A comparative study of multifetal pregnancy reduction from triplets to twins in the first versus early second trimesters after detailed fetal screening.

OBJECTIVES: To compare the outcome of multifetal pregnancy reduction from triplets to twins performed either early (at 11-12 weeks' gestation) or late (at 13-14 weeks). METHODS: Ninety-five high-order pregnancies following assisted conception were studied. Transabdominal sonographically guided multifetal pregnancy reduction was performed early in 46 women, while 49 women first underwent a sonographic fetal anomaly scan before undergoing selective reduction. RESULTS: Sonographic screening led to selective termination of a specific fetus in nine cases due to increased nuchal translucency and relative intrauterine growth restriction in three cases each, and meningomyelocele, abdominal cyst and cystic hygroma in one case each. In the early reduction group a diagnosis of hypoplastic left heart in the two remaining twins was subsequently made, and one pair of twins suffers from cerebral palsy. The rate of pregnancy loss was not statistically different between the early (4.3%; 2/46) and late (4.0%; 2/49) termination groups. The birth weight and gestational age at birth were not statistically different between the early ( n = 85) and late ( n = 94) groups (2110 +/- 580 vs. 2140 +/- 490 g, and 35.8 +/- 3.0 vs. 35.7 +/- 3.5 weeks). Similarly there was no statistically significant difference between early and late groups in the incidence of very premature (24-32 weeks; 9.3 vs. 8.3%) and premature (33-36 weeks; 46.5 vs. 47.9%) births. CONCLUSIONS: Early second-trimester multifetal pregnancy reduction from triplets to twins may allow more selective termination of abnormal fetuses without an adverse effect on the outcome of pregnancy. However, further studies are needed in order to confirm our observations in a larger series.

[Indications of fetal chromosome abnormalities in 1st trimester ultrasound]. / Hinweise auf fetale Chromosomenstörungen Ersttrimester-Ultraschall.

The measurement of the nuchal translucency and the evaluation of other sonographic signs in the first trimester scan allow a detection rate of 70-80% of aneuploid pregnancies, significantly more than with consideration of the maternal age alone (30%). The sonographic signs include the early growth retardation, deviations of the fetal heart rate, exomphalos, megacystis, holoprosencephaly and enlargement of the cisterna magna. Maternal serum biochemistry alone (PAPP-A and beta-hCG or alpha-fetoprotein, estriol and beta-hCG) detects about 65% of aneuploid pregnancies. The best individual risk estimation is based on maternal age, measurement of the nuchal translucency and the maternal biochemistry.

[Ultrasound indications of fetal chromosome abnormalities in the 2nd trimester]. / Sonographische Hinweiszeichen auf fetale Chromosomenstörungen im zweiten Trimenon.

The most common fetal chromosomal disorders have structural abnormalities, which can be detected during second trimester ultrasound examination. Major malformations, also known as hardmarkers, when single or in combination, should raise the suspicion for a specific syndrome. But it is known, that even more subtile findings can increase the background risk based on the maternal age, especially for Down syndrome. A combination of these so called "soft-markers" can be used for second trimester screening in a high and low risk population. Here were report on the sonographic features of the common chromosomal anomalies and their significance in prenatal diagnosis.

Fetal transcerebellar diameter and chromosomal abnormalities.

OBJECTIVE: To evaluate the association between chromosomal abnormalities and fetal cerebellar size. DESIGN: A retrospective cross-sectional study. METHODS: Ultrasound measurements of transcerebellar diameter, head and upper-abdominal circumference from 88 fetuses with chromosomal abnormalities were analyzed. Abnormalities included trisomy 21 ( n = 23), trisomy 18 ( n = 17), 'other numerical chromosomal abnormalities' ( n = 9), sex chromosomal abnormalities ( n = 9), mosaicism ( n = 12), balanced translocations ( n = 9) and unbalanced translocations ( n = 9). Multiple regression analysis was performed to compare transcerebellar diameters between the reference group and each of the subsets of chromosomal abnormalities and between trisomies 18 and 21. Also, in the latter two subsets, comparison of the transcerebellar diameter before and after 25 weeks of gestation was carried out. RESULTS: Fetal transcerebellar diameter was reduced in relation to gestational age but was normal when control was made for fetal size in all chromosomal subsets, except for balanced translocations. The transcerebellar diameter in trisomy 18 was significantly smaller than that in trisomy 21. No difference in cerebellar size was found when comparing the gestational age period before and after 25 weeks in each of these two subsets. CONCLUSIONS: A reduction in fetal transcerebellar diameter was demonstrated in all chromosomal abnormalities with imbalance of genetic material. Cerebellar hypoplasia was more severe in trisomy 18 than in trisomy 21. The degree of reduction in fetal transcerebellar diameter in these subsets seems to be independent of the time period during which the transcerebellar diameter measurement was performed.

Ductus venosus studies in fetuses at high risk for chromosomal or heart abnormalities: relationship with nuchal translucency measurement and fetal outcome.

OBJECTIVE: To investigate, in a high-risk group of fetuses, the role of ductus venosus Doppler velocimetry as a prognostic factor, in addition to nuchal translucency measurement, for predicting chromosomal anomalies and, where the karyotype was normal, for predicting fetal outcome. METHODS: Nuchal translucency was measured and ductus venosus pulsatility index and late diastolic flow (a-wave) were recorded in 186 fetuses at a median gestational age of 12.6 weeks (range, 10-17). Fetal karyotype, the presence of structural anomalies, pregnancy outcome, neonatal examination at birth and postnatal follow up were the outcome values. RESULTS: Nuchal translucency measurement was increased in 112 fetuses. The outcome of pregnancy was normal in 130 fetuses. Fifty-six fetuses had an adverse outcome (46 chromosomal anomalies, three intrauterine deaths, six structural anomalies and one developmental disorder). The sensitivity of an abnormal ductus venosus pulsatility index or of absent or reversed flow during the a-wave was 65% for chromosomal anomalies and 68% for an adverse outcome. The specificity was 79%. There was a significant correlation between nuchal translucency and ductus venosus pulsatility index. In chromosomally normal fetuses with an enlarged nuchal translucency an abnormal ductus venosus flow was associated with a nearly nine-fold increase in adverse outcome (odds ratio 11.7). CONCLUSION: Ductus venosus Doppler velocimetry can be used in addition to nuchal translucency measurement as a predictor of chromosomal anomalies. However, as the ductus venosus blood flow pattern is correlated with nuchal translucency measurement it cannot be used as an independent variable to reduce the indication for fetal karyotyping. Ductus venosus Doppler velocimetry may have a role in the counseling of parents in the case of an enlarged nuchal translucency and normal karyotype by identifying those fetuses in need of an intensive follow up due to an increased risk of adverse outcome.

The role of ductus venosus blood flow assessment in screening for chromosomal abnormalities at 10-16 weeks of gestation.

OBJECTIVE: To evaluate the role of ductus venosus blood flow assessment at 10-16 weeks' gestation in screening for chromosomal abnormalities. METHODS: Ductus venosus blood flow was prospectively evaluated in 1371 consecutive pregnancies between 10 and 16 weeks of gestation. The pulsatility index for veins was calculated. All cases were screened for chromosomal defects combining maternal age and fetal nuchal translucency thickness. RESULTS: A chromosomal abnormality was found in 20 cases. The overall detection rate, specificity, positive predictive value, negative predictive value and odds ratio for chromosomal abnormalities were 65%, 95.7%, 18.3%, 99.5% and 41 (95% CI 16-108), respectively, when using the 95th centile pulsatility index as a cut-off. CONCLUSIONS: These preliminary results suggest that evaluation of the ductus venosus pulsatility index at 10-16 weeks' gestation is a useful second-line screening test for chromosomal defects. A combination of nuchal translucency measurement and ductus venosus assessment might increase specificity while maintaining an optimal detection rate for chromosomal abnormalities. Such a policy could identify 55% of all chromosomal abnormalities and about 69% of autosomal trisomies, reducing the need for invasive testing to less than 1%.

The variability in the interpretation of prenatal diagnostic ultrasound.

OBJECTIVES: Although prenatal ultrasound is broadly used to detect abnormal fetuses, the variability in the interpretation of second-trimester prenatal ultrasound examinations is unknown. We sought to evaluate the consistency of the interpretation of prenatal ultrasound examinations. DESIGN: Physicians who perform prenatal ultrasound and who participate in the California Maternal Serum Expanded AFP program were asked to interpret a series of test ultrasound examinations. The series of cases was selected to include a random sample of fetal structural abnormalities, ultrasound markers that have been associated with chromosomal abnormalities, and normal cases. Interobserver agreement was evaluated using a kappa statistic for each organ system. The sensitivity and false-positive rate were calculated for detecting specific anatomic abnormalities within each organ system. RESULTS: Of the 210 sonologists eligible for inclusion in the study, completed responses were received from 148 (70%). There was moderate to substantial agreement between physicians in reporting the presence of fetal abnormalities for all organ systems (kappa range 0.40-0.88, P < 0.001). The consistency was highest for the central nervous system (CNS), neck, and face. Within each organ system, the consistency was similar for major structural abnormalities and ultrasound markers of chromosomal abnormalities. The sensitivity ranged from 62% (95% confidence interval (CI) 58-66%) for major renal abnormalities to 91% (95% CI 88-94%) for CNS abnormalities, with corresponding false-positive rates of 7% (95% CI 6-9%) for renal abnormalities and 9% (95% CI 7-11%) for CNS abnormalities. For most organ systems, the sensitivity for detecting ultrasound markers of chromosomal abnormalities was similar to the sensitivity for detecting structural abnormalities. CONCLUSION: There is moderate to substantial agreement in the interpretation of second-trimester prenatal ultrasound examinations. Whether the identification of specific ultrasound abnormalities and markers is overall beneficial to patients remains to be determined.

The importance of high resolution transvaginal sonography in early screening of fetal chromosomal pathology.

BACKGROUND: Continuous technological improvement made in the field of ultrasound applied to obstetric diagnostics (see tridimensional sonography) has contributed to a better and non-invasive early diagnosis of fetal malformations. METHODS: To evaluate the usefulness of ultrasound in detecting early chromosomal derangements, the authors carried out a high resolution transvaginal sonography (> 6.5 mHz), between the 10th and 14th week of gestational age, on 650 pregnant women at risk for congenital anomalies and afterwards they were subjected to early amniocentesis RESULTS: Sonographic fetal anomalies were seen in 61 cases (9.3%). The incidence of fetal anomalies in these cases was 52.5%. Trisomies and number of sexual chromosome anomalies were seen, especially, in the cases of cystic septated hygroma and fetal nuchal translucency > or = 3 mm which are the most frequent sonographic markers of chromosomopathies. CONCLUSIONS: Although further studies are necessary, these findings suggest the usefulness of high resolution transvaginal sonography for the early screening of chromosomopathies.

Outcome in prenatally diagnosed fetal agenesis of the corpus callosum.

This study of the outcome and prognostic factors in prenatally diagnosed agenesis of the corpus callosum (ACC) was undertaken to see if there are any differences between subgroups, what relationship they have to neurodevelopmental outcome and whether this information aids the counselling of parents of fetuses with the condition. The outcome of 14 prenatally diagnosed fetuses with ACC and 61 postnatally diagnosed patients was assessed in terms of clinical problems, developmental milestones and neurological signs; each patient was then given a score out of 10, 0 being a normal outcome and 10 being the worst outcome, i.e. death or termination of pregnancy. Comparing patients diagnosed pre- and postnatally, several similarities were found indicating that the postnatal group can provide useful information about the prenatal group. There was a higher incidence of ACC in males than females. In the prenatally diagnosed patients complete ACC was more common than partial ACC, although this might be because partial ACC was easily missed. Complete ACC has a worse prognosis than partial ACC (p = 0.001), and when associated with other anomalies, especially of the central nervous system, the outcome is very bad (p < 0.01). The only neurodevelopmentally normal patients were in the isolated partial ACC group. This study highlights the need to perform a detailed review of fetal anatomy and the desirability of determining the karyotype of the fetus in all newly diagnosed cases of ACC so that as much information as possible is available before parents are counselled about the likely outcome.

Outcome of fetuses with increased nuchal translucency.

Recent reports on nuchal translucency screening in unselected patient populations show results that are comparable with those reported by the thus far largest series on screening for Down's syndrome based on maternal age and nuchal translucency measurement. Much interest is focused on the prognostic value of increased nuchal translucency in fetuses with normal chromosomes. Increased nuchal translucency is regarded as a clear sign of declining fetal health, which can be associated with fetal demise, structural anomalies, rare genetic syndromes, and in particular congenital heart defects. A clear association is demonstrated between nuchal translucency above the 99th centile and congenital cardiac defects. Such a finding should prompt specialized echocardiography. However, on the whole the sensitivity of nuchal translucency screening is too low to consider this as the sole criterion to screen for critical heart defects.

The value of minor ultrasound markers for fetal aneuploidy.

As a result of improvements in ultrasound image quality and scanning technique, an increasing number of subtle morphological changes in fetal anatomy have been identified in the second trimester. Most of these ultrasound features were originally described as normal variants of development with no clinical significance. However, subsequent studies in high-risk populations showed that some of these variants were more prevalent in fetuses with chromosomal defects and therefore proposed as prenatal markers for the detection of aneuploidy. The implications for pregnancy management when one of these so-called minor ultrasound markers is detected have been a matter of continuous controversy in the field of prenatal diagnosis and yet the definitive answer on their clinical significance in the low-risk population is still debated.

A large-scale evaluation of amnio-PCR for the rapid prenatal diagnosis of fetal trisomy.

OBJECTIVE: Traditional chromosome preparation from amniotic fluid samples often involves lengthy culture procedures in order to obtain cells for analysis. Multiplex quantitative fluorescent polymerase chain reaction (PCR) is a new molecular biological technique capable of quantifying in-situ DNA without the need for cell culture. Our objective was to test the reliability of PCR using fetal DNA from amniotic fluid (amnio-PCR) for the rapid prenatal diagnosis of the common trisomies. DESIGN: This was a large prospective study of 5000 amniocentesis specimens. Multiplex quantitative fluorescent PCR was performed specifically for short tandem repeat sequences within chromosomes 21, 18, 13, X and Y. All amniocentesis samples were subsequently analyzed by traditional karyotyping methods. RESULTS: Amnio-PCR detected all 89 major autosomal trisomies in this cohort. Diagnosis of sex chromosome anomalies was accurate for cases involving first meiotic division nondisjunction. However, further markers were necessary to detect sex chromosome anomalies arising from second meiotic division nondisjunction, highlighting the importance of using specific markers that enable the quantification of both the X and the Y chromosomes simultaneously. CONCLUSIONS: Rapid prenatal diagnosis of trisomies 21, 18, and 13 and the sex chromosome anomalies using amnio-PCR is a reliable technique that aids the clinical management of pregnancy. The speed of the methodology will help to minimize the period of parental anxiety in the wait for a diagnostic test result.

Ductus venosus blood flow in chromosomally abnormal fetuses at 11 to 14 weeks of gestation.

This article reviews the role of ductus venosus (DV) Doppler evaluation in the screening for aneuploidies at 11 to 14 weeks of gestation. Ductus venosus flow velocity waveforms were obtained immediately before fetal karyotyping in 515 consecutive singleton pregnancies at 11 to 14 weeks. We found 446 normal and 69 abnormal karyotypes. Abnormal flow in the DV was the only significant difference between both groups. Sensitivity of the test was 80% and false positive rate < 1%. Normal karyotype but abnormal flow in the DV was recorded in 17 of 446 cases, 7 presenting a cardiac defect. Increased nuchal translucency seems to be related, in most cases, to early cardiac dysfunction. Chromosomal abnormalities and/or cardiac defects were often found in cases with increased nuchal translucency and abnormal flow in the DV. We suggest that the evaluation of ductal flow between 11 to 14 weeks of gestation should be adopted as a second level screening test to reduce invasive test rate derived from the exclusive measurement of nuchal translucency.

A correlative study of prenatal ultrasound and post-mortem findings in fetuses and infants with an abnormal karyotype.

OBJECTIVE: To compare ultrasound and post-mortem findings in 98 fetuses and infants with an abnormal karyotype. DESIGN: Criteria for inclusion were an ultrasound examination at the National Center for Fetal Medicine (NCFM), an abnormal karyotype, and an autopsy performed during the period 1985-94. RESULTS: Trisomy 18 and 21 were the two most common abnormal karyotypes. The highest number of congenital anomalies was observed in cases with trisomy 13 and 18; congenital heart defects (CHD) were most prevalent among fetuses with trisomy 18. In 80% of cases there was full agreement between the ultrasound and autopsy findings; in another 8% of cases there was nearly complete concordance. Thus, in 88% of cases, the main prenatal sonographic diagnosis was correct. In 6% major autopsy findings were not detected by ultrasound examination, in 1% none of the autopsy findings were detected by routine ultrasound and in 5% ultrasound findings were not verified at autopsy. Where the correlation was related to individual autosomal trisomies, structural anomalies were most often correctly diagnosed in fetuses with trisomy 13, with the main diagnosis correct in all cases; second in accuracy were the ultrasound diagnoses in fetuses with trisomy 21 with the main diagnosis correct in 96%; for trisomy 18 the concordance was less good, with the main diagnosis correct in 71%. CONCLUSION: The present comparison of sonographic diagnoses with post-mortem findings demonstrates good accordance between the two methods. It also demonstrates the importance of awareness of the anomalies known to occur with different aneuploidies.

Efficacy of community-based second trimester genetic ultrasonography in detecting the chromosomally abnormal fetus.

We sought to assess prospectively the efficacy of community-based genetic ultrasonography in detecting chromosomally abnormal fetuses in a high-risk population and determine independent markers of aneuploidy. Patients 18 years old and older who were between 14 and 24 weeks' gestation were included if referred for maternal age greater than 35 years, increased risk of Down syndrome or trisomy 18 by second trimester serum screen, or prior affected offspring. All women had a targeted ultrasonographic examination between April 1997 and June 1999 and were offered fetal chromosomal analysis. Markers of aneuploidy and pregnancy outcomes were recorded prospectively. The primary outcome was prenatally or postnatally detected chromosomal abnormalities. Of the 1030 fetuses seen during the study, 789 had outcome data available and constituted the study group. In this group, 694 (87.9%) ultrasonograms were normal, 73 (9.2%) had one marker present, 17 (2.2%) had two markers present, and 5 (0.6%) had three or more markers present. Fourteen of 17 (82.3%) aneuploid fetuses had an abnormal ultrasonogram (one or more markers present), including 5 of 7 (71.4%) with Down syndrome. Logistic regression showed abnormal four-chamber view, structural anomaly, and intracardiac echogenic focus to be significant aneuploidy markers. The amniocentesis rate was 334 of 1030 (32.4%), and it increased with the number of sonographic markers noted (0 = 29.9%, 1 = 60.2%, 2 = 70.6%, 3 or more = 80%). Genetic ultrasonography is highly effective in identifying chromosomally abnormal fetuses in a community-based practice.

Ultrasound markers of fetal chromosomal abnormality: a survey of policies and practices in UK maternity ultrasound departments.

OBJECTIVE: To evaluate the management of pregnancies where the fetus was found to have one or more sonographic markers of possible fetal chromosomal abnormality. DESIGN: Prospective anonymous postal survey of UK obstetric ultrasound units. MAIN OUTCOME MEASURES: The management of pregnancies where the fetus is found to have a sonographic marker of aneuploidy. POPULATION: All 252 maternity ultrasound units in the United Kingdom. METHODS: Postal questionnaire to the superintendent sonographer in routine maternal ultrasound departments. RESULTS: Questionnaires were returned from 179 maternity units (71%). Of the respondents 94% offered a fetal anomaly scan at 16-20 weeks' gestation and 59% performed a dating scan at 10-14 weeks. Screening for Down syndrome was available in 99% of all maternity units. The recognition of sonographic 'soft signs' for possible fetal chromosomal abnormality varied considerably between the units. When sonographers were asked about their unit's policy regarding offering amniocentesis to women with sonographic markers, 8-78% discussed amniocentesis when the marker was isolated and 53-88% when another abnormality was found. Eighty nine percent of units documented the abnormal ultrasound findings in the hospital notes and 88% of the women were informed of the findings regardless of the intention to offer amniocentesis. CONCLUSION: The practice of routine ultrasound examination is well established in UK, though precise policies vary. The existing wide variations in management policies possibly reflect a lack of data derived from low risk populations. There is a need to collect such data from low risk populations with known screening practices so that national guidelines to standardize practice can be formulated.