Abnormal Prenatal Findings Research Articles

Optimizing prenatal diagnosis and referral of classic bladder exstrophy: Lessons from a single-institution experience

Classic bladder exstrophy (CBE) is a malformation of the genitourinary system that occurs due to failure of abdominal wall closure. Unlike other malformations of similar incidence, prenatal diagnosis of CBE relies on suggested, rather than formal, diagnostic criteria. This report describes prenatal diagnosis of CBE in the largest single-institutional cohort to date and delineates key sonographic findings and protocols for specialist referral. A single-institutional database was reviewed for CBE patients born since 2000. Data on screening ultrasound use, gestational age at ultrasound, and abnormal findings were extracted. Where possible, time of prenatal diagnosis (pre- or postnatal and gestational age), ultrasound findings and other imaging data, specialist referral, institution of birth and closure, and outcome of primary closure attempt were compared. Of 557 patients born with CBE between 2000 and 2022, 284 met inclusion criteria and complete data were available for 280 (229 born domestically and 51 born internationally) who were included for analysis. Abnormal sonography suggestive of CBE was present for 48% (n=134) of patients, for whom absent bladder was the most common abnormal finding (76% [102/134]). Of domestic patients, 46% (n=106) were diagnosed prenatally at a median gestational age of 22 weeks (inter-quartile range [IQR]: 20-24), and 14% (n=32) underwent confirmatory fetal magnetic resonance imaging. Of domestic patients with abnormal prenatal findings, 75% (n=80/106) consulted with maternal-fetal medicine and 58% (n=62/106) consulted with pediatric urology. On univariate analysis, prenatal diagnosis was positively associated with primary repair at Association for the Bladder Exstrophy Community-recognized centers of excellence (54% vs. 38%, p=0.02) and negatively associated with osteotomy at primary closure (41% vs 59%, p=0.003) but not success of primary closure (74% vs. 82%, p=0.07). Rates of prenatal diagnosis in this cohort were similar to previous reports of smaller cohorts. Diagnosis allows for comprehensive pre- and postnatal follow-up with a pediatric urologist, with implications on birth planning and decisions on termination of pregnancy. Because of the previously-reported association between exstrophy and invitro fertilization, these pregnancies should undergo detailed sonography. Any nonvisualization of the fetal bladder should prompt a detailed exam, and any finding characteristic of bladder exstrophy warrants referral to pediatric urology. Although CBE is a rare disorder, it is underdiagnosed during pregnancy. Sonographers and obstetricians should be aware of characteristic findings and best practices following diagnosis. Early referral to pediatric urology and maternal-fetal medicine is important for counseling and postnatal planning.

Expansion of the clinical and molecular spectrum of WWOX-related epileptic encephalopathy.

WWOX biallelic loss-of-function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX-related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA). SNVs and intragenic deletions of one or more exons were commonly reported in WOREE syndrome patients which made the genetic diagnosis challenging and required a combination of different diagnostic technologies. These patients presented with severe, developmental and epileptic encephalopathy (DEE), and other cardinal features consistent with WOREE syndrome. This report expands the clinical phenotype associated with this condition, including failure to thrive in most patients and epilepsy that responded to a ketogenic diet in three patients. Dysmorphic features and abnormal prenatal findings were not commonly observed. Additionally, recurrent pancreatitis and sensorineural hearing loss each were observed in single patients. In summary, these phenotypic features broaden the clinical spectrum of WOREE syndrome.

Congenital Cytomegalovirus Infection Following Second and Third Trimester Maternal Infection Is Associated With Mild Childhood Adverse Outcome Not Predicted by Prenatal Imaging.

While it is clear that first trimester congenital cytomegalovirus (CMV) infection can lead to serious neonatal and childhood adverse outcome, the extent of the effect of second and third trimester congenital CMV infection is still unclear. Our aim was to study the short- and long-term outcomes following second and third trimester infection and to evaluate the contribution of prenatal imaging in a prospective cohort. We studied pregnant women with primary CMV infection in the second and third trimesters, as diagnosed by well-dated seroconversion, and proof of vertical CMV transmission. All patients underwent serial prenatal ultrasound (US) and most of them fetal magnetic resonance imaging (MRI). Follow-up information was obtained from hospital charts and by telephone interviews with parents. Primary CMV infection occurred in 135 patients, 107 and 28 with second and third trimester infection, respectively. The incidence proportion of composite outcome (hearing loss or neurodevelopmental impairment) following second trimester infection was 7% (7/100, after excluding cases that were terminated) with a 3% incidence of partial unilateral sensory neural hearing loss and a 5% incidence of minor neurodevelopmental abnormalities, including slight verbal and motor delay. Following third trimester infection, there was one case of a very mild motor delay. The incidence proportion of abnormal prenatal findings on US or MRI was not significantly correlated to hearing loss or neurodevelopmental abnormalities. Second trimester infection is associated with a slight risk of developing mild childhood sequelae, mostly partial unilateral hearing loss, which may develop late in childhood. Prenatal imaging failed to predict the development of childhood adverse outcome.

Revisiting short- and long-term outcome after fetal first-trimester primary cytomegalovirus infection in relation to prenatal imaging findings.

To determine the short- and long-term outcome of pregnancies with proven first-trimester fetal cytomegalovirus (CMV) infection in a large prospective cohort. This was a prospective cohort study of pregnancies with documented primary maternal CMV infection in the first trimester and evidence of fetal infection, referred for further evaluation between January 2011 and January 2018. Maternal serological diagnosis of primary CMV infection was documented by seroconversion. Vertical CMV transmission was identified by amniocentesis with polymerase chain reaction (PCR) for the CMV genome. After birth, fetal infection was re-tested by PCR in neonatal urine or saliva samples. All patients underwent serial prenatal ultrasound scans and fetal magnetic resonance imaging (MRI) at 32-33 weeks' gestation. All neonates underwent ocular fundus examination, an ultrasound brain scan and hearing evaluation, and were followed periodically for a median of 2 years (range, 6 months to 10 years). Follow-up information was obtained from hospital charts and by telephone interviews with parents. The CMV-associated outcomes assessed were sensorineural hearing loss (SNHL), neurodevelopmental abnormality, composite clinical outcome (including SNHL and neurodevelopmental abnormality) and composite outcome (additionally including termination of pregnancy (TOP)). The association between prenatal ultrasound or MRI findings and abnormal outcome was assessed. Primary CMV infection in the first trimester occurred in 123 patients. The rate of an abnormal ultrasound finding was 30.9%, and the rate of an abnormal MRI finding was 30.1% overall and 14.1% in the subgroup of patients with normal ultrasound. Of the 85 patients with normal ultrasound, 12 had an abnormal MRI finding, of whom five (5.9%) had true anatomical findings. Fifteen patients decided to terminate the pregnancy owing to abnormal prenatal findings on either ultrasound or MRI. Overall, the rate of CMV-associated postnatal and childhood sequelae was 27.8%, with a rate of 16.7% for SNHL and 11.1% for neurodevelopmental abnormalities, mostly slight motor or verbal delay. Approximately half of the cases with CMV-associated sequelae did not have any abnormal prenatal imaging findings. Abnormal prenatal findings on ultrasound were not associated significantly with SNHL, neurodevelopmental delay or composite clinical outcome (P = 0.084, 0.109 and 0.176, respectively), but they were associated with the composite outcome including TOP (P < 0.001). We identified a non-significant trend for a higher rate of SNHL in the group with abnormal ultrasound than in those with normal ultrasound. For abnormal MRI findings, we found a correlation only with neurodevelopmental abnormality and composite outcome (P = 0.014 and P < 0.001, respectively). The risk of childhood sequelae after first-trimester fetal CMV infection is most often associated with abnormal prenatal imaging findings. However, normal imaging does not rule out the development of SNHL and minor neurodevelopmental abnormalities. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Risk of cytomegalovirus‐associated sequelae in relation to time of infection and findings on prenatal imaging

To determine the outcome of pregnancies with documented fetal cytomegalovirus (CMV) infection with and without abnormal findings on ultrasound examination and magnetic resonance imaging (MRI). In this prospective cohort study of pregnant women with documented fetal CMV infection, vertical CMV transmission occurred during the first and second trimesters following primary maternal infection. Patients underwent serial prenatal ultrasound scans and fetal MRI. All neonates underwent ocular fundus examination, ultrasound brain scan and hearing evaluation, and were then followed periodically by a pediatrician. Primary CMV infection occurred during the first and second trimesters of pregnancy in 71 and 74 patients, respectively. Seven patients (4.8%) decided to terminate pregnancy because of prenatal findings and one neonate died because of CMV complications. Patients with first-trimester infection had infants with significantly more associated sequelae (either auditory damage or neurodevelopmental disabilities) than did patients with second-trimester infection (19.7% vs 5.6%, respectively; P = 0.01). Abnormal prenatal findings on ultrasound examination were associated with increased risk of sequelae. When both ultrasound and MRI findings were normal, the rate of sequelae was decreased to 15.6% for first-trimester infections and to 2.0% for second-trimester infections, partial hearing loss being the sequela in most cases. In the presence of abnormal ultrasound and/or MRI findings the risk was 25% and 16%, respectively, and in most cases the sequelae were deafness and neurodevelopmental delay. The rate of intrauterine growth restriction (IUGR) in the study group was 11.7% and was not affected by the time of onset of maternal infection. Isolated IUGR was not associated with increased risk of sequelae. The risk of sequelae is higher following first-than second-trimester CMV infection. However, the risk of severe sequelae is significantly reduced in the presence of normal prenatal ultrasound and MRI findings.

Evaluation of fetal autopsy findings in the hatay region: 274 cases

The aim of this study was to present the incidence of fetal anomalies in our region of Hatay, Turkey in order to determine the efficiency of prenatal diagnosis through fetal autopsy, and to compare our statistical data with other national and international studies. This study was conducted on 274 fetuses from terminated pregnancies due to abnormal prenatal findings and intrauterine deaths from 2005 to September 2010. Fetuses were evaluated through postmortem examination, external measurements, X-rays, Magnetic Resonance Images, Multislice Computerized Tomography and photographs. The autopsy was completed by the histological examination of each organ. Autopsy was conducted on 274 fetuses. A fetal anomaly was detected in 160 (58.39%) cases. The central nervous system contained the most frequent structural defects (79 cases, 49.38%), followed by malformations in the musculoskeletal system in 36 cases (22.5%). The most frequent multiple system anomalies were central nervous system defect and bilateral adrenal agenesis, musculoskeletal system malformations and urinary system defects. Fetal autopsy provided additional findings in 43 cases (26.88%). Fetal autopsy is a very important procedure and an integral part of the general prenatal management. New findings through this method may suggest invaluable data for parents about potential risks in future pregnancies.

Prenatal features of Noonan syndrome: prevalence and prognostic value

Noonan syndrome (NS) is a common autosomal dominant developmental disorder, mainly characterized by congenital heart defects, short stature, and a variable degree of developmental delay. We have reviewed the prenatal findings in NS and we have correlated them with genotype and postnatal phenotype. The cohort consisted of 47 patients with molecular diagnosis of NS. Prenatal and postnatal phenotypes were assessed by analysis of medical records, and clinical follow-up. Postnatal clinical phenotype, congenital heart disease, neuropsychomotor development, and growth pattern were arbitrarily scored in terms of severity. Mean age at diagnosis of NS was 7 years (ranging from birth to 38 years). Abnormal maternal serum triple screen was present in 36% of cases, nuchal translucency > 2.5 mm in 41%, polyhydramnios in 38% and fetal anomalies at prenatal ultrasonography in 21%. No statistical association was observed between prenatal findings and NS genotype or scores of postnatal clinical phenotype, congenital heart disease, neuropsychomotor development, or short stature. Presence of morphologic fetal anomalies at ultrasonography was associated with developmental delay/intellectual disabilities (p < 0.001) and juvenile myelomonocytic leukaemia (p = 0.006). Abnormal prenatal findings are frequent in NS pregnancies, though they are not specific and most are not useful for the prediction of the postnatal phenotype.

Integration of genetics and ultrasonography in prenatal diagnosis: Just looking is not enough

OBJECTIVE: There has been a gradual shift of the focus of prenatal diagnosis from genetics to ultrasonography. We assessed our primary genetics approach to determine what would be missed without the genetics component. STUDY DESIGN: We evaluated referral indications for patients with normal and abnormal prenatal findings from Jan. 1, 1990, to March 31, 1995, and categorized them according to type of fetal anomalies and genetic abnormalities found. Discordance among initial indication, identified risk factors, and observed abnormalities was assessed. RESULTS: The proportion of patients referred for very-high-risk indications increased over time; 13.5% of all patients (1992 of 14,725) had abnormalities. Abnormal outcomes were categorized as 26% chromosomal, 58% ultrasonographic dysmorphologic features, 11% biochemical or deoxyribonucleic acid disorders, 5% infectious, and 11% other. Of the cases of ultrasonographic dysmorphism (exclusive of the aneuploidies), 3.5% were ultimately determined to be syndromic and 2.5% to be discrepant, that is, having a different abnormality than the referred diagnosis. Including the whole spectrum of disorders seen, half of the abnormalities would not be detectable with even high-quality ultrasonography. CONCLUSION: A large number of abnormal findings were not consistent with initial indication for referral. Correct diagnosis depended on increased acuity provided by genetic pedigree analysis and recognition of syndromes. Diligence in the search for associated anomalies, aneuploidy, pedigree analysis, and syndromic abnormalities remain critical components in the differential diagnosis. The elucidation of unexpected findings suggests the advantages of early counseling and a genetics-based approach combined with tertiary ultrasonography rather than primary ultrasonography with counseling only when anomalies are detected. (Am J Obstet Gynecol 1996;174:1925-33.)

Trisomy 22 with holoprosencephaly: A clinicopathologic study

Trisomy 22 (47, XY, +22) was found at 17 weeks gestation in one fetus of a twin gestation. The karyotypes of both parents and of the other twin were normal. Abnormal prenatal findings included maternal pre-eclampsia, fetal growth retardation, and progressive intracranial sonolucency of the trisomic fetus. Delivery by cesarean section at 36 weeks gestation yielded a normal healthy female weighing 2,822 grams and a markedly macerated dysmorphic male weighing 642 grams. Holoprosencephaly was found in the trisomic fetus, an unusual feature in trisomy 22. Additional findings in this case are compared to other findings in the literature.