H. S. Cuckle

MATERNAL SERUM ALPHA-FETOPROTEIN MEASUREMENT: A SCREENING TEST FOR DOWN SYNDROME

The median maternal serum alpha-fetoprotein (AFP) level at 14-20 weeks gestation in 61 pregnancies associated with Down syndrome was 0.72 multiples of the median (MoM) value for a series of 36 652 singleton pregnancies unaffected by Down syndrome or neural-tube defect--a statistically significant reduction. The difference is great enough to form the basis of a screening test. By selecting for amniocentesis women with serum AFP levels less than or equal to 0.5 MoM at 14-20 weeks gestation (excluding any of these that ultrasound cephalometry shows to have been due to the overestimation of gestational age) 21% of pregnancies with Down syndrome would be identified as well as 5% of unaffected pregnancies. If amniocentesis were offered to all women aged 38 years or more and, in addition, to younger women with serum AFP below specified maternal age-dependent cut-off levels (less than or equal to 1.0 MoM at 37 years, less than or equal to 0.9 at 36, less than or equal to 0.8 at 35, less than or equal to 0.7 at 34, less than or equal to 0.6 at 32-33, less than or equal to 0.5 at 25-31) 40% of pregnancies with Down syndrome and 6.8% unaffected pregnancies would be selected.

Low second trimester maternal serum unconjugated oestriol in pregnancies with Down's syndrome

Summary. Second trimester maternal serum unconjugated oestriol levels were measured in the stored serum samples from 22 pregnancies associated with Downs syndrome and 110 unaffected control pregnancies, matched for maternal age, gestational age, duration of storage of the serum sample, smoking habits and maternal weight. The serum unconjugated oestriol level of each affected pregnancy was expressed as a multiple of the median (MoM) of its five matched controls. The unconjugated oestriol levels were significantly lower in the affected pregnancies than in the unaffected pregnancies; the median MoM was 0·79 (P<0·05). This association between low serum unconjugated oestriol and fetal Downs syndrome early in pregnancy raises the possibility that serum unconjugated oestriol measurement may be added to maternal age and alpha‐fetoprotein measurement in the antenatal screening for Downs syndrome.

Antenatal maternal serum screening for Down's syndrome: results of a demonstration project.

OBJECTIVES--To assess the implementation of antenatal screening for Downs syndrome in practice, using individual risk estimates based on maternal age and the three serum markers: alpha fetoprotein, unconjugated oestriol, and human chorionic gonadotrophin. DESIGN--Demonstration project of Downs syndrome screening; women with a risk estimate at term of 1 in 250 or greater were classified as screen positive and offered diagnostic amniocentesis. SETTING--Hospital and community antenatal clinics in four health districts in London. SUBJECTS--12,603 women of all ages with singleton pregnancies seen between February 1989 and the end of May 1991, with follow up of the outcome of pregnancy completed to the end of 1991. MAIN OUTCOME MEASURES--Uptake of screening, detection rate for Downs syndrome, false positive rate, odds of being affected given a positive result, and uptake of amniocentesis in women with positive screening results, together with the costs of the screening programme. RESULTS--The uptake of screening was 74%. The detection rate was 48% (12/25), and the false positive rate was 4.1%, consistent with results expected from previous work based on observational studies. There was a loss of detection due to the selective use of ultrasound scans among women with positive screening results. One affected pregnancy occurred among 205 reclassified as negative; this illustrated the danger of false negatives occurring in this group and lends weight to the view that if an ultrasound estimate of gestational age is used it should be carried out routinely on all women rather than selectively among those with positive results. The estimated cost of avoiding the birth of a baby with Downs syndrome was about 38,000 pounds, substantially less than the lifetime costs of care. CONCLUSION--Antenatal maternal serum screening for Downs syndrome is effective in practice and can be readily integrated into routine antenatal care. It is cost effective and performs better than selection for amniocentesis on the basis of maternal age alone.

Maternal serum screening for Down's syndrome: the effect of routine ultrasound scan determination of gestational age and adjustment for maternal weight.

Objective To investigate the effect of using a routine ultrasound estimate of gestational age and maternal weight adjustment on maternal serum alpha‐fetoprotein (AFP), unconjugated oestriol (uE3) and human chorionic gonadotrophin (hCG) levels in antenatal screening for Downs syndrome.

Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome

Summary. The median maternal serum unconjugated oestriol level between 13 and 27 weeks gestation in 77 pregnancies associated with Downs syndrome was lower than the median level in 385 unaffected control pregnancies matched for maternal age, gestational age, and duration of serum sample storage (P<0·001). The median level for the affected pregnancies was 73% of that in the controls. Low unconjugated oestriol levels can be used to detect fetal Downs syndrome; at cut‐off levels selected to detect at least 35% of affected pregnancies, unconjugated serum oestriol was a better screening test than either maternal age or serum alpha‐fetoprotein (AFP). The use of all three variables in combination to select women with a 1:250 or greater risk of a Downs syndrome term pregnancy would yield a 45% detection rate with a falsepositive rate of 5.2%. The same detection rate using maternal age alone or using age and serum AFP in combination would yield higher falsepositive rates, 15% and 9.8% respectively. The addition of unconjugated oestriol to a Downs syndrome screening programme would therefore be more efficient than the use of age and AFP alone; for a given detection rate fewer women would need an amniocentesis or, for a given percentage of women having an amniocentesis, more pregnancies with Downs syndrome would be detected.

First trimester concentrations of pregnancy associated plasma protein A and placental protein 14 in Down's syndrome.

study more than a third of the abused women had been admitted five times or more. The greater differences in admissions in the ages over 30 might be related to ongoing domestic violence. Several studies indicate that the risk ofbeing the victim of wife beating is most pronounced in the fourth decade of life. 24 The abused woman, in her exposed and desolate situation, does not always seek medical care for specific somatic diseases.3 The battered wife syndrome consists of somatic, psychosomatic, and psychiatric symptoms, and psychosocial support is an important reason for seeking hospital care.5 Any physician should consider the possibility of ongoing domestic violence when confronted with a female patient lacking other obvious reasons for frequent hospital admissions.

The effect of smoking in pregnancy on maternal serum alpha-fetoprotein, unconjugated oestriol, human chorionic gonadotrophin, progesterone and dehydroepiandrosterone sulphate levels

H. S. Cuckle, N. J. Wald, J. W. Densem, P. Royston Department of Environmentaland Preventive Medicine, St Bartholomew’s Hospital Medical College, Charterhouse Square, London EClM6BQ. G. J. Knight, J. E. Haddow, G. E. Palomaki Foundation fo r Blood Research, P O Box 190, Scarborough, Maine 04074, USA & J. A. Canick. Department of Pathology and Laboratory Medicine, Brown University, Women and Infants’ Hospital, 120 Dudley Street, Providence, RI 0290-5-2401, USA

Ultrasound fetal femur length measurement in the screening for Down's syndrome

The fetal femur length determined by an ultrasound examination at between 13 and 39 weeks gestation in 83 pregnancies associated with Downs syndrome was statistically significantly less than the expected value for pregnancies with the same biparietal diameter examined in the same ultrasound department (P<0.0001). Expected values were based on linear regressions of femur length on biparietal diameter in 1340 control pregnancies from 27 ultrasound departments. The median value for the affected pregnancies was 0.94 times the expected value (95% CI 0.92 to 0.97). Eleven per cent of affected and 14% of control pregnancies had values ≤0.85 times the expected. The reduction in femur length in affected pregnancies was not related to biparietal diameter or to maternal age. Fetal femur length may be useful as an ancillary screening variable in the antenatal screening for Downs syndrome.

Pregnancy associated plasma protein A in Down's syndrome.

detected.3 As some undescended testes descend spontaneously we suggest that all boys with an undescended testis at 8 months should be reviewed at 1 year and, if the testis has still not descended, referred to a surgeon so that orchidopexy can be arranged during the second year of life. To reduce the toll of testicular cancer better health education is required as this would also benefit all potential victims, 90% of whom have normally descended testes. Self examination should be taught at an early age and may lead to earlier presentation of testicular tumours.

The effect of estimating gestational age by ultrasound cephalometry on the sensitivity of alpha-fetoprotein screening for Down's syndrome

Women whose pregnancies are associated with fetal Down’s syndrome have, on average, low serum alpha-fetoprotein (AFP) levels (Merkatz et al. 1984; Cuckle et al. 1984; Fuhrmann et al. 1984; Taboret al. 1984; Cowchock & Ruch 1984; Seller 1984; Guibaud et al. 1984; Trigg et al. 1984; Spencer & Carpenter 1985; Murday & Slack 1985; Hershey et al. 1985; Doran et al. 1986; Brambati et al. 1986) and screening for Down’s syndrome based on combining information on a low serum AFP level and maternal age is now in progress in several centres. The clinical interpretation of a maternal serum AFP result depends on judging whether it is high or low for the established range for pregnancies of the same gestational age. Since maternal serum AFP increases in the second trimester of pregnancy by about 17% per week at the time when AFP tests are usually done, under-estimation of gestational age will lead to a given AFP result appearing relatively high while the overestimation of gestational age will make it appear low. When gestational age is estimated by means of an ultrasound biparietal diameter (BPD) measurement any systematic tendency for a particular group of fetuses to have small BPD results will lead to the under-estimation of gestational age and any tendency for fetuses to have large BPD measurements will lead to over-estimated gestational age. For example, spina bifida fetuses between 15 and 22 weeks gestation have BPD values that are on average 0.83 cm smaller than those of unaffected fetuses of the same gestational age and so are credited with a less advanced gestational age than they actually have