or termination

of pregnancyof pregnancy


Audit testAudit test If termination of pregnancy:If termination of pregnancy:

Foetal skin/placentaFoetal skin/placenta Result consistent or inconsistentResult consistent or inconsistent

If pregnancy continuing:If pregnancy continuing: Await appropriate sample from baby Await appropriate sample from baby Result of biochemistry or DNA analysis on Result of biochemistry or DNA analysis on

neonatal sampleneonatal sample Result consistent or inconsistentResult consistent or inconsistent


Second chaseSecond chase 3 months after live birth expected3 months after live birth expected If no audit sample or appropriate If no audit sample or appropriate

clinical reportclinical report Repeat request for audit sampleRepeat request for audit sample If still no reply or no sample after a If still no reply or no sample after a

further 3 months record as unauditedfurther 3 months record as unaudited

Conclusions (1)Conclusions (1)

Essential to ensure awareness of Essential to ensure awareness of audit in clinical team and counsel audit in clinical team and counsel family before prenatal test performedfamily before prenatal test performed

Audit is routineAudit is routine Attempt to audit all prenatal testsAttempt to audit all prenatal tests Parents may decline audit specimenParents may decline audit specimen Parents may chose not to be Parents may chose not to be

informed of the audit result if TOPinformed of the audit result if TOP

Conclusions (2)Conclusions (2) Clinical and lab audit is essential to good practiceClinical and lab audit is essential to good practice

Our results show value of antenatal auditOur results show value of antenatal audit

Systems are easily set up – high success rate of audit completionSystems are easily set up – high success rate of audit completion

Audit permits evaluation of new methods and checking Audit permits evaluation of new methods and checking performance of established methodsperformance of established methods

Failure to detect technical error (e.g. atypical enzyme deficiency or Failure to detect technical error (e.g. atypical enzyme deficiency or anomalous mutation test) would mean the same misdiagnosis anomalous mutation test) would mean the same misdiagnosis could be repeated in subsequent pregnanciescould be repeated in subsequent pregnancies

Antenatal screening committee document on “Prenatal screening Antenatal screening committee document on “Prenatal screening standards and protocols” April 2008 will have a standard on audit standards and protocols” April 2008 will have a standard on audit of amniocentesis and CVS diagnostic procedures and outcomes of of amniocentesis and CVS diagnostic procedures and outcomes of pregnancypregnancy

What is done in other labs?What is done in other labs?

What is the current practice in ACC What is the current practice in ACC and CMGS laboratories?and CMGS laboratories?

Are audits attempted on all antenatal Are audits attempted on all antenatal diagnoses, some or none?diagnoses, some or none?

If only some, how are they selected?If only some, how are they selected?

Documents

Auditing antenatal diagnoses – what is good practice?