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Canada, December 1990. Montreal: International Society of Hypertension, 1990.

7. Wilkes BM, Mento PF, Hollander AM, Maita ME, Sung S, Giradi EP. Endothelin receptors in human placenta: rela- tionship to vascular resistance and thromboxane release. Am J Physiol 1990;258:E864-70.

8. Hemsen A, Gillis C, Larsson 0, Haegerstrand A. Charac- terization, localization and action of endothelins in umbili- cal vessels and placenta of man. Acta Physiol Stand 1991; 143:395-404.

9. Nunez DJR, Brown MJ, Davenport AP, Neylon CB, Schoe- field JP, Wyse RK. Endothelin-1 mRNA is widely expressed in porcine and human tissues. J Clin Invest 1990;85:153’7- 41.

10. Benigni A. Gasnari F. Orisio S. et al. Human nlacenta ” I I

expresses the endothelin-1 gene and the corresponding protein is excreted in the urine in increased amounts during the course of normal pregnancy. AM J OBSTET GYNECOL 1991;164:844-8.

11 Hagerstrand A, Hemsen A, Gillis C, Larsson 0, Lundberg JM. Endothelin: presence in human umbilical vessels, high levels in fetal blood and potent constrictor effect. Acta Physiol Stand 1989;137:541-2.

12. Nisell H, Hemsen A, Lunell NO, Wolff K, Lundberg MJ. Maternal and fetal levels of a novel polypeptide, endothelin: evidence for release during pregnancy and delivery. Gynecol Obstet Invest 1990;30:129-32.

13. Iwata I, Takagi T, Yamaji K, Tanizawa 0. Increase in the concentration of immunoreactive endothelin in human pregnancy. J Endocrinol 1991;129:301-7.

14. Isozaki-Fukuda Y, Kojima T, Hirata Y, et al. Plasma im-

munoreactive endothelin-1 concentration in human fetal blood: its relation to asphyxia. Pediatr Res 1991;30:244-7.

15. Radunovic N, Lockwood CJ, Ghidini A, Alvarez M, Berkowitz RL. Is fetal blood sampling associated with increased beta-endorphin release into the fetal circula- tion? Am J Perinatol 1993;lO: 112-4.

16. Schiff E, Zael Y, Friedman SA, Shalev E. Fetal circulatory endothelin- 1,2 in the midtrimester. Gynecol Obstet Invest 1993;35:185-6.

17. Nakamura T, Kasai K, Konuma S, et al. Immunoreactive endothelin concentrations in maternal and fetal blood. Life Sci 1990;46:1045-50.

18. Usuki S, Saitoh T, Sawamura T, et al. Increased maternal plasma concentration of endothelin-1 during labor pain or on delivery and the existence of large amount of endothe- lin-1 in amniotic fluid. Gynecol Endocrinol 1990;4:85-97.

19. McQueen J, Kingdom JCP, Connell JMC, Whittle MJ. Fetal endothelin levels and placental vascular endothelin recep- tors in intrauterine growth retardation. Obstet Gynecol 1993;82:992-8.

20. Hakkinen LM, Vuolteenaho OJ, Leppaluoto JP, Laati- kainen TJ. Endothelin in maternal and umbilical cord blood in spontaneous labor and at elective cesarean deliv- ery. Obstet Gynecol 1992;80:72-5.

21. Hartikainen-Sorri AL, Vuolteenaho 0, Leppaluoto J, Rushoaho H. Endothelin in umbilical artery vasospasm. Lancet 1991;337:619.

22. Haugen G, Stray-Pedersen SS. Effects of endothelin-1 on vascular tension in human umbilical vessels. Early Hum Dev 1991;27:25-32.

Crown-rump length in chromosomally abnormal fetuses at 10 to 13 weeks’ gestation

Peter Kuhn, MD, Maria de Lourdes Brizot, MD, Pranav P. Pandya, MD, Rosalinde J. Snijders, PhD, and Kypros H. Nicolaides, MD

London, United Kingdom

OBJECTIVE: Our purpose was to investigate whether fetuses with aneuploidies demonstrate evidence of growth retardation during the first trimester. STUDY DESIGN: This was a retrospective, cross-sectional study of singleton pregnancies undergoing fetal karyotyping at 10 to 13 weeks’ gestation. Measurements of crown-rump length in 135 chromosomally abnormal fetuses were compared with those in 700 chromosomally normal fetuses. RESULTS: The median crown-rump length of fetuses with trisomy 18 (n = 32) was significantly reduced. In contrast, in fetuses with trisomy 21 (n = 72), trisomy 13 (n = 1 l), 47,XxX (n = 6), 47,XXY (n = 6), 45,X (n = 5), and triploidy (n = 3) the crown-rump length was not lower than normal. CONCLUSION: At 10 to 13 weeks’ gestation fetuses with trisomy 18 are growth retarded, whereas in trisomy 21, trisomy 13, and sex chromosome aneuploidy growth is normal. (AM J Oesm GYNECOL 1995;172:32-5.)

Key words: Crown-rump length, chromosomal abnormality, fetal karyotyping, maternal serum biochemistry

From the Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical School. Supported by the Swiss National Science Foundation (P.K.) Received for publication March 22, 1994; revised May IO, 1994; accepted June 21, 1994.

32

Reprint requests: K.H. Nicolaides, MD, Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical School, London, United Kingdom SE5 8RX. Copyright 0 1995 by Mosby-Year Book, Inc. 0002.9378/95 $3.00 + 0 6/l/58505

Volume 172, Number 1, Part 1 Am J Obstet Gynecol

Kuhn et al. 33

CRL (mm) CRL (mm) CRL (mm) 120

1

120

1 120 1

OJ 1 1 / 99

01, 01 / 70 77 84 91 70 77 84 91 98 70 77 84 91 98

Gestation (days) Gestation (days) Gestation (days)

Fig. 1. Crown-rump length (CRLJ in chromosomally normal fetuses (Zef) and in fetuses with trisomy 21 (center) and trisomy 18 (right) plotted on reference range with gestational age (mean, 5th and 95th percentiles).

Low birth weight is a common feature of many chromosomal abnormalities.‘, ’ Furthermore, prenatal studies during the second and third trimesters of preg- nancy have reported a high incidence of aneuploidies in severe intrauterine growth retardation3 The aim of this study was to investigate whether fetuses with aneu- ploidies demonstrate evidence of growth retardation during the first trimester.

Patients and methods This was a retrospective, cross-sectional study of

singleton pregnancies undergoing first-trimester fetal karyotyping. Measurements of crown-rump length in 135 chromosomally abnormal fetuses were compared with those in 700 chromosomally normal fetuses.

Patients were selected from our database with details on the 23,200 pregnancies that were investigated in our center between 1987 and 1993. The selection criteria were (1) known last menstrual period with a cycle length of 26 to 30 days, (2) no history of pregnancy or use of oral contraceptives in the 3-month period before con- ception, (3) ultrasonographic examination at 70 to 97 days since the first day of the last menstrual period, and (4) first-trimester fetal karyotyping. For those with a normal karyotype it was also required that there were no fetal malformations or pregnancy complications and that infants of normal weight (between the 3rd and 97th percentile)4 were born alive after 37 weeks’ gestation. The normal range of crown-rump length with gestation was constructed from data of 700 chromosomally nor- mal fetuses (25 cases for each gestational day between 70 and 97 days).

In each case, immediately before amniocentesis or chorionic villus sampling, the fetal crown-rump length was measured transabdominally with a real-time ultra- sonography system with a 3.5 or 5.0 MHz curvilinear transducer (Aloka SSD 650, Aloka, Tokyo). Measure-

ments were made on the screen by placing the calipers at the outer edge of the cephalic pole and at the outer edge of the fetal rump.

Statistical analysis. To establish a normal range for fetal crown-rump length with gestational age, regres- sion analysis was applied examining linear, quadratic, and cubic models for the association with gestational age (in days). Because the SD increased with gestation, logarithmic transformation was applied to stabilize vari- ance.5 Individual values from chromosomally abnormal fetuses were expressed as multiples of the normal me- dian for gestation. The Student t test was used to examine whether crown-rump length in chromosomally abnormal fetuses was significantly different from that in normals.

Results In the chromosomally normal group the fetal crown-

rump length increased exponentially with gestation (Log,, (Crown-rump length + 5) = 0.7156 + 0.0125 Gestational age (days), SD = 0.0526, r = 0.887, p < 0.0001). The median crown-rump length in the fetuses with trisomy 2 1 (n = 72) and trisomy 13 (n = 11) was not significantly different from normal; in contrast, fetuses with trisomy 18 (n = 32) had a significantly lower crown-rump length (Figs. 1 and 2 and Table I). The number for each group of fetuses with triploidy (n = 35), 45,X (n = 5), 47,XxX (n = 6) and 47,XXY (n = 6) was too small for statistical analysis, but crown- rump length appeared to be normal.

Comment The data of this study indicate that during the first

trimester of pregnancy the crown-rump length of fe- tuses with trisomy 2 1 or trisomy 13 is not significantly different from normal, but that of fetuses with trisomy 18 is decreased.

34 Kuhn et al. January 1995 Am J Obstet Gynecol

CRL (MOM) 1.10 1 .

0.85 3 Tr21 Tr18 Tr13 45x 47XXY 47xxx 69XxX I

69XXY

Fig. 2. Crown-rump length (CM) in chromosomally abnormal fetuses expressed as multiples of normal median (MOM) for gestational age. Shaded area, Normal 5th and 95th percentiles.

Table I. Median and range for crown-rump length of chromosomally abnormal fetuses expressed as multiples of normal median for gestational age

Karyotype I I Crown-rump length No. (median and range) I t

Trisomy 21 72 Trisomy 18 32 Trisomy 13 11 47,XXX 6 47,XXY 6 45,x 5 Triploidy 3

1.003 (0.907-1.086) 0.88 (NS) 0.957 (0.907-1.019) 6.74 (p -c 0.0001) 0.985 (0.925-1.028) 1.93 (NS) 0.991 (0.946-1.025) -* 1.025 (0.963-1.039) -* 1.030 (0.995-1.033) -* 0.961 (0.901-0.992) -*

NS, Not significant. *Numbers too small for statistical analysis.

Trisomy 18 is associated with severe growth retarda- tion at birth and contributes > 35% of the chromosomal abnormalities in second- and third-trimester intrauter- ine growth retardation.3 The findings of this study indicate that in this aneuploidy growth retardation is apparent from the first trimester. Similarly, Lynch and Berkowitz’ reported low crown-rump length in their five fetuses with trisomy 18. Drugan et al.? examined 16 fetuses with lethal chromosomal abnormalities and found that the mean gestational age calculated from crown-rump length was 7 days less than expected from the maternal menstrual history.

The findings that fetuses with trisomy 21 do not demonstrate growth retardation in the first trimester are compatible with those of two previous multicenter studies. Wald et a1.8 reported that the median crown- rump length of 55 trisomic fetuses was identical to that of 275 normal fetuses. Drugan et al.’ found the mean crown-rump length of 27 trisomic fetuses to be shorter

by 1 day of gestation. These findings indicate that measurement of crown-romp length is not useful as a method of screening for fetal trisomy 2 1.

In 10% to 45% of pregnancies women are uncertain of the last menstrual period, they have irregular men- strual cycles, or they became pregnant soon after stop- ping oral contraceptives.‘, lo Additionally, because of considerable variations in the day of ovulation, in ap- proximately 10% of women with certain dates and regular 28-day cycles there is a > 7 day discrepancy in gestation calculated from the menstrual history and ultrasonography.” For these reasons accurate dating of pregnancy necessitates ultrasonographic examination. This is especially important in maternal serum bio- chemical screening for trisomy 2 1.”

The findings of our study suggest that a policy of routine pregnancy dating by measurement of crown- rump length will not affect the interpretation of results from biochemical screening, because the crown-rump

Volume 172, Number 1, Part 1 Am J Obstet Gynecol

de Haan et al.

length in fetuses with trisomy 21 is not different from normal. Although a policy of routine dating by crown- rump length could miss early-onset intrauterine growth retardation resulting from trisomy 18, this aneuploidy is found in < 1: 1000 pregnancies.13 Furthermore, ap- proximately 90% of fetuses with trisomy 18 have in- creased nuchal translucency thickness that can be de- tected at the time of measuring the crown-rump length.14

1.

2.

3.

4.

5.

REFERENCES

Reisman IE. Chromosomal abnormalities and intrauterine growth retardation. Pediatric Clin North Am 1970;17:101- 10.

Chen ATL, Chan YK, Falek A. The effects of chromosomal abnormalities on birth weight in man. Hum Hered 1972; 22:209-24. Snijders RJ, Sherrod C, Gosden CM, Nicolaides KH. Fetal growth retardation: associated malformations and chro- mosomal abnormalities. AM J OBSTET GYNECOL 1993;168: 547-55. Yudkin PL, Aboualfa M, Eyre JA, Redman CWG, Wilkin- son AR. New birth weight and head circumference centiles for gestational ages 24-42 weeks. Early Hum Dev 1987; 15:45-52. Royston P. Constructing time-specific reference ranges. Stat Med 1991;10:675-90.

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Lynch L, Berkowitz RL. First trimester growth delay in trisomy 18. Am J Perinatol 1989;6:237-9. Drugan A, Johnson MP, lsada NB, et al. The smaller than expected first-trimester fetus is at increased risk for chro- mosome anomalies. AM J OBSTET GYNECOL 1992;167: 1525-8. Wald NJ, Smith D, Kennard A, et al. Biparietal diameter and crown-rump length in fetuses with Down’s syndrome: implications for antenatal serum screening for Down’s syndrome. Br J Obstet Gynaecol 1993;100;430-5. Campbell S, Warsof SL, Little D, Cooper DJ. Routine ultrasound screening for the prediction of gestational age. Obstet Gynecol 1985;65:613-20. Bergsio P, Denman DW III, Hoffman J, Meirik 0. Dura- tion of human singleton pregnancy. Acta Obstet Gynecol Stand 1990;69:197-207. Geirsson RT. Ultrasound instead of last menstrual period as the basis of gestational age assignment. Ultrasound Obstet Gynecol 1991;1:212-9. Wald NJ, Cuckle HS, Densem JW, Kennard A, Smith D. Maternal serum screening for Down’s syndrome: the effect of routine ultrasound scan determination of gestational age and adjustment for maternal weight. Br J Obstet Gynaecol 1992;99:144-9. Snijders RJ, Holzgreve W, Cuckle HS, Nicolaides KH. Maternal age-specific risks for trisomies at 9-14 weeks’ gestation. Prenat Diagn 1994;14:543-52. Nicolaides KH, Brizot M, Snijders RM. Fetal nuchal translucency: ultrasound screening for fetal trisomy in the first trimester of pregnancy. Br J Obstet Gynaecol 1994; 101:782-6.

The T/QRS ratio of the electrocardiogram does not reliably reflect well-being in fetal lambs

Harmen H. de Haan, MD, PhD, Anke C.M. Ijzermans, Jelte de Haan, MD, PhD, and Tom H.M. Hasaart, MD, PhD

Maastricht, The Netherlands

OBJECTIVE: Our purpose was to determine the diagnostic power of the T/QRS ratio of the electrocardiogram to predict fetal well-being. STUDY DESIGN: In 47 fetal lambs (3 to 5 days after surgery, gestational age 123.5 r 3.0 days) asphyxia was induced by restriction of uterine perfusion. Fetuses were either pretreated with an adenosine transport inhibitor (n = 16) or a calcium channel blocker (n = 12) or served as controls (n = 19). Arterial oxygen content 2 1.5 mmol/L or pH z 7.15 were chosen as limits for fetal well-being. RESULTS: Arterial oxygen content was reduced from 3.3 (? 1 .O) to 1.3 (-c 0.5) mmol/L, and pH decreased to 7.03 (-c 0.10). Mortality was 53%. Both drugs did not affect well-being, survival, or the T/QRS ratio. Maximum T/QRS ratios were reached at the peak of asphyxia. Sensitivity and specificity of the T/QRS ratio were 24.0% and 42.6% to predict hypoxemia and 25.1% and 45.3% to predict acidemia. Pearson correlation coefficients for T/QRS ratio versus oxygen content and pH were 0.169 and 0.192, respectively. CONCLUSIONS: (1) In fetal lambs the T/QRS ratio failed to predict hypoxemia or acidemia. (2) Fetal survival was not correlated with the height of the T/QRS ratio during or after asphyxia. (AM J OBSTET

GYNECOL 1995;172:35-43.)

Key words: Asphyxia, fetal lamb, electrocardiogram, T/QRS ratio, fetal well-being

From the Department of Obstetrics and Gynecology, University Hos- pital. Received for publication December 10, 1993; revised March 30, 1994; accepted June 15, 1994. Reprint requests: Harmen H. de Haan, MD, PhD, Department of

Obstetrics and Gynecology, University Hospital, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. Copyright 0 1995 by Mosby-Year Book, Inc. OOOZ-9378/95 $3.00 + 0 &/l/58413

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