Patrizia Vergani

Clinical outcome of mild fetal ventriculomegaly

OBJECTIVEnOur purpose was to evaluate the outcome of fetuses with mild cerebral ventriculomegaly.nnnSTUDY DESIGNnWe prospectively collected all cases of mild cerebral ventriculomegaly (transverse diameter of the atrium of the cerebral lateral ventricles between 10 and 15 mm) diagnosed antenatally between January 1990 and December 1996. Associated ultrasonographic abnormalities including markers of aneuploidy, presence of chromosomal anomalies, structural malformations detected at birth, and neurologic outcome were recorded. Outcome information was available on all cases. In addition, published series of cases of fetal mild cerebral ventriculomegaly were reviewed to identify prognostic indicators.nnnRESULTSnEighty-two cases fulfilled the inclusion criteria: 48 were isolated and 34 were associated with other ultrasonographic markers or anomalies. Among the 45 surviving euploid isolated cases, neurologic follow-up was normal at a mean age of 28 months (range 3 to 72 months). Male fetuses and those with a transverse atrial size <12 mm had a good prognosis. Ventricular atria > or =12 mm were more often associated with other anomalies (56% vs 6%) and, when isolated, with abnormal postnatal neurodevelopment (23% vs 3%). Aneuploidy was present in two cases of isolated mild cerebral ventriculomegaly, both of which were associated with advanced maternal age, and in seven cases associated with other anomalies.nnnCONCLUSIONSnMild cerebral ventriculomegaly should prompt targeted ultrasonographic examination, inclusive of markers of aneuploidies, visualization of the corpus callosum, and echocardiogram as well as serologic evaluation for congenital infections. In isolated mild cerebral ventriculomegaly genetic counseling should take into account clinical, laboratory, and ultrasonographic findings. A review of the published series suggests that cognitive or motor delay is predominantly mild and that it occurs in about 9% of cases of isolated mild cerebral ventriculomegaly.

Intraventricular hemorrhage and periventricular leukomalacia in preterm infants

OBJECTIVE: To evaluate whether intraventricular hemorrhage and periventricular leukomalacia are characterized by different risk factors. METHODS: In a cohort of 653 consecutive singleton neonates born after preterm membrane rupture, spontaneous preterm labor, or indicated preterm delivery at 24 to 33 weeks of gestation from January 1, 1993, to December 31, 2002, we evaluated the obstetric and histopathologic placental variables in reference to the development of intraventricular hemorrhage (n = 44), periventricular leukomalacia (n = 19), or no ultrasonographic cerebral lesion (n = 589). Excluded were stillbirths and congenital anomalies. Statistical analysis included Fisher exact test, Student t test, and stepwise logistic regression analysis with a 2-tailed P < .05 considered significant. RESULTS: Multivariate analysis showed that occurrence of neonatal intraventricular hemorrhage and periventricular leukomalacia were associated only with spontaneous prematurity (odds ratio = 1.9; 95% confidence interval 1.1–3.4) and gestational age at delivery in weeks (odds ratio = 0.8; 95% confidence interval 0.7–0.9). Neonates with intraventricular hemorrhage did not differ from those with periventricular leukomalacia in any obstetric or neonatal variable, but there was a higher risk of neurodevelopmental delay associated with periventricular leukomalacia. CONCLUSION: Among premature infants born at less than 34.0 weeks of gestation, intraventricular hemorrhage and periventricular leukomalacia share common clinical characteristics, with spontaneous preterm delivery and gestational age at delivery as the only independent antenatal predictors. LEVEL OF EVIDENCE: II-2

Isolated fetal choroid plexus cysts: role of ultrasonography in establishment of the risk of trisomy 18.

OBJECTIVEnThe significance of isolated choroid plexus cysts found by ultrasonographic scan during the second trimester as a marker for trisomy 18 is still debated. We analyzed our data and reviewed the series published in the English-language literature to calculate the likelihood ratio of trisomy 18 in the presence of isolated choroid plexus cysts; that is, the factor by which the individual risk of trisomy 18 is increased in the presence of isolated choroid plexus cysts.nnnSTUDY DESIGNnLikelihood ratios were calculated as ratio of the sensitivity to the false-positive rate. Sensitivity was defined as the rate of isolated choroid plexus cysts detected at midgestation among fetuses with trisomy 18. False-positive rate was defined as the rate of choroid plexus cysts detected at midgestation in the population without trisomy 18. The sensitivities of all published series reporting rates of choroid plexus cysts at the time of the first ultrasonographic examination between 14 and 24 weeks gestation in populations with trisomy 18 and in low-risk populations were included in the analysis. To these we added all cases of trisomy 18 diagnosed at our institution during the period January 1, 1988, through June 30, 1998, in which prenatal ultrasonographic examination was performed between 14 and 24 weeks gestation.nnnRESULTSnThe prevalence of second-trimester ultrasonographic detection of isolated choroid plexus cysts among fetuses with trisomy 18 was 6.7% (13/194), whereas that in the population without trisomy 18 was 0.9% (752/79,583). The likelihood ratio associated with isolated choroid plexus cysts was therefore 7.09 (95% confidence interval, 3.97-12.18).nnnCONCLUSIONnThe presence of isolated second-trimester choroid plexus cysts increases the base risk of trisomy 18 by a factor of 7.09. This likelihood ratio can be multiplied by the risk calculated according to maternal age to obtain the individual risk of trisomy 18 and thus permit more accurate counseling of the patient.

Doppler predictors of adverse neonatal outcome in the growth restricted fetus at 34 weeks' gestation or beyond

OBJECTIVEnThe study was undertaken to assess whether prenatal Doppler variables can identify cases of fetal growth restriction (FGR) approaching term who are at risk for adverse neonatal outcome.nnnSTUDY DESIGNnFrom a cohort of FGR cases delivered at >or=34 weeks, fetal biometry and pulsatility indices (PI) of fetal arteries obtained less than 2 weeks before delivery were related to adverse neonatal outcome, defined as admission to the neonatal intensive care unit (NICU) for indications other than low birth weight alone.nnnRESULTSnStepwise regression analysis showed that after controlling for gestational age at delivery and fetal biometry, only the last umbilical artery (UA) PI percentile was significantly predictive of adverse neonatal outcome (odds ratio=1.02, 95% CI 1.01-1.03, P=.02). Receiver operating characteristic curve analysis identified a UA PI at the 65th percentile as optimal predictor of adverse neonatal outcome (sensitivity=60%, false-positive rate=30%).nnnCONCLUSIONnIn FGR cases delivered at >/=34 weeks gestation, Doppler PI at the UA independently predicts the likelihood of admission to the NICU for reasons other than low birth weight alone.

Ultrasonographic differential diagnosis of fetal intracranial interhemispheric cysts

OBJECTIVEnUltrasonographic differentiation between intracranial supratentorial interhemispheric pathologic cystlike lesions and those related to physiologic median structures is essential because the latter have no clinical relevance, whereas the former may carry a poor prognosis. We reviewed our experience with 19 consecutive cases of interhemispheric hypoechoic lesions without parenchymal involvement diagnosed between January 1990 and June 1997 to establish their clinical significance and provide prenatal ultrasonographic criteria to distinguish between pathologic cystlike lesions and those related to physiologic midline structures.nnnSTUDY DESIGNnAll patients underwent targeted prenatal scans of intracranial anatomy to establish the relationship between the fluid collections and the surrounding parenchymal and ventricular structures. In addition, a detailed anatomic survey was performed to rule out associated malformations. Follow-up, including neurologic examination, imaging, autopsy evaluation, or a combination was performed in all cases. Statistical analysis used the Wilcoxon rank sum test, the Fisher exact test, and the chi2 test for trend. P <.05 was considered significant.nnnRESULTSnCystlike lesions related to physiologic median structures (n = 12) included enlargement of the cavum septi pellucidi (n = 3), enlargement of the cavum vergae (n = 2), and cysts of the velum interpositum (n = 7). These lesions were unilocular and had a median size of 10 mm (range 10-30 mm); they resolved in 5 cases and remained stable in the remainder. They were not associated with overt abnormalities, other than borderline ventriculomegaly in 2 cases. Pediatric follow-up (median 26 months, range 3-84 months) showed normal neurodevelopment in all cases. Pathologic cystlike lesions (n = 7) were significantly larger (median 40 mm, range 10-80 mm, P =.004) and had a significantly worsening trend, growing more at serial prenatal ultrasonographic examinations (P =.039) than fluid collections related to physiologic median structures. Moreover, prenatal ultrasonographic evidence of associated intracranial abnormalities, in the form of partial or total agenesis of the corpus callosum and overt hydrocephalus, was present in 5 of 7 cases of pathologic cystlike lesions and in none of the 12 related to physiologic structures (P =.002). Median gestational age at diagnosis was not different between those with cystlike lesions related to physiologic median structures and those with pathologic lesions (30 and 31 weeks, respectively). Among the latter group, 1 pregnancy was voluntarily terminated, 1 infant died at 4 months of age, 2 infants had neurodevelopmental delay, and 3 infants were neurologically healthy at a mean follow-up of 43 months. Cyst shunting was necessary in 5 of 6 cases.nnnCONCLUSIONSnInterhemispheric cystlike lesions related to physiologic structures can be prenatally distinguished from pathologic fluid collections on the basis of location, cyst size, change in size with time, and absence of associated anomalies.

Critical appraisal of the use of nuchal fold thickness measurements for the prediction of Down syndrome.

OBJECTIVEnNuchal fold thickness is the best ultrasonographic predictor of fetal trisomy 21. However, the risk assigned on the basis of the commonly used threshold of nuchal fold thickness >/=6 mm does not take into consideration the significant associations between nuchal fold thickness and gestational age and between maternal age and Down syndrome. We propose a new method of calculating Down syndrome probability that takes into account both gestational age at examination and previously assessed probability of Down syndrome.nnnSTUDY DESIGNnNuchal fold thickness was measured at ultrasonographic examination at 14 to 22 weeks gestation without previous knowledge of the fetal karyotype. Nuchal cystic hygromas were excluded from analysis. Statistical analyses included correlation, logistic regression to control for other ultrasonographic predictors of trisomy 21 and for maternal age, receiver operating characteristic curve, and likelihood ratios (defined as the ratio of the sensitivity to the false-positive rate). P <.05 was considered significant.nnnRESULTSnMean gestational age at ultrasonography was 16.9 weeks gestation (range, 14-22 weeks gestation). Mean (+/-SD) nuchal fold thickness in fetuses with trisomy 21 (4.7 +/- 1.6 mm; n = 29) was greater than in euploid fetuses (3.2 +/- 0.9; n = 780; P <.001). Logistic regression analysis established that nuchal fold thickness was a significant predictor of trisomy 21 independent both of the other ultrasonographic markers and of maternal age (P <.001). Regression analysis showed that nuchal fold thickness was significantly correlated with gestational age among both fetuses with trisomy 21 and euploid fetuses and that the regression line of fetuses with trisomy 21 had a slope similar to that of euploid fetuses. The difference between observed and expected nuchal fold thicknesses on the basis of the biparietal diameter (as a function of gestational age) was used to obviate the confounding effect of gestational age. Differences between observed and expected nuchal fold thicknesses were then used to calculate likelihood ratios. These likelihood ratios could then be multiplied by the individual prior probability to obtain a patient-specific Down syndrome probability.nnnCONCLUSIONnNuchal fold thickness is correlated with gestational age in both euploid fetuses and fetuses with Down syndrome. Use of the difference between observed and expected nuchal fold thicknesses to determine likelihood ratios allows the calculation of individual posterior probabilities of Down syndrome that take into consideration both gestational age and maternal age.

Role of FISH on Uncultured Amniocytes for the Diagnosis of Aneuploidies in the Presence of Fetal Anomalies

Objective: To assess the accuracy of fluorescent in situ hybridization (FISH) on amniocytes in fetuses affected by structural malformations suggestive of chromosomal anomalies. Methods: FISH of uncultured amniotic fluid cells and conventional cytogenetic analysis were performed on 48 pregnancies with ultrasonographic (US) evidence of fetal anomalies. The AneuVysion® assay (Vysis) with specific probes for chromosomes 13, 18, 21, X and Y, was used. Amniotic fluid samples were obtained between the 14th and 34th weeks of gestation. Results: In cases with a single abnormal US finding (n = 15), 5 aneuploidies were detected (1 case of trisomy 13 and 4 of trisomy 21). In the group with two or more malformations (n = 33) there were 15 aneuploidies (9 cases of trisomy 18, 2 of trisomy 21, 2 monosomy X, 1 trisomy 13, and 1 triploidy). In this group, conventional cytogenetic analysis revealed two additional chromosomal anomalies not detectable by FISH (1 trisomy 16 mosaic, and a terminal deletion 4p). No sex aneuploidies were observed. Conclusions: The lack of false-positive diagnosis in the FISH analysis in our sample prompts us to consider interphase FISH as a useful tool in pregnancies at high risk for chromosomal aneuploidies. When FISH analysis is normal, the overall risk of chromosomal abnormalities is significantly reduced. However, the finding of two chromosomal anomalies undetectable by AneuVysion® assay confirms the need for conventional chromosome analysis to complement FISH results. Moreover, the results collected here, in agreement with those already reported in the literature, indicate that FISH analysis on uncultured amniocytes can play an important role in counselling and decision-making, especially in cases at risk for aneuploidies, such as those with structural abnormalities at US.

Predictors of adverse perinatal outcome in twins delivered at < 37 weeks.

OBJECTIVEnMultiple gestations are at increased risk for prematurity as well as perinatal mortality and morbidity. The aim of this study was to identify the independent risk factors for adverse perinatal outcome in a large uniform population of twins delivered preterm.nnnMETHODSnWe accessed a cohort of twin gestations for the period 1990-2000 delivered at < 37.0 weeks gestation. Chorionicity was established by ultrasound assessment of the dividing membrane, neonatal gender and histologic examination of the placenta at birth. Adverse perinatal outcome was defined as stillbirth, neonatal death, or major neonatal complications. Statistical analysis used contingency tables, Students t test, one-way ANOVA and logistic regression, with a two-tailed p < 0.05 considered significant.nnnRESULTSnA total of 356 twin gestations (712 twins) were included in the database, and 183 twins (25.7%) had adverse perinatal outcome. Logistic regression analysis demonstrated that gestational age at delivery (p < 0.001), premature rupture of membranes (PROM) (p = 0.004), birth weight discordance (p = 0.009), and 5-min Apgar scores (p = 0.001) were significant and independent predictors of adverse perinatal outcome, whereas monochorionicity and twin-twin transfusion syndrome were not.nnnCONCLUSIONSnGestational age at delivery and birth weight discordance are the most important independent predictors of perinatal mortality or morbidity among preterm twins.

Caveats for the Use of Humerus Length in the Prediction of Fetal Down Syndrome

Objective: To assess the reliability and reproducibility of fetal humerus length in the diagnosis of trisomy 21. Methods: Cohort study inclusive of 22 trisomy 21 fetuses, who underwent ultrasonographic examination between 14 and 22 weeks’ gestation, and 457 euploid controls. Regression analysis was performed for humerus length as function of biparietal diameter. Based on the generated regression equation in euploid fetuses, expected values of humerus length for a given biparietal diameter were calculated. The ratios of observed to expected (O/E) humerus length values were compared between euploid and trisomy 21 fetuses using Student’s t test. Receiver operating characteristic (ROC) curve analysis was used to detect optimal thresholds of O/E humerus length for diagnosis of trisomy 21. In addition, a MEDLINE search was conducted for articles published on humerus length as predictor of trisomy 21. Results: No differences were present between the regression lines of trisomy 21 and euploid fetuses (mean ± standard deviation O/E humerus length in euploid and aneuploid fetuses: 1.00 ± 0.10 vs. 0.97 ± 0.11, p = 0.21). The optimal threshold O/E humerus length <0.88 identified by ROC curve analysis had a sensitivity of 18% and a false-positive rate of 9% for the diagnosis of trisomy 21. From a review of the evidence provided by the 17 published series on humerus length as predictor of Down syndrome, the following caveats emerge: (1) with a median false-positive rate of 5% (range 1–12%), the median sensitivity of humerus length was only 28% (range 15–64%); (2) differences were present among centers in the regression lines of euploid fetuses and in the optimal diagnostic thresholds of humerus length, suggesting inter-center variability, and (3) most populations studied were at high genetic risk for trisomy 21, hence the diagnostic ability of humerus length in low risk populations has not been tested. Conclusions: The ability of humerus length to predict trisomy 21 is inconsistent. Only institutions with locally generated regression equations and documented predictive ability of this marker should utilize humerus length as a screening test for trisomy 21, alone or incorporated into diagnostic algorithms with serum or other sonographic markers of trisomy 21. The diagnostic ability of humerus length in low risk populations is currently unknown.