PRENATAL DIAGNOSIS,VOL.
10,71-77 (1990)
MATERNAL SERUM ALPHA-FETOPROTEIN SCREENING FOR OPEN NEURAL TUBE DEFECTS IN TWIN PREGNANCIES H. C:UCKLE*, N. WAI>D*,J. D. STEVENSON?, H. M. MAY?, M. A. FERGUSON-SMITH?**, A. MII~FORD WARDS, H. M. BARBOURS, K. M. LAURENCE~~ AND B. NORGAARD-PEDERSEN~
*Department of Environmental and Preventive Medicine, St Bartholomew's Medical College, Charterhouse Square, London E C l M 6BQ, U.K.; 7 Duncan Guthrie Institute of Medical Genetics. Yorkhill. Glasgow G3 8SL, U.K.; $Supraregional Protein Reference Unit, Department of Immunology. Royal Hallamshire Hospital, Shefield SIO ZJF, U.K.;$Department of Clinical Chemistry, Western General Hospital, Edinburgh EH4 ZXU, U.K.; Ij Child Health Laboratories, Department of Child Health. Heath Park, Cardiff CF4 4 X N , U.K.; fistaten Seruminstitut, Hormone Department, Amager Boulevard 80, DK-2300 Copenhagen S , Denmark
SUMMARY Data e n maternal serum alpha-fetoprotein (AFP) levels at 13-24 weeks' gestation in 46 twin pregnancies with open neural tube defects (22 with anencephaly, 24 with open spina bifida) and 169 unaffected twins were used to estimate the detection and false-positive rates associated with different cut-off levels. Using the conventional cut-off level of 2.5 multiples of the median (MOM)for unaffected singleton pregnancies of the same gestation and laboratory, the detection rate in twins was 99 per cent for anencephaly and 89 per cent for open spina bifida, with a false-positive rate of 30 per cent. Using a 5.0MOM cut-off level to maintain a similar false-positive rate to that found among singleton pregnancies at 16-18 weeks' gestation (about 3 per cent), the detection rate was 83 per cent for anencephaly and 39 per cent for open spina bifida. Estimates are provided of the odds of having a n affected twin pregnancy given a positive AFP result as well as the odds for individual women with a raised AFP level. K E Y WORDS
Alpha-fetoprotein Twin pregnancies Neural tube defects Antenatal screening Maternal serum
INTRODUCTION In maternal serum alpha-fetoprotein (AFP) screening programmes for open neural
tube defects (NTDs) data are available to estimate, in singleton pregnancies, the detection rate, the false-positive rate, and the odds of being affected in women with positive results (either as a group or for individuals) (Fourth Report of the U.K. Collaborative AFP Study, 1982; Wald et al., 1984). In twin pregnancies, only the false-positive rate can be estimated (Wald and Cuckle, 1990a); insufficient data have been published on affected twin pregnancies (in which one or both fetuses have an NTD) to estimate the detection rate and the odds of being affected for women with positive results (First Report of the U.K. Collaborative AFP Study, 1977; Ghosh et a/., 1982). T o obtain these estimates we pooled data from six centres.
**Presentaddress: Cambridge University, Department of Pathology, Tennis Court Road, Cambridge CB2 IQP, U.K.
0197--3851/90/020071-07$05.00 C1 1990 by John Wiley & Sons, Ltd.
Received8 August I989 Accepted 4 November 1989
72
H. CUCKLE E T A L .
MATERJALS AND METHODS Each of the six centres was asked to obtain information on twin pregnancies in which one or more of the fetuses had an open neural tube defect and an AFP test had been performed between 13 and 24 weeks’ gestation. When more than one AFP test was done, only the first was included in this analysis. Forty-six pregnancies were available for study: from Glasgow (20), Sheffield (9), Edinburgh (7), Oxford (4), Cardiff (4), and Copenhagen (2). In 20 cases, one of the fetuses had anencephaly; in 23 cases, one had open spina bifida (without anencephaly); and there here three affected concordant sets of twins-two with anencephaly (one conjoined) and the other with open spina bifida. An unselected series of 169 twin pregnancies from Oxford, which were not asociated with neural tube defects and on which AFP tests had been performed between 13 and 24 weeks’ gestation, were also studied. AFP levels were expressed in multiples of the normal median (MOM) for unaffected singleton pregnancies of the same gestational age (usually based on ‘dates’, i.e., the time since the first day of the last menstrual period) in the appropriate laboratory. Eleven of the 20 cases from Glasgow had previously been reported (Ghosh et al., 1982) with the MOM values calculated using normal medians based on 1620 pregnancies tested over a short period. In this paper we used concurrent normal medians in the calculation. Detection rates, false-positive rates, and the odds of being affected for women with positive results wereestimated by fitting log Gaussian distributions to the AFP results from affected and unaffected pregnancies (Fourth Report of the U.K. Collaborative AFP Study, 1982; Cuckle et al., 1988). The odds of being affected given a positive result were estimated by multipl!ying the birth prevalence of anencephaly and spina bifida in twins (expressed as an odds) by the appropriate likelihood ratio; for all women with a positive result as a group the appropriate likelihood ratio is the detection rate divided by the false-positive rate, and for an individual it is the relative heights of the two Gaussian distributions at that woman’s AFP level. The birth prevalence of twins associated with a neural tube defect was taken to be 2.28 times that for singletons (Wald and Cuckle, 1987). In estimating means and standard deviations of the Gaussian distributions, we used the method described in Appendix (1) of the Fourth Report of the U.K. Collaborative AFP Study (1982) to exclude extreme outliers. The median was used as an estimate of the mean, and the interval between the 10th and 90th centiles divided by 2.56 was used to estimate the standard deviation. RESULTS Table 1 shows the individual AFP levels (in MOM)from affected twin pregnancies arranged in ascending order. There were insufficient data to assess whether, like with singleton pregnancies, discrimination between affected and unaffected pregnancies was greater at 16-18 weeks’ gestation than at other gestational ages (First Report of the U.K. Collaborative AFP Study, 1977). The three concordant twin pregnancies did not have results substantially different from those of the discordant twins. For this reason we included them with all affected twins. Figure 1 is a probability plot of the MOM values from affected and unaffected pregnancies. The straight lines in the figure represent Gaussian distributions of log, (,
MSAFP IN TWIN PREGNANCIES
73
Table 1. Maternal serum AFP levels (in MOM) in twin pregnancies with one or both twins affected by an open neural tube defect Anencephaly AFP level
(weeks’
gestation)
Open spina bifida AFP level
(weeks’ gestation)
1 .o 2.1 3.2 5.0 5.2 5.2 5.5 5.9*t 6.4 7.0 7.1 7.3 7.7 7.9* 8.1 8.7 8.8 9.5 11.0 14.0 14.3 14.7
*Both twins affected; otherwise only one affected. tConjoined twins. MOM= Multiple of the normal median for singletons at the same gestation and laboratory.
AFP with the means and standard deviations specified in Table 2 that were derived from the data after excluding the outlying values of 1.0 and 2.1 MOMrelating to two anencephalic pregnancies and 0.3 MOM from an unaffected pregnancy. The figure shows that the distribution of AFP levels in twin pregnancies are approximately log Gaussian over a wide range of values. Table 3 shows the estimated detection and false-positive rates based on the means and standard deviations specified in Table 2 according to AFPcut-off level, together with the odds of being affected for women with positive results as a group, assuming that the singleton birth prevalence in the absence of antenatal diagnosis and selective abortion is 1 per 1000 each for anencephaly and open spina bifida. Table 4 shows the estimated odds for individual women with a specified AFP result. If the birth prevalence were higher (or lower) in a particular community, the left-hand side of the odds ratio should be multiplied by the extent to which it is higher (or lower).
74
H. CUCKLE ETAL.
/
o
cSMJATIvE PFFCEm
Figure 1. Probability plot of centiles of AFP in multiples of the median (MOM)among 22 anencephalic ( A ) , 24 open spina bifida (O), and 169 unaffected (.) twin pregnancies after excluding outlying values specified in the footnote in Table 2. The continuous lines are those defined by fitted Gaussian distributions with means and standard deviations in Table 2
Table 2. Means and standard deviations of AFP in anencephalic, open spina bifida, and unaffected twin pregnancies
Anencephaly Open spina bifida Unaffected
No. of twin pregnancies*
Mean (log,, MOM)
(MOM)
Standard deviation (log,,, MOM)
22 24 169
0.8749 0.6435 0.2788
(7.50) (4.40) (1.90)
0.1829 0.1987 0.2280
*Three with outlying AFP values were not used in the estimations: two with anencephaly (1.0 and 2.1 MOM)and one unaffected (0.3 MOM). MOM= Multiple of the normal median for singleton pregnancies at the same gestation and laboratory
DISCUSSION Our estimates of the detection ‘rate, the false-positive rate, and the odds of being affected given a positive result in twin pregnancies (Table 3) should be of use to those responsible for AFP screening programmes for open NTDs. A centre using the conventional cut-off level of 2.5 MOM based on ‘dates’ at 16-1 8 weeks’ gestation can expect, in singleron pregnancies, detection rates of 89 per cent for anencephaly and 75 per cent for open spina bifida with a false-positive rate of 3.3 per cent or less. The
75
MSAFP IN TWIN PREGNANCIES
Table 3. Detection rate, false-positive rate, and odds of being affected by anencephaly or open spina bifida given a positive result (OAPR) for twin pregnancies according to A F P level (assuming a singleton birth prevalence of 1 per 1000 births for each defect in the absence of antenatal diagnosis and selective abortion)* Detection rate AFP level
(MOM)
22.5 :? 3.0 I? 3.5 ._ .> 4.0 124.5 I> 5.0 I? 5.5 ;> 6.0
Anencephaly (YO)
99 98 96 93 89 83 77 70
Open spina bifida (%)
89
80 69 58 48 39 31 25
Falsepositive rate (%)
30 19 12 7.8 5.0 3.3 2.2 1.4
OAPR Anencephaly
:130 :85 :55 :37 :25 :17 :13 :8.8
Open spina bifida
1:150
1:lOO 1:76 159 1:46 1 :37 1:31 1:25
*Derivedfrom Gaussian distributions of log,, AFP using the means and standard deviationsspecified in Table 2. M O M =Multiple of the normal median for singletonsat the same gestation and laboratory.
detection rates will be higher in twins (99 and 89 per cent), but as many as one-third of women with unaffected twin pregnancies will have positive results and the odds of being affected given a positive result will not be high (1 :130 for anencephaly, 1:150 for spina bifida, if the birth prevalence in singletons is 1 per 1000 for each defect). To achieve a similar false-positive rate in twin pregnancies as for singleton pregnancies at 16-18 weeks’ gestation, the cut-off level would need to be raised to 5.0 MOM (false-positive rate 3.3 per cent); the correponding detection rate would be 83 per cent for anencephaly and 39 per cent for open spina bifida. To achieve a similar open spina bifida detection rate in twin pregnancies as for singleton pregnancies, the cutoff level would need to be 3-3.5 MOM; the corresponding false-positive rate would be I S 2 0 per cent. Regardless of the screening policy and the cut-off level that is selected for use with twin pregnancies, the estimates of the odds of an individual woman with a raised AFP level having an affected twin pregnancy (Table 4) should be helpful when counselling women with positive screening results. In practice, the ultrasound scan examination which normally follows a positive result will exclude anencephaly. The finding of twins in the absence of anencephaly at that examination is often taken to he the reason for the raised AFP level and no further action is taken. The reluctance to terminate an unaffected co-twin or to attempt a selective termination of the affected twin both lend support to this policy. However, using the estimates in Table 4. offers the option of making an informed decision on the possibility of having a diagnostic ultrasound examination or amniocentesis. The detection rate of these diagnostic procedures in twin pregnancies is not known. While for ultrasound it is unlikely to be much different from that found in singleton pregnancies (100 per cent for anencephaly and 88 per cent in spina bifida-based on the combined results of
76
H. CUCKLE ET AL.
Table 4. Odds of being affected by anencephaly or spina bifida for individual twin pregnancies according to AFP level (assuming a singleton birth prevalence of 1 per 1000 birthis for each defect in the absence of antenatal diagnosis and selective abortion)*
AFP level (MOM)
2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8 6.0
Anencephaly
Open spina bifida
1 :48 000
1:1700 1:1200 1:830 1:620 1 :470
1 :23 000 1:12 000 1:6900 1:4100 1:2600 ]:I700 1:llOO 1:760 1:540 1:390 1 :290 1:220 1:170 1:130 1:lOO 1:82 1:66 1:54 1 :44 1:37
1:370
1:300 1 :240 1:200 :170 :140 :120 :I 10 :93 :82 :73 :65 1:58 153 1:48 1:44
*Derived from Gaussian distributions of log,, AFP using the means and standard deviations specified in Table 2. MOM= Multiple of the normal median for singletons at the same gestation and laboratory.
seven studies (Wald and Cuckle, 1990b)),for amniotic fluid tests it might be lower in twins because of diffusion of AFP or acetylcholinesterase from the amniotic sac containing the affected twin to the other sac. In one study, only two out of six discordant twins had raised amniotic fluid AFP levels, although it was not known for certain which sac had been s,ampled(Second Report of the U.K. Collaborative AFP Study, 1979). ACKNOWLEDGEMENT
We thank Nora Jones for help in the identification of cases from Oxford. REFERENCES Cuckle, H., Wald, N., Thompson, S. (1988). Estimating a woman’s risk of havinga pregnancy associated with Down’s syndrome using her age and serum alpha-fetoprotein level, Br. J . Obstet Gynaecol., 94,387-402.
MSAFP IN TWIN PREGNANCIES
77
First Report of the 7I.K. Collaborative Study on Alpha-fetoprotein in Relation to Neural Tube Defects (1977). Maternal serum alpha-fetoprotein measurement in antenatal screen-. ing for anencephaly and spina bifida in early pregnancy, Lancet, i, 1323-1332. Fourth Report of the U.K. Collaborative Study on Alpha-fetoprotein in Relation to Neufal Tube Defects (1982). Estimating an individual's risk of having a fetus with open spina bifida and the value of repeat alpha-fetoprotein testing, J . Epidemiol. Community Health, 36,87-95. Ghosh, A., Woo, J.S.K., Rawlinson, H.A., Ferguson-Smith, M.A. (1982). Prognostic significance of raised serum alpha-fetoprotein levels in twin pregnancies, Br. J . Obstet. Gynaecol., 89,8 17-820. Second Report of the U.K. Collaborative Study on Alpha-fetoprotein in relation to Neural Tube Defects (1979). Amniotic fluid alpha-fetoprotein measurement in the antenatal diagnosis of anencephaly and open spina bifida in early pregnancy, Lancet, ii, 651-662. Wald, N., Cuckle, €I. ( I 987). Recent advances in screening for neural tube defects and Down syndrome. In: Rodeck, C. (Ed.). Prenatal Diagnosis, London: Bailliere Tindall. Wald, N.J., Cuckle H.S. (1990a). The complementary use of biochemical tests and ultrasound in the detection of neural tube defects and Down's syndrome. Part I-Screening. In: Chervenak, F.A., lsaacson, F., Campbell, S. (Eds). Textbook of Ultrasound in Obstetrics and Gynecology, New York: Little Brown, in press. %"Id. N.J., Cuckle, H.S. (1990b). The complementary use of biochemical tests and ultrasound in the detection of neural tube defects and Down's syndrome. Part 11-Diagnosis. In: Chervenak, F.A., Isaacson, F., Campbell, S. (Eds). Textbook of Ultrasound in Obstetrics and Gynecology, New York: Little Brown, in press. Wald, N.J., Cuckle, H.S., Boreham, J. (1984). Alpha-fetoprotein screening for open spina bifida: effect of routine biparietal diameter measurement to estimate gestational age, Rev. Epidemiol. Sante Publique, 32,62-69.
10,71-77 (1990)
MATERNAL SERUM ALPHA-FETOPROTEIN SCREENING FOR OPEN NEURAL TUBE DEFECTS IN TWIN PREGNANCIES H. C:UCKLE*, N. WAI>D*,J. D. STEVENSON?, H. M. MAY?, M. A. FERGUSON-SMITH?**, A. MII~FORD WARDS, H. M. BARBOURS, K. M. LAURENCE~~ AND B. NORGAARD-PEDERSEN~
*Department of Environmental and Preventive Medicine, St Bartholomew's Medical College, Charterhouse Square, London E C l M 6BQ, U.K.; 7 Duncan Guthrie Institute of Medical Genetics. Yorkhill. Glasgow G3 8SL, U.K.; $Supraregional Protein Reference Unit, Department of Immunology. Royal Hallamshire Hospital, Shefield SIO ZJF, U.K.;$Department of Clinical Chemistry, Western General Hospital, Edinburgh EH4 ZXU, U.K.; Ij Child Health Laboratories, Department of Child Health. Heath Park, Cardiff CF4 4 X N , U.K.; fistaten Seruminstitut, Hormone Department, Amager Boulevard 80, DK-2300 Copenhagen S , Denmark
SUMMARY Data e n maternal serum alpha-fetoprotein (AFP) levels at 13-24 weeks' gestation in 46 twin pregnancies with open neural tube defects (22 with anencephaly, 24 with open spina bifida) and 169 unaffected twins were used to estimate the detection and false-positive rates associated with different cut-off levels. Using the conventional cut-off level of 2.5 multiples of the median (MOM)for unaffected singleton pregnancies of the same gestation and laboratory, the detection rate in twins was 99 per cent for anencephaly and 89 per cent for open spina bifida, with a false-positive rate of 30 per cent. Using a 5.0MOM cut-off level to maintain a similar false-positive rate to that found among singleton pregnancies at 16-18 weeks' gestation (about 3 per cent), the detection rate was 83 per cent for anencephaly and 39 per cent for open spina bifida. Estimates are provided of the odds of having a n affected twin pregnancy given a positive AFP result as well as the odds for individual women with a raised AFP level. K E Y WORDS
Alpha-fetoprotein Twin pregnancies Neural tube defects Antenatal screening Maternal serum
INTRODUCTION In maternal serum alpha-fetoprotein (AFP) screening programmes for open neural
tube defects (NTDs) data are available to estimate, in singleton pregnancies, the detection rate, the false-positive rate, and the odds of being affected in women with positive results (either as a group or for individuals) (Fourth Report of the U.K. Collaborative AFP Study, 1982; Wald et al., 1984). In twin pregnancies, only the false-positive rate can be estimated (Wald and Cuckle, 1990a); insufficient data have been published on affected twin pregnancies (in which one or both fetuses have an NTD) to estimate the detection rate and the odds of being affected for women with positive results (First Report of the U.K. Collaborative AFP Study, 1977; Ghosh et a/., 1982). T o obtain these estimates we pooled data from six centres.
**Presentaddress: Cambridge University, Department of Pathology, Tennis Court Road, Cambridge CB2 IQP, U.K.
0197--3851/90/020071-07$05.00 C1 1990 by John Wiley & Sons, Ltd.
Received8 August I989 Accepted 4 November 1989
72
H. CUCKLE E T A L .
MATERJALS AND METHODS Each of the six centres was asked to obtain information on twin pregnancies in which one or more of the fetuses had an open neural tube defect and an AFP test had been performed between 13 and 24 weeks’ gestation. When more than one AFP test was done, only the first was included in this analysis. Forty-six pregnancies were available for study: from Glasgow (20), Sheffield (9), Edinburgh (7), Oxford (4), Cardiff (4), and Copenhagen (2). In 20 cases, one of the fetuses had anencephaly; in 23 cases, one had open spina bifida (without anencephaly); and there here three affected concordant sets of twins-two with anencephaly (one conjoined) and the other with open spina bifida. An unselected series of 169 twin pregnancies from Oxford, which were not asociated with neural tube defects and on which AFP tests had been performed between 13 and 24 weeks’ gestation, were also studied. AFP levels were expressed in multiples of the normal median (MOM) for unaffected singleton pregnancies of the same gestational age (usually based on ‘dates’, i.e., the time since the first day of the last menstrual period) in the appropriate laboratory. Eleven of the 20 cases from Glasgow had previously been reported (Ghosh et al., 1982) with the MOM values calculated using normal medians based on 1620 pregnancies tested over a short period. In this paper we used concurrent normal medians in the calculation. Detection rates, false-positive rates, and the odds of being affected for women with positive results wereestimated by fitting log Gaussian distributions to the AFP results from affected and unaffected pregnancies (Fourth Report of the U.K. Collaborative AFP Study, 1982; Cuckle et al., 1988). The odds of being affected given a positive result were estimated by multipl!ying the birth prevalence of anencephaly and spina bifida in twins (expressed as an odds) by the appropriate likelihood ratio; for all women with a positive result as a group the appropriate likelihood ratio is the detection rate divided by the false-positive rate, and for an individual it is the relative heights of the two Gaussian distributions at that woman’s AFP level. The birth prevalence of twins associated with a neural tube defect was taken to be 2.28 times that for singletons (Wald and Cuckle, 1987). In estimating means and standard deviations of the Gaussian distributions, we used the method described in Appendix (1) of the Fourth Report of the U.K. Collaborative AFP Study (1982) to exclude extreme outliers. The median was used as an estimate of the mean, and the interval between the 10th and 90th centiles divided by 2.56 was used to estimate the standard deviation. RESULTS Table 1 shows the individual AFP levels (in MOM)from affected twin pregnancies arranged in ascending order. There were insufficient data to assess whether, like with singleton pregnancies, discrimination between affected and unaffected pregnancies was greater at 16-18 weeks’ gestation than at other gestational ages (First Report of the U.K. Collaborative AFP Study, 1977). The three concordant twin pregnancies did not have results substantially different from those of the discordant twins. For this reason we included them with all affected twins. Figure 1 is a probability plot of the MOM values from affected and unaffected pregnancies. The straight lines in the figure represent Gaussian distributions of log, (,
MSAFP IN TWIN PREGNANCIES
73
Table 1. Maternal serum AFP levels (in MOM) in twin pregnancies with one or both twins affected by an open neural tube defect Anencephaly AFP level
(weeks’
gestation)
Open spina bifida AFP level
(weeks’ gestation)
1 .o 2.1 3.2 5.0 5.2 5.2 5.5 5.9*t 6.4 7.0 7.1 7.3 7.7 7.9* 8.1 8.7 8.8 9.5 11.0 14.0 14.3 14.7
*Both twins affected; otherwise only one affected. tConjoined twins. MOM= Multiple of the normal median for singletons at the same gestation and laboratory.
AFP with the means and standard deviations specified in Table 2 that were derived from the data after excluding the outlying values of 1.0 and 2.1 MOMrelating to two anencephalic pregnancies and 0.3 MOM from an unaffected pregnancy. The figure shows that the distribution of AFP levels in twin pregnancies are approximately log Gaussian over a wide range of values. Table 3 shows the estimated detection and false-positive rates based on the means and standard deviations specified in Table 2 according to AFPcut-off level, together with the odds of being affected for women with positive results as a group, assuming that the singleton birth prevalence in the absence of antenatal diagnosis and selective abortion is 1 per 1000 each for anencephaly and open spina bifida. Table 4 shows the estimated odds for individual women with a specified AFP result. If the birth prevalence were higher (or lower) in a particular community, the left-hand side of the odds ratio should be multiplied by the extent to which it is higher (or lower).
74
H. CUCKLE ETAL.
/
o
cSMJATIvE PFFCEm
Figure 1. Probability plot of centiles of AFP in multiples of the median (MOM)among 22 anencephalic ( A ) , 24 open spina bifida (O), and 169 unaffected (.) twin pregnancies after excluding outlying values specified in the footnote in Table 2. The continuous lines are those defined by fitted Gaussian distributions with means and standard deviations in Table 2
Table 2. Means and standard deviations of AFP in anencephalic, open spina bifida, and unaffected twin pregnancies
Anencephaly Open spina bifida Unaffected
No. of twin pregnancies*
Mean (log,, MOM)
(MOM)
Standard deviation (log,,, MOM)
22 24 169
0.8749 0.6435 0.2788
(7.50) (4.40) (1.90)
0.1829 0.1987 0.2280
*Three with outlying AFP values were not used in the estimations: two with anencephaly (1.0 and 2.1 MOM)and one unaffected (0.3 MOM). MOM= Multiple of the normal median for singleton pregnancies at the same gestation and laboratory
DISCUSSION Our estimates of the detection ‘rate, the false-positive rate, and the odds of being affected given a positive result in twin pregnancies (Table 3) should be of use to those responsible for AFP screening programmes for open NTDs. A centre using the conventional cut-off level of 2.5 MOM based on ‘dates’ at 16-1 8 weeks’ gestation can expect, in singleron pregnancies, detection rates of 89 per cent for anencephaly and 75 per cent for open spina bifida with a false-positive rate of 3.3 per cent or less. The
75
MSAFP IN TWIN PREGNANCIES
Table 3. Detection rate, false-positive rate, and odds of being affected by anencephaly or open spina bifida given a positive result (OAPR) for twin pregnancies according to A F P level (assuming a singleton birth prevalence of 1 per 1000 births for each defect in the absence of antenatal diagnosis and selective abortion)* Detection rate AFP level
(MOM)
22.5 :? 3.0 I? 3.5 ._ .> 4.0 124.5 I> 5.0 I? 5.5 ;> 6.0
Anencephaly (YO)
99 98 96 93 89 83 77 70
Open spina bifida (%)
89
80 69 58 48 39 31 25
Falsepositive rate (%)
30 19 12 7.8 5.0 3.3 2.2 1.4
OAPR Anencephaly
:130 :85 :55 :37 :25 :17 :13 :8.8
Open spina bifida
1:150
1:lOO 1:76 159 1:46 1 :37 1:31 1:25
*Derivedfrom Gaussian distributions of log,, AFP using the means and standard deviationsspecified in Table 2. M O M =Multiple of the normal median for singletonsat the same gestation and laboratory.
detection rates will be higher in twins (99 and 89 per cent), but as many as one-third of women with unaffected twin pregnancies will have positive results and the odds of being affected given a positive result will not be high (1 :130 for anencephaly, 1:150 for spina bifida, if the birth prevalence in singletons is 1 per 1000 for each defect). To achieve a similar false-positive rate in twin pregnancies as for singleton pregnancies at 16-18 weeks’ gestation, the cut-off level would need to be raised to 5.0 MOM (false-positive rate 3.3 per cent); the correponding detection rate would be 83 per cent for anencephaly and 39 per cent for open spina bifida. To achieve a similar open spina bifida detection rate in twin pregnancies as for singleton pregnancies, the cutoff level would need to be 3-3.5 MOM; the corresponding false-positive rate would be I S 2 0 per cent. Regardless of the screening policy and the cut-off level that is selected for use with twin pregnancies, the estimates of the odds of an individual woman with a raised AFP level having an affected twin pregnancy (Table 4) should be helpful when counselling women with positive screening results. In practice, the ultrasound scan examination which normally follows a positive result will exclude anencephaly. The finding of twins in the absence of anencephaly at that examination is often taken to he the reason for the raised AFP level and no further action is taken. The reluctance to terminate an unaffected co-twin or to attempt a selective termination of the affected twin both lend support to this policy. However, using the estimates in Table 4. offers the option of making an informed decision on the possibility of having a diagnostic ultrasound examination or amniocentesis. The detection rate of these diagnostic procedures in twin pregnancies is not known. While for ultrasound it is unlikely to be much different from that found in singleton pregnancies (100 per cent for anencephaly and 88 per cent in spina bifida-based on the combined results of
76
H. CUCKLE ET AL.
Table 4. Odds of being affected by anencephaly or spina bifida for individual twin pregnancies according to AFP level (assuming a singleton birth prevalence of 1 per 1000 birthis for each defect in the absence of antenatal diagnosis and selective abortion)*
AFP level (MOM)
2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8 6.0
Anencephaly
Open spina bifida
1 :48 000
1:1700 1:1200 1:830 1:620 1 :470
1 :23 000 1:12 000 1:6900 1:4100 1:2600 ]:I700 1:llOO 1:760 1:540 1:390 1 :290 1:220 1:170 1:130 1:lOO 1:82 1:66 1:54 1 :44 1:37
1:370
1:300 1 :240 1:200 :170 :140 :120 :I 10 :93 :82 :73 :65 1:58 153 1:48 1:44
*Derived from Gaussian distributions of log,, AFP using the means and standard deviations specified in Table 2. MOM= Multiple of the normal median for singletons at the same gestation and laboratory.
seven studies (Wald and Cuckle, 1990b)),for amniotic fluid tests it might be lower in twins because of diffusion of AFP or acetylcholinesterase from the amniotic sac containing the affected twin to the other sac. In one study, only two out of six discordant twins had raised amniotic fluid AFP levels, although it was not known for certain which sac had been s,ampled(Second Report of the U.K. Collaborative AFP Study, 1979). ACKNOWLEDGEMENT
We thank Nora Jones for help in the identification of cases from Oxford. REFERENCES Cuckle, H., Wald, N., Thompson, S. (1988). Estimating a woman’s risk of havinga pregnancy associated with Down’s syndrome using her age and serum alpha-fetoprotein level, Br. J . Obstet Gynaecol., 94,387-402.
MSAFP IN TWIN PREGNANCIES
77
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