LETTERS TO THE EDITOR 223

Table 1. Concentrations of pregnancy associated plasma protein A (PAPP-A) in 30 pregnancies affected by fetal Down

syndrome

Case Gestational age PAPP-A No.* (completed weeks) (MOM)?

1 2 3 4 5 6 7 8 9

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Median value for the 30 cases

16 16 16 16 16 16 17 17 18 17 18 18 17 15 17 17 17 16 16 15 16 15 19 15 15 18 17 19 19 17

0.4 1 0.42 0.48 0.53 0.54 0.6 1 0.61 0-66 0.69 0.73 0.76 0.77 0.87 0.94 0.99 1.02 1.08 1.14 1-18 1.22 1.27 1.37 1.37 1-39 1.55 1.57 1.60 1.63 2-19 2.8 1

1.01

These results, taken together with the two previous reports, indicate little or no dif- ference in PAPP-A values in cases of fetal Down syndrome in the second trimester. Thus, PAPP-A appears not to be useful for second-trimester screening.

GEORGE J. KNIGHT*, GLENN E. PALOMAKI*,

JAMES E. HADDOW*,

NIKLAUS A. BERSINGER~ AND HENNING SCHNEIDER~

*Foundation f o r Blood Research, Scarborough, ME, U.S.A.

iPrenatal Diagnostic Center, Lexington, M A , U.S.A.

1 University Department of Obstetrics and Gynaecology,

Berne, Switzerland

WAYNE MILLER?,

REFERENCES

Brambati, B., Lanzani, A., Tului, L. (1991). Ultrasound and biochemical assessment of first trimester pregnancy. In: Chapman, M., Grudzinkas, G., Chard, T. (Eds). The Embryo: Normal and Abnormal Development and Growth, London: Springer-Verlag, 181-194.

Cuckle, H., Lilford, R.J., Teisner, B., Holding, S., Chard, T., Grudzinskas, J.G. (1992). Preg- nancy associated plasma protein A in Down’s syndrome, Br. Med. J., 305,425.

Hemmila, I. (1988). Lanthanides as probes for time-resolved fluorometric immunoassays, Scand. J . Clin. Lab. Invest., 48,389400.

Wald, N., Stone, R. , Cuckle, H.S., Grudzinskas, G., Barkai, G., Brarnbati, B. (1992). First tri- mester concentrations of pregnancy associated plasma protein A and placental protein 14 in Down’s syndrome. Br. Med. J., 305,28.

Wald, N., Voller, A. (1992). Pregnancy associated plasma protein A in Down’s syndrome, Br. Med. J., 305,425.

*Arranged in ascending order by PAPP-A

tMOM =Multiple of the unaffected population concentration.

median value.

Table 1 shows the PAPP-A values, expressed as a MOM value, for the 30 affec- ted pregnancies (gestational age range 15-19 completed weeks). The median value for the cases is 1.01 MOM, and this value is not significantly different from the 1.02 MOM found for unaffected pregnancies (matched rank sum test, chi-square=0.94, 1 degree of freedom, p = 0.3).

Low maternal serum oestriol and chorionic gonadotropin in the prediction of adverse pregnancy outcome

In their multi-marker screening programme for neural tube defects and Down syndrome, Beekhuis e t al. (1992) found a complication of pregnancy in 10 out of 11 women with raised maternal serum levels of both alpha- fetoprotein (AFP) and human chorionic gonadotropin (hCG). We have identified a similar group of women at high risk of adverse pregnancy outcome, namely those

224 LETTERS TO THE EDITOR

Table 1. Marker levels and pregnancy outcome in 1 1 cases of fetal loss among 163 women with raised or low maternal serum uE3 and hCG levels

Marker level Gestation (MOM) (weeks)

Case No. uE3 hCG AFP Test Delivery Outcome

1 2 3 4 5 6 7 8 9

10 11

0.03 0.07 0.03 0.23 0.04 0.09 0.04 0.32 0.04 0.59 0.04 12 0.20 0.14 0.35 0.06 0.82 4.64 1.66 0.20 3.08 0.97

< 0.02 0.84 0.34 3.05 1.17 1.62 1.78 0.57 0.89 0.98 0.77

16 18 16 18 15 15 17 18 16 23 16 18 16 19 16 34 15 29 17 38 16 23

Blighted ovum Miscarriage Blighted ovum Missed abortion (13 weeks size) Intrauterine death Miscarriage Miscarriage Macerated stillbirth Intrauterine death Stillbirth Miscarriage

with low maternal serum levels of both unconjugated oestriol (uE3) and hCG.

Women with raised maternal serum AFP levels have a high rate of fetal loss as do those with low levels, though to a lesser extent (Wald and Cuckle, 1984). This prompted us to investigate pregnancy outcome in women with either raised or low levels of the two other markers which are now routinely measured in many Downsyndrome screening programmes.

In Kingston General Hospital, Hull, between June 1989 and February 1991,3525 women were routinely tested at 15-20 weeks’ gestation for all three markers. An hCG level was raised if it was above 4.0 multiples of the normal gestation-specific median (MOM), and low if it was below 0.25 MOM. For uE3, two non-parallel assays were used at differ- ent time periods. Using the Biotecx assay, a level was raised if above 2.7 MOM and low if below 0.05MOM; using an Amersham assay, the levels were 2.4 and 0-4MOM, respectively. Excluding twins, neural tube defects, Down syndrome, and Edwards syn- drome, there were 163 pregnancies with raised or low levels and 11 (7 per cent) ended in fetal loss.

Seven of the fetal losses were in the 50 women with low uE3 levels, a rate of 14 per cent [95 per cent confidence interval (CI) 4-24 per cent]; one was in the 48 with raised uE3; six were in the 52 women with low hCG (12 per cent; 95 per cent CI 3-20 per cent);

and two were in the 31 with raised hCG. The details of all I 1 cases are shown in Table 1 together with the marker levels. The women with the highest risk were the five with low levels of both uE3 and hCG, four of whom had fetal losses (80 per cent; 95 per cent CI 45-100 per cent). Another case (No. 8) with low hCG had a borderline low uE3, and one (No. 4) with a low uE3 had a borderline low hCG. The table also shows the AFP levels. It is noteworthy that in the two cases of blighted ovum all three marker levels were low, and in the missed abortion the AFP was raised in the presence of low uE3 and borderline low hCG.

The low marker levels in the cases of blighted ovum are probably due to the absence of the fetus, and the abnormal levels in the missed abortion could reflect the fact that the pregnancy was no longer viable at the time of the test. Some of the other cases might be explained by undiagnosed chromo- somal abnormality-Down syndrome for raised hCG and low uE3, Edwards syndrome for low hCG and low uE3 (Canick et af., 1990), and triploidy for low uE3 with either raised or low hCG (Mason et al., 1992; Oyer and Canick, 1992). Two of the cases (Nos. 6 and 9) were examined cytogenetically and these were found to be normal. The macerated stillbirth had a number of features indicative of Edwards syndrome but this could not be confirmed due to failure of cell culture.

LETTERS TO THE EDITOR 225

Our findings suggest that in Down syn- drome screening there is a need to act on low maternal serum levels of both uE3 and hCG by performing an ultrasound scan. If the fetus is alive and there are other pointers amniocentesis might be offered, otherwise it would be worth considering increased obser- vation throughout the rest of the pregnancy with a view to intervention if needed.

GERALD MASON*, STEVE LINDOW*,

CLIVE RAMSDEN', HOWARD CUCKLE?

AND STEPHEN HOLDING$ *Department of Obstetrics and Gynaecology.

St James's University Hospital, Leeds. LS9 7TF. U.K.

?Institute of Epidemiology and Health Services Research,

Depart men t of Clin ical Medicine, Leeds, LS2 PLN, U.K.

$Department of Haematology, Kingston General Hospital,

Hull, HU3 IUR, U.K.

REFERENCES Beekhuis, J.R. , van Lith, J.M.M., de Wolf,

B.T.H.M., Mantingh, A. (1992). Increased maternal serum alpha-fetoprotein and human chorionic gonadotropin in compromised preg- nancies other than for neural tube defects or Down syndrome, Prenat. Diagn., 12,643447.

Canick, J.E., Palomaki, G.E., Osathanondh, R. (1990). Prenatal screening for trisomy 18 in the second trimester, Prenat. Diagn., 10,546548.

Mason, G., Linton, G., Cuckle, H., Holding, S. (1992). Low maternal serum human chorionic gonadotrophin and unconjugated oestriol in a triploidy pregnancy, Prenat. Diagn., 12,

Oyer, C.E., Canick, J.A. (1992). Maternal serum hCG levels in triploidy: variability and need to consider molar tissue, Prenat. Diagn., 12, 621-628.

Wald, N.J., Cuckle, H.S. (1984). Open neural-tube defects. In: N.J. Wald (Ed.). Antenatal and Neonatal Screening. Oxford: Oxford University Press, 25-13.

545-552.

Vaginosonography and chorionic villus sampling (CVS)

In their paper 'Transvaginal chorionic villus sampling', Sidransky et al. (1990) stress that transvaginal CVS (TV-CVS) is especially useful in patients with posteriorly placed placentae in retroverted uteri and in women with large obstructing fibroid tumours. In

late 1985 we developed this new CVS tech- nique because of the following consider- ations: (1) using a single sampling method, CVS is not possible in 100 per cent of patients; (2) the need to avoid ascending infection; (3) to keep the sampling site at the margin of the placenta; and (4) to have an ultrasonic prognostic evaluation of the preg- nancy before sampling (Ghirardini et al . , 1986a,b,c). These possibilities in the appli- cation of transvaginal sonography have found wide acceptance. Jansen and van 0 s (1989) in their review on vaginal ultrason- ography stress that in the near future it will be considered malpractice not to employ vaginal ultrasonography in certain cases. In another review (Popp and Ghirardini, 1990), the value of the original ideas is further sub- stantiated. In terms of preoperative diag- nosis, vaginosonography is the method of choice. The small depth of penetration of the needle under high-resolution ultrasound guidance is a striking advantage of this method. The tip of the needle can be located accurately for biopsy in the margin of the placenta, avoiding the formation of retro- chorionic haematomas. Vaginosonography is the method of choice to identify the placen- tal insertion and to study the viability of pregnancy in difficult cases (e.g., obese women). The larger needles (0.9mm or more) used in TV-CVS avoid repeated need- ling in order to obtain sufficient material, and the duration of sampling is shorter than for other sampling methods. TV-CVS is a single- operator technique: the operator holds the transducer with one hand and with the other, the syringe connected to the needle. TV-CVS can be used not only in retroverted uteri with posterior placentae, but also in other cases, particularly if the placenta is low. The presence of large fibroid tumours is often a contraindication, because the high resol- ution of transvaginal scanning has a limited depth of penetration. Fipally, vaginosonog- raphy and TV-CVS are of great value in twins and uterine malformations.

G. GHIRARDINI*

*Division of Obstetrics and Gynaecology. Franchini Hospital.

I-Montecchio Emilia, RE, Italy;

t University Clinic for Women and Michaelis Midwifery School,

D-Kiel, Germany

AND L. w. POPP?