R. J. M. Snijders

UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10–14 weeks of gestation

BACKGROUND Prenatal diagnosis of trisomy 21 currently relies on assessment of risk followed by invasive testing in the 5% of pregnancies at the highest estimated risk. Selection of the high-risk group by a combination of maternal age and second-trimester maternal serum biochemistry gives a detection rate of about 60%. We investigated assessment of risk by a combination of maternal age and fetal nuchal-translucency thickness, measured by ultrasonography at 10-14 weeks of gestation. METHODS The risk of trisomy 21 was estimated for 96127 women of median age 31 years (range 14-49) with singleton pregnancies. Ultrasonography was done by 306 appropriately trained sonographers in 22 centres. Risk of trisomy 21 was calculated from the maternal age and gestational-age-related prevalence, multiplied by a likelihood ratio depending on the deviation from normal in nuchal-translucency thickness for crown-rump length. The distribution of risks was investigated and the sensitivity of a cut-off risk of 1 in 300 was calculated. Phenotype was assessed by fetal karyotyping or clinical examination of liveborn infants. FINDINGS The estimated trisomy-21 risk, from maternal age and fetal nuchal-translucency thickness, was 1 in 300 or higher in 7907 (8.3%) of 95476 normal pregnancies, 268 (82-2%) of 326 with trisomy 21, and 253 (77.9%) of 325 with other chromosomal defects. The 5% of the study population with the highest estimated risk included 77% of trisomy-21 cases. INTERPRETATION Selection of the high-risk group for invasive testing by this method allows the detection of about 80% of affected pregnancies. However, even this method of risk assessment requires about 30 invasive tests for identification of one affected fetus.

Ultrasonographically detectable markers of fetal chromosomal abnormalities.

Screening for fetal chromosomal abnormalities on the basis of maternal age has not resulted in a substantial fall in the proportion of infants born with an abnormal karyotype. Most fetuses with major chromosomal abnormalities have defects that can be recognised on detailed ultrasonographic examination. Therefore, provided the cardinal signs of each chromosomal syndrome are recognised, it is possible that screening by ultrasound examination could have a greater impact. We karyotyped 2086 fetuses after ultrasonographic examination had revealed fetal malformations, growth retardation, or both. Chromosomal abnormalities were detected in 301 (14%) cases and were more common among fetuses with multisystem malformations (29%) than among those with isolated defects (2%). The commonest chromosomal abnormality was trisomy 18, followed by trisomy 21, triploidy, Turners syndrome, unbalanced chromosomal rearrangements, and trisomy 13. Trisomy 18 was associated with strawberry-shaped head, choroid plexus cysts, facial cleft, micrognathia, heart defects, exomphalos, malformations of hands and feet, and growth retardation. In trisomy 21, the associated defects were subtle and included nuchal oedema, macroglossia, atrioventricular septal defects, mild hydronephrosis, clinodactyly, and sandal gap. The frequency of autosomal abnormalities increased with maternal age, but if fetal karyotyping had been restricted to mothers older than 35 years, large proportions of chromosomally abnormal fetuses would not have been diagnosed prenatally (64-97%). Our findings provide guidelines as to which defects to search for in screening studies for the detection of chromosomal abnormalities.

Maternal Age and Gestational Age-Specific Risk for Chromosomal Defects

This study provides estimates of risks for a wide range of chromosomal defects taking into account maternal age as well as the gestation at assessment. The estimates make it possible to counsel patients presenting at different stages of pregnancy. At the same time, they offer the possibility of evaluating the efficacy of biochemical and ultrasonographic markers in identifying fetuses with chromosomal defects.

Letter. Correct estimation of parameters for ultrasound nuchal translucency screening

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Fetal gastro-intestinal and abdominal wall defects: associated malformations and chromosomal abnormalities.

During an 8-year period (1983-1991), blood karyotyping was performed in 235 fetuses with abdominal wall or gastro-intestinal tract defects. The overall incidence of chromosomal abnormalities was 29% (trisomy 21, n = 12; trisomy 18, n = 44; trisomy 13, n = 7; deletion of the short arm of chromosome 5, n = 1; unbalanced translocation involving chromosomes 4 and 15, n = 1; triploidy, n = 1; Klinefelters syndrome, n = 1; and Beckwith-Wiedemann syndrome with mosaic duplication 11p15, n = 1). The karyotype was abnormal in 42 (36%) of the 116 fetuses with exomphalos, in none of the 26 with gastroschisis, in 10 (43%) of the 23 with duodenal atresia, in 18 (75%) of the 24 with lack of visible stomach, in 1 (4%) of the 24 with dilated bowel and in 2 (7%) of the 27 with echogenic hepatic nodules or abdominal cysts. Abnormal karyotypes were more commonly encountered when there was ultrasonographic evidence of multiple malformations (43%) compared to isolated defects (2%). Survival in fetuses with exomphalos (33%), absent stomach (4%), and large bowel obstruction (13%) was poor, whereas in those with gastroschisis (73%) or abdominal cysts (88%) survival was high; in small bowel obstruction and in duodenal atresia, survival was 65 and 57%, respectively.

Fetal renal defects: associated malformations and chromosomal defects.

During a 6-year period (1985-1990) blood karyotyping was performed in 682 fetuses with renal defects. There were: 276 fetuses with mild hydronephrosis; 206 with moderate/severe hydronephrosis; 173 with multicystic dysplasia, and 27 with renal agenesis. The overall incidence of chromosomal abnormalities was 12% (trisomies, n = 63; deletions, n = 9; triploidies, n = 5, and sex chromosome aneuploidies, n = 8). There were more than twice as many males than females, but the incidence of chromosomal defects in females was almost double (18%) than in males (10%). Furthermore, compared to the overall maternal age-related risk, the risk for fetal chromosomal abnormalities was three times higher when there was an isolated renal defect and thirty times higher when there were additional malformations. The risk of chromosomal abnormalities was similar for fetuses with unilateral or bilateral involvement, different types of renal defects, urethral or ureteric obstruction, and oligohydramnios or normal/reduced amniotic fluid volume. Nevertheless, the patterns of chromosomal abnormalities, and consequently that of associated malformations, were related to the different types of renal defects.

Fetal Lateral Cerebral Ventriculomegaly: Associated Malformations and Chromosomal Defects

In 267 consecutive cases of fetal lateral cerebral ventriculomegaly, additional fetal malformations were detected by ultrasonography in 209 (78%) of the cases. On the basis of the ultrasound findings, the patients were subdivided into three groups: (i) isolated ventriculomegaly (n = 58), (ii) ventriculomegaly and open spina bifida only (n = 172), and (iii) ventriculomegaly and other malformations (n = 37) with or without spina bifida. Antenatal karyotyping was performed in 64 cases from groups (i) and (iii), and 11 (18%) of the fetuses had chromosomal abnormalities. The incidence of chromosomal abnormalities was strongly related to the presence of multisystem malformations. Thus, only 3% of fetuses with isolated ventriculomegaly as opposed to 36% of those with additional malformations had chromosomal defects. Furthermore, the degree of ventriculomegaly in the chromosomally abnormal fetuses was relatively mild. In the chromosomally normal fetuses, mild, static ventriculomegaly was associated with apparently normal subsequent mental development.

Fetal Facial Defects: Associated Malformations and Chromosomal Abnormalities

During an 8-year period, facial defects were observed in 146 (7%) of the 2,086 fetuses that underwent karyotyping in our unit because of fetal malformations and/or growth retardation. Chromosomal abnormalities were detected in 37 of 56 (66%) fetuses with micrognathia, in 10 of 13 (77%) with macroglossia, in 31 of 64 (48%) with cleft lip and palate, in 5 of 11 (45%) with severe hypotelorism or cyclops, and in 6 of 19 (32%) with nasal hypoplasia, proboscis or single nostril. Macroglossia was mainly associated with trisomy 21, micrognathia with trisomy 18 and triploidy, facial cleft with trisomies 13 and 18, and ocular or nasal defects with trisomy 13. In all chromosomally abnormal fetuses with facial defects, there were additional multisystem defects, and the pattern of these malformations was compatible with the type of the underlying chromosomal abnormality. In the total series of 2,086 fetuses with malformations and/or growth retardation, there were 31 with trisomy 13, 83 with trisomy 18 and 69 with trisomy 21; facial defects were found in 71, 36 and 14% of these fetuses, respectively.

Maternal serum hCG and fetal nuchal translucency thickness for the prediction of fetal trisomies in the first trimester of pregnancy

Objective To compare the potential value of maternal serum total hCG and free β‐hCG in predicting the risk for fetal trisomies during the first trimester of pregnancy and to examine whether data on maternal hCG and fetal nuchal translucency thickness can be combined to derive risks.

Twin-Twin Transfusion Syndrome during the 2nd Trimester Is Associated with Small Intertwin Hemoglobin Differences

In four twin pregnancies presenting with acute 2nd-trimester polyhydramnios due to presumed twin-twin transfusion syndrome, the fetal hemoglobin concentration was measured in samples obtained by cordocentesis. In no instance did the twin pair difference in the hemoglobin concentration exceed 2.7 g/dl.