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Objectives: The purpose of this retrospective study was to determine whether objective assessment of cardiac shifting on two-dimensional ultrasonography can predict postnatal outcome in fetuses with isolated left-sided congenital diaphragmatic hernia (CDH)., Materials and Methods: Still images at the level of the four-chamber view were obtained in 23 fetuses with left-sided CDH. A group of 12 fetuses (3 non-survivors and 9 survivors) were examined at two periods, between 20 and 30 weeks and between 31 and 40 weeks. A further 11 fetuses (2 non-survivors and 9 survivors) were examined between 31 and 40 weeks. Fetal heart axis and position were determined manually and associated with postnatal outcome., Results: The cardiac axis remained constant in the 9 survivors (15.5 +/- 3.2 versus 17.2 +/- 3.3, p = 0.71) and 3 non-survivors (19.0 +/- 11.5 versus 18.5 +/- 11.8, p = 0.97). There was no statistical difference between the 9 survivors and 3 non-survivors at the two periods. Cardiac displacement remained constant in the 9 survivors (0.2 +/- 0.02 versus 0.2 +/- 0.02, p = 0.32) but increased significantly in the 3 non-survivors (0.2 +/- 0.04 versus 0.4 +/- 0.02, p = 0.015). The difference between survivors and non-survivors was statistically significant between the18 survivors and 5 non-survivors examined between 31 and 40 weeks of gestation (0.2 +/- 0.02 versus 0.4 +/- 0.02, p = 0.037)., Conclusion: This study does not support the hypothesis that objective assessment of mediastinal shift in fetuses with left-sided CDH has a role in predicting postnatal outcome before fetal viability, which is when it would be more useful for counseling patients regarding whether to continue with the pregnancy or to opt for termination., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Objectives: The aim of this study was to evaluate whether fetuses with trisomy 21 and detectable nasal bones have a distinct facial anthropometry that can be objectively defined using three-dimensional (3D) ultrasonography., Methods: A prospective cross-sectional study of 40 fetuses in the second trimester, 17 with trisomy 21 and 23 controls, was performed. The 3D volume datasets of each case were evaluated for documentation of the nasal bones using the multiplanar and the maximum mode. The nasal bone length and the angle formed by the two maxillary bones at the level of the frontal process were then measured., Results: The nasal bones were absent in 7 (41%) of the 17 fetuses with Down syndrome. All of the 23 normal fetuses had detectable nasal bones. The difference between nasal bone length in trisomy 21 fetuses and controls did not reach statistical significance (p = 0.087). The mean maxillary angle in trisomy 21 fetuses with nasal bones was significantly wider compared to controls (p = 0.029)., Conclusions: The nasal bones are present in the majority of fetuses with trisomy 21 in the second trimester. This group of fetuses has a characteristic mid-facial anthropometry (wider maxillary angle) that can be assessed by means of 3D ultrasonography., (Copyright 2006 John Wiley & Sons, Ltd.)

Background: Infection with oncogenic-type human papillomavirus (HPV) and consecutive cytologic abnormalities of the uterine cervix precede the evolution of carcinoma. However, the specificity of both changes is too low to predict the true malignant potential of the change in a given time point, because the majority of the HPV infections revert to normal with time. In preliminary studies, the authors demonstrated that, among many dysregulatory phenomena at the cytologic level, the occurrence of significant DNA content aberrations were in good correlation with progressive cervical changes; and, as a marker for this, the significance of cells with nuclear DNA content > 9c (9c cells) was investigated using slide-based cytometry. The objective of the current study was to determine whether 9c cells in cytologic samples that presented with dysplasia and with high-risk HPV types were associated with the development of higher grade cervical intraepithelial neoplasia (CIN II+)., Methods: Samples with positive cytologic diagnoses (atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion [LSIL], and high-grade squamous intraepithelial lesion [HSIL]) were evaluated for both parameters and were related to outcomes and, if available, to histology results over a follow-up of up to 4 years., Results: Although the presence of high-risk HPV was demonstrable in almost all samples with CIN II+ (96.7%), the virus genome alone proved to have a poor positive predictive value (56.1%) for higher grade CIN. Cytology and the demonstration of 9c cells resulted in less sensitivity compared with the occurrence of high-risk HPV (70.4% and 73.7%, respectively) but in significantly greater specificity (91.3% and 89.2%, respectively). Moreover, a positive predictive value of 81.8% for CIN II+ could be calculated for 9c cells. HSIL morphology, unfavorable HPV type, and DNA cytometry together excluded the highest rate of CIN > or = II with 100% sensitivity and 91.3% specificity., Conclusions: Biologic parameters, in addition to cytology, help to define the nature of cervical dysplasias more accurately. Oncogenic HPV types and hyperdiploid cells with DNA content > 9c disclosed cytologic changes with the greatest malignant potential. Cancer, (2005 American Cancer Society.)

Objectives: Intra-uterine bowel perforation can occur secondary to a variety of abnormalities and cause sterile peritonitis in the fetus (generalised = type I). If sealing of the perforation does not take place, a thick-walled pseudo-cyst can form (type II)., Methods: Over a 12-year period, 21 616 pregnancies were screened for gastro-intestinal malformations using prenatal ultrasound. We identified 1077 cases suspicious of surgically correctable malformations. Post-natal diagnoses and outcome were worked up retrospectively., Result: We found 96 fetuses with suspected gastro-intestinal malformations. Prenatal bowel perforation with meconium peritonitis was confirmed in 11 cases. In 5 of these 11, the correct diagnosis had been predicted prenatally. One child presented as a fetal and neonatal emergency (case report). Ten of the eleven infants were operated on during their first day of life. Intra-operative findings were atresia (n = 4), meconium ileus (n = 6) and no obvious cause (n = 1). Two children suffered fatal complications., Conclusion: Meconium peritonitis and meconium pseudo-cysts as its special manifestation are assessable by prenatal diagnosis but present in different ways. They can present as fetal ascites or echogenic bowel and cause fetal or neonatal distress, requiring close observation and highly specialised care., (Copyright 2003 John Wiley & Sons, Ltd.)

Background: The Bethesda System of cervical cytologic findings introduced the term ASCUS (atypical squamous cells of undetermined significance) to cover the broad zone separating normal cytomorphology from definitive squamous intraepithelial lesions (SILs). The management of patients with ASCUS is particularly problematic as approximately 10% of ASCUS patients develop SIL and 1 per 1000 develop cervical carcinoma., Methods: Our aim was to demonstrate the combined use of polymerase chain reaction for human papillomavirus (HPV) typing and laser scanning cytometry for DNA content measurements in the subcategorization of ASCUS cases according to the risk for progression toward cancer. Liquid- based monolayer preparation (ThinPrep, Cytyc, Boston, MA) of the cytologic material was used for cytomorphologic analysis. DNA content measurements using laser scanning cytometry and direct sequencing of HPV using the consensus primers GP5+/GP6+ and MY09/MY11 were performed from the same material., Results: Twelve of the 44 cases (27.2%) with ASCUS carried a high-risk HPV genome whereas only 3 of the 195 normal control cases (1.5%) showed positivity for a high-risk HPV genome. Six of 12 (50%) of the high-risk HPV-positive ASCUS cases presented isolated cells with a DNA content above 5c, whereas cells with a DNA content above 9c were found in 3 of 12 cases (25%) and were exclusively found in combination with high-risk HPV infection. In these three cases, the histologic follow-up resulted in cervical intraepithelial neoplasia (CIN) I (one case) and CIN III (two cases). None of the other ASCUS or normal cases displayed DNA aneuploidy above 9c. They returned to normal cytology (within normal limits/benign cellular changes) in the follow-up., Conclusions: Human papillomavirus typing and DNA content measurements may delineate a distinct group of ASCUS. Our preliminary data suggest that ASCUS cases with high-risk HPV positivity and with rare cells with abnormally high DNA content represent similar biologic features as high-grade SIL and are at elevated risk to develop cancer., (Copyright 2003 American Cancer Society.)

Background: Infection by high-risk human papillomavirus (HPV) plays a role in the evolution of cervical carcinoma. Cellular atypia and consecutive DNA content alterations in cytologic samples are consequences of a preexisting viral infection., Methods: We analyzed the frequency and association of HPV types and the presence of rare cells with abnormally high DNA content. We also evaluated whether these findings support the cytologic diagnosis in 112 routine cases with low and high-grade squamous intraepithelial lesions (LSIL/HSIL) when performed from liquid-based cytologic samples (ThinPrep). For DNA content measurements, laser scanning cytometry was applied and at least 10,000 cells were analyzed. HPV typing was performed by a direct sequencing approach using the consensus primers GP5+/GP6+ and MY09/MY11., Results: Of 112 SIL cases, 110 (98.2%) were HPV positive and 95 (84.8%) had a high-risk type HPV infection. Almost one-half of the cases (46 of 95, 48.4%) with a high-risk HPV infection presented aneuploid squamous cells with greater than 9c DNA content, whereas none of the low-risk HPV-positive or HPV-negative SIL cases showed any aneuploid cells in this range. Although 91.8% of the HSIL cases displayed greater than 9c aneuploid cells, only 7.9% of the LSIL cases were positive for such cells with abnormally high DNA content., Conclusions: HPV typing and DNA measurements help in the objectivation of cytologic atypia and both can be performed efficiently from the same liquid-based cytologic samples., (Copyright 2003 American Cancer Society.)

We report on a case of gastroschisis in which sudden dilatation of extra-abdominal bowel at 34+1 weeks was followed by an unusual umbilical flow velocity waveform (diastolic notching). The condition was associated with normal umbilical Doppler indices, brain sparing effect and a non-reactive cardiotocograph (CTG). Findings at postnatal surgery strongly suggested severe cord compression by the herniated dilated bowel. The significance of notching in the umbilical artery waveform is discussed, as is the potential importance of this sign in the prepartum management of fetuses with gastroschisis., (Copyright 2002 John Wiley & Sons, Ltd.)

A fetus with thanatophoric dysplasia type 2 (TD2) associated with cloverleaf skull and abnormal development of the corpus callosum is reported. This case represents the first prenatal direct visualization of a partial agenesis of the corpus callosum (ACC) using high-resolution ultrasonography and colour power Doppler, which was confirmed by post-mortem magnetic resonance imaging (MRI). The causal link between cloverleaf skull in TD and partial ACC is discussed., (Copyright 2002 John Wiley & Sons, Ltd.)

Objective: The purpose of the present study was to assess the value of biometric lung measurements for the diagnosis of severe fetal pulmonary hypoplasia by investigating whether a significant correlation between two-dimensional lung biometry measurements and autopsy findings could be established., Methods: This was a prospective study carried out between 1995 and 1997. Nomograms for normal fetuses of the anterior-posterior and transverse inner thoracic diameters, which describe the growth and shape of the lung, were used as a basis for diagnosis of pulmonary hypoplasia in fetuses at high risk of developing the condition (the fetuses had bilateral renal agenesis or multicystic kidneys; chronic PROM <25 gestational weeks or hydrothorax). Pregnancy was terminated by abortion or intrauterine death in 29/43 high-risk fetuses and autopsies were performed. Only the 29 fetuses for which there were autopsy findings were included in the study., Results: The best plane for diagnosing pulmonary hypoplasia was the four-chamber view. The diagnostic accuracy for this view as expressed by the sensitivity was 57% for the anterior-posterior diameter and 44% for the transverse diameter; as expressed by the specificity it was 42% for the anterior-posterior diameter and 50% for the transverse diameter. The results for the four-chamber view for the various high-risk conditions were as follows: for fetuses with chronic PROM we obtained sensitivities of 75% and 50% (anterior-posterior and transverse dimensions, respectively) and specificities of 80% and 60% (anterior-posterior and transverse dimensions, respectively). The sensitivities of lung biometry in fetuses with hydrothorax were 1% and 80% for the two diameters, but there was a low specificity. In fetuses with bilateral renal agenesis or multicystic kidneys we obtained sensitivities of 36% and 30% (anterior-posterior and transverse dimensions, respectively) and a specificity of 50% (anterior-posterior dimension)., Conclusions: The present results show that two-dimensional lung biometry is not a suitable method for antenatal detection of pulmonary hypoplasia. However, in individual cases with high risk for pulmonary hypoplasia, lung biometry might prove to be an additional diagnostic parameter., (Copyright 2001 John Wiley & Sons, Ltd.)

Background: Developed in 1989, the Bethesda System has largely replaced previous classifications of Papanicolaou (Pap) smears from the uterine cervix. The system is binary, dividing smears into two groups - low-grade, squamous, epithelial lesions (LSIL) or high-grade, squamous, epithelial lesions (HSIL). A third category, atypical squamous cells of undetermined significance (ASCUS), is used to classify minimal cellular changes that do not satisfy the criteria for the low- or high-grade categories. This study was designed to confirm the utility of this binary division and to compare the results with another classification system (the Munich II Nomenclature) that is not binary but contains three divisions or grades for dysplasia - low, intermediate, and high., Methods: Pap smears were obtained from 593 women with a cytologic diagnosis of dysplasia based on the Munich System. Smears were then classified by the Bethesda System into LSIL or HSIL. Patients were followed for 2 years either with biopsy or repeat cytology. The initial smears were restained by the Feulgen method, and ploidy was evaluated by interactive DNA cytometry., Results: Of 241 cases of LSIL, 39% were diploid, 57% polyploid, and 4% aneuploid. Of 352 cases classified HSIL, 4% were diploid, 17% polyploid, and 79% aneuploid. After 2 years of follow-up, 2 of 108 patients who were biopsied and who were originally classified as diploid progressed to cervical intraepithelial neoplasia/carcinoma in situ (CIN/CIS) whereas 109 of 217 patients who were aneuploid and biopsied were found to have CINIII/CIS., Conclusions: The two divisions of the Bethesda System, LSIL and HSIL, correlated with ploidy as evaluated by cytometry. Aneuploidy was found to be useful to separate cases of HSIL from those of LSIL as defined in the Bethesda System. Because of the binary division, use of a system with three divisions for dysplasia, such as the Munich II Nomenclature, creates a therapeutic dilemma because a single diagnostic category (usually the intermediate grade) may contain both self-limiting and progressive lesions. DNA cytometry of Pap smears was found to be useful as a routine procedure., (Copyright 2001 American Cancer Society.)

We report our results from the analysis of Doppler measurements of breathing-related fluid flow velocity waveforms in the trachea in human fetuses. Our aim was to determine whether, using the proposed method, reproducible patterns can be recognized over the latter half of gestation. Breathing-related tracheal fluid flow velocity of 47 normal fetuses at 20-39 weeks' gestation were analysed. Colour Doppler was used to document 'streaming' of fluid in the trachea, followed by spectral Doppler to record flow velocity waveforms. More than 40 (median 94; range 42-725) continuous breathing cycles (inspiration+expiration) were obtained in each case. Although breathing-related fetal tracheal fluid flow waveforms were found to be highly variable, we were able to distinguish by visual analysis between a regular and an irregular pattern. Among the regular patterns, we further differentiate between a regular symmetric (sinusoidal type) and a regular asymmetric (deep inspiration with expiratory flow retardation) pattern. The regular pattern occurred consistently in all age groups studied and there were no significant (p<0.05) differences in the occurrence rate of the regular symmetric and asymmetric pattern. The incidence of the regular pattern increased significantly (p<0.05) from 11.74+/-3.38% (mean +/- SEM) at 24-27 weeks to 20.72+/-1.75% at 28-31 weeks of gestation and remained constant thereafter. This study shows that the proposed method can provide detailed information on breathing-related tracheal fluid flow velocity as early as 20 weeks of gestation. The information that a regular symmetric pattern was observed throughout the second half of gestation is important. Hence, a higher standardization of on-going fetal breathing movements studies may be achieved by measuring breathing-related tracheal fluid flow velocity waveform parameters only during this pattern.

We report the ultrasound, cytogenetic and morphologic findings in a case of trisomy 10 mosaicism prenatally detected by chorionic villus sampling (CVS). CVS sampling was carried out at the 13th week of gestation because of ultrasound diagnosis of hydrops fetalis and hygroma colli. Trisomy 10 mosaicism was diagnosed in cells from the cytotrophoblast (short-term culture) and the chorionic villus core (long-term culture). Fetal mosaicism was confirmed after termination of pregnancy in umbilical cord cells, placenta and fetal skin fibroblasts.

The purpose of the present study was to obtain normative data for the fetal upper respiratory tract by using high-resolution ultrasound techniques. Furthermore, we wanted to test the potential utility of the resulting normograms in diagnosing obstructive lesions of the trachea and oesophagus. Sonographic measurements of the diameters of the trachea, larynx and pharynx were obtained at well-defined planes from a prospective cross-sectional sample of 198 normal patients of known gestational age between 15 and 40 weeks' gestation. All measurements were performed during fetal apnea and in the absence of swallowing. The same measurements were also obtained from two cases with laryngeal atresia and three cases with oesophageal atresia, all of which were diagnosed prenatally. The data obtained were plotted on the constructed normograms. In normal fetuses approximately linear relationships existed between tracheal, laryngeal and pharyngeal diameter, on the one hand, and gestational age, on the other, with the measurements correlating significantly (p<0.0001) with gestational age. The linear regression coefficients (r2) for the tracheal, laryngeal and pharyngeal diameters were 0.66, 0.55 and 0.32, respectively. The 95 per cent prediction limits were also calculated. In fetuses with laryngeal atresia only the tracheal diameter was significantly higher as compared with that of normal fetuses. Data of the fetuses with oesophageal atresia showed that there were no changes in the upper airway anatomy. Our study provides normative data for the upper respiratory tract. In the prenatal diagnosis of obstructive neck anomalies the usefulness of the data would seem to be limited to those affecting the respiratory tract. Among the structures measured, only the trachea may prove to be of clinical significance.

Varicella syndrome (VS) specific malformations were sonographically seen at 22 weeks and 3 days of gestation. Fetal infection was demonstrated by detection of varicella-zoster virus (VZV) DNA in fetal blood and amniotic fluid by polymerase chain reaction (PCR). Following therapeutic abortion, fetal infection was confirmed by detection of VZV DNA in several fetal tissues and placenta, and by histopathological findings like miliary calcified necroses in fetal organs.

Complete occlusion of the upper airways is known to cause secondary morphological changes, including bilaterally enlarged hyperechogenic lungs, dilated trachea, and hydrops. Prenatal diagnosis of upper airway obstruction has been described in several cases. In these reports, the diagnosis was primarily attributed to indirect signs, and the authors were in doubt as to whether the location of the obstructed area (larynx, glottis or trachea) could be precisely visualized by ultrasound. In this paper two cases are reported presenting the features of congenital high airway obstruction syndrome (CHAOS) diagnosed at the 22nd week of gestation. In both cases, the upper neck was perfectly visualized in a coronal plane. At the onset of fetal breathing movements, the stenotic larynx remained in a closed position. By positioning a colour signal on the fluid-filled dilated trachea, we noticed absence of flow throughout the onset of breathing activity. We conclude that the atretic area must be situated at the level of the larynx. Because of the poor prognosis of laryngeal stenosis and the presence of associated anomalies, both pregnancies were terminated in the 23rd week. This report shows that the application of colour and spectral Doppler may be helpful in the differential diagnosis of fetuses with CHAOS.

The concentrations of alpha-1-microglobulin, beta-2-microglobulin, and retinol binding protein were determined in fetal blood sampled by cordocentesis. The blood values of 126 fetuses without ultrasonographic findings of urinary tract abnormalities as controls were found to be independent of the week of gestation. In nine fetuses affected by a severe bilateral renal dysplasia or agenesis, elevated values of alpha-1-microglobulin but normal values of retinol binding protein were obtained. The authors recommend the determination of alpha-1-microglobulin and, with some restriction, also of beta-2-microglobulin in prenatal renal function diagnosis.

Few reports concerning intrauterine shunting are available. We investigated the impact of this method. In order to evaluate intrauterine shunting and the complication rate for different indications, we sent a questionnaire to all German-speaking level 3 centres. In four level 3 centres, 52 intrauterine catheters were inserted in 34 fetuses. The indications were uni- or bilateral hydrothorax in nine cases, cystic adenomatoid malformation of the lung in four cases, infravesical stenosis in 13 cases, and fetal ascites in eight cases. In three cases (6 per cent), difficulties occurred when the drain was inserted. In 15 cases (29 per cent), the function of the drain was reduced by dislocation or occlusion. The mortality rate caused by shunting was as high as eight per cent (four cases). The application of an intrauterine shunt currently represents a rarely performed ultrasound-guided therapeutic intervention in the fetus. In all cases, the indication for shunting is to avoid compression of normal tissue by cystic structures. A high complication rate restricts the application of drainage to selected cases.

The study of the fetal platelet count and size can, according to the literature, be used for the prenatal diagnosis of the Wiskott-Aldrich syndrome (WAS). So far, no affected fetuses have been identified by this method. All pregnancies in which this method had been applied to resulted, as correctly predicted, in the birth of normal children. Here we report on a familial case of WAS where the haematological parameters failed to reveal the affected second child. Hence we assume that the platelet count and size of platelets remain normal in fetuses with WAS to the gestational age of 22 weeks and cannot be used for prenatal diagnosis.

An enzyme immunoassay especially designed for the quantification of Cu/Zn superoxide dismutase (SOD) in erythrocytes has been applied to measure the SOD of outcomes with high risk for Down's syndrome. From 148 fetuses SOD was quantified from erythrocytes of umbilical vein blood and related to the number of cells, the content of haemoglobin (Hb), and to the haematocrit (Hc). Comparative studies between the SOD content of erythrocytes from the fetuses and their mothers resulted in similar SOD levels (14.09 +/- 1.20 for fetal and 14.48 +/- 1.63 for maternal cells) with a 1.84-fold smaller variance for fetal cells. The best differentiation between normal fetuses and fetuses with Down's syndrome resulted from the SOD/cell ratio followed by the SOD/Hb ratio. Fixing a cut-off value from the probability density functions that the method results in a specificity of 99.99 per cent, the sensitivity to detect cases of Down's syndrome was 99.71 per cent for the SOD/cell ratio, 70.92 per cent for the SOD/Hb ratio, and 60.21 per cent for the SOD/He ratio. Nine cases with Down's syndrome were correctly diagnosed by the SOD/cell ratio determination. Eight of these were confirmed as free trisomy 21 by karyotype analysis and one was found to be a triploidy. The latter was not detected by the SOD/Hb and SOD/Hc ratios because of the one-third higher content of haemoglobin and the larger volume of the erythrocytes which resulted in ratios within the normal range.