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.

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.

Prenatal Diagnosis and Outcome of Congenital Corrected Transposition of the Great Arteries - A Multicenter Report of 69 Cases.

OBJECTIVE: Congenital corrected transposition of the great arteries (ccTGA) is a rare congenital cardiac anomaly which remains difficult to diagnose prenatally. We aim to investigate the natural history, associated anomalies and the outcome of patients in prenatally diagnosed ccTGA. METHOD: This was an international multicenter retrospective analysis of fetuses with a diagnosis of ccTGA from 2002 to 2017. We reviewed clinical and echocardiographic databases of seven centers. Anatomic survey and fetal echocardiography were performed according to international guidelines of ISUOG. RESULTS: We considered 69 fetuses with prenatally suspected ccTGA. There was an overall survival rate of 91 % among 54 patients with a confirmed diagnosis. Survival to live birth was 96 % (52/54) and survival on an intention-to-treat basis was 94 % (49/52). The mean gestational age at the time of diagnosis was 25.6 ±â€Š5.9 weeks of gestation. In 7 out of 54 fetuses (13 %), ccTGA was an isolated finding. Dextro/mesocardia was present in 15 cases (27.8 %). Intracardiac anomalies were present in 46/54 cases (85.2 %) with the most frequent anomaly being a ventricular septal defect present in 41 fetuses (75.9 %). Complete heart block was diagnosed in 10 cases (18.5 %). Extracardiac anomalies were observed in 9 out of 54 cases (16.7 %). Prenatal karyotyping of the fetus was available in 30/54 (55.6 %) cases with chromosomal anomalies in 4/30 (13.3 %). CONCLUSION: ccTGA is a rare cardiac anomaly often accompanied by a variable spectrum of further intracardiac abnormalities. Accurate diagnosis of ccTGA, which can be integrated into parental counselling, is feasible with a favorable short-term outcome for affected neonates.

Absent pulmonary valve syndrome - diagnosis, associations, and outcome in 71 prenatally diagnosed cases.

OBJECTIVE: The objective of this study was to analyze the spectrum of prenatally diagnosed absent pulmonary valve syndrome (APVS) and the outcome from diagnosis onwards. Fetuses with APVS and tetralogy of Fallot (TOF/APVS) and with APVS and intact ventricular septum (APVS/IVS) were included. METHOD: Multicenter retrospective study of the International Prenatal Cardiology Collaboration Group. Clinical and echocardiographic databases of nine referral centers were reviewed from 2012-2016. RESULTS: The cohort included 71 cases, 59 with TOF/APVS and 12 with APVS/IVS. In 18.3% of cases, diagnosis was achieved within first trimester. Association with hydrops fetalis was high within first trimester (69%). No fetus with known outcome survived after first trimester diagnosis. Karyotype anomalies occurred in 45% of cases with known karyotype. Intrauterine fetal demise occurred in 14.3%. Overall survival after initial diagnosis in the total cohort was 28.1% (28.8% TOF/APVS and 25.0% APVS/IVS). Survival to birth was 50% in TOF/APVS and 44.4% in APVS/IVS. Survival of subjects born alive beyond neonatal period was 84.6% in TOF/APVS and 100% in APVS/IVS. CONCLUSION: Diagnosis of APVS is feasible within first trimester. Outcomes remain guarded, especially if first trimester diagnosis is included into the analysis because of associated karyotypic anomalies, the presence of hydrops fetalis, and patent ductus arteriosus. © 2017 John Wiley & Sons, Ltd.

Fetal cephaloceles: prenatal diagnosis and course of pregnancy in 65 consecutive cases.

PURPOSE: To scrutinize the characteristics of all cases with antenatally established diagnosis of cephalocele in two tertiary referral centers. METHODS: We retrospectively reviewed 65 cases diagnosed with cephaloceles and tabulated sonographic findings and autopsy recordings as well as medical charts of all survivors in terms of clinical outcome. RESULTS: The case notes of 65 fetuses were available for final analysis. Gestational age (GA) at diagnosis ranged from 10.4 to 38.1 weeks. Of our cohort, 53/65 cases (80%) had occipital protrusions, 10 (15%) were found to have frontal lesions, and another two had parietal cephaloceles. A total of 52 pregnancies were terminated or resulted in intrauterine fetal demise (78%). In 18 cases (11%), the cephalocele was part of underlying syndromic disorders (e.g., Meckel-Gruber syndrome). Thirteen pregnancies were continued until term, out of which all affected individuals were live-born. Neurosurgical intervention was prompted within the first 7 months postnatally. CONCLUSIONS: In general, the outcome of fetuses with cephaloceles is rather poor as four out of five pregnancies were terminated. Postnatal outcome of all survivors in our cohort was rather determined by localization of the cele and more important by the presence and severity of concomitant malformations than the extent of the lesion.

Indications for Fetal Invasive Procedures at the End of an Era.

Purpose The introduction of first trimester screening has changed the attitude towards and the number of invasive procedures in prenatal medicine. We evaluated the indications in patients who underwent an invasive procedure before the introduction of the analysis of cell-free fetal DNA in maternal plasma in prenatal medicine. Materials and Methods 680 pregnant women between the 10th and 35th week of gestation were included in the study from July 1, 2010 to June 30, 2013. Retrospectively, we reviewed the data for indications, type, gestational age at the time of, and result of the invasive procedure. Results We performed 247 chorionic villus samplings (CVSs) and 433 amniocenteses (ACs) during the study interval. The main indication for CVS was an abnormal result from the first trimester screening (75 %), whereas in AC it was advanced maternal age (39 %). 33 % of all CVSs and 8 % of all ACs revealed an abnormal karyotype. All these findings were significantly different. Conclusion Despite the broad acceptance of first trimester screening, there are still women undergoing AC for advanced maternal age, whereas abnormal results from the first trimester screening are the most common indication for CVS. Based on our results, we can conclude that indications derived from first trimester findings have the highest positive predictive value.

Confirmation of etiology in fetal hydrops by sonographic evaluation of fluid allocation patterns.

OBJECTIVE: To evaluate patterns of fluid allocations in different etiologies of hydrops fetalis. STUDY DESIGN: This report is a retrospective cohort study on 20,395 fetal sonographic evaluations in a single tertiary center from 2000 to 2014. Special emphasis was placed on the exact description of the distinct fluid allocation sites in each fetus. Postmortem/postnatal records were evaluated additionally. Mean follow up of the surviving neonates was 34 days (10-60 days). RESULTS: There seem to be distinctive patterns of fluid allocation in some etiologies leading to fetal hydrops including aneuploidies and Parvovirus B19 related infections. CONCLUSION: Due to the allocation patterns of fluid filled sites in fetuses with hydrops fetalis the spectrum of possible etiologies may be narrowed already during initial ultrasound scan. It can contribute substantially to diagnostic accuracy as well as to parental counseling. This knowledge may also help to omit delay in diagnostic routines.

Reproducibility of fetal ductus venosus blood flow velocity waveforms during first stage of labor.

OBJECTIVES: Fetal ductus venosus (DV) blood flow velocity waveforms are significantly altered during contractions in first stage of labor. We have evaluated the reproducibility of these waveforms during and between contractions. METHODS: 90 women between 37th and 41st week of gestation were included in the study. The measurements of the DV were obtained by three different investigators during and between contractions. The pulsatility index for veins (PIV), peak velocity index for veins (PVIV), and fetal heart rate (FHR) were calculated offline. Furthermore, differences in PVIV (PVIVdiff) and PIV (PIVdiff) and a mean of FHR (FHRmean) were calculated. Statistical analysis was used to verify differences in the PIV, PVIV and FHR during and between contractions of each subgroup as well as for the PVIVdiff, PIVdiff and FHRmean between the subgroups. RESULTS: Investigator 1 examined 49 patients (group 1); investigator 2, 17 patients (group 2) and investigator 3, 24 patients (group 3), respectively. In all subgroups, there was a significant difference for the PVIV and PIV during and between contractions, but not for FHR. There was a correlation between gestational age and PVIVdiff, PIVdiff and FHRmean as well as for maternal age and PVIVdiff and PIVdiff. PVIVdiff and PIVdiff showed significant differences in group 1 compared to groups 2 and 3 (p < 0.001), but not between groups 2 and 3. CONCLUSIONS: Significant differences in the measurements in the three subgroups have been revealed, which may be due to different timing of measurement during the contraction. For future studies further standardization of the measurement protocol should be established.

Prenatal detection and postnatal management of double outlet right ventricle (DORV) in 21 singleton pregnancies.

OBJECTIVES: To evaluate the prenatal features, associated anomalies and the postnatal management in fetuses with prenatally detected double-outlet right ventricle (DORV). METHODS: Retrospective analysis of prenatal, pediatric and cardiosurgical records for all fetuses with prenatally diagnosed DORV at a single tertiary referral center. RESULTS: 21 cases were detected prenatally with DORV (average gestational age 23(3/7) weeks). Fetal karyotyping was available in all cases revealing 3 cases with trisomy 18 and one fetus with trisomy 21. 10/21 (47.6%) cases had additional cardiac anomalies only, one fetus (4.8%) had extra-cardiac anomalies only. 8/21 cases (38.1%) presented with both additional cardiac- and extra-cardiac anomalies. A total of 13/21 (61.9%) fetuses were live-born. Average gestational age at delivery was 37(3/7) gestational weeks. There were four Rastelli maneuvers, one Fontan intervention and three children with resection of a coarctation of the aorta among the group of the surviving infants. CONCLUSIONS: Prenatal, sonographic detection of DORV is feasible. The majority of the cases shows a normal karyotype. Outcome strongly depends on the presence and severity of additional anomalies of the fetus. Surgical intervention in DORV can lead to a favorable outcome in simple DORV. DORV not aggravated by additional defects seems to be no contraindication for a vaginal delivery.

Arthrogryposis multiplex congenita and Pena-Shokeir phenotype: challenge of prenatal diagnosis--report of 21 cases, antenatal findings and review.

OBJECTIVE: To elaborate the antenatal sonographic findings of fetuses with the suspicion of fetal akinesia, thereby focusing on the accuracy of prenatal differentiation between subtypes of fetal akinesia, namely Pena-Shokeir phenotype (PSP) and arthrogryposis multiplex congenita (AMC). METHODS: We herein present our experience of 21 patients with PSP and AMC diagnosed antenatally at a tertiary prenatal referral center. During the study period 30,485 consecutive high- and low-risk pregnancies were examined. The prenatal sonograms, pediatric charts and autopsy data of affected individuals were reviewed. Our findings were analyzed together with findings retrieved from the literature. RESULTS: The diagnosis of AMC has been established between 12+0 and 30+1 gestational weeks, whereas cases found to have PSP were all diagnosed in advanced pregnancy. In accordance to previous findings, our data suggest that pulmonary hypoplasia is obligatory in PSP and cannot be found in AMC. Therefore, all pregnancies (9/9) affected by PSP were terminated on parental request. Of those fetuses with AMC, 3/12 were liveborn, 2 of which have neuromotoric disabilities. CONCLUSIONS: Establishing the correct prenatal diagnosis of PSP and AMC at an early stage and its diligent prognostic evaluation play a crucial role in order to provide adequate advice to the afflicted parents and to enable appropriate intervention at an early stage.

Results of early foetal echocardiography and cumulative detection rate of congenital heart disease.

OBJECTIVE: The aim of this study is to evaluate the cumulative detection rate of foetal echocardiography during gestation and in the early neonatal period, with a special emphasis on early foetal echocardiography. METHODS: We conducted a retrospective survey of all singleton pregnancies from 1993 to 2007, with complete sequential echocardiography from 11 plus 0 to 13 plus 6 weeks of gestation. It was mandatory to have at least one foetal echocardiography in the second or third trimester and one postnatally. RESULTS: Our study included 3521 pregnancies, in which 77 cases were diagnosed with congenital heart disease. Of them, 66 were detected in the first trimester - 11 plus 0 to 11 plus 6 weeks: 22 cases; 12 plus 0 to 12 plus 6 weeks: 23 cases; 13 plus 0 to 13 plus 6 weeks: 21 cases - with an 85.7% detection rate of congenital heart disease in early foetal echocardiography. In the second trimester, seven cases were found, with a detection rate of 9.1%. The third trimester reported two cases, with a detection rate of 2.6%. Postnatally, two (2.6%) cases were detected. The overall in utero detection rate of congenital heart disease was 97.4%. CONCLUSIONS: Foetal echocardiography performed at the time of anomaly screening in the first trimester results in high detection rates of congenital heart disease. Cardiac pathology may evolve, and further examinations at later stages of pregnancy could improve the detection rate of congenital heart disease.

Pierre-Robin syndrome: a case report.

We report a case of a fetus diagnosed with micro-retrognathism at routine ultrasound examination in the 22nd week of gestation. The diagnosis of Pierre-Robin syndrome was made postnatally. The possible differential diagnoses and the main complications of retrognathism are reviewed.

Reduced penetrance in a family with X-linked dominant chondrodysplasia punctata.

X-linked dominant chondrodysplasia punctata (Conradi-Hünermann disease, CDPX2) is characterised by short stature, stippled epiphyses, cataracts, ichthyosiform erythroderma and patchy alopecia of the scalp. The disorder is caused by mutations within the emopamil binding protein (EBP) gene encoding a 3beta-hydroxysteroid-Delta(8),Delta(7)-isomerase. The intrafamilial variation of disease severity is a known feature of CDPX2 probably caused by skewed X-inactivation. We report on a female fetus with typical symptoms of CDPX2 such as short limbs, postaxial polydactyly, ichthyotic skin lesions and punctate calcifications. Molecular genetic analysis of the EBP gene revealed a nonsense mutation (c.328C>T, p.R110X), which was previously detected in one CDPX2 patient and in a second female patient, who was only affected on one body side and erroneously diagnosed as CHILD syndrome. Surprisingly, the mother of our fetus carries the same mutation without having any signs of CDPX2. X-inactivation studies did not reveal any evidence of skewing neither in the mother nor in the fetus.

The role of maternal body mass index in outcomes of vaginal births after cesarean.

OBJECTIVE: To evaluate the association between maternal body mass index and obstetrical outcome in patients with a prior cesarean undergoing a trial of labor versus elective repeat cesarean. STUDY DESIGN: A perinatal database between 1991 and 1997 was used to identify secundipara at term after a previous cesarean section. In different groups according to maternal body mass index, the rates of successful vaginal birth after caesarean, uterine scar separation, and other obstetrical outcomes were evaluated. RESULTS: Of 8580 patients with a prior cesarean, 1862 (21.7%) underwent an elective repeat cesarean and 6718 (78.3%) underwent a trial of labor. Maternal body mass index correlated inversely with the rate of successful vaginal birth after caesarean but not with the rate of uterine scar separation. After adjustment for confounding factors including maternal age, birth weight, induction of labor, and preeclampsia, maternal body mass index remained associated with a lower rate of successful vaginal birth after cesarean. CONCLUSION: Maternal body mass index is an independent factor associated with a lower rate of successful vaginal birth after cesarean.

Smoking in pregnancy revisited: findings from a large population-based study.

OBJECTIVE: The purpose of this study was to characterize the effect of smoking on the incidence of various pregnancy complications. STUDY DESIGN: A population-based retrospective analysis with a perinatal database of 170,254 singleton pregnancies was performed. The rate of pregnancy complications was calculated in 4 strata of smokers: Nonsmokers, 1 to 5 cigarettes per day, 6 to 10 cigarettes per day, and >10 cigarettes per day. Logistic regression was used to calculate odds ratios as measures of an association of smoking with various pregnancy complications after correction for confounding factors. RESULTS: The mean age of the study population was 29 +/- 4.8 years. The odds ratio for preeclampsia was 0.64 (95 % CI, 0.59-0.70), for intrauterine growth restriction was 2.4 (95% CI, 2.34-2.53), and for preterm delivery was 1.2 (95% CI, 1.13-1.28). CONCLUSION: Smoking decreased the incidence of preeclampsia in a dose-effect manner and was shown to increase the rate of intrauterine growth restriction and preterm delivery.

The syndrome of left isomerism: sonographic findings and outcome in prenatally diagnosed cases.

OBJECTIVE: The purpose of this study was to evaluate the accuracy of the prenatal diagnosis of left isomerism and to assess possible diagnostic and prognostic markers. METHODS: We conducted a retrospective review of all previously unpublished cases of left isomerism diagnosed in the prenatal and postnatal periods in 2 tertiary referral centers in Germany over 15 years. RESULTS: Among 34 fetuses, 31 had a correct prenatal diagnosis of left isomerism; 31 had an interruption of the inferior vena cava with azygos continuation; 22 had different types of viscerocardiac heterotaxy; 13 had heart block; and 28 had cardiac defects, with a high prevalence of atrioventricular septal defects (n = 24), right outflow tract obstruction (n = 11), double-outlet right ventricles (n = 6), and anomalous pulmonary venous return (n = 6). Among the 34 cases, 9 underwent termination of pregnancy; 2 fetuses died in utero; 5 children died in the neonatal period; and 4 children died in infancy. Only the presence of heart block and hydrops was significantly correlated with nonsurvival (P < .05). Fourteen children survived, with a mean follow-up +/- SD of 2.9 +/- 2.6 years. Three survivors underwent single-ventricle palliation, and 1 had successful biventricular repair. Three children were awaiting cardiac repair. The remaining 7 children had minor or no associated cardiac defects and were doing well. CONCLUSIONS: Prenatal diagnosis of left isomerism is feasible, with high accuracy. Important diagnostic pointers are viscerocardiac heterotaxy, complex cardiac malformations, heart block, and interruption of the inferior vena cava. The mortality in fetuses and neonates is high in the presence of heart block and hydrops, whereas the cardiac defects influence the long-term outcome.

Study of the third stage of labor by color Doppler sonography.

We wanted to evaluate whether improvement in ultrasound equipment in the last 5 years altered our perception of the phases of placental separation during the third stage of labor. We also investigated the influence of active management on the third stage of labor after sonographically verified placental separation. Between January and November 2001, the third stage of labor was examined in 55 women at 37-41 weeks of gestation by color Doppler sonography. The duration of blood flow between the myometrium and the placenta, the latent phase, the detachment phase, and the expulsion phase were measured and compared with the corresponding values of an earlier cohort of 57 patients investigated between November 1994 and August 1995. In the later cohort, both the duration of maternal blood flow and the detachment phase were significantly longer than in the earlier cohort (33 s +/- 48 s vs 0 s, P<0.0001 and 56 s+/-45 s vs 37 s+/-21 s, P<0.01, respectively), whereas the latent phase was significantly shorter (101 s+/-87 s vs 213 s+/-180 s, P<0.0001). There was no statistically significant difference in the length of the expulsion phase or the third stage of labor. The later cohort showed a statistically significantly more frequent multiphasic placental detachment ( P<0.05). Improvement in ultrasound equipment resulted in an earlier detection of the onset of placental separation, leading to a shorter latent phase and consecutively increased duration of the detachment phase, whereas the total duration of the third stage of labor remained unchanged. Furthermore, increased sensitivity of Doppler sonography led to a longer visualization of blood flow between the myometrium and the placenta in the normal third stage of labor.

First-trimester sonographic diagnosis of distal urethral atresia with megalourethra in VACTERL association.

Congenital megalourethra is a rare disorder. We present an early case diagnosed in the first trimester. Prenatal ultrasound showed a megalourethra with a normal fetal bladder, hyperechogenic cystic right kidney and single umbilical artery. After termination of pregnancy, necropsy confirmed all sonographic findings and revealed other malformations (spina bifida occulta, anal atresia, tracheo-oesophageal fistula, brachydactylia) resulting in the diagnosis of VACTERL association. The prenatal diagnostician should seek histological examination firstly to confirm his findings and secondly to avoid missing associations and inherited malformations.