CALIDAD DE VIDA RELACIONADA CON LA SALUD (CVRS)

Extrinsic false positive and false negative results are due to problems outwith the inborn errors laboratory, such that the Guthrie cards which arrive at the laboratory do not accurately represent childbearing women in Scotland. An example of an extrinsic false positive would be a twin pregnancy to an HIV-infected mother. An example of an extrinsic false negative would be an infant of an HIV-infected mother 'unscreened' due to lack of Guthrie sample collection.

Non-participation bias

One reason for 'missed' cases of congenital hypothyroidism and phenylketonuria has been babies who did not have a card arrive at the Inborn Errors Screening laboratory (MRC Steering Committee for the MRC/ DHSS Phenylketonuria Register, 1981, Pitt etal., 1983, Holtzman etal., 1986, Fisher, 1987) and were therefore not tested. This can be due to death before 7 days of age when the Guthrie sample is taken, unwillingness of parents to allow their infant to have a blood specimen taken perhaps for religious reasons, or because the baby has been completely

'unscreened' by the system and the parents and infant have not been approached for a specimen. To master the problem of being 'unscreened', in Scotland a list of negative screening results is routinely sent from the screening laboratory to all health boards. There the list of babies born, (from SMR2 discharge notifications from obstetric units in a health board area), can be compared with negative results from the screening laboratory so that 'unscreened' babies can be uncovered. Once pinpointed, 'unscreened' infants can have a Guthrie sample sent.

Despite similar back-up systems. Neonatal Screening Programs have missed cases of hypothyroidism and phenylketonuria due to non-receipt of a specimen (MRC Steering Committee for the MRC/ DHSS Phenylketonuria Register, 1981). Previous audit studies have used 'missed' cases of the index disease, which later manifested clinically, as a measure of completeness of the screening programs. 'Missed' cases

due to lack of specimen arriving at the screening laboratory were between 0.2% and 3 % (MRC Steering Committee for the MRC/ DHSS Phenylketonuria Register, 1981, Pitt etal., 1983, Holtzman etal., 1986, Fisher, 1987).

The General Register Office for Scotland (Population Statistics Branch, Lady well House, Lady well Road, Edinburgh EH12 7TF) also known as the Registrar General's Office (RGO) receives registration notices of all births in Scotland. Parents register the birth of their child at their local office. This is published on a yearly basis by date of registration not date of birth(General Register Office, 1989). One way to audit if all babies had a Guthrie card sent was to look at the total cards received at Stobhill Hospital and cross-checking this with the RGO information on births.

Table 8. Guthrie card screening compared with registrations of birth in Scotland

Year Babies screened for Inborn Errors

Babies Registered Different

1984 65843 65106 +737 1985 67338 66667 +671 1986 66187 65808 +379 1987 67204 65970 +1234 1988 66975 66212 +763 1989 63827 63480 +347 1990 66765 65971 +794 Total 464139 459214 +4925

It can be seen that on average just over 700 more Inborn Errors tests were performed than babies registered in a year. Excess Guthrie cards were tested because two cards were sent on some babies. These were either due to insufficient

blood on the first card for Inborn Errors screening when the laboratory would request a further sample, or because two cards were sent, often one from hospital and one from home. Sometimes, especially if an Infant was unwell,

hospital/community staff sent a card on the 7th day and another when they felt the infant had been on milk feeds for a few days. This did not necessarily mean that all babies had been covered and none 'unscreened'.

Audit of babies 'unscreened' by Guthrie testing

'Unscreened' babies were defined by the author as those infants who did not have a Guthrie card sample which arrived at the Inborn Errors Screening Laboratory, for whatever reason.

A systematic 1 in 8 sample of records(8,379) of babies registered in Scotland during 1991 was provided by the Registrar General's Office(RGO). This sample size was selected so that with an 'unscreened' rate of 2%, 95% confidence intervals would be

1.7% and 2.3%. Each record included, father's surname, mother's surname,

address, the date of birth of the infant, and the hospital code of birth. Records were imported into DataEase (DataEase U.K.Limited, 1 Coventry Road, Ilford, Essex, IG1 4QR), a database management software package.

The Scottish National Inborn Errors Screening Laboratory(Guthrie) at Stobhill Hospital, Glasgow recorded all infants screened since 1985 on a computer, in FORTRAN language, without standard database punctuation. Eighty-one thousand four hundred and eighty-five records from babies screened between December 1990 and March 1992 inclusive were exported in ASC II format and imported into a second DataEase database. This transfer of information was not perfect and 367 Guthrie records (0.5%) were unrecognisably corrupted. Another 3,507(4.3%) Guthrie records were partially corrupted.

RGO records were matched with Guthrie records by mother's surname and infant date of birth using an automated technique. Paired records were checked by hand. Unmatched and incorrectly matched RGO records were then searched for

individually. This search started with incorrect spelling of the surname e.g.

McDonald instead of MacDonald. Father's name was then substituted for mother's. If address and mother's or father's name matched and the date of birth was absent or wrong by a few days, a match was made. If hospital of birth, date of birth and address were the same and father or mother's name was corrupted this was

accepted. Pairings with the same date of birth and hospital of birth alone were not accepted.

RGO records which were still unmatched were investigated individually by a clerical officer at the Inborn Errors Screening Laboratory. The office of the health board Regional Medical Officer was telephoned to see if a negative Guthrie notification had been received. A second check was made by searching the stored hard copy, produced by data entry from Guthrie card Inborn Errors screening.

Liaison with other studies

A further check was made on known HIV-infected mothers and their babies. The Edinburgh Perinatal Transmission Study follows all babies bom to known HIV- infected mothers who live in Edinburgh and surrounding areas. Dr N Croft working with Dr JYQ Mok, came to Stobhill hospital in May 1991 with a confidential list of all HIV-Infected women known to have given birth during 1990. These were checked by him against records of Guthrie cards received at Stobhill hospital. A Guthrie card arrived from all Infants of known HIV-infected mothers who gave birth during 1990 from Edinburgh.

Opt-out

The Medical Research Council after instruction from the Secretary of State(K. Clarke Secretary of State, 1988) produced guide-lines for Ethics Committees. This

included provision for individuals to spontaneously opt out from Unlinked-

Anonymous testing. Cards from mothers who spontaneously opted out were not tested for HIV-1 antibody. A disc of blood free filter paper was punched out and the number noted on the day sheet, so that the result "opting out" could be entered on the computer.

No ethics committee approval

The Ethics Committee from Orkney did not give approval for the study. An 'O' for Orkney was marked on the back of the cards. Samples were treated as for opt-out. In June 1993, Orkney granted ethics approval for this study.