Prenatal vs postnatal diagnosis of 22q11.2 deletion syndrome: cardiac and noncardiac outcomes through 1 year of age.

BACKGROUND: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis. OBJECTIVE: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. STUDY DESIGN: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site. RESULTS: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019). CONCLUSION: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection.

Multicenter clinical experience with non-invasive cell-free DNA screening for monosomy X and related X-chromosome variants.

OBJECTIVE: We aimed to investigate how the presence of fetal anomalies and different X chromosome variants influences Cell-free DNA (cfDNA) screening results for monosomy X. METHODS: From a multicenter retrospective survey on 673 pregnancies with prenatally suspected or confirmed Turner syndrome, we analyzed the subgroup for which prenatal cfDNA screening and karyotype results were available. A cfDNA screening result was defined as true positive (TP) when confirmatory testing showed 45,X or an X-chromosome variant. RESULTS: We had cfDNA results, karyotype, and phenotype data for 55 pregnancies. cfDNA results were high risk for monosomy X in 48/55, of which 23 were TP and 25 were false positive (FP). 32/48 high-risk cfDNA cases did not show fetal anomalies. Of these, 7 were TP. All were X-chromosome variants. All 16 fetuses with high-risk cfDNA result and ultrasound anomalies were TP. Of fetuses with abnormalities, those with 45,X more often had fetal hydrops/cystic hygroma, whereas those with "variant" karyotypes had different anomalies. CONCLUSION: Both, 45,X or X-chromosome variants can be detected after a high-risk cfDNA result for monosomy X. When there are fetal anomalies, the result is more likely a TP. In the absence of fetal anomalies, it is most often an FP or X-chromosome variant.

Turner syndrome-omphalocele association: Incidence, karyotype, phenotype and fetal outcome.

OBJECTIVE: Omphalocele is known to be associated with genetic anomalies like trisomy 13, 18 and Beckwith-Wiedemann syndrome, but not with Turner syndrome (TS). Our aim was to assess the incidence of omphalocele in fetuses with TS, the phenotype of this association with other anomalies, their karyotype, and the fetal outcomes. METHOD: Retrospective multicenter study of fetuses with confirmed diagnosis of TS. Data were extracted from a detailed questionnaire sent to specialists in prenatal ultrasound. RESULTS: 680 fetuses with TS were included in this analysis. Incidence of small omphalocele in fetuses diagnosed ≥12 weeks was 3.1%. Including fetuses diagnosed before 12 weeks, it was 5.1%. 97.1% (34/35) of the affected fetuses had one or more associated anomalies including increased nuchal translucency (≥3 mm) and/or cystic hygroma (94.3%), hydrops/skin edema (71.1%), and cardiac anomalies (40%). The karyotype was 45,X in all fetuses. Fetal outcomes were poor with only 1 fetus born alive. CONCLUSION: TS with 45,X karyotype but not with X chromosome variants is associated with small omphalocele. Most of these fetuses have associated anomalies and a poor prognosis. Our data suggest an association of TS with omphalocele, which is evident from the first trimester.

Thymus Growth and Fetal Immune Responses in Diabetic Pregnancies.

Type 1 diabetes (T1D) during pregnancy possibly affects the development of the thymus and the maturation of the immune system in the offspring. The aim of the ImmunDiabRisk study was to investigate thymus growth and maternal and fetal immune responses in pregnancies with and without T1D. The thymus circumferences of the fetuses of pregnant women with T1D (n=49) and without diabetes (n=59) were measured using ultrasound around the 29th gestational week and standardized for gestational age. Simultaneously, the frequencies and total numbers of cell markers were analyzed by flow cytometry in maternal peripheral blood, and at birth in umbilical cord blood. The standardized circumference of the thymus was similar in fetuses of mothers with and without T1D (p=0.26). We observed higher numbers of FOXP3 Tregs, memory Tregs, erythrocytes, and lymphocytes in the cord blood from T1D pregnancies (p=0.01, p=0.002, p=0.002 and p=0.02, respectively). The frequencies of CD4+/CD8+ T cells correlated positively in maternal blood and umbilical cord blood of mother-child pairs, as did the levels of neutrophils (Spearman's correlation coefficient r=0.43, p=0.02 for CD4+/CD8+ cells; r=0.46, p=0.03 for neutrophils), while no significant correlations were observed between thymus circumference and any cell markers in the child. Parts of the prenatal immune system seem to develop differently in the offspring of mothers with and without T1D. The correlation of Tregs between maternal blood and cord blood may indicate a significant cross-talk between the maternal and fetal immune system.

The Incidence of Chromosomal Aberrations in Prenatally Diagnosed Isolated Agenesis of the Corpus Callosum.

PURPOSE: To establish the prevalence of chromosomal aberrations in fetuses with an apparently isolated agenesis of the corpus callosum (ACC) on prenatal ultrasound. MATERIALS & METHODS: This was a retrospective study of complete isolated ACC at the time of ultrasound evaluation with respect to karyotype information. Within this group, a subgroup with non-malformation minor abnormalities, such as a single umbilical artery (SUA), polyhydramnios or fetal growth restriction (FGR), was investigated. RESULTS: Complete ACC was diagnosed in 343 cases. Of them, 143 (41.6 %) were isolated, with 16 fetuses showing additional minor findings. In 76.2 % (109/143) karyotyping was performed. Additional array CGH analysis was performed in 7.7 % (11/143). Chromosomal aberrations were found in 4.6 % (5/109) overall, in 3.1 % (3/98) of those without any additional sonographic findings (all represented mosaic trisomy 8) and in 18.2 % (2/11) of those with minor abnormalities. The prevalence of pathogenic submicroscopic copy number variant (CNV) was 9 % (1/11). CONCLUSION: Fetal karyotyping is recommended in ACC, as trisomy 8 mosaicism should be considered despite otherwise unremarkable ultrasound. The role of novel techniques such as array CGH and its implication has to be explored in prospective studies.

Serological and virological analysis of maternal and fetal blood samples in prenatal human parvovirus b19 infection.

BACKGROUND: Intrauterine parvovirus B19 (B19V) infection can be asymptomatic or may cause severe fetal complications. Information on serological and virological findings of infection in the fetus is scarce. METHODS: We determined B19V-DNA and anti-B19V antibodies in maternal and fetal blood samples obtained from 41 pregnancies that were complicated by prenatal B19V infection. Most fetuses presented with moderate to severe anemia or hydrops. RESULTS: At the time of fetal blood sampling, all mothers were B19V-DNA positive and B19V-IgG positive. B19V-IgM was detected in 95% of maternal blood samples. B19V-DNA, B19V-IgM, and B19V-IgG were detected in 100%, 28%, and 24% of fetal blood samples, respectively. The probability of a positive B19V-IgG or B19V-IgM finding in fetal blood increased with gestational age. B19V-IgG levels in maternal blood did not correlate with the likelihood of a positive B19V-IgG test in the fetus. The presence of B19V-IgG in fetal blood was accompanied by lower B19V-DNA levels and less severe clinical findings. CONCLUSIONS: The lack of B19V-IgG in fetuses with B19V-derived anemia or hydrops is most likely due to a limited materno-fetal transfer of IgG and a poor fetal antibody response. Fetal B19V infection is poorly controlled in the absence of specific antibodies.

Maternal Risk Factors and Their Effect on Outcome and Procedure-Related Complications in Cordocentesis: A Multicenter Retrospective Study.

BACKGROUND: Cordocentesis is used in clinical situations in which lower-risk diagnostic procedures do not deliver the desired results. The aim of this study was to evaluate the risk for procedure-related complications and fetal loss in correlation to maternal risk factors. METHODS: This is a multicenter retrospective study investigating the complications, risk factors and perinatal outcome of diagnostic cordocentesis between 1998 and 2019 in three different centers. RESULTS: A total of 1806 cordocenteses were performed and procedure-related complications (IUFD within 48 h, contractions, bradycardia, unsuccessful puncture, chorioamniotic separation) were noted in 1.6% of cases. Fetuses with chromosomal aberrations, intrauterine growth restriction and hydropic fetuses had a significantly higher rate of fetal loss compared to other indications. Fetal blood sampling (FBS) performed before 17+0 weeks of gestation was associated with a higher risk of procedure-related complications. Maternal BMI ≥ 40 increased the risk for fetal loss, whereas maternal age, number of previous miscarriages, number of previous abortions, history of vaginal bleeding or nicotine abuse did not affect the risk for complications or overall fetal loss rate. CONCLUSIONS: In the hands of experienced operators, FBS is a safe way to further fetal diagnostics, and the risk of complications is low.

Is Fetal Hydrops in Turner Syndrome a Risk Factor for the Development of Maternal Mirror Syndrome?

Mirror syndrome is a rare and serious maternal condition associated with immune and non-immune fetal hydrops after 16 weeks of gestational age. Subjacent conditions associated with fetal hydrops may carry different risks for Mirror syndrome. Fetuses with Turner syndrome are frequently found to be hydropic on ultrasound. We designed a retrospective multicenter study to evaluate the risk for Mirror syndrome among pregnancies complicated with Turner syndrome and fetal hydrops. Data were extracted from a questionnaire sent to specialists in maternal fetal medicine in Germany. Out of 758 cases, 138 fulfilled our inclusion criteria and were included in the analysis. Of the included 138, 66 presented with persisting hydrops at or after 16 weeks. The frequency of placental hydrops/placentomegaly was rather low (8.1%). Of note, no Mirror syndrome was observed in our study cohort. We propose that the risk of this pregnancy complication varies according to the subjacent cause of fetal hydrops. In Turner syndrome, the risk for Mirror syndrome is lower than that reported in the literature. Our observations are relevant for clinical management and parental counseling.

Diagnosis and management of heterokaryotypic monochorionic twins.

The diagnosis, management, and outcome of six consecutive heterokaryotypic monochorionic twins were evaluated. All suspected cases, based on discordant ultrasound findings, underwent amniocentesis of both sacs. Two cases also had chorionic villous sampling (CVS). Dual amniocentesis was superior to CVS in diagnosing heterokaryotypic monochorionic twins. In four cases, the X-chromosome was involved and autosomal aneuploidy was noted in the others. In five cases, the anomalous twin was selectively reduced by cord coagulation. All pregnancies ended with a phenotypically normal liveborn and all children are developing normally at 1-7 years of age.