Does autopsy of antenatally diagnosed malformed foetuses aid genetic counselling?

BACKGROUND: Many pregnancies are terminated because of ultrasonographic diagnosis of malformation in the foetus. A detailed foetal autopsy is needed to arrive at a definite diagnosis on the basis of which genetic counselling can be provided. METHODS: Sixty-one foetuses, terminated because of antenatal diagnosis of congenital malformations by ultrasound, were autopsied. The ultrasound diagnosis was compared with the diagnosis reached after autopsy. RESULTS: In 31 cases (51%) the autopsy provided additional findings. In 21 cases (34.4%), the autopsy changed the primary diagnosis. The revised diagnosis led to a change in the risk of recurrence in 18 cases (29.5%). CONCLUSION: Genetic counselling depending solely on ultrasonographic foetal diagnosis may be erroneous. For appropriate genetic counselling, a detailed foetal examination should be carried out after termination in cases with ultrasonographically detected congenital malformations.     

Long-term effects of bicycle-ergometry training on exercise endurance and dyspnea in patients with chronic pulmonary emphysema]

OBJECTIVE: To evaluate prenatal diagnosis of limb-body wall complex (LBWC) by ultrasonography in eight cases. STUDY DESIGN: The diagnosis was based on two of the following: exencephaly/encephalocele with facial clefts, thoracoschisis and/or abdominoschisis and limb defect. The ultrasonographic findings were compared with the autopsy findings in each case. RESULTS: The average weeks of gestation at which malformations were diagnosed by ultrasonography was 21.7 +/- 4.7 (mean +/- SD, n = 8). All eight fetuses were diagnosed as having characteristic abnormalities and six of them as having scoliosis by ultrasonography. Four of the eight were examined for maternal serum alpha-fetoprotein (MSAFP); the levels exceeded 2.5 multiples of the mean according to the standard value at our hospital. Chromosomal analysis was performed for six cases and revealed that they were normal in karyotype. All eight cases showed abdominoschisis, scoliosis and abnormalities of the lower extremities. A single umbilical artery was present in seven cases (87.5%), and a short umbilical cord was present in seven (87.5%). CONCLUSION: Ultrasonographic detection of abdominoschisis, scoliosis abnormalities of the lower extremities, a single umbilical artery and a short umbilical cord is important for the prenatal diagnosis of LBWC. An extremely elevated level of MSAFP is also indicative of the complex.     

Echographic markers of fetal chromosomopathies. Diagnostic possibilities with transvaginal ultrasonography and our experience

OBJECTIVE: Aim of this study was to evaluate, during early pregnancy, the correlation of some anomalies and malformations with fetal chromosomopathies. EXPERIMENTAL DESIGN: Morphostructural and biometric anomalies in chromosomopathic fetuses were evaluated. PATIENTS: 1331 pregnancies at high risk for genetic disease and malformations referred to our center for prenatal diagnosis. METHOD: Scans were performed using endovaginal convex probes (5.0 to 7.0 MHz). SURVEYS: Urinary, cardiac and cerebral malformations as well as alterations of bone growth were evaluated. RESULTS: With respect to the other malformations, cystic hygroma is more frequently associated with an abnormal fetal karyotype. CONCLUSIONS: The majority of morphostructural abnormalities diagnosed during first trimester by transvaginal sonography cannot, in according to personal experience, be used as markers of chromosomopathies.     

The effects of acute phencyclidine treatment on neuropeptide Y (NPY) neuronal system in the rat arcuate nucleus studied by immunocytochemistry and in situ hybridization

The clinical, radiological and pathological findings of four cases of primary intraventricular haemorrhage secondary to choroid plexus arteriovenous malformations (AVM) are described and the relevant literature reviewed. In three of the cases the diagnosis was confirmed or made at autopsy. The fourth case survived to undergo craniotomy followed by radiosurgery with excellent results. All AVMs originated in the choroid plexus of the lateral ventricle, and autopsy confirmation required a high degree of suspicion and the systematic microscopic examination of serial coronal sections of the ventricle with the clot in situ.     

Pathological evidence of prolonged umbilical cord encirclement as a cause of fetal death

A case is presented in which autopsy findings (deep groove around the fetal waist and buttock), and gross and microscopic umbilical cord and placental examination (linear ulcer of umbilical cord histologically rimmed by fetal epidermal implants with evidence of remote bleeding) established the diagnosis of umbilical cord encirclement as a cause of intrauterine fetal death despite the lack of prenatal or postnatal obstetrical evidence.     

Fetal enterolithiasis and anhydramnios; due to in utero hepatorenal syndrome?

Enterolithiasis is a rare, prenatal ultrasonographic finding. Previously reported cases were invariably associated with major fetal malformations. We describe a case of fetal enterolithiasis and anhydramnios in an anatomically normal fetus who, at autopsy, showed end-stage fetal liver disease. Fetal hepatorenal syndrome is the most probable cause of this in utero sonographic combination.     

Tissue iron storage patterns in fetal hydrops associated with congestive heart failure

To learn whether fetal congestive heart failure causes a characteristic tissue iron storage pattern, we selected 15 neonatal autopsy cases of hydrops fetalis in which both the clinical and gross autopsy findings suggested intrauterine congestive heart failure. The latter appeared to be due to functional causes in 10 (3 nonhemolytic anemia, 4 cardiac dysrhythmia, 3 dilated cardiomyopathy) and was associated with cardiac malformation in 5. We graded the amount of hepatocellular siderosis, reticuloendothelial siderosis, and renal tubular siderosis in Perls-stained microscopic sections of liver, spleen, and kidney and compared the iron storage pattern with that in 15 normally developed neonatal autopsy controls (4 preterm, 11 term) and a further 7 with hemolytic anemia (5 alpha-thalassemia, 2 parvovirus B19 infection). Liver cell siderosis was absent in the three cases with nonhemolytic anemia. It was increased in 11 of the remaining 12 cases, as in hemolytic anemia controls. Among the five cardiac malformation cases, three had proximal renal tubular siderosis (as in hemolytic anemia controls) attributed to turbulent blood flow through the heart. Among the five, hydrops appeared to be due to prenatal closure of the foramen ovale in one and to prenatal constriction of the ductus arteriosus in another. In one of the five, and despite complex malformation of the heart, hydrops appeared to be due to complete heart block. We concluded that, although clinical information and morphologic assessment of the heart were basic to identifying a cardiac cause of fetal hydrops, histologic assessment of the pattern of iron storage helped confirm the pathologic diagnosis. Analysis of the pathologic findings led to a scheme for categorizing cardiogenic fetal hydrops.     

Fetal central nervous system anomalies: MR imaging augments sonographic diagnosis

PURPOSE: To evaluate fetuses with sonographically suspected central nervous system anomalies to determine the frequency with which obstetric magnetic resonance (MR) imaging adds clinically useful information to that provided by ultrasonography (US). MATERIALS AND METHODS: US and MR images and diagnoses in 18 pregnant women were reviewed and compared by two radiologists. Postnatal physical examination and imaging findings and fetal autopsy results were standards. Referring physicians were questioned as to how the additional information provided by MR imaging changed patient counseling. RESULTS: In 10 (55%) patients, MR imaging demonstrated 11 additional findings. These findings were agenesis of the corpus callosum (n = 4), cerebellar hypoplasia (n = 2), cortical cleft (n = 2), polymicrogyria (n = 1), porencephaly (n = 1), and partial agenesis of the septi pellucidi (n = 1). In seven (39%) patients, additional information provided by MR imaging altered counseling. In one case of suspected agenesis of the corpus callosum, diagnosis at MR imaging was at least partially incorrect. CONCLUSION: US and MR imaging are complementary imaging methods in the evaluation of high-risk pregnancy. When a central nervous system anomaly is suspected at US, MR imaging may demonstrate additional findings that can alter patient counseling.     

Possibilities of ultrasonic diagnosis in fetal abdominal monstrosities (author's transl)

The diagnostic possibilities of intrauterine ultrasonic assessment of the fetal abdomen by rapid B-scan are described on the basis of two cases (megalocystis/megaloureter syndrome and omphalocele with cloaca formation). Other examination methods of prenatal diagnosis to confirm the findings are also discussed, but their diagnostic significance is even more limited than that of sonography, individual cases excepted. Although early detection of neural tube anomalies is the most important application of ultrasound, pronounced monstrosities of the fetal abdominal region are also definitely recognisable via ultrasonic examination.     

Prenatal diagnosis of holoprosencephaly. A series of twelve cases

OBJECTIVE OF THE STUDY: To determine the prenatal ultrasound criteria of holoprosencephaly and their correlation with embryogenesis. MATERIAL AND METHODS: We report 12 cases of holoprosencephaly that have been discovered between January 1990 and June 1996 (eleven alobar holoprosencephalies and one semilobar holoprosencephaly) at La Grave Hospital, Toulouse. RESULTS: In all cases, severe facial anomalies have been (cyclopia, cebocephaly or ethmocephaly). Prenatal ultrasound diagnosis was based on the association of brain anomalies (wide monoventricular cavity, thalami fusion, lacking of median structures) and facial dysmorphia (hypotelorism, orbital anomalies, median cleft lip ...). Finding microcephaly was a frequent sign of holoprosencephaly (64% of all cases). Chromosomal abnormalities have been found in 36% of the fetuses (Trisomy 13 is the most common). All patients underwent therapeutic abortions. CONCLUSION: Transvaginal sonography diagnosis can be made around the 14th to 16th week amenorrhea. An early diagnosis allows an easier pregnancy termination, when such severe anomalies are found. In order to provide genetic counseling, a cytogenetic study of the fetus is necessary.     

Roe v. Wade and the euthanasia debate

Epidermolysis bullosa (EB) is a group of heritable diseases which manifest with blistering and erosions of the skin and mucous membranes. Due of life-threatening complications and significant long-term morbidity associated with the severe, neonatal lethal (Herlitz) form of junctional EB (H-JEB), there has been a demand for prenatal diagnosis from families at risk for recurrence. Previously, the only reliable method of prenatal diagnosis of EB was a fetal skin biopsy performed at 16-20 weeks' gestation and analysed by electron microscopy. Recently, the genes LAMA3, LAMB3, and LAMC2, encoding the polypeptide subunits of laminin 5, an anchoring filament protein, have been shown to contain mutations in H-JEB. In this study, direct detection of pathogenetic mutations in the laminin 5 genes was used to perform polymerase chain reaction (PCR)-based prenatal testing. DNA was obtained by chorionic villus sampling (CVS) at 10-15 weeks or amniocentesis at 12-19 weeks' gestation in 15 families at risk for recurrence of JEB. In 13 cases, the fetus was predicted to be either genetically normal or a clinically unaffected carrier of a mutation in one allele. These predictions have been validated in all cases by the birth of a healthy child. In two cases, an affected fetus was predicted, and the diagnosis was confirmed by subsequent fetal skin biopsy. These results demonstrate that DNA-based prenatal testing offers an early, expedient, and accurate method of prenatal diagnosis or an exclusion of Herlitz JEB.     

Clinical and ultrasonographic features of dextroposition of the fetal heart

OBJECTIVE: Our purpose was to characterize the findings associated with dextroposition of the fetal heart. STUDY DESIGN: A fetal echocardiography database was retrospectively searched from January 1990 through December 1996 to identify all cases referred or diagnosed with dextroposition of the fetal heart. Dextroposition was defined as most of the normally connected fetal heart found on the right side of the fetal chest. Intracardiac and extracardiac fetal anomalies were reviewed. All available karyotypes and postnatal examinations were reviewed. RESULTS: During the study period 2882 fetal echocardiograms were performed, of which 297 (10.3%) were abnormal. Of these, 14 had dextroposition. Associated anomalies included atrioventricular canal (29%), diaphragmatic hernia (21%), and aneuploidy (14%). Isolated dextroposition with no other significant anomalies was seen in only 1 case. In another, no anomalies were noted except for suspected agenesis of 1 lobe of the right lung; karyotype and postnatal evaluation revealed no other abnormalities in both cases. CONCLUSIONS: Dextroposition of the fetal heart was seen in 0.5% of our fetal echocardiograms and was associated with significant anomalies in 86% of our cases. When diagnosed, a targeted ultrasonogram, fetal echocardiogram, and karyotype should be offered.     

Anatomo-clinical conference. Pitié-Salpêtrière Hospital. Case No 2--1997. Recurrent febrile pancytopenia

Modern ultrasonic diagnostic instruments with high resolution and color Doppler sonography allow the obstetrician to describe pathological findings very precisely and at an early stage of pregnancy. The use of high-resolution ultrasound makes it possible to detect heart malformations already between the 8th and 10th week of gestation. This development has essentially changed the clinical requirements on fetal autopsy which in its traditional way no longer meets the increased demands. Unless the pathologists faces this challenge the importance of fetal autopsy will diminish. Modern image databases and communication techniques allow the pathologist to have direct access to text and images of pre-findings by other clinics. Great importance, however, must be attached to the interdisciplinary cooperation with obstetricians and geneticists. We report on routine fetal autopsy by using an interdisciplinary database an the Charité.     

6-year experience of prenatal diagnosis in an unselected population in Oxford, UK

BACKGROUND: The benefits and harm associated with prenatal diagnosis are open to debate. We give a 6-year overview of the experience of one prenatal-diagnosis unit using a defined, unselected population. METHODS: All congenital malformations suspected prenatally and all congenital malformations, including chromosome anomalies, confirmed at birth were identified from the local Congenital Malformation Register. All fetuses or infants of women booked for delivery at the Oxford Women's Centre who had an OX postcode and date of delivery between 1991 and 1996 were eligible for the study. FINDINGS: 725 (2%) of 33,376 babies, were judged abnormal at delivery. 396 (55%) malformed fetuses and infants had been correctly identified prenatally. 174 fetuses had a suspected abnormality identified on scan and subsequently proved to be normal. 160 (92%) of these false-positive results were attributable to the reporting of so called ultrasound soft markers. Accuracy of ultrasound diagnosis was good for structural malformations. Ultrasound soft markers were responsible for a 4% increase in detection of malformations (from 51% to 55%) and a 12-fold increase in false-positive rate (one in 2332 to one in 188). 171 pregnancies (43% of prenatally diagnosed malformed babies) were terminated because of suspected abnormality. Suspicion of abnormality in these cases was first aroused after ultrasound scan in 136 (79%); chromosome analysis because of advanced maternal age, family history, or higher risk in biochemical screening test in 25 (15%); and molecular analysis of single gene defect because of family history in ten (6%). There was a 20% reduction in prevalence of conditions compatible with survival beyond the neonatal period because of termination of such pregnancies. INTERPRETATION: More than half of all malformed fetuses can be identified prenatally in routine practice, mostly following initial suspicion from ultrasound examination. Ultrasound soft markers lead to a small increase in detection of malformations but a large increase in false positives. Further research on the impact, including psychological, and value of markers is required to determine whether the benefits of reporting them exceeds the harm. Because methods and techniques continually change, ongoing surveillance of prenatal diagnostic services is vital.     

Screening for fetal anomalies in the 12th week of pregnancy by transvaginal sonography in an unselected population

The advantages and limitations of transvaginal (TV) sonography in detecting fetal anomalies in the 12th week of pregnancy were examined in a prospective screening study of an unselected population. During a 3-year period, 3991 examinations were performed and 35 fetuses were identified as having 43 anomalies (0.9 per cent). Most of these malformations were either severe structural disorders or isolated nuchal changes when karyotyping revealed chromosomal aberration in six cases. Twenty-one pregnancies were terminated and three fetuses died. Routine transabdominal (TA) ultrasonographic examinations were performed at 18 and 30 weeks in all those pregnancies where the TV scan had not found fetal anomalies. TA sonography identified 19 abnormal fetuses and ten cases remained undetected. TV sonography detected 51 per cent of malformed fetuses which were diagnosed prenatally (not including cases with nuchal oedema) and 41 per cent of the total were found in this study. Besides offering the possibility of early termination, first trimester screening has the advantage of identifying a transient sonographic sign, nuchal oedema, which can be used as a marker in screening for fetal chromosomal abnormalities. However, standard mid-second-trimester TA scanning is still recommended, since a significant number of malformations cannot be detected so early in pregnancy.     

Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines

OBJECTIVE: Given concerns about use of psychotropic medication during pregnancy, the authors reviewed the literature regarding the effects of prenatal exposure to psychotropic medications on fetal outcome. METHOD: A MEDLINE search of all articles written in English from 1966 to 1995 was performed to review information on the effects of psychotropic drug use during pregnancy on fetal outcome. Where sufficient data were available and when methodologically appropriate, meta-analyses were performed to assess risk of fetal exposure by psychotropic medication class. RESULTS: Three primary effects are associated with medication use during pregnancy: 1) teratogenicity, 2) perinatal syndromes (neonatal toxicity), and 3) postnatal behavioral sequelae. For many drug classes there are substantial data regarding risk for teratogenicity. Tricyclic antidepressants do not seem to confer increased risk for organ dysgenesis. The available data indicate that first-trimester exposure to low-potency phenothiazines, lithium, certain anticonvulsants, and benzodiazepines may increase the relative risk for congenital anomalies. However, the absolute risk of congenital malformations following prenatal exposure to most psychotropics is low. CONCLUSION: Exposure to certain psychotropic drugs in utero may increase the risk for some specific congenital anomalies, but the rate of occurrence of these anomalies even with the increased risk remains low. Use of psychotropic medications during pregnancy is appropriate in many clinical situations and should include thoughtful weighing of risk of prenatal exposure versus risk of relapse following drug discontinuation. The authors present disorder-based guidelines for psychotropic drug use during pregnancy and for psychiatrically ill women who wish to conceive.     

Magnetic resonance imaging of the fetus: a study of 20 cases performed without curarization

Twenty patients underwent magnetic resonance imaging (MRI) at a mean gestational age of 32 weeks. There were 12 patients with suspected fetal brain abnormality and four with intrauterine growth retardation (IUGR), while the remaining four cases were studied for other reasons. The MRI examinations were performed on a 0.5 Tesla machine, with surface coils. One minute acquisition time T1 sequences were used. All the studies were performed without fetal curarization, and only under maternal sedation using flunitrazepam given per os 1 h before MRI examination. Three examinations were incomplete because of fetal movement artefacts. In the remaining cases, MRI allowed the examination of fetal brain anatomy. In five cases, it helped to differentiate isolated hydrocephalus and corpus callosum agenesis. Sub-ependymal nodules were depicted in a case of fetal tuberous sclerosis. One suspected arachnoid cyst was proved to be an ultrasound artefact. Decreased fetal fat on MR images was correlated with low birth weight in cases of IUGR. Due to its better spatial resolution, ultrasonography was more accurate for the diagnosis of facial and lumbar anomalies. Fetal MRI may be performed without curarization. Surface coils allow the detailed analysis of brain parenchyma, and thus MRI is especially useful in the difficult prenatal diagnosis of fetal brain abnormalities.     

Axial ultrasonographic imaging of the fetal maxilla for accurate characterization of facial clefts

The purpose of this study was to determine whether scanning of the fetal midface in the axial plane allows accurate characterization of facial clefts. During fetal anatomic survey, facial clefts were identified in six fetuses. The midface anatomy was evaluated with ultrasonography in the coronal and axial planes, and the clefts were characterized prospectively as unilateral or bilateral and as involving the lip alone or both the lip and the palate. The integrity of the upper lip was assessed in the coronal and axial planes. The continuity of the normal C-shaped curve of the tooth-bearing alveolar ridge and the anterior six tooth sockets was assessed in the axial plane. The prospective prenatal diagnosis was correlated with postnatal findings in all cases. The clefts where characterized prospectively as unilateral cleft lip (one case), unilateral cleft lip and cleft palate (four cases), and bilateral cleft lip and cleft palate (one case). The prenatal characterization was confirmed to be correct postnatally in all cases. Prenatal sonographic evaluation of the axial view of the tooth-bearing alveolar ridge of the maxilla allows accurate determination of whether a cleft is confined to the lip or involves both the lip and the palate.     

Modification of IgH PCR clonal analysis by the addition of sucrose and cresol red directly to PCR reaction mixes

We present the findings of a "new" sublethal MCA syndrome in three siblings, one female and two boys, the only children of healthy, non-consanguineous parents. In addition to prenatal growth retardation and early demise, they presented the same pattern of multiple malformations: relative microcephaly with bird-headed face, microphthalmos/coloboma iris/cloudy corneae, genital anomalies with hypospadias and cryptorchidism in the two males. Associated anomalies included: cardiac defects (2/3), unilateral cleft lip/cleft palate (1/3), anal stenosis (2/3) and unilateral renal agenesis (1/3).     

Antimicrobial activity of ethanol, glycerol monolaurate or lactic acid against Listeria monocytogenes

Cytogenetic data about 145 chorionic villus samples obtained between the 13th and 35th week of gestation are reported. 'Late' chorionic villus sampling (CVS) was used to resolve different situations: failed amniotic fluid cell cultures (5 cases); confirmation of an abnormal karyotype, previously diagnosed as mosaic (14 cases); and ultrasound fetal malformation (23 cases). Most of the samples (103 cases) were analysed for the classical indications and in these cases, the principal aim was to obtain a rapid fetal karyotype. Excluding the cases used to check fetal karyotype, a chromosomal aberration was found in 11 out of 131 biopsies. In four cases of the group in which the fetal karyotype was checked (14 cases), the pathology observed at the first diagnosis was confirmed, while in the remaining ten cases the anomaly was not observed.