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.

Isolated non-immune hydrops fetalis: an observational study on complete spontaneous resolution, perinatal outcome, and long-term follow-up.

PURPOSE: The aim of our study was to investigate spontaneous resolution and postnatal outcome in non-immune hydrops fetalis (NIHF). We specifically studied NIHF cases that occurred without any other anomalies in the prenatal diagnostic workup, defined as isolated NIHF (iNIHF). METHODS: To identify iNIHF we retrospectively classified prenatal findings of 700 NIHF singletons, diagnosed in our prenatal referral center between 1997 and 2016. We studied the occurrence of prenatal resolution in iNIHF and linked it to the perinatal outcome. We obtained long-term outcome by contacting the parents, children, and the pediatricians and listed all functional and structural anomalies and temporary logopedic, psychosocial and motoric impairments. RESULTS: Among 70 iNIHF cases, 54 (77.1%) resolved completely prenatally. The baby-take-home rate was 98.1% in these cases. In contrast, the baby-take-home rate in the subgroup without complete resolution was 25.0%. We achieved pediatric long-term outcome in 27 of 57 survivors (47.4%) of iNIHF with a mean follow-up period of 10.9 years. Among these 27 children, fetal hydrops had completely resolved prenatally in 26 cases and had regressed to a mild effusion in one case. In the pediatric development, two children had significant functional impairment and two children showed recurrent skin edema. CONCLUSION: Complete spontaneous resolution was the most common intrauterine course of iNIHF in our collective. Completely resolved iNIHF had a favorable perinatal outcome in our study. Our data on the long-term outcomes are consistent with the assumption of an increased rate of functional impairments. TRIAL REGISTRY: Internal study number of Heinrich-Heine-University, Duesseldorf: 6177R. Date of registration: December 2017.

DEGUM Recommendations on Diagnostic Puncture in Prenatal Medicine. / Empfehlungen der DEGUM zu diagnostischen Punktionen in der Pränatalmedizin.

Diagnostic puncture (amniocentesis, chorionic villus sampling, and fetal blood sampling) is an essential part of prenatal diagnostics and the only established and sufficiently scientifically evaluated possibility of diagnosing genetic diseases from pregnancy-specific cells. The number of diagnostic punctures in Germany, as in other countries, has fallen significantly. This is largely due to the introduction of first-trimester screening with further detailed ultrasound examination of the fetus and the analysis of cf-DNA (cell-free DNA) from maternal blood (noninvasive prenatal test - NIPT). On the other hand, knowledge about the incidence and appearance of genetic diseases has increased. The development of modern molecular genetic techniques (microarray and exome analysis) makes a differentiated investigation of these diseases increasingly possible. The requirements for education and counseling regarding these complex correlations have thus increased. The studies performed in recent years make it clear that diagnostic puncture performed in expert centers is associated with a low risk of complications. In particular, the procedure-related miscarriage risk hardly differs from the background risk for spontaneous abortion. In 2013, the Section of Gynecology and Obstetrics of the German Society for Ultrasound in Medicine (DEGUM) published recommendations on diagnostic puncture in prenatal medicine 1. The developments described above and new findings in recent years make it necessary to revise and reformulate these recommendations. The aim of this review is to compile important and current facts regarding prenatal medical puncture (including technique, complications, genetic examinations). It is intended to provide basic, comprehensive, and up-to-date information on diagnostic puncture in prenatal medicine. It replaces the publication from 2013 1.

Antenatal screening for chromosomal abnormalities.

Screening for chromosomal disorders, especially for trisomy 21, has undergone a number of changes in the last 50 years. Today, cell-free DNA analysis (cfDNA) is the gold standard in screening for trisomy 21. Despite the advantages that cfDNA offers in screening for common trisomies, it must be recognized that it does not address many other chromosomal disorders and any of the structural fetal anomalies. In the first trimester, the optimal approach is to combine an ultrasound assessment of the fetus, which includes an NT measurement, with cfDNA testing. If fetal structural defects are detected or if the NT thickness is increased, an amniocentesis or a CVS with at least chromosomal microarray should be offered.

The femur too short? 1373 fetuses with short femur during second-trimester screening.

PURPOSE: A short fetal femur in prenatal diagnosis might be an indicator for intrauterine growth retardation (IUGR), a genetically determined small child (SGA) with or without associated fetal malformations and/or an adverse fetal outcome. METHODS: 1373 singleton pregnancies with a femoral length < 5th percentile detected between 1999 and 2015 during second-trimester screening in a tertiary prenatal diagnostic center were subjected to a descriptive retrospective analysis with regard to fetal characteristics as well as pregnancy outcome. RESULTS: 685 (49.9%) fetuses presented an isolated short femur, while 688 (50.1%) showed additional abnormalities. 293 (42.6%) of those were SGA babies without any malformation, while 395 (57.4%) had one or more severe anomaly of the following organ systems: 157 (11.5%) cardiovascular, 101 (7.4%) musculoskeletal, 82 (6.0%) urogenital, 72 (5.2%) cerebrocephalic, 50 (3.6%) gastrointestinal, and 5 (0.4%) thoracic. 75 (5.5%) of the fetuses showed chromosomal aberrations of which Trisomy 13, 18 and 21 were found in 2, 13 and 27 of the cases, respectively. Fetuses with associated malformations had a significantly lower live birth rate than those without (64.2% vs. 98.1%, p < 0.001); in addition, a higher rate of preterm births 36.6% vs. 11.3%, p < 0.001) and SGA babies (51.4% vs. 30.4%, p < 0.001) were observed in the first collective. CONCLUSION: Diagnosis of a short fetal femur should lead to an extended organ screening; in the case of associated abnormalities, additional genetic testing has to be offered, as well as intensified pregnancy monitoring in pregnancies at risk for IUGR and/or preterm birth.

Universal Cell Free DNA or Contingent Screening for Trisomy 21: Does It Make a Difference? A Comparative Study with Real Data.

OBJECTIVE: The aim of the objective was to compare the detection rate for trisomy 21 of universal cell free DNA (cfDNA) screening with contingent screening. METHODS: Retrospective study was carried out at 3 German centers. The study included euploid and trisomy 21 pregnancies where cfDNA and first trimester (FT) screening assessment was carried out. The FT risk for trisomy 21 was computed based on combined screening and stratified into the following classes: high risk ≥1:10, intermediate risk 1:11-1,000, low risk ≤1,001. For universal cfDNA screening, the cfDNA test results were examined. For the contingent screening model, the result of the cfDNA test was taken into account in case of an intermediate FT risk. Different strategies combining maternal age, nuchal translucency, nasal bone, beta-hCG, and PAPP-A were evaluated. Screen positivity was defined as either a high risk after FT screening or a cfDNA test indicating a high-risk result. An inconclusive cfDNA test was also considered as screen positive. RESULTS: The search of the database identified 2,255 euploid and 163 affected pregnancies. All affected fetuses were identified by universal cfDNA screening. 1.3% of the euploid fetuses were classified as screen positive due to final inconclusive cfDNA test result. The detection and false-positive rate of a contingent approach that is based on combined screening and cfDNA screening in the intermediate group would be 98.4% and 0.7%, respectively. With this approach, cfDNA screening would be necessary in only about 27% of all pregnancies. CONCLUSION: This study demonstrates that a contingent approach provides similar detection rates for trisomy 21 as universal cfDNA screening, by a reduction of 73% the number of cfDNA tests.

Prenatally Diagnosed Single Umbilical Artery (SUA) - Retrospective Analysis of 1169 Fetuses.

PURPOSE: The incidence of a fetal single umbilical artery (SUA) is about 0.5 % and has been associated with an increased risk of congenital malformations, fetal aneuploidy and intrauterine growth restriction (IUGR). MATERIALS AND METHODS: A retrospective analysis of 1169 women with singleton pregnancies diagnosed with fetal SUA between 1997 and 2014 in a specialized practice for prenatal diagnostics has been performed. Data was obtained on maternal and fetal findings as well as pregnancy outcome. RESULTS: 989 (84.6 %) fetuses showed an isolated SUA (iSUA) while 180 (15.4 %) presented with SUA and additional structural and/or chromosomal abnormalities. Structural malformations were distributed as follows: 9.0 % cardiovascular, 3.5 % urogenital, 2.9 % musculoskeletal, 3.0 % gastrointestinal and 2.1 % cerebral. 2.1 % of the fetuses had chromosomal aberrations. 50.8 % (49.2 %) of the fetuses were female (male) and right vs. left SUA was found in 64.2 % (35.8 %) of the cases. Fetuses with SUA and additional abnormalities showed lower rates of live births (85.0 % vs. 98.5 %, p < 0.001), a lower median birth weight (2825 g vs. 3220 g, p < 0.001), higher rates of preterm delivery before week 34 + 0 (13.7 % vs. 3.8 %, p < 0.001) and weighed less than the 5th growth percentile in 21.6 % vs. 9.3 % (p < 0.001) of the fetuses with iSUA. In 5.1 % (60) of the children, chromosomal or structural abnormalities were detected post-partum. CONCLUSION: Once fetal SUA is diagnosed, intense sonoanatomy of the fetus is required and, if associated malformations are found, genetic testing must be offered. In iSUA intermittent biometry is recommended for the early detection of IUGR but additional genetic testing is not necessarily recommended.

DEGUM, ÖGUM, SGUM and FMF Germany Recommendations for the Implementation of First-Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures. / Empfehlungen der DEGUM, der ÖGUM, der SGUM und der FMF Deutschland zum Einsatz von Ersttrimester-Screening, früher Fehlbildungsdiagnostik, Screening an zellfreier DNA (NIPT) und diagnostischen Punktionen.

First-trimester screening between 11 + 0 and 13 + 6 weeks with qualified prenatal counseling, detailed ultrasound, biochemical markers and maternal factors has become the basis for decisions about further examinations. It detects numerous structural and genetic anomalies. The inclusion of uterine artery Doppler and PlGF screens for preeclampsia and fetal growth restriction. Low-dose aspirin significantly reduces the prevalence of severe preterm eclampsia. Cut-off values define groups of high, intermediate and low probability. Prenatal counseling uses detection and false-positive rates to work out the individual need profile and the corresponding decision: no further diagnosis/screening - cell-free DNA screening - diagnostic procedure and genetic analysis. In pre-test counseling it must be recognized that the prevalence of trisomy 21, 18 or 13 is low in younger women, as in submicroscopic anomalies in every maternal age. Even with high specificities, the positive predictive values of screening tests for rare anomalies are low. In the general population trisomies and sex chromosome aneuploidies account for approximately 70 % of anomalies recognizable by conventional genetic analysis. Screen positive results of cfDNA tests have to be proven by diagnostic procedure and genetic diagnosis. In cases of inconclusive results a higher rate of genetic anomalies is detected. Procedure-related fetal loss rates after chorionic biopsy and amniocentesis performed by experts are lower than 1 to 2 in 1000. Counseling should include the possible detection of submicroscopic anomalies by comparative genomic hybridization (array-CGH). At present, existing studies about screening for microdeletions and duplications do not provide reliable data to calculate sensitivities, false-positive rates and positive predictive values.

Mitotic stability of small supernumerary marker chromosomes: a study based on 93 immortalized cell lines.

Small supernumerary marker chromosomes (sSMC) are known for being present in mosaic form as 47,+mar/46 in >50% of the cases with this kind of extra chromosomes. However, no detailed studies have been done for the mitotic stability of sSMC so far, mainly due to the lack of a corresponding in vitro model system. Recently, we established an sSMC-cell bank (Else Kröner-Fresenius-sSMC-cellbank) with >150 cell lines. Therefore, 93 selected sSMC cases were studied here for the presence of the corresponding marker chromosomes before and after Epstein-Barr virus-induced immortalization. The obtained results showed that dicentric inverted duplicated-shaped sSMC are by far more stable in vitro than monocentric centric minute- or ring-shaped sSMC. Simultaneously, a review of the literature revealed that a comparable shape-dependent mitotic stability can be found in vivo in sSMC carriers. Additionally, a possible impact of the age of the sSMC carrier on mitotic stability was found: sSMC cell lines established from patients between 10-20 years of age were predominantly mitotically unstable. The latter finding was independent of the sSMC shape. The present study shows that in vitro models can lead to new and exciting insights into the biology of this genetically and clinically heterogeneous patient group.

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.

Identification of response bias on apparent pregnancy outcome after second trimester ultrasound.

OBJECTIVES: To investigate whether there is a response bias in outcome studies after prenatal ultrasound and to quantify this potential effect by information source. MATERIALS AND METHODS: All normal ultrasound scans between week 17 and week 24 and 6 days performed in the years 2004 and 2005 were investigated. A multinomial logistic regression model was applied to investigate the association between responders' outcome (questionnaire, phone interview and inquiry to birth clinic) and the following explanatory variables: maternal age, smoking status, body mass index, congenital anomaly status, low birthweight and preterm deliveries. RESULTS: From the 12 439 women, 7747 (62.3%) sent back the questionnaire, 3032 (24.4%) were interviewed by telephone and in 1660 cases (13.3%) the outcome was obtained from the birth clinic. Maternal age > 34 years [odds ratio (OR) 0.72, confidence interval (CI) 0.61-0.85/0.35, CI 0.29-0.42, telephone/birth clinic] and minor anomalies (OR 0.52, CI 0.28-0.98, birth clinic) were significantly underrepresented in nonresponders. Preterm delivery (OR 1.29, CI 1.11-1.50/1.30, CI 1.08-1.57), maternal smoking (OR 1.14, CI 1.07-1.25/1.31, CI 1.22-1.40) and stillbirths (OR 2.30, CI 1.09-4.87, birth clinic) were significantly, major anomalies (OR 1.83, CI 0.94-3.55/1.80, CI 0.79-4.10) were considerably overrepresented in these groups. CONCLUSION: Spontaneous responding to prenatal follow-up questionnaires is significantly biased towards older and nonsmoking mothers with normal pregnancy outcome.

A Bayesian risk analysis for Trisomy 21 in isolated choroid plexus cyst: combining a prenatal database with a meta-analysis.

OBJECTIVE: The purpose of this study was to quantify the possible additional risk of a fetus with an isolated choroid plexus cyst (ICPC) for Trisomy 21 by combining a large controlled cohort study with data from existent studies. METHODS: We searched our prenatal database between 2000 and 2014 for all singleton pregnancies between 18 + 0 and 26 + 6 gestational weeks with either an isolated choroid plexus cyst (study group) or no abnormality found in the detailed ultrasound scan (control group). We assessed all prenatal karyotyping results if invasive testing was performed and attempted to collect the postnatal outcome reports of all patients. The prevalence of Down syndrome was calculated. By using previous studies that met our inclusion criteria, a meta-analysis following the Bayesian Independent Model was created. From this meta-analysis, we computed the posterior predictive distribution of the probability (Trisomy 21 | ICPC) = P1 including posterior means, standard deviations, quantiles (2.5, 50, and 97.5%). By calculating the posterior of the difference (Δ) between the probability (Trisomy 21 | ICPC) and the probability (Trisomy 21 | Normal Ultrasound) = P2, we investigated the additional risk of an ICPC (ΔB = P1-P2). RESULTS: Overall, we detected 1220 fetuses with an isolated plexus cyst at 19-27 weeks of gestational age (GA). In our study group, the prevalence of Trisomy 21 was 2/1220 (0.16, 95% CI: 0.1-0.6%). The median of the pooled probability of Trisomy 21 given isolated PC across the studies included in the meta-analysis was 0.2% (CI: 0.1-0.4%). In the given periods (GA and time), 66,606 (74.8%) out of 89,056 investigated fetuses met the inclusion criteria and had a normal ultrasound result without any abnormality. The Δ between our study group and the control group was 0.08% (CIΔA: 0-0.5%). Including the meta-analysis, the median of the posterior distribution of Δ between P1 and P2 was 0.08% (CIΔB: 0-0.4%) (ΔB = P1-P2). CONCLUSION: The posterior distribution of Δ between P1 and P2 including the meta-analysis corresponds to showing no difference between the cases and controls (95% CIΔB: 0-0.4%). The additional risk of a fetus with an ICPC for Trisomy 21 is 97.5% likely to be lower than 0.4% (about 1/250). However, in our collective, the positive predictive value of ICPC for Down syndrome was 0.16% (about 1/625). In prenatal counseling, the additional risk should be added to the individual risk (based on maternal age, earlier screening test results, and sonographic markers) and the diagnostic options including fetal DNA and diagnostic procedures should be discussed according to the posterior individual risk.

Partial amniotic carbon dioxide insufflation (PACI) during minimally invasive fetoscopic surgery: early clinical experience in humans.

BACKGROUND: The technical performance of minimally invasive fetoscopic surgery may be severely hindered by poor visualization of intra-amniotic contents. Partial amniotic carbon dioxide insufflation (PACI) allows the visual limitations of operating within the fluid environment to be overcome. PATIENTS AND METHODS: When amniotic fluid exchange failed to improve fetoscopic visualization, PACI was attempted during 37 fetoscopic procedures between 17 + 5 and 33 + 2 weeks of gestation. PACI was attempted with filtered carbon dioxide using a commercially available insufflator via one to three trocars that were percutaneously introduced into the amniotic cavity. The maximum pressure during PACI was limited by the maximum insufflation pressure (30 mmHg) generated by the insufflator. Improvement of fetoscopic visualization as well as technical, maternal, and fetal safety aspects surrounding PACI were analyzed. RESULTS: PACI could successfully be instituted in 36 of the 37 procedures. In one case, when in the presence of increased uterine tone the opening pressure exceeded the maximum insufflation pressure of the insufflator, the strategy was abandoned. In all cases where PACI could be instituted successfully, the approach offered far superior visualization of the fetoscopic procedure than would have been possible within amniotic fluid. Acute or chronic maternal or fetal complications were observed in only one case (intraoperative membrane rupture). CONCLUSION: PACI greatly improves fetal visualization during fetoscopic interventions when fetoscopy within fluid meets with difficulties. Continued assessment of its benefits, risks, and safety margins at specialist centers is required.

Concordance-analysis and evaluation of different diagnostic algorithms used in first trimester screening for late-onset preeclampsia.

Objective: Concordance-analysis and evaluation of existing algorithms detecting late-onset preeclampsia during first trimester screeningMethods: Retrospective cohort study investigating risk algorithms of late-onset preeclampsia during first trimester screening in a German prenatal center. Three previously developed algorithms including anamnestic factors (Apriori) and biophysical markers (BioM) were investigated by using detection rates (DR) with fixed FPR 10% and fixed cutoff >1:100. Furthermore, we set up a concordance-analysis of test results in late-onset preeclampsia cases to examine the effect of influencing factors and to detect potential weaknesses of the algorithms. Therefore, we modeled the probability of discordances as a function of the influencing factors based on a logistic regression, that was fitted using a Bayesian approach.Results: 6,113 pregnancies were considered, whereof 700 have been excluded and 5,413 pregnancies were analyzed. 98 (1.8%) patients developed preeclampsia (79 late-onsets, 19 early-onsets). The Apriori-algorithm reaches a DR of 34.2%, by adding BioM (MAP and UtA-PI) the DR improves to 57.0% (FPR of 10%). In concordance-analysis of Apriori algorithm and Apriori+BioM algorithms, influencing factor BMI<25 increases the chance of discordances sigificantly. Additional, in the subgroup of late-onset preeclampsias with BMI<25 the DR is higher in Apriori+BioM algorithms than in Apriori algorithm alone. If both compared algorithms include BioM, influencing factor MAP decreases the chance of discordances significantly. All other tested influencing factors do not have a statistically significant effect on discordancesConclusion: Normal-weight patients benefit more from the integration of MAP and UtA-PI compared to overweight/obese patients.

Isolated Echogenic Cardiac Focus: Assessing Association with Trisomy 21 by Combining Results from a Prenatal Center with a Bayesian Meta-Analysis.

Objective To investigate the clinical relevance of an isolated echogenic cardiac focus (iECF) as a marker for trisomy 21 using a large second-trimester collective including a low-risk subgroup. Materials and Methods We retrospectively evaluated 1 25 211 pregnancies from 2000-2016 and analyzed all iECF cases with regard to chromosomal anomalies. It consisted of an early second-trimester collective from 14+0-17+6 weeks (n=34 791) and a second-trimester anomaly scan collective from 18+0-21+6 weeks. Two a priori risk subgroups (high and low risk) of the latter were built based on maternal age and previous screening test results using a cut-off of 1:300. Likelihood ratios (LR) of iECF for the detection of trisomy 21, trisomy 13, trisomy 18 and structural chromosomal anomalies were estimated. Results In total, 1 04 001 patients were included. An iECF was found in 4416 of 1 02 847 euploid fetuses (4.29%) and in 64 of 557 cases with trisomy 21 (11.49%) giving a positive LR of 2.68 (CI: 2.12-3.2). The sensitivity was 11.5% at a false-positive rate of 4.29% (CI:4.17-4.42) with p≤0.01%. In the high-and low-risk subgroups, the prevalence of iECF was comparable: 5.08% vs. 5.05%. The frequency of trisomy 21 was 0.39%, 98/24 979 vs 0.16%, 69/44 103. LR+was 3.86 (2.43-5.14) and 2.59 (1.05-4). For both subgroups the association of iECF with trisomy 21 was statistically significant. The prevalence of structural chromosomal anomalies in the second-trimester anomaly scan collective was 0.08% (52/68 967), of which 2 showed an iECF. Conclusion The detection of an iECF at the time of 14+0-21+6 weeks significantly increases the risk for trisomy 21 in the high-risk and in the low-risk subgroups and does not statistically change the risks for trisomy 13/18 or structural abnormalitie.

Prenatal testosterone exposure is associated with delay of gratification and attention problems/overactive behavior in 3-year-old boys.

Sex differences in self-control become apparent during preschool years. Girls are better able to delay their gratification and show less attention problems and overactive behavior than boys. In this context, organizational effects of gonadal steroids affecting the neural circuitry underlying self-control could be responsible for these early sex differences. In the present study testosterone levels measured in amniotic fluid (via ultra performance liquid chromatography and tandem mass spectrometry) were used to examine the role of organizational sex hormones on self-control. One hundred and twenty-two 40-month-old children participated in a delay of gratification task (DoG task) and their parents reported on their attention problems and overactive behavior. Girls waited significantly longer for their preferred reward than boys, and significantly more girls than boys waited the maximum period of time, providing evidence for sex differences in delay of gratification. Boys that were rated as suffering from more attention problems and overactive behavior waited significantly shorter in the DoG task. Amniotic testosterone measures were reliable in boys only. Most importantly, boys who waited shorter in the DoG task and boys who were reported to suffer from more attention problems and overactive behavior had higher prenatal testosterone levels. These findings extend our knowledge concerning organizational effects of testosterone on the brain circuitry underlying self-control in boys, and are of relevance for understanding how sex differences in behavioral disorders are connected with a lack of self-control.

Sex specific relationships between infants' mental rotation ability and amiotic sex hormones.

Sex differences in mental rotation, robust in adults, have recently been reported for infants' looking times although the pattern of results is not completely conclusive. In this context, organizational effects of gonadal steroids affecting the neural circuitry underlying spatial cognition could be (partly) responsible for the early sex difference. In the present study testosterone and estradiol levels measured in amniotic fluid via ultra performance liquid chromatography and tandem mass spectrometry were used to examine the role of prenatal sex hormones on infants' looking times during mental rotation. N = 208 six-month-old infants participated in an expectation of violation task with 3D cube figures. Mental rotation was defined as the difference in looking times for familiar versus mirrored cube figures whereas vigilance was defined as the sum of both looking times. Sex differences were absent for mental rotation as well as for vigilance. Most importantly, however, for boys mental rotation but not vigilance was correlated with prenatal testosterone but not with estradiol. For girls mental rotation but not vigilance was correlated with prenatal estradiol but not with testosterone although it has to be noted that the testosterone values for girls suffered from a floor effect. Only 5% of the within-sex variance was due to prenatal sex hormones indicating small effects. These findings extend our knowledge concerning organizational effects of prenatal sex hormones on the brain circuitry underlying spatial cognition.

Total hip arthroplasty in the underweight.

The outcomes of 20 patients diagnosed with osteoarthritis or rheumatoid arthritis with body mass index less than 18.5 (considered underweight) who received total hip arthroplasty at a single institution were reviewed. Surgical complications in the first 30 days after surgery included 1 prolonged surgical site drainage and 3 posterior dislocations. Two patients experienced medical complications that included hematemesis, confusion, aspiration pneumonia, and death. Sixty-five percent of the patients received at least one blood transfusion. Harris hip scores improved from 35 to 81 (P < .05) at an average of 6.1 years (2-10.1 years) of follow-up. Total hip arthroplasty is effective in patients who are underweight; however, they appear to be at an increased risk of dislocation and blood transfusion.