The impact of screening for open neural tube defects in England and Wales

Using information derived from the voluntary system of notification of congenital malformations in England and Wales, the birth prevalence of anencephaly and spina bifida was estimated to have declined by 80 per cent from 31.5 to 6.2 per 10 000 between 1964–1972 and 1985. Over the same period, notified terminations of pregnancy with a suspected fetal central nervous system abnormality increased from less than 1 per cent to 56 per cent of neural tube defect births and central nervous system terminations combined, accounting for 31 per cent of the decline in births. Routinely collected national statistics provide a method for monitoring the impact of screening for open neural tube defects. However because they are incomplete and lack detail an alternative method of monitoring is needed. This paper includes an outline of such a method, together with the results of a pilot study designed to assess the feasibility of monitoring screening in the Oxford Region.     

MATERNAL SERUM ALPHA-FETOPROTEIN SCREENING FOR OPEN NEURAL TUBE DEFECTS IN TWIN PREGNANCIES

Data on 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 5·0 MoM 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 an affected twin pregnancy given a positive AFP result as well as the odds for individual women with a raised AFP level.     

Amniotic fluid acetylcholinesterase measurement in the prenatal diagnosis of open neural tube defects. Second report of the collaborative acetylcholinesterase study

Seventeen centres from Australia, Britain, France, and the United States collaborated in a study to compare amniotic fluid acetylcholinesterase (AChE) determination by gel electrophoresis and amniotic fluid alpha-fetoprotein (AFP) measurement as diagnostic tests for open neural tube defects. The study was based on 32 642 women with singleton pregnancies (including 428 with open spina bifida and 238 with anencephaly) who had an amniocentesis at 13–24 weeks' gestation. The AChE test yielded a detection rate for open spina bifida of 99 per cent (95 per cent confidence interval 98–100 per cent), 98 per cent for anencephaly (95 per cent confidence interval 96–100 per cent), and a false-positive rate of 0.34 per cent (95 per cent confidence interval 0.28–0.40 per cent) excluding miscarriages, intrauterine death, and serious fetal abnormalities. The false-positive rate was 0.30 per cent among the 13 centres that used a specific AChE inhibitor in the test. Comparable rates for the AFP test were less favourable. (For example, the open spina bifida detection rate was 90 per cent and the false-positive rate was 0.46 per cent using the cut-off levels specified in the U.K. Collaborative AFP Study.) The AChE false-positive rate was lower in samples that were not bloodstained (0.16 per cent) than in those that were (2.4 per cent). It was higher in women who had an amniocentesis on account of a raised maternal serum AFP level (0.56 per cent) than in those who had one for other reasons (0.29 per cent). The best results were obtained by a combination of the two tests, an effective and economical policy being to perform the AFP measurement on all amniotic fluid samples and an AChE test on samples with AFP levels greater than or equal to 2.0 multiples of the normal median (about 5 per cent of all samples). Using this policy, the open spina bifida detection rate was 96 per cent and the false-positive rate was 0.14 per cent (0.06 per cent for samples that were not bloodstained and 1.2 per cent for those that were; 0.40 per cent for women with raised serum AFP levels and 0.09 per cent for other women). This policy offers a useful improvement to the prenatal diagnosis of open spina bifida.     

A comparison of amniotic fluid alpha-fetoprotein and acetylcholinesterase in the prenatal diagnosis of open neural tube defects and anterior abdominal wall defects

Amniotic fluid samples received for routine prenatal diagnosis of open neural tube defects were used for a study to compare amniotic fluid acetylcholinesterase (AChE) determination using a monoclonal antibody (4F19) enzyme antigen immunoassay and amniotic fluid alpha-fetoprotein (AFP) measurement as diagnostic tests for open neural tube defects. The study was based on 9964 women with singleton pregnancies and known outcome (including 6 with anencephaly and 18 with open spina bifida) having an amniocentesis at 14–23 weeks of gestation. The AChE immunoassay yielded detection rates for anencephaly of 100 per cent (95 per cent confidence interval (CI) 54·07–100 per cent), for open spina bifida of 100 per cent (95 per cent CI 81·47–100 per cent), for anterior abdominal wall defects of 20 per cent (95 per cent CI 0-51-71-64 per cent), and a false-positive rate of 0·22 percent (95 per cent CI 0·14–0·34 per cent) excluding anencephaly, open spina bifida, and anterior abdominal wall defects. For similar detection rates the false-positive rate of the AFP test was significantly higher, 0·74 per cent (95 per cent CI 0·58–0·94 per cent). On the basis of these findings, it is recommended that the technically simple AChE immunoassay should be used on all samples; the AFP test should only be used on the 0·5 per cent of the samples with concentrations of AChE activity ⩾ 8·5 nkat/1 for clear samples and blood-stained samples becoming clear after centrifugation, and ⩾ 25·0 nkat/1 for blood-stained samples that are discoloured after centrifugation; an AFP cut-off level of 2·0 MOM is recommended for this policy. Thereby, the detection rates for anencephaly, open spina bifida, and anterior abdominal wall defects would be 100, 100, and 20 per cent, respectively (95 per cent CIs 54·07–100, 81·47–100, and 0·51–71·64 per cent, respectively), and the false-positive rate would be 0·08 per cent (95 per cent CI 0·03–0·16 per cent) (excluding anencephaly, open spina bifida, and anterior abdominal wall defects).     

The impact of maternal serum alpha fetoprotein screening on open neural tube defect births in North-East Scotland

Over the three years period 1980–1982, 18 256 pregnancies in the Grampian Region of N-E Scotland including the islands of Orkney and Shetland were screened for raised levels of maternal serum alpha fetoprotein (MSAFP) in the second trimester. Thirty six cases of fetal open neural tube defect in singletons were detected (18 anencephaly and 18 spina bifida). Four additional cases of open spina bifida were associated with normal MSAFP levels although two of these were detected by amniotic fluid AFP measurement when amniocentesis was carried out because of previous NTD history. A further three cases of open spina bifida and two of anencephaly occurred in unscreened pregnancies. The MSAFP screening programme alone was thus instrumental in reducing the birth incidence of open neural tube defects by 36 out of 45 cases (80 per cent) in singletons.     

Four years' experience of maternal alpha-fetoprotein screening and its effect on the pattern of antenatal care

Estimation of alpha-fetoprotein (A.F.P.) in maternal serum was used as a screening method for the detection of fetal neural tube defect (N.T.D.) in 7315 women over a four year period. Of these, 5668 pregnancies were tested between 15 and 21 weeks. Action was advised in 129 patients (2·3 per cent). In 74 patients, the only action required was reviewing the notes, including the report of any ultrasound examination, and repeating the blood A.F.P. Detailed ultrasound including scanning the fetal spine was requested in 47 patients and amniocentesis was advised in 19 of these (0·33 per cent). In practice the incidence of amniocentesis was 0·28 per cent as three patients declined our advice. The programme gave detection rates between 15 and 21 weeks of 100 per cent and 75 per cent respectively for anencephaly and open spina bifida. A high fetal mortality was associated with persistently elevated blood A.F.P. levels whether amniocentesis was performed or not.     

Amniotic fluid fibrinolytic system in fetal neural tube defects

Second trimester amniotic fluid fibrinolytic system was examined in normal pregnancies and those complicated by anencephaly, spina bifida and fetal chromosome abnormalities. No significant difference was demonstrated between the fibrinolytic systems from normal pregnancies and those complicated by fetal chromosome abnormalities. In pregnancies complicated with anencephaly and spina bifida no significant difference was demonstrated for alpha-1-antitrypsin, alpha-1-antichymotrypsin and urokinase. Plasminogen was significantly lower (p < 0.02) and plasmin significantly higher (p < 0.001) than levels from normal amniotic fluid. Alpha-2-macroglobulin, fibrinogen, FDP-D and FDP-E were detected only in pregnancies complicated with anencephaly and spina bifida.     

Cystic hygroma simulating an encephalocele

An ultrasound examination at 17 weeks gestation on a woman with a family history of spina bifida suggested that the fetus had a closed encephalocele. Amniotic fluid alphafetoprotein, rapidly adhering cells and acetylcholinesterase gel electrophoresis were normal. The pregnancy was terminated and the fetus was found to have a large cystic hygroma. It is suggested that in counselling parents of an infant or fetus with a cystic hygroma and with a normal chromosome constitution, ultrasound examination in future pregnancies is advisable, because of the possibility of autosomal recessive inheritance.     

Second-trimester levels of maternal serum unconjugated oestriol and human chorionic gonadotropin in pregnancies affected by fetal anencephaly and open spina bifida

Unconjugated oestriol (uE3) and human chorionic gonadotropin (hCG) levels were determined in second-trimester maternal serum (MS) samples from 21 pregnancies associated with fetal anencephaly and 15 pregnancies associated with fetal open spina bifida. Each measurement was expressed as a multiple of the median (MoM) for unaffected pregnancies for each completed week of gestation. In pregnancies associated with anencephaly, the median value for MSuE3 was very low (0–17 MoM, range <0·12–0·33 MoM), suggesting a functional defect in the fetal adrenal prior to 20 weeks' gestation; the median value for MShCG was also low (0–73 MoM), although not to the same extent as for MSuE3. A biological explanation for the hCG result is not apparent. In pregnancies associated with open spina bifida, the MSuE3 and MShCG values were unremarkable, consistent with a lack of involvement of these open fetal defects in the synthesis and secretion of uE3 and hCG.     

Is maternal alpha-fetoprotein screening still of value in a low-risk area for neural tube defects?

Estimation of maternal serum alpha-fetoprotein (AFP) was used as a screening method for the detection of neural tube defects (NTDs) in 6344 women over three years. Of 88 (1.4 per cent) who had one or more serum AFP levels equal to, or greater than, 2.5 multiples of the median (MoM) for the relevant gestational age, 43 (0.68 per cent) underwent amniocentesis. There were eight NTDs. Four of these were screened by serum AFP, and all cases of spina bifida had serum AFP levels greater than 3.0 MoM, including one small open defect which was not seen on ultrasound. The other four cases of NTD, which were not screened, were identified by ultrasound. Of 64 singleton pregnancies 32 (50 per cent) had serum AFP levels between 2.5 and 3.0 MoM, and low birthweight (⪕2500 g) occurred in 29 per cent. Because of improvements in ultrasound techniques and the apparent falling incidence of NTD, the role of serum AFP as the primary screening procedure should be regularly reviewed. Effective screening is dependent on mothers booking early.     

Justification of maternal serum alphafetoprotein screening in a population with low incidence of neural tube defects

A prospective study of maternal serum alphafetoprotein (α-FP) screening of 9838 women in an area with low prevalence of neural tube defects and predominance of anencephalics revealed that an intervention point of single serum α-FP level above 2·8 times the median was appropriate for this population. Ninety per cent of anencephalics and all fetuses with anterior abdominal wall defects were detected. There was no spina bifida among the population screened. Two per cent of the population screened had serum α-FP level above this cut-off level. Thirty-two per cent of twin pregnancies, 7 per cent of small-for-gestational age infants and 9 per cent of pregnancies which ended in either abortion or perinatal death in the population screened also had one serum α-FP level above this intervention point. The false positive rate was 66 per cent. This false positive rate was only reduced to 63 per cent if instead of one, two serum α-FP level above this intervention point was considered abnormal. Using this strategy there was no significant reduction in the detection rate of fetal anomalies and other pregnancy complications. Because of the predominance of anencephalics in this population the diagnosis of fetal anomaly in women with abnormal serum a-FP level was made by ultrasound examination alone. The reason amniocentesis was not performed in these patients was to avoid unnecessary loss of normal pregnancies which may result from this procedure.     

Detecting neural tube defects by amniocentesis between 11 and 15 weeks' gestation

Forty-two open neural tube defects (NTDs) were identified in our series of 7440 amniocenteses tested between 11 and 15 weeks of gestation. Using a cut-off of ≥2.0 MOM, the detection rate for open NTDs was 95 per cent; 100 per cent each for anencephaly and spina bifida; and 78 per cent for encephalocele. Two encephaloceles had AFP levels less than 2.0 MOM and negative AChEs. Thirty-four (81 per cent) of these NTDs were tested between 13 and 15 weeks and 8 (19 per cent) before 13 weeks. There were 0.6 per cent false positives by AFP (excluding serious abnormalities and fetal death) and 0.1 per cent after AChE. The likelihood of an open NTD after an elevated AFP (≥2.0 MOM) was 24 and 77 per cent for any serious abnormality. These results, when combined with an earlier study, indicate that amniotic fluid AFP appears to be as sensitive a test for open NTDs between 13 and 15 weeks as between 16 and 20 weeks. Additional experience is necessary to determine this before 13 weeks.     

Neural tube defects in the sample of genetic counselling

Objective This study was conducted to evaluate the major demographic details, diagnostical and clinical features, as well as the risk of recurrence of cases with the major types of neural tube defects (NTD). We also examined the efficiency of ultrasonography based on autopsy examinations during 26 years. Methods The investigations were made into the sample of 743 NTD diagnosed between 1 January 1976 and 31 December 2002. A computerized database was used to sum up the available information about the individual cases; in addition to surveying the couples' major demographic details, we also had the opportunity to collect detailed information about the history, diagnostics (ultrasound) and outcome of the pregnancies as well as the results of the autopsies during the investigation. Results In the 743 cases of NTD, maternal and paternal median ages turned out to be 23.7 years (±5.22 years) and 28.7 years (±5.81 years), respectively. The male:female ratio was 0.78. Comparable samples of anencephaly and spina bifida allowed for the conclusion that a positive genetic history was equally often found while a positive obstetrical history was almost twice as common in anencephaly. The sensitivity of the maternal serum-alpha fetoprotein (AFP) screening test is the highest in anencephaly and lowest in encephalocele. While the majority of cases of anencephaly were diagnosed before the 24th gestational week, examples of diagnosing spina bifida and encephalocele at a later time could also be found. Among the associated malformations other than those of the central nervous system special mentioning should be made of fetal pyelectasia, cleft palate as well as diaphragmatic herniation. No pathological karyotypes were found in association with encephalocele or spina bifida, but anencephaly was accompanied with trisomy 21 and trisomy 18 in one case each. Anencephaly was found to have the highest risk of recurrence in both nervous system malformations and malformations other than those of the nervous system. Sonography proved to be the most reliable method in cases of enecephalocele. Conclusion The respective median values of maternal and paternal age show that aetas has no role in the occurrence of NTDs. NTDs are more common among girls. Positive genetic, obstetrical and medical findings are of great importance in the incidence of NTDs. Although reliable to only a limited extent, maternal serum-AFP tests are considered to be useful and necessary in screening NTDs, while sonography is the gold standard method in recognizing these frequent malformations. The knowledge of the eventual associated malformations is mainly important in certain cases of spina bifida, which may also yield a good post-natal prognosis. Our data obtained from the sample of 26 years also confirm that the periconceptional administration of folic acid reduces the incidence and risk of recurrence of NTDs. Copyright © 2007 John Wiley & Sons, Ltd.     

Amniocentesis carried out for neural tube indications in South Wales 1973–1981: Outcome of pregnancies and findings in the malformed abortuses

The 2872 second trimester amniocenteses followed by amniotic alphafetoprotein (AFP) estimations carried out in South Wales between 1973 and 1981 on women known to be at increased risk for neural tube defect (NTD) and those who had a raised serum AFP level in an NTD screening programme led to the identification of 78 pregnancies of a fetus with anen-cephalus, 61 with ‘open’ spina bifida, 8 with gastroschisis, 3 with exomphalos, 2 with encephalo-cele and 6 with chromosome abnormality. Pregnancies of fetuses having 4 potentially identifiable NTDs were missed because of an equivocal AFP level and there were two false positive results leading to the termination of one normal fetus. It is emphasized that both the latter problems of one normal fetus. It is emphasized that both the latter problems would not have occurred had gel-electrophoresis for isoenzymes of acetyl cholinesterase been available. Follow-up of pregnancies showed that 7 children with ‘closed’ NTD and 3 with congenital hydrocephalus were born. The anencephalics and the ‘open’ spina bifidas had a more florid lesion than is usual at term. Nearly all the spina bifidas were associated with hydrocephalus, often severe and with an obvious Arnold-Chiari malformation. All but 13 had leg or back deformation or malformations in other systems, mostly in the renal tract.     

The effect of the introduction of prenatal diagnosis on the reproductive history of women at increased risk from neural tube defects

The reproductive history of 45 couples at increased risk for neural tube defect (NTD) who came for genetic counselling in 1970 and 1971 were compared with a similar number counselled in 1975 and 1976, when prenatal diagnostic tests were freely offered. They were subsequently interviewed in their homes and had their reproductive history recorded to the end of 1973 and 1978 respectively. Nearly all had a previous child with an NTD and none of the women were pregnant at the time of counselling. The effect of prenatal diagnosis was to speed somewhat the decision about further pregnancies, but the number of couples deciding on no further children and on having further pregnancies were almost identical in the two groups. The average number of pregnancies was 2·8 per family, with only 1·2 surviving children. The pregnancy outcomes are discussed as are the reasons for not attempting further pregnancies in both groups, which included very high risk of recurrence, a surviving spina bifida child, inability to accept the tests or its implications. Ninety per cent of the second group had tests. Their reactions to the tests were favourable but all complained of the waiting time between amniocentesis and obtaining the results. They all would have tests again in any future pregnancy. The reason for women not having prenatal diagnostic tests included inability to accept termination. It is concluded that couples in South Wales decide either to have no more children or to have further pregnancies regardless of tests. but tests speed a decision and enable the women to enjoy the pregnancy after obtaining the results, and that an NTD greatly reduces the number of children per family. A termination for an NTD is much more acceptable to most than an NTD at term. The reasons for this are discussed.     

Amniotic fluid acetylcholinesterase in the prenatal diagnosis of open neural tube defects and abdominal wall defects: A comparison of gel electrophoresis and a monoclonal antibody immunoassay

Stored amniotic fluid samples collected in Oxford and East Birmingham as part of the Collaborative Acetylcholinesterase Study were assayed for the presence of acetylcholinesterase (AChE) using a monoclonal antibody (4F19) enzyme antigen immunoassay. These results were compared with the results of a gel AChE which had been performed earlier. A total of 5689 samples from singleton pregnancies were analysed (including 36 with anencephaly, 77 with open spina bifida and 17 with anterior abdominal wall defects). The gel test yielded detection rates of 97% for anencephaly, 99% for open spina bifida and 94% for abdominal wall defects; the false positive rate (excluding pregnancies associated with serious abnormalities, miscarriages and intrauterine deaths) was 0·24%. The monoclonal test yielded similar results; using appropriate cut-off values to allow for differences in acetylcholinesterase levels in blood stained and clear samples, a similar false-positive rate of 0·22% was associated with detection rates of 97%, 95 % and 71 % respectively for the three types of defect. Although the detection rates and the false positive rate were slightly higher for the gel test, a result that might be explained by a decrease in AChE activity caused by storage of the samples, the monoclonal test has the advantages of requiring less interpretative expertise, it can be performed on a larger number of samples a day and it is not affected by contamination with fetal calf serum.     

Birth prevalence of down's syndrome in England and Wales

The natural birth prevalence of Down's syndrome for England and Wales in 1974–1987 (i.e., the birth prevalence in the absence of prenatal diagnosis and the induced abortion of affected pregnancies) was estimated by applying the maternal age-specific birth prevalence derived from epidemiological studies to the number of births in single-year age groups tabulated by the Office of Population Censuses and Surveys (OPCS). On average, the natural birth prevalence was 12.6 per 10 000 births and increased slightly from 12.2 to 13.2 per 10 000 births over the 14-year period. Using data on induced abortions carried out on account of Down's syndrome reported to OPCS under the statutory abortion notification scheme, 14 per cent of affected births were avoided by the induced abortion of affected pregnancies, so that the actual birth prevalence of Down's syndrome was estimated at 10.8 per 10000 births. Using data on Down's syndrome births reported to OPCS under the voluntary congenital malformation notification scheme, the prevalence was 7.2 per 10000 births, so only 67 per cent of the estimated number of affected births were, in fact, notified to the scheme.     

Attitudes toward abortion for fetal anomaly in the second vs. the third trimester: A survey of Parisian obstetricians

Cross-cultural differences exist in prenatal diagnosis and abortion for fetal anomaly, stemming from variations in laws, reimbursement policies, litigation, physicians' decision-making authority, and attitudes toward the prevention of handicaps. The first part of this paper discusses such differences in France and the U.S. The second part describes a survey of practising obstetricians in Paris, designed to assess (1) their attitudes toward pregnancy termination for various conditions, (2) their concern about fetal viability, (3) their desire for diagnostic certainty before justifying a late abortion, and (4) their perceived role in such decision-making. Among the 64.8 per cent (N = 217) who responded, the majority supported third-trimester termination (TTT) for diseases such as spina bifida, trisomy 21 , microcephaly, and Duchenne muscular dystrophy; 30–59 per cent supported TTT for cystic fibrosis and sickle cell disease; and 22–29 per cent supported TTT for haemophilia, tetralogy of Fallot, limb amputation, and Turner and Klinefelter syndromes. Obstetricians who approved of abortion across trimesters were less concerned with the certainty of diagnosis than its severity, more likely to think that abortion ought to be the parents' choice, but more likely to report making a recommendation to the parents about whether to abort a fetus. Such permissive abortion attitudes might imply more permissive prenatal diagnosis and abortion practice among Parisian obstetricians, which might lead to increased migration of patients from other E.C. countries. Cross-cultural variation in obstetric practice suggests that an international registry of pregnancies terminated for medical reasons, enabling further study of this issue, would be valuable.     

Selective feticide of the affected twin by fetoscopic air embolism

Three twin pregnancies, each with one affected fetus (by microcephaly, haemophilia A and spina bifida respectively) were encountered. Selective feticide was performed at the patient's request by injection of filtered air into an umbilical vessel by fetoscopy. The method was successful in all three pregnancies two of which resulted in a live, healthy baby.     

A survey of diagnostic amniocenteses in Oxford from 1974–1981

A survey was conducted of the results of mid-trimester diagnostic amniocenteses in the Oxford Region from 1974 to 1981. The survey used data relating to all 4357 singleton pregnancies in which an amniocentesis was performed during this period. Follow-up information on outcome was obtained in respect of 4284 (98 per cent) pregnancies. A cell culture to determine karyotype and an alpha-fetoprotein determination was carried out in all cases. From 1974 to 1981 amniocenteses became increasingly common, rising from 2 to 32 per 1000 births. The most common indication for amniocentesis was a high risk of a chromosome abnormality–56 per cent of all amniocenteses. Within this group advanced maternal age was responsible for 89 per cent of the cases. The next most common indication was a high risk of a neural tube defect (37 per cent of all amniocenteses)–in 1974 a raised maternal serum alpha-fetoprotein level accounted for only 4 per cent of these; by 1981 this had risen to 67 per cent. There were seven false-positive and 132 true-positive diagnoses of neural tube defect; since 1981, with the introduction of amniotic fluid acetylocholinesterase determination as a secondary diagnostic test for neural tube defects, there have been no further false-positive diagnoses. In 1981 76 per cent of women aged 35 years or more did not have an amniocentesis. It is not known to what extent this was due to not offering women in this age group amniocentesis or to women not accepting such an offer.