Sustained activation of the renin-angiotensin-aldosteron system after fetal exposure to AT1 blockers: Effects on kidney and bone in a preterm newborn.

The renin-angiotensin-aldosterone system (RAAS) plays a key role in development of fetal kidney. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor type 1 (AT1) antagonists alter RAAS-signaling compromising metanephrogenesis, and vascular and tubular development. The result is a fetal "RAS blockage syndrome" that may occur not only following exposure during the second and third trimester, but also after the use of these drugs at the beginning of pregnancy. The in-utero exposure to AT1 antagonists is not confined exclusively to the risk of neonatal renal failure, but also to skull ossification defect that worsens the neonatal prognosis. We report the case of early arterial hypertension development, marked increase of plasma renin and aldosterone, severe hypocalvaria, and low bone mineralization in a female preterm infant in-utero exposed to AT1 antagonists.

Cell-free DNA analysis of maternal blood in prenatal screening for chromosomal microdeletions and microduplications: a systematic review.

BACKGROUND AND AIM OF THE STUDY: Scientific Societies do not recommend the use of cell-free DNA (cfDNA) testing as a first-tier screening for microdeletion and microduplication syndromes (MMs). The aim of this study was to review the current available literature on the performance of cell-free DNA as a screening for MMs. METHODS: Medline, Embase and the Cochrane Library were searched electronically from 2000 to January 2020 and articles reporting the diagnostic performance of cfDNA screening for MMs in large (>5000 cases) series were included. Between-study heterogeneity and random effect model for screen positive rate (SPR), false positive rate (FPR) and positive predictive value (PPV) were calculated. RESULTS: We identified 42 papers, seven included, for a total of 474,189 pregnancies and 210 cases of MMs. Diagnostic verification of positive cases was available overall in 486 (71.68 %) of 678 cases. The weighted pooled SPR, FPR and PPV were 0.19% (95% CI = 0.09-0.33), 0.07 (95% CI = 0.02-0.15) and 44.1 (95% CI = 31.49-63.07). In conclusion, the pooled PPV of cfDNA testing in screening for MMs was about 40%, ranging from 29% to 91%, for an overall FPR <0.1%. CONCLUSIONS: No confirmatory analysis was available in cases that did not undergo invasive testing, which were the vast majority of cases with a negative test, and therefore, the DR and the negative predictive value cannot be determined.

Incidence of chromosomal abnormalities in fetuses with first trimester ultrasound anomalies and a low-risk cell-free DNA test for common trisomies.

OBJECTIVE: To examine the incidence and type of chromosomal abnormalities in fetuses with first trimester ultrasound anomalies and a low-risk cfDNA test for common trisomies. METHODS: In 486 singleton pregnancies undergoing invasive testing after combined screening, a detailed first trimester ultrasound assessment was carried out and a maternal blood sample was sent for cfDNA analysis. Ultrasound and cfDNA data were analyzed in relation to fetal karyotype. RESULTS: Invasive testing demonstrated a chromosomal abnormality in 157 (32.3%) of 486 fetuses. In 348 cases with a low-risk cfDNA test for common trisomies, NT ≥ 3.5 mm and/or a major structural defect were observed in 92 (26.4%) fetuses. A chromosomal abnormality was found in 17 (18.5%; 95%CI 10.55-26.41) of these pregnancies, including 1 (1.1%) case of trisomy 21 and 16 (17.4%) fetuses with abnormalities different from common trisomies. The respective incidence in the 256 cases with a low-risk cfDNA test result and no ultrasound anomalies was 2.3% (95% CI 0.49-4.20; n = 6). CONCLUSIONS: In fetuses with first trimester ultrasound anomalies and a low-risk cfDNA result for trisomy 21, 18 and 13, diagnostic testing should be offered with the main objective to detect chromosomal abnormalities beyond common trisomies.

Tetralogy of Fallot and Outlet Ventricular Septal Defect with Anterior Malalignment Detected at Early Fetal Echocardiography.

OBJECTIVES: To examine the evolution of tetralogy of Fallot (TOF) and outlet ventricular septal defect (VSD) with anterior malalignment (am) from the initial diagnosis at early fetal echocardiography through the gestation and to evaluate the impact of the first-trimester scan on the outcome. METHODS: We identified cases of TOF or outlet VSD with am diagnosed before 16 weeks' gestation. For all cases, prenatal data and pregnancy outcomes were evaluated. In continuing pregnancies, the evolution in severity of the disease was assessed. RESULTS: Fifty-one fetuses with TOF or outlet VSD with am were diagnosed at early fetal echocardiography. Parents opted for termination of pregnancy in all 23 cases associated with additional anomalies. In 2 of 28 continuing pregnancies, there was an intrauterine death. In the remaining 26, there was progression in severity in 7 (by 20-22 weeks in 3 cases and during the third trimester in the remaining 4). CONCLUSIONS: TOF and outlet VSD with am diagnosed before 16 weeks' gestation can progress in severity throughout pregnancy in over one-quarter of cases. In addition, a high proportion of cases diagnosed in the first trimester may have associated extracardiac anomalies, with a significant impact on clinical management and on the rate of early termination of pregnancy.

Cleft Palate with or without Cleft Lip: The Role of Retronasal Triangle View and Maxillary Gap at 11-14 Weeks.

OBJECTIVE: To evaluate the presence of maxillary gap (MG) and abnormal retronasal triangle (RT) as markers of cleft palate (CP) with and without cleft lip in the first trimester and to assess their association with the type of orofacial cleft (OC). METHODS: The RT and the mid-sagittal view of the face were evaluated retrospectively by two operators in 26 fetuses with OC and in 80 normal controls to detect abnormal RT and/or MG. The agreement between operators was calculated. RESULTS: Amongst the 26 fetuses, there were 15 cases of bilateral, 6 cases of unilateral, and 4 cases of median cleft lip and palate, and 1 case of CP alone. The MG was observed in 18 cases by operator 1 and in 17 cases by operator 2; an abnormal RT was detected in 21 cases by operator 1 and in 22 cases by operator 2. Great agreement between operators was obtained. In controls, MG or abnormal RT was suspected in 6 and 2-4% of cases, respectively. CONCLUSIONS: RT seems to be more sensitive compared to MG; however, the latter showed an additional diagnostic ability when the secondary palate was involved. Both approaches in combination could be useful in detecting OC in the first trimester.

Risk of Fetal Loss in Pregnancies Undergoing Midtrimester Amniocentesis after Inconclusive Chorionic Villus Sampling.

OBJECTIVE: To estimate the procedure-related risk of miscarriage in pregnancies undergoing amniocentesis (AC) following inconclusive results for a chorionic villus sampling (CVS). METHODS: This was a multicentric retrospective cohort study of patients in which both CVS at 11-13 weeks' gestation and AC at 16-22 weeks were performed between January 1st, 2008, and July 31st, 2017. The primary outcome measure was pregnancy loss prior to 24 weeks gestation; the secondary one was intrauterine demise after 24 weeks. RESULTS: A total of 287 patients underwent transabdominal CVS and AC. Nine patients were lost at follow-up; therefore, the analysis was conducted on a population of 278 patients (275 singletons and 3 dichorionic twin pregnancies). AC was performed because of placental mosaicism (93.6%), failure of direct/semidirect preparation of trophoblastic cells (3.2%), or targeted genetic testing after the diagnosis of an anomaly in the second trimester (3.2%). In continuing pregnancies, there were no fetal losses prior to 24 weeks' gestation. Two intrauterine demises (including 1 fetus with multiple anomalies and growth restriction) in the third trimester were recorded. CONCLUSION: Patients undergoing midtrimester AC because of an inconclusive result of CVS can be reasonably reassured that in general the risk of miscarriage and fetal loss following the procedure is very small.

The three-vessel and trachea view (3VTV) in the first trimester of pregnancy: an additional tool in screening for congenital heart defects (CHD) in an unselected population.

OBJECTIVE: The aim of the study was to evaluate the feasibility of obtaining the three-vessel and trachea view (3VTV) in an unselected population undergoing first trimester screening for aneuploidy, and to investigate its role in the early detection of congenital heart defects (CHD). METHODS: Cardiac examination was performed by expert sonographers. Abnormal findings of 3VTV were classified in three different subgroups: number, size and spatial relationship of the vessels. RESULTS: We enrolled 6350 consecutive singleton pregnancies and included 5343 cases. Examination of 3VTV was feasible in 94% of cases. Fifty-seven (1%) CHD were present in the study period; 24 cases were excluded because parents opted for termination of pregnancy. Of the remaining 33 cases, 25 were suspected at the first trimester and eight were detected only at the mid-trimester. An abnormal 3VTV was suspected in 22 cases, and it was confirmed in 21. Five cases that were erroneously classified in the subgroup of abnormal vessel number were actually characterized by a diminutive size of one of the great arteries. The detection rate for CHD, including 4-CV and 3VTV, was 75.8%. CONCLUSIONS: Our study demonstrates that 3VTV is an easy plane to obtain by expert sonographers in an unselected population during first trimester. Typical suspicions include detection of abnormal number, size or spatial relationship of the vessels. © 2017 John Wiley & Sons, Ltd.

Cell-free DNA testing in the maternal blood in high-risk pregnancies after first-trimester combined screening.

OBJECTIVE: The objective of this study was to investigate a strategy for clinical implementation of cell-free DNA (cfDNA) testing in high-risk pregnancies after first-trimester combined screening. METHODS: In 259 singleton pregnancies undergoing invasive testing after first-trimester combined screening, a maternal blood sample was sent to the laboratory Natera for cfDNA testing using a single-nucleotide polymorphism-based methodology. RESULTS: The cfDNA test provided a result in 249 (96.1%) pregnancies and, among these, identified as being at high risk 35 of 36 cases of trisomy 21, 13 of 13 with trisomy 18, five of five with trisomy 13 and three of four with sex chromosome aneuploidies. A policy of performing an invasive test in women with a combined risk of ≥1 in 10 or NT ≥4 mm and offering cfDNA testing to the remaining cases would detect all cases of trisomy 21, 18 or 13, 80% of sex aneuploidies and 62.5% of other defects and would avoid an invasive procedure in 82.4% of euploid fetuses. CONCLUSION: In high-risk pregnancies after combined screening, a policy of selecting a subgroup for invasive testing and another for cfDNA testing would substantially reduce the number of invasive procedures and retain the ability to diagnose most of the observed aneuploidies.

Diagnosis of congenital heart disease by early and second-trimester fetal echocardiography.

OBJECTIVES: The aim of this study was to compare the cardiac findings at 11 to 14 weeks' gestation with the second-trimester findings to evaluate the reliability of first-trimester echocardiography and the possibility of congenital heart disease evolution. METHODS: The database of our fetal medicine unit was searched for all patients who had undergone fetal echocardiography at 11 to 14 and 18 to 22 weeks' gestation from 2005 to 2010. In all of the antenatally suspected cases of congenital heart disease, the diagnosis was established conclusively by postnatal echocardiography, surgery, or autopsy. RESULTS: Among the 870 fetuses included in the study, 802 were considered to have no abnormalities on both examinations. Thirty-six cases had abnormal findings on both examinations, and 32 had discordant findings. Among the 32 discordant findings, 6 cases had a false-positive diagnosis of congenital heart disease on early echocardiography, and 26 had a different diagnosis. In 14 of these 26 cases, the diagnosis was slightly different on the second-trimester examination, or the defect misdiagnosed in the first trimester was a minor one. In 6 of the remaining 12 fetuses, a major congenital heart disease was missed on the early echocardiography. In 6 cases, the congenital heart disease developed or progressed in severity in the second trimester. CONCLUSIONS: First-trimester echocardiography is feasible and seems to allow considerably earlier detection of major congenital heart disease. However, it should be kept in mind that although most forms of heart defects can be diagnosed early in pregnancy, some may develop and become apparent only later in gestation.

Fetal cardiac evaluation at 11-14 weeks by experienced obstetricians in a low-risk population.

OBJECTIVE: The aim of this study was to evaluate the detection rate of congenital heart diseases (CHD) in a low-risk population by performing cardiac evaluation during the first-trimester screening for chromosomal abnormalities. In this context, the role of four-chamber view, tricuspid regurgitation and abnormal ductus venosus flow in the screening for cardiac anomalies in a low-risk population was also investigated. METHOD: The cardiac examination was performed by obstetricians with extensive experience in first- and second-trimester ultrasound (US). Follow-up US evaluations during the second and third trimesters were offered to all patients. In case of abnormal findings during routine assessment, fetal echocardiography was performed by a fetal cardiologist. RESULTS: Among the 4445 fetuses included in the study, 42 CHD were detected (39 diagnosed prenatally and 3 postnatally). In 27 cases, the fetal cardiologist confirmed the type of CHD diagnosed at US screening. In 1 case, the diagnosis was slightly different in the second trimester, and in 3 of the 26 correctly diagnosed in the first-trimester cases, the CHD developed and progressed in severity. A significant association of major CHD and US first-trimester markers was observed. CONCLUSIONS: First-trimester assessment of the fetal heart is feasible in a low-risk population when performed by experienced obstetricians. However, although most types of CHD can be diagnosed early in pregnancy, some may become apparent later in gestation.

Nasal bone in first-trimester screening for trisomy 21.

OBJECTIVE: This study was undertaken to investigate the impact of incorporating assessment of the nasal bone into first-trimester combined screening by fetal nuchal translucency (NT) thickness and maternal serum biochemistry. STUDY DESIGN: In this prospective combined screening study for trisomy 21, the fetal nasal bone was also examined and classified as present or absent. A multivariate approach was used to calculate patient-specific risks for trisomy 21 and the detection rate (DR) and false-positive rate (FPR) were estimated. We examined 2 screening strategies; first, integrated first-trimester screening in all patients and second, first-stage screening of all patients using fetal NT and maternal serum free beta-hCG and PAPP-A, followed by second-stage assessment of nasal bone only in those with an intermediate risk of 1 in 101 to 1 in 1000 after the first-stage. RESULTS: The nasal bone was absent in 113 (0.6%) of the 20,165 chromosomally or phenotypically normal fetuses and in 87 (62.1%) of the 140 fetuses with trisomy 21. With combined first-trimester NT and serum screening, the DR of 90% was achieved at a FPR of 5%. Inclusion of the nasal bone, either in all cases or in about 10% of the total in the 2-stage approach, halved the FPR to 2.5%. CONCLUSION: Inclusion of the nasal bone in first-trimester combined screening for trisomy 21 achieves a DR of 90% for a FPR of 2.5%.

Integrated ultrasound and biochemical screening for trisomy 21 using fetal nuchal translucency, absent fetal nasal bone, free beta-hCG and PAPP-A at 11 to 14 weeks.

BACKGROUND: Screening for trisomy 21 by a combination of maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-hCG and pregnancy-associated plasma protein-A (PAPP-A) at 11 to 14 weeks of gestation is associated with a detection rate of 90% for a false-positive rate of 5%. Recent evidence suggests that in about 70% of fetuses with trisomy 21, the nasal bone is not visible at the 11th- to 14th-week scan (Cicero et al., 2001). The aim of this study was to examine whether fetal NT thickness and the level of maternal serum biochemical markers is independent of the presence or absence of the nasal bone, and to estimate the performance of a screening test that integrates the two sonographic and the two biochemical markers. METHODS: This was a retrospective case-control study comprising 100 trisomy 21 and 400 chromosomally normal singleton pregnancies at 11 to 14 weeks of gestation. Ultrasound examination was carried out for measurement of fetal NT and assessment of the presence or absence of the fetal nasal bone. Maternal serum free beta-hCG and PAPP-A were measured using the Kryptor rapid random-access immunoassay analyser (Brahms Diagnostica GmbH, Berlin). The distribution of fetal NT, maternal serum free beta-hCG and PAPP-A in trisomy 21 fetuses with absent and present nasal bone was examined. RESULTS: The nasal bone was absent in 69 and present in 31 of the trisomy 21 fetuses. There were no significant differences in median maternal age, median gestational age, NT delta, free beta-hCG MoM and PAPP-A MoM in trisomy 21 fetuses with and without a visible nasal bone. For a false-positive rate of 5%, it was estimated that screening with the four markers in combination with maternal age would be associated with a detection rate of 97%. For a false-positive rate of 0.5%, the detection rate was 90.5%. CONCLUSIONS: An integrated sonographic and biochemical test at 11 to 14 weeks can potentially identify about 90% of trisomy 21 fetuses for a false-positive rate of 0.5%.