British Journal of Obstetrics and Gynaecology February 1979. Vol86. pp 87-90
MATERNAL SERUM ALPHA-FETOPROTEIN SCREENING IN A PROVINCIAL HEALTH DISTRICT BY
J . WOOLFSON
E. M. HOLT A. E. WHYMAN AND
D. V. MABBS
Department of Obstetrics and Gynaecology and Radioirnmunoassay Unit Royal Berkshire Hospital, Reading, Berkshire Summary Maternal serum alpha-fetoprotein (AFP) estimation as a routine screening test for neural tube defect (NTD) was introduced into the West Berkshire Health District, where 17 per cent of all deliveries and most of the antenatal care is undertaken by the general practitioners. In the first year, 4458 patients were screened and 43 of those (0.96 per cent) had raised serum AFP levels. Amniocentesis was performed on 31 patients (0.69 per cent). Ten fetuses with severe NTDs and one with exomphalos were detected and the pregnancies terminated. In six patients, raised serum AFP levels were due to fetal death. No normal pregnancy was terminated. Acceptability by patients was high. Provided that a good diagnostic ultrasound facility is available locally, maternal serum AFP estimation seemed to be a valuable screening test. Serum was initially obtained at 14 to 20 weeks gestation, but this was narrowed to 16 to 18 weeks after publication of the UK Collaborative Study (1977). We now describe the introduction of the screening test and the first year’s results.
BROCKet a1 (1973 a and b) were the first to suggest that maternal serum alpha-feroprotein (AFP) estimation might be useful as a screening test for gross fetal neural tube defect. Several other groups of workers agreed (Wald et al, 1973; UK Collaborative Study, 1977) and confirmed that the most accurate results were obtained between 16 and 18 weeks gestation. In March 1977, routine serum AFP estimation was started to assess the practicability of screening all patients in the West Berkshire Health District, where 17 per cent of all deliveries were in the general practitioner maternity units and some patients were not referred to the consultant unit until the third trimester.
METHODS Organization Circulars were sent to all general practitioners in the Health District advising them of the nature and purposes of the screening test. The Nursing Officer in charge of the general practitioner maternity units and the community services was asked to organize collection of 87
88
WOOLFSON, HOLT, WHYMAN AND MABBS
samples through the practice and District midwives, as well as in the antenatal clinic. Assay Maternal serum AFP was measured in weekly batches by a radioimmunoassay method in the Radioisotope Laboratory at the Royal Berkshire Hospital, using standards supplied by the maternal serum AFP quality control scheme (BS 72/227). For the first six months, results were expressed as centiles. After publication of the UK Collaborative Study (1977) results were given as multiples of the median value. The antenatal clinic Sister was the one person informed of all AFP levels above the 95th centile or twice the median value. The Consultant involved was then told. All these patients had an ultrasound scan as a matter of urgency. If the raised AFP level was not attributable to wrong dates, multiple pregnancy or fetal death, and anencephaly was not diagnosed at ultrasound, a further maternal blood sample was obtained. Amniocentesis was done on those patients with repeat serum AFP levels greater than the 97th centile or 245 times the median value and only after full discussion with the patient and her husband. Amniocentesis was done under ultrasound control and the amniotic fluid was analysed either by Dr N. Gregson at Salisbury, or in the Regional Genetics Unit at Oxford. With very few exceptions, a result was obtained within one week.
were 43 patients (0.96 per cent) with genuinely raised serum AFP levels (Table I). All these patients agreed to further investigation and said they would request therapeutic abortion if the fetus was found to be abnormal. The outcome of these pregnancies is shown in Table 11. Three patients aborted spontaneously before ultrasound, and in three others no fetal heartbeat was present. Four fetuses with anencephaly and two with spina bifida were diagnosed by ultrasound alone and the pregnancies terminated without preliminary amniocentesis. Of the 31 patients (72 per cent) having TABLEI Analysis of patients reported as having raised serum AFP levels and in whom no further action was taken Serum AFP level between 95th and 97th centile or 2 and 2 . 5 times the median value
97 patients
Wrong dates
44 patients
Twins not previously suspected
146 patients
_____
TABLEI1 Outcome of pregnancy in 43 patients with raised maternal serum AFP levels
REsu LTs All patients screened in the first year of the study were delivered before the results were analysed. The hospital and general practitioner maternity unit delivery registers were scrutinized for any infants affected by NTD. The screening test was introduced without major difficulties. The number of patients screened was 64.9 per cent at three months after introduction of the scheme, 80 per cent at seven months and over 85 per cent after that. In the first year we screened 4458 patients (79.1 per cent of all bookings); serum AFP levels were reported as raised in 189 patients (4.2 per cent of those screened). After ultrasound scans and repeat serum AFP estimation there
5 patients
Spontaneous abortion before ultrasound Fetus already dead at ultrasound NTD diagnosed on ultrasound alone Raised amniotic fluid AFP and NTD Raised amniotic fluid AFP and exomphalos Abortion after amniocentesis Third trimester intrauterine fetal death Hare lip Normal live infants
Number
Percentage of group with raised serum AFP levels
3
6.9
3
6.9
6
13.9
4
9.3
1 1
2.3 2-3
2 1 22 43
4.6 2.3 51-2
100
SERUM AFP SCREENING
amniocentesis, five had amniotic fluid AFP levels diagnostic of fetal abnormality and therapeutic abortion was performed; four fetuses had spina bifida and one had an exomphalos. The remaining 26 patients had normal amniotic fluid AFP levels and 22 subsequently delivered normal live infants. There were two third trimester intrauterine deaths, one resulting from severe preeclampsia and intrauterine fetal growth retardation and the other unexplained. One patient was delivered of a live child with a hare lip. One patient aborted a macerated fetus without apparent congenital malformation three days after amniocentesis. In this case, the ultrasound scan was restricted to placental location, and it is possible that the fetus was already dead at the time of amniocentesis. No pregnancy with a normal fetus was terminated. The screening programme was introduced in March 1977. The number of infants with an NTD born in the 12 months between July 1976 and June 1977 was 12. However, in the 12 months between July 1977 and June 1978 (when the impact of the screening programme could be felt) the number was only 3; and of these, 2 had closed defects. There were two false negative results. One patient who had a normal serum AFP at 14 weeks delivered a baby with open spina bifida which died after four days. The second was in a patient who had had a previous infant with an NTD and a normal maternal serum AFP level at 15 weeks in the current gestation: anencephaly was diagnosed at a routine ultrasound scan and the pregnancy was terminated. Had the maternal serum AFP level been measured at 16 to 18 weeks the error might not have occurred. In the year under review, in addition to the 31 amniocenteses already described, 41 second trimester amniocenteses were done for other reasons. Only one patient (mentioned above) aborted, giving an overall abortion rate of 1.3 per cent. CONCLUSIONS The introduction of maternal serum AFP estimation as a routine screening test has led to a reduction in the number of babies born with NTD from an expected 14 to 3, two ofwhich were closed defects. One fetus with exomphalos was
89
diagnosed and the pregnancy terminated. Although there were two false negative results, no normal pregnancy was terminated. The cost of the screening programme was just under E l .OO per test including all materials and technician time. When set against the cost of special care for the severely affected infants this appears to be economically justifiable. Moreover, the psychological and emotional effects on the parents and siblings of an abnormal baby must be considered. The readiness with which all our patients with raised serum AFP levels accepted further investigation, and possible therapeutic abortion if the fetus was thought to be abnormal, confirms our belief that this is a worthwhile test. In addition, an increasing number of patients are now specifically requesting measurement of their serum AFP levels. Implementation of the screening test was rapid and effective, much of the credit for which must go to the midwives and general practitioners. Although some patients are still not being screened, largely due to late booking with general practitioners, it is hoped that their number will decrease. Some might raise ethical objections to the fact that only those patients with a raised serum AFP level were given details about the screening test and its implications. In future, we hope to include a note about serum AFP levels in our antenatal booklet so that those patients who object to such a screening test could ask for it not to be performed. At least one good diagnostic ultrasound department at a central unit is an integral part of a screening programme such as we have described. ACKNOWLEDGEMENTS We thank the Senior Nursing Officer in charge of general practitioner maternity units and community services for helping to implement the screening programme and the consultants at the Royal Berkshire Hospital for allowing us to study their patients. Particular thanks must go to Sister C . M. Sefton for her meticulous efficiency as ‘AFP Officer’, and to Dr A. Milne and the technicians in the Ultrasound Department without whom this study could not have been done.
90
WOOLFSON, HOLT, WHYMAN AND MABBS
REFERENCES Brock, D. J. H., Bolton, A. E., and Monaghan, J. M. (1973~): Lancet, 2,923. Brock, D. J. H., Bolton, A. E., and Scrimgeour, J. B. (1973b): Lancet, 2,767.
U.K. Collaborative Study on Alphafetoprotein in Relation to Neural Tube Defects (1977): Lancet, 1, 1323. Wald, N. J., Brock, D. J. H., and Bonnar, J. (1973): Lancet, 2,765.
MATERNAL SERUM ALPHA-FETOPROTEIN SCREENING IN A PROVINCIAL HEALTH DISTRICT BY
J . WOOLFSON
E. M. HOLT A. E. WHYMAN AND
D. V. MABBS
Department of Obstetrics and Gynaecology and Radioirnmunoassay Unit Royal Berkshire Hospital, Reading, Berkshire Summary Maternal serum alpha-fetoprotein (AFP) estimation as a routine screening test for neural tube defect (NTD) was introduced into the West Berkshire Health District, where 17 per cent of all deliveries and most of the antenatal care is undertaken by the general practitioners. In the first year, 4458 patients were screened and 43 of those (0.96 per cent) had raised serum AFP levels. Amniocentesis was performed on 31 patients (0.69 per cent). Ten fetuses with severe NTDs and one with exomphalos were detected and the pregnancies terminated. In six patients, raised serum AFP levels were due to fetal death. No normal pregnancy was terminated. Acceptability by patients was high. Provided that a good diagnostic ultrasound facility is available locally, maternal serum AFP estimation seemed to be a valuable screening test. Serum was initially obtained at 14 to 20 weeks gestation, but this was narrowed to 16 to 18 weeks after publication of the UK Collaborative Study (1977). We now describe the introduction of the screening test and the first year’s results.
BROCKet a1 (1973 a and b) were the first to suggest that maternal serum alpha-feroprotein (AFP) estimation might be useful as a screening test for gross fetal neural tube defect. Several other groups of workers agreed (Wald et al, 1973; UK Collaborative Study, 1977) and confirmed that the most accurate results were obtained between 16 and 18 weeks gestation. In March 1977, routine serum AFP estimation was started to assess the practicability of screening all patients in the West Berkshire Health District, where 17 per cent of all deliveries were in the general practitioner maternity units and some patients were not referred to the consultant unit until the third trimester.
METHODS Organization Circulars were sent to all general practitioners in the Health District advising them of the nature and purposes of the screening test. The Nursing Officer in charge of the general practitioner maternity units and the community services was asked to organize collection of 87
88
WOOLFSON, HOLT, WHYMAN AND MABBS
samples through the practice and District midwives, as well as in the antenatal clinic. Assay Maternal serum AFP was measured in weekly batches by a radioimmunoassay method in the Radioisotope Laboratory at the Royal Berkshire Hospital, using standards supplied by the maternal serum AFP quality control scheme (BS 72/227). For the first six months, results were expressed as centiles. After publication of the UK Collaborative Study (1977) results were given as multiples of the median value. The antenatal clinic Sister was the one person informed of all AFP levels above the 95th centile or twice the median value. The Consultant involved was then told. All these patients had an ultrasound scan as a matter of urgency. If the raised AFP level was not attributable to wrong dates, multiple pregnancy or fetal death, and anencephaly was not diagnosed at ultrasound, a further maternal blood sample was obtained. Amniocentesis was done on those patients with repeat serum AFP levels greater than the 97th centile or 245 times the median value and only after full discussion with the patient and her husband. Amniocentesis was done under ultrasound control and the amniotic fluid was analysed either by Dr N. Gregson at Salisbury, or in the Regional Genetics Unit at Oxford. With very few exceptions, a result was obtained within one week.
were 43 patients (0.96 per cent) with genuinely raised serum AFP levels (Table I). All these patients agreed to further investigation and said they would request therapeutic abortion if the fetus was found to be abnormal. The outcome of these pregnancies is shown in Table 11. Three patients aborted spontaneously before ultrasound, and in three others no fetal heartbeat was present. Four fetuses with anencephaly and two with spina bifida were diagnosed by ultrasound alone and the pregnancies terminated without preliminary amniocentesis. Of the 31 patients (72 per cent) having TABLEI Analysis of patients reported as having raised serum AFP levels and in whom no further action was taken Serum AFP level between 95th and 97th centile or 2 and 2 . 5 times the median value
97 patients
Wrong dates
44 patients
Twins not previously suspected
146 patients
_____
TABLEI1 Outcome of pregnancy in 43 patients with raised maternal serum AFP levels
REsu LTs All patients screened in the first year of the study were delivered before the results were analysed. The hospital and general practitioner maternity unit delivery registers were scrutinized for any infants affected by NTD. The screening test was introduced without major difficulties. The number of patients screened was 64.9 per cent at three months after introduction of the scheme, 80 per cent at seven months and over 85 per cent after that. In the first year we screened 4458 patients (79.1 per cent of all bookings); serum AFP levels were reported as raised in 189 patients (4.2 per cent of those screened). After ultrasound scans and repeat serum AFP estimation there
5 patients
Spontaneous abortion before ultrasound Fetus already dead at ultrasound NTD diagnosed on ultrasound alone Raised amniotic fluid AFP and NTD Raised amniotic fluid AFP and exomphalos Abortion after amniocentesis Third trimester intrauterine fetal death Hare lip Normal live infants
Number
Percentage of group with raised serum AFP levels
3
6.9
3
6.9
6
13.9
4
9.3
1 1
2.3 2-3
2 1 22 43
4.6 2.3 51-2
100
SERUM AFP SCREENING
amniocentesis, five had amniotic fluid AFP levels diagnostic of fetal abnormality and therapeutic abortion was performed; four fetuses had spina bifida and one had an exomphalos. The remaining 26 patients had normal amniotic fluid AFP levels and 22 subsequently delivered normal live infants. There were two third trimester intrauterine deaths, one resulting from severe preeclampsia and intrauterine fetal growth retardation and the other unexplained. One patient was delivered of a live child with a hare lip. One patient aborted a macerated fetus without apparent congenital malformation three days after amniocentesis. In this case, the ultrasound scan was restricted to placental location, and it is possible that the fetus was already dead at the time of amniocentesis. No pregnancy with a normal fetus was terminated. The screening programme was introduced in March 1977. The number of infants with an NTD born in the 12 months between July 1976 and June 1977 was 12. However, in the 12 months between July 1977 and June 1978 (when the impact of the screening programme could be felt) the number was only 3; and of these, 2 had closed defects. There were two false negative results. One patient who had a normal serum AFP at 14 weeks delivered a baby with open spina bifida which died after four days. The second was in a patient who had had a previous infant with an NTD and a normal maternal serum AFP level at 15 weeks in the current gestation: anencephaly was diagnosed at a routine ultrasound scan and the pregnancy was terminated. Had the maternal serum AFP level been measured at 16 to 18 weeks the error might not have occurred. In the year under review, in addition to the 31 amniocenteses already described, 41 second trimester amniocenteses were done for other reasons. Only one patient (mentioned above) aborted, giving an overall abortion rate of 1.3 per cent. CONCLUSIONS The introduction of maternal serum AFP estimation as a routine screening test has led to a reduction in the number of babies born with NTD from an expected 14 to 3, two ofwhich were closed defects. One fetus with exomphalos was
89
diagnosed and the pregnancy terminated. Although there were two false negative results, no normal pregnancy was terminated. The cost of the screening programme was just under E l .OO per test including all materials and technician time. When set against the cost of special care for the severely affected infants this appears to be economically justifiable. Moreover, the psychological and emotional effects on the parents and siblings of an abnormal baby must be considered. The readiness with which all our patients with raised serum AFP levels accepted further investigation, and possible therapeutic abortion if the fetus was thought to be abnormal, confirms our belief that this is a worthwhile test. In addition, an increasing number of patients are now specifically requesting measurement of their serum AFP levels. Implementation of the screening test was rapid and effective, much of the credit for which must go to the midwives and general practitioners. Although some patients are still not being screened, largely due to late booking with general practitioners, it is hoped that their number will decrease. Some might raise ethical objections to the fact that only those patients with a raised serum AFP level were given details about the screening test and its implications. In future, we hope to include a note about serum AFP levels in our antenatal booklet so that those patients who object to such a screening test could ask for it not to be performed. At least one good diagnostic ultrasound department at a central unit is an integral part of a screening programme such as we have described. ACKNOWLEDGEMENTS We thank the Senior Nursing Officer in charge of general practitioner maternity units and community services for helping to implement the screening programme and the consultants at the Royal Berkshire Hospital for allowing us to study their patients. Particular thanks must go to Sister C . M. Sefton for her meticulous efficiency as ‘AFP Officer’, and to Dr A. Milne and the technicians in the Ultrasound Department without whom this study could not have been done.
90
WOOLFSON, HOLT, WHYMAN AND MABBS
REFERENCES Brock, D. J. H., Bolton, A. E., and Monaghan, J. M. (1973~): Lancet, 2,923. Brock, D. J. H., Bolton, A. E., and Scrimgeour, J. B. (1973b): Lancet, 2,767.
U.K. Collaborative Study on Alphafetoprotein in Relation to Neural Tube Defects (1977): Lancet, 1, 1323. Wald, N. J., Brock, D. J. H., and Bonnar, J. (1973): Lancet, 2,765.
