Trisomy 18 and maternal serum and amniotic fluid alpha-fetoprotein

Maternal serum and amniotic fluid alpha-fetoprotein levels were studied retrospectively in a total of 58 pregnancies with trisomy 18. In those pregnancies uncomplicated by either fetal exomphalos or neural tube defect the midtrimester maternal serum alpha-fetoprotein (MSAFP) levels were markedly reduced, the median value for 38 such pregnancies being 0.6 multiples of the median (MoM). Trisomy 18 with exomphalos was associated with a higher median MSAFP, but still within the normal range: 1.1 MoM, (nine pregnancies); trisomy 18 with exomphalos and neural tube defect (NTD) was associated with grossly raised levels: median MSAFP was 4-5 MoM (three pregnancies). Amniotic fluid alpha-fetoprotein (AFAFP) levels were normal in uncomplicated trisomy 18 pregnancies: median AFAFP, for 19 pregnancies, was 1.1 MoM. Exomphalos alone, or together with neural tube defect, was associated with greatly elevated levels of AFAFP; for exomphalos alone median AFAFP was 9.59 MoM (four pregnancies), and for exomphalos with neural tube defect the median AFAFP was 23.95 Mom (three pregnancies). Screening with low and high MSAFP, routine ultrasound, and amniocentesis on all women aged 35 years or over, together might identify over 50 per cent of pregnancies with trisomy 18.     

The 48,XXYY syndrome: A case detected by maternal serum alpha-fetoprotein screening

A 17-year-old woman was referred for amniocentesis due to a low maternal serum alpha-fetoprotein (AFP) concentration in a voluntary screening test. The fetal karyotype was 48,XXYY, and the pregnancy was terminated. Autopsy of the fetus disclosed agenesis of the corpus callosum and unusual facial features.     

The psychological effects of false-positive results in prenatal screening for fetal abnormality: A prospective study

The purpose of the study was to describe the impact of false-positive results from initial maternal serum alpha-fetoprotein (MS-AFP) screening. The analyses compared two groups of women, those receiving a negative result (n = 346) and those receiving an initial positive result (n = 26), over four time points—prior to testing, immediately after testing, later in pregnancy, and in the post-partum period. Receiving an abnormal result was associated with high levels of anxiety which were reflected in increased worry about the baby's health and a more negative attitude towards the pregnancy and the baby. Women who had an initial abnormal result were offered a variety of further tests. Those women who went on to have amniocentesis were less worried about their baby's health in the third trimester and also less anxious post-partum than those who did not have amniocentesis. In view of the increasing number of screening tests available, it is necessary to establish whether and how these levels of distress can best be reduced.     

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.     

Racial differences in maternal serum human chorionic gonadotropin and unconjugated oestriol levels

We assayed maternal serum samples from 134 black and 268 white women from 16 to 18 weeks of gestation for intact human chorionic gonadotropin (hCG), and unconjugated oestriol (uE3). Serum from women with high ( ⩾ 2·5 MOMs) or low (risk for Down syndrome ⩾ 1/365) maternal serum alpha-fetoprotein (MSAFP) levels were excluded. After correcting for maternal weight, we found that median hCG levels were 16 per cent higher in black women but uE3 levels were not significantly different. These results confirm three other studies for hCG and one study for uE3. Corrections are recommended for both maternal serum hCG and AFP before calculating the risk for Down syndrome in black women.     

Adverse perinatal outcome in patients screen-positive for neural tube defects and fetal down syndrome

An association between various abnormal mid-trimester maternal serum analyte values and adverse perinatal outcome has been reported. From an original sample of 14 857 women, we observed five women who were ‘screen-positive’ for both neural tube defects [maternal serum alpha-fetoprotein (MSAFP) ≥2·5 multiples of the median] and Down syndrome [risk ≥1/274 using MSAFP, maternal serum unconjugated oestriol (MSuE3), maternal serum human chorionic gonadotropin (MShCG), and maternal age]. The four patients who elected to undergo amniocentesis all demonstrated both normal karyotype and normal amniotic fluid AFP levels. All five cases were associated with intrauterine growth retardation (IUGR) and abnormal pregnancy outcomes. Two cases exhibiting severe IUGR on ultrasound examination were terminated at 19·1 and 21·2 weeks, respectively; the former also exhibited fetal calcifications and positive maternal serology for toxoplasmosis. In another case, fetal demise occurred at 36 weeks' gestation in a patient who had been treated for syphilis in the second trimester. Neither infection was confirmed in fetal tissue studies. Though resulting in live births, the remaining two cases required operative deliveries; emergency Caesarean sections for fetal distress were performed at 38 and 32 weeks, respectively, the latter case being associated with severe pre-eclampsia. We conclude that elevated mid-trimester MSAFP levels concurrent with maternal serum analyte values associated with increased risk for fetal Down syndrome may presage a poor perinatal outcome, particularly IUGR and possibly congenital infection.     

Risk-based prenatal screening for trisomy 18 using alpha-fetoprotein,unconjugated oestriol and human chorionic gonadotropin

Nine centres collaborated to examine the feasibility of a screening method for trisomy 18 that was based on assigning individual risk, using a combination of maternal age and measurements of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). Second-trimester measurements of these analytes were obtained from 94 trisomy 18 pregnancies. In the 89 pregnancies without an associated open defect, the median levels for AFP, uE3, and hCG were 0.65, 0.43 and 0.36 multiples of the unaffected population median, respectively. The strongest individual predictor of risk for trisomy 18 was uE3, followed by hCG, AFP, and maternal age, in that order. Using a method of individual risk estimation that is based on the three markers and maternal age, 60 per cent of pregnancies associated with trisomy 18 would be detected at a risk cut-off level of 1:100, with a false-positive rate of about 0.2 per cent. One in nine pregnancies identified as being at increased risk for trisomy 18 would be expected to have an affected pregnancy. This risk-based screening method is more efficient than an existing method that is based on fixed analyte cut-off levels. Even though the birth prevalence of trisomy 18 is low, prenatal screening can be justified when performed in conjunction with Down syndrome screening and when a high proportion of women offered amniocentesis have an affected fetus.     

Prospective intervention trial of a screening protocol to identify fetal trisomy 18 using maternal serum alpha-fetoprotein,unconjugated oestriol,and human chorionic gonadotropin

Two prenatal centres in New England, routinely using a screening protocol for fetal Down syndrome that included maternal serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG) measurements in combination with maternal age, adopted a separate screening protocol for trisomy 18. That protocol identified a pregnancy as being at high risk when AFP, uE3, and hCG measurements all fell at or below specified cut-offs (0.75, 0.60, and 0.55 multiples of the median, respectively), regardless of maternal age. Among the first 19 491 women screened, 98 (0.5 per cent) were found to have values which placed them in the high-risk category. Four of these women were subsequently found not to be pregnant. In two others, samples from non-pregnant individuals were found to have been incorrectly submitted for analysis in place of the samples from the pregnant women. All of the remaining 92 women were counselled and offered amniocentesis and fetal karyotyping. Eighty-eight (96 per cent) accepted. Karyotypes or birth outcomes were available on all 92 pregnancies. Six cases of trisomy 18 and one case of Turner syndrome were identified by karyotype. One case of trisomy 18 was identified for every 14 unaffected pregnancies offered amniocentesis. In the present prospective study, an estimated 85 per cent of the cases of trisomy 18 were identified. However, given the small number ofcases (six), the 95 per cent confidence interval for the detection rate is broad (40–95 per cent).     

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.     

Psychological impact of amniocentesis on low-risk women

The study comprised 85 young (25–34 years old) women who underwent genetic amniocentesis, 80 comparable young women who had an ultrasoundscan at the same gestational age and 74 women (35–40 years old) who had amniocentesis. The State-Trait Anxiety Inventory and Visual Analogue Scales concerning anxiety and worry were used on four occasions to evaluate psychological changes during pregnancy. The anxiety level in the younger women decreased after amniocentesis and a further decrease was observed after the results were communicated to them. However, similar changes were seen in the group of younger women after ultrasonography, and there was no difference in anxiety level between the two groups of younger women in the 16th or in the 35th week of pregnancy. Thus, in younger women at low genetic risk amniocentesis was neither anxiety-relieving, nor anxiety-creating. The level of anxiety before amniocentesis was not higher in the older than in the younger women having amniocentesis. However, in the younger women a significant decrease in anxiety was seen as soon as amniocentesis had been performed, while in the older women this decrease was delayed until after the results were known.     

Screening for Down's syndrome in older women based on maternal serum alpha-fetoprotein levels and age: Preliminary results

We report the results of screening for Down's syndrome (DS) in older women using published rate schedules based on maternal serum alpha-fetoprotein (MSAFP) and age. Five hundred and seventeen patients aged 35 years and older, who were referred for a mid-trimester genetic amniocentesis, were first tested for MSAFP and then underwent an amniocentesis. Individual risks for DS, combining MSAFP and age, were derived using three different published rate schedules. Theoretical selection for amniocentesis was made using the cut-off level of the average collective risk for a 35-year-old woman (1:380 at live birth or 1:270 at amniocentesis). Six affected pregnancies (five with DS and one with trisomy 18), which were diagnosed prenatally, were all found to be at a higher risk than the specified cut-off. These cases would have been diagnosed in any event, using any of the published rate schedules. According to these rate schedules, between 39 and 45 per cent of the patients would be in the lower risk group and therefore would have been counselled not to undergo amniocentesis. Further studies should be conducted in order to reach conclusive screening policies for DS in older women.     

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.     

Prospective maternal serum human chorionic gonadotropin screening for the risk of fetal chromosome anomalies and of subsequent fetal and neonatal deaths

A prospective study of maternal serum human chorionic gonadotrophin (hCG) measurement for the selection of pregnancies with an increased risk of fetal trisomy 21 was undertaken in 24 000 pregnancies from 1 January 1989 to 31 December 1990. Maternal serum was sampled at 15-18 weeks of gestation. hCG was measured in one laboratory, with one technique. This ‘hCG high level’ technique was developed for this screening. Amniocentesis was offered to each woman with a maternal serum hCG level above the cut-off. The follow-up of the pregnancies is known in 92 per cent of cases. The combination of hCG values and maternal age gave a detection efficiency of 63 per cent for trisomy 21 with rates of amniocentesis of 30 per cent for patients aged 37 years, 20 per cent for patients aged 35 or 36 years, and 5 per cent for patients under 35 years of age. Based on this prospective study, an individual risk was calculated combining the serum hCG value and maternal age. Seventy-four per cent of trisomy 13, trisomy 18, triploidy, and 5p- deletion were detected either in the same selected group of women or in combination with ultrasonography performed when hCG values were very low. The follow-up study showed that women who had high or low hCG values represented a group at high risk for fetal or perinatal death.     

First-trimester maternal serum alpha-fetoprotein and human chorionic gonadotropin screening for chromosome defects

The aim of this study was to determine the efficacy of combined maternal serum alpha-fetoprotein (MSAFP) and maternal serum human chorionic gonadotropin (MShCG) screening in detecting chromosome defects in the first trimester of pregnancy. Sera of 492 women (previously assayed for MSAFP) were analysed for MShCG under code without knowledge of cytogenetic results. Overall, 48 of 492 patients (9·8 per cent) had either an MSAFP multiple of the median ⩽0·5 or an MShCG β/a z ratio multiple of the median ⩽ 0·25, eight of whom had a fetus with a serious chromosome defect. A third of fetuses with Down' s syndrome and 83 per cent with trisomy 18 were detected at a potential‘cost’ of providing chorionic villus sampling or amniocentesis in 8·6 percent of women screened.     

Prenatal screening and diagnosis of neural tube defects in England and Wales in 1985

A survey was carried out to determine the effect of prenatal screening and therapeutic abortion on births in 1985 with anencephaly and spina bifida in England and Wales. Maternal serum alpha-fetoprotein tests were done on 399 288 women (60 per cent of pregnant women): 4 per cent were reported as being screen-positive and 1 per cent had an amniocentesis. An estimated 534 pregnancies associated with anencephaly were terminated and an estimated 445 pregnancies associated with spina bifida (but without anencephaly) were terminated. Most (63 per cent) of the anencephalic pregnancies were first suspected from an ultrasound examination; 57 per cent of the spina bifida pregnancies were first suspected from a positive maternal serum alpha-fetoprotein test, 35 per cent by ultrasound, and the remaining 8 per cent by other means. The birth prevalence of anencephaly declined by 94 per cent between 1964–1972 and 1985, but when the terminations of pregnancy on account of having a fetus with anencephaly are added to the births the decline in prevalence was only 50 per cent. The birth prevalence of spina bifida declined by 68 per cent over the same period but when the terminations were added to the births the decline in prevalence was only 32 per cent. Among births with anencephaly 66 per cent had had no screening or diagnostic tests in early pregnancy, but in those that did nearly all were positive–usually in twin pregnancies where one fetus was affected but not the other. Among births with spina bifida, 48 per cent had no tests and in those that did the results were mainly negative. We conclude that in order to monitor adequately the national screening programme for anencephaly and spina bifida a special neural tube defects register should be formed.     

Prenatal ascertainment of triploidy by maternal serum alpha-fetoprotein screening

We report our experience in ascertaining fetal triploidy during routine maternal serum alpha-fetoprotein (MSAFP) screening. Three cases were identified after elevated MSAFP tests. Two of the three had normal amniotic fluid alpha-fetoprotein (AFAFP). The third had amniocentesis too late for AFAFP interpretation. Three additional cases were detected by amniocentesis without prior MSAFP screening and none had an elevated AFAFP. A literature review revealed eight triploid fetuses detected as a result of an elevated MSAFP. Of the five with AFAFP quantitation, only one had an abnormal value and the elevation was minimal. In these 14 cases from our own and other reports, ultrasound findings of placental and fetal abnormalities were often noted, but a pattern diagnostic of triploidy was not present. We conclude that, for optimal prenatal detection of triploidy, fetal karyotyping should be included when an amniocentesis is performed for elevated MSAFP.     

The influence of serum screening on the amniocentesis rate in women of advanced maternal age

We investigated the effect of maternal serum screening on the amniocentesis (AC) rate in women of advanced maternal age. The AC rate after maternal serum screening was compared in two groups of women with a singleton pregnancy, 855 women of 30–35 years and 98 of 36 years and older. In our population, 34·1 per cent of the women of 36 years or older were ‘screen-positive’ for Down syndrome. Only 41·2 per cent of these women chose to undergo AC as opposed to 88·2 per cent in the younger age group. Within the older age group, the tendency to avoid AC increased with increasing age. Maternal serum screening led to a significant decrease in the AC rate in the older women. In this group, a comparison between the ‘a priori’ and the calculated risk might have had more influence on the decision to undergo AC than being screen-positive or screen-negative as such. We conclude that maternal serum screening had a major effect on the AC rate in women of advanced maternal age. This is of importance in a society in which the average maternal age is steadily increasing.     

Prenatal diagnosis of spina bifida aperta after first-trimester valproate exposure

In the context of a prospective study on the adverse effects of anti-epileptic drugs on fetal outcome, we evaluated our experience with prenatal diagnosis by ultrasonography and α- fetoprotein (AFP) determination in amniotic fluid. We compared these results with AFP values in maternal serum obtained prior to amniocentesis. From November 1985 to July 1990, amniocentesis at 16–18 weeks of gestation was performed in 267 pregnancies of 237 different women using anti-epileptic drugs. Among 92 pregnancies with maternal valproic acid use, five (including one concordantly affected monozygotic twin-pair) were terminated because of a spina bifida aperta, all prenatally diagnosed by AFP determination and acetylcholinesterase electrophoresis in amniotic fluid. The maternal serum AFP level was raised (⩾ 2.5 multiples of the median (MOM) for singleton pregnancies and ⩾ 4.5 MOM for twin pregnancies) in only two of these five affected pregnancies. We emphasize that maternal serum AFP levels may be unreliable for prenatal screening for fetal neural tube defects in women taking valproate and recommend that amniocentesis and fetal ultrasound examination should be offered directly.     

Economic assessment of maternal serum screening for Down's syndrome using human chorionic gonadotropin

The effectiveness and costs of prenatal screening programmes for Down's syndrome using maternal serum markers will vary significantly depending on the biological cut-off values chosen in order to select women, at each maternal age, who will be sent for amniocentesis. On the basis of the first French prospective study of human chorionic gonadotropin (hCG) measurement in maternal serum, this paper shows that the screening protocol currently used in France, where hCG cut-off values are defined in order to offer amniocentesis to women of all ages with a 1 percent fetal risk of Down's syndrome, would detect 64·06 per cent of all cases of trisomy 21 at birth and would be highly profitable for the French social security system. On the basis of a representative sample of 100 000 pregnant women, the total costs of screening would reach $8 302 000 but would generate net potential savings of $32 186 000 in terms of life-long costs of care for trisomic 21 children which would be ‘avoided’ by termination of pregnancy following a positive diagnosis of Down's syndrome. Economic assessment shows that cost-benefit analysis would justify lower hCG cut-off values and a higher detection rate of fetal Down's syndrome (74·45 per cent) than the current French protocol. This paper concludes that it is ethical and value-laden issues, such as the consequences for women and couples of false positives and false negatives of screening, rather than economic and financial arguments that may set limits to the utilization of screening for Down's syndrome using maternal serum markers like hCG.     

Increased maternal serum alpha-fetoprotein and human chorionic gonadotropin in compromised pregnancies other than for neural tube defects or Down syndrome

Intrauterine fetal death occurred in four women who were ‘screen-positive’ in a screening programme for neural tube defects (NTDs) and Down syndrome (DS). These women had very high levels of maternal serum alpha-fetoprotein (MSAFP) and maternal serum human chorionic gonadotropin (MShCG). Therefore, we evaluated all ‘screen-positive’ women in whom both of these markers were ⩾ 2.0 multiples of the median. The cases fulfilling these criteria totalled 11, and only one of them had no complications. High concentrations of both MSAFP and MShCG in a number of these cases might have been caused by an increased placental volume, which, in turn, might have been induced by decreased perfusion of the placenta. We conclude that screening programmes wrongly determine a high risk of fetal NTD or DS if the concentrations of both these parameters are very high. Invasive diagnostic procedures should be avoided in these cases, particularly in view of the increased risk of an adverse pregnancy outcome.