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Objectives Chromosomal microarray analysis (CMA) is the method of choice for genetic work-up in cases of fetal malformations. We assessed the detection rate of CMA in cases of abnormal fetal head circumference (HC). Methods The study cohort was based on 81 cases of amniocenteses performed throughout Israel for the indication of microcephaly (53) or macrocephaly (28), from January 2015 through December 2018. We retrieved data regarding the clinical background, parental HCs and work-up during the pregnancy from genetic counseling summaries and from patients’ medical records. Results There was only one likely pathogenic CMA result (1.89%): a 400-kb microdeletion at 16p13.3 detected in a case of isolated microcephaly. No pathogenic results were found in the macrocephaly group. Most fetuses with microcephaly were female (87.8%), while the majority with macrocephaly were males (86.4%). Conclusions The results imply that CMA analysis in pregnancies with microcephaly may carry a small yield compared to other indications. Regarding macrocephaly, our cohort was too small to draw conclusions. In light of the significant gender effect on the diagnosis of abnormal HC, standardization of fetal HC charts according to fetal gender may normalize cases that were categorized outside the normal range and may increase the yield of CMA for cases of abnormal HC.

To identify whether older primiparas have more complications than do women who continue to deliver children into their late reproductive age. Patients of at least 35 years of age at delivery were included. Within this cohort, data from primiparous and multiparous women were compared. This retrospective study was based on electronic medical records from a single academic center, with more than 7000 deliveries annually. The impact of parity on maternal complications was assessed using a multivariate logistic regression model that adjusted for baseline maternal characteristics and medical history. During the study period, there were 54 283 deliveries in our medical center. A total of 13,982 (25.7%) patients were at least 35 years old at delivery. The rate of twin pregnancy was higher in the primiparous group (1.9%) as compared to the multiparous group (0.8%, 95% CI 0.30–0.64, P

OBJECTIVE Sonographic diagnosis of short corpus callosum (SCC) is based on measurement of a short for gestational age antero-posterior length of the corpus callosum (CC) in the midsagittal plane. We suggest a new method for evaluating SCC without referring to biometry tables. METHODS We measured the ratio between the CC length and the internal cranial occipitofrontal dimension (ICOFD) in the midsagittal plane in 399 normal fetuses at 20 + 6 to 35 + 3 weeks of gestation and in 31 fetuses with a diagnosis of a SCC and compared the mean ratio between two groups. The impact of cephalic biometric parameters, fetal presentation, and gender was assessed. RESULTS The ICOFD/CC length for normal pregnancies was constant throughout the pregnancy (2.35 ± 0.11). There was no correlation between the ICOFD/CC length and cephalic index, Biparietal Diameter (BPD), head circumference, fetal sex, or fetal presentation. The ratio of pregnancies with SCC was significantly higher: 3.20 ± 0.84 (P < .0001). CONCLUSION The ICOFD/CC length practically does not change throughout a normal pregnancy. The ratio was significantly higher in pregnancies with SCC. Measuring this ratio during fetal anatomical scan may enable rapid evaluation of the CC without the need to refer to biometry tables.

Objective: Spontaneous multiple artery dissection is a relatively rare phenomenon. Early clinical signs are often nonspecific, making it difficult to diagnose. Case Report: This is a case of a 51-year-old female who presented with spontaneous dissection of 4 visceral arteries, both iliac arteries, and of the right internal carotid artery. The patient underwent urgent successful endovascular repair. Later complications included acute respiratory distress syndrome and pneumonia after massive blood transfusion. She recovered gradually and was discharged after 21 days. Due to this rare presentation, genetic investigation was performed in search of a connective tissue disorder. Results revealed a new COL3A1 subtype mutation. The pathogenicity of this variant remains unclear. Conclusion: We recommend a high index of suspicion for visceral artery dissection in the differential diagnosis for abdominal pain with concurrent uncontrolled hypertension. Early diagnosis and intervention are crucial to reducing the mortality rate.

The objective of this study is to shed light on the phenotype and inheritance pattern of rare 13q33-q34 microdeletions. Appropriate cases were retrieved using local databases of two largest Israeli centers performing CMA analysis. In addition, literature search in PubMed, DECIPHER and ClinVar databases was performed. Local database search yielded eight new patients with 13q33.1-q34 microdeletions (three of which had additional copy number variants). Combined with 15 cases detected by literature search, an additional 23 cases were reported in DECIPHER database, and 17 cases from ClinVar, so overall 60 patients with isolated 13q33.1-q34 microdeletions were described. Developmental delay and/or intellectual disability were noted in the vast majority of affected individuals (81.7% = 49/60). Of the 23 deletions involving the 13q34 cytoband only, in 3 cases, developmental delay and/or intellectual disability was not reported. Interestingly, in two of these cases (66.7%), the deletions did not involve the terminal CHAMP1 gene, as opposed to 3/20 (15%) of patients with 13q34 deletions and neurocognitive disability. Facial dysmorphism and microcephaly were reported in about half of the overall cases, convulsions were noted in one-fifth of the patients, while heart anomalies, short stature and hypotonia each involved about 10-30% of the cases. None of the 13q33-q34 deletions were inherited from a reported healthy parent. 13q33-q34 microdeletions are rare chromosomal aberrations, associated with high risk for neurodevelopmental disability. The rarity of this chromosomal aberration necessitates continuous reporting and collection of available evidence, to improve the ability to provide accurate genetic counseling, especially in the context of prenatal setting.

Introduction: We evaluated the yield of chromosomal microarray analysis in pregnancies complicated with fetal growth restriction (FGR) according to specific clinical parameters. Methods: The study was based on national records from the Israeli Ministry of Health. Chromosomal microarray analyses of amniocenteses performed nationwide for the indication of FGR, from January 2016 to March 2018, were included. The CMA yield was compared to 2 cohorts that reported the background risk. Results: Of 174 tests performed for the indication of FGR, there were 11 cases with a pathogenic/likely pathogenic result (6.3%). The yield of CMA was significantly higher in cases with major structural findings (29.4 vs. 3.4%, p = 0.001), compared to isolated FGR but not for minor structural findings (6.1 vs. 3.4%, p = 0.5). The rate of chromosomal aberrations was significantly higher for all cases with FGR, when compared to the background risk of a cohort of normal pregnancies (odds ratio [OR] 4.7, 95% CI 2.5–9 and OR 6.09, 95% CI 3.2–11.4) but not for isolated cases or cases diagnosed after 24 weeks of pregnancy. Conclusions: Chromosomal microarray analysis should be performed for all pregnancies complicated with FGR diagnosed before 24 weeks and for cases with major structural anomalies.

Aim To evaluate factors predictive of the success of dinoprostone slow release vaginal insert for cervical ripening. Methods A total of 169 women who underwent cervical ripening with dinoprostone slow release vaginal insert were included in the study cohort. The correlation between parameters present before cervical ripening with dinoprostone slow release and its success, as well as complications and adverse outcomes were analyzed. Results Dinoprostone slow release vaginal insert was successful in achieving vaginal delivery in 148 of 169 (87.6%), while sufficient ripening was achieved in 140 (83%) cases. Factors associated with successful vaginal delivery were multiparity and younger gestational age at delivery. Factors predictive of the success of cervical ripening with dinoprostone slow release vaginal insert were lower body mass index (BMI), higher parity and perceived contractions prior to insertion. Intrauterine growth restriction was associated with a significant risk for dinoprostone insert removal. Neonatal outcomes were similar in cases of successful or failed ripening. Conclusion The success of cervical ripening with dinoprostone slow release vaginal insert can be predicted by factors that can be recognized at admission.

This study evaluated the association of fetal lateral neck cysts (FLNC) with adverse pregnancy outcomes, in relation to specific sonographic characteristics and co-existing findings. Pregnancies in which FLNC were detected by a single examiner in early anatomical scans (14–16 weeks) were included. Data regarding the pregnancy and its outcome were retrieved from telephone-based questionnaires, patient charts and from the examiner’s reports. 654 cases of FLNC were detected among 9446 early anatomical scans (6.9%). Complete data regarding 219 pregnancies were available. FLNC were significantly more prevalent in males (65.2%). The prevalence of heart malformations was 3.2% [all were non-isolated cases or with abnormal nuchal translucency (NT) and/or nuchal fold (NF)]. Amniocentesis performed in 165 pregnancies was abnormal in 1.2%. Among 206 children born from this cohort, adverse medical outcomes were reported in 5.3%. The likelihood of adverse pregnancy outcomes was significantly higher in non-isolated cases and in cases with abnormal NT or NF. Sonographic characteristics such as cyst size and bilateral findings were not linked to adverse pregnancy outcomes. Isolated FLNC are benign findings which do not require additional work up. FLNC with additional sonographic abnormalities are associated with a significantly increased risk for adverse pregnancy outcomes.

To evaluate the impact of genetic counseling (GC) during the third trimester by analyzing changes in pregnancy management and the correlation with postnatal findings. This was a retrospective study. Pregnancy course and neonatal follow-up were analyzed according to the reason for referral and implementation of recommendations. The records of neonates born to 181 women were retrieved. Fifty-two women (group 1—29%) qualified for pregnancy termination under Israeli guidelines and laws, and 129 (group 2—71%) were not at the time they were referred. By another division: 104 women (group 3—57%) followed the physician’s diagnostic recommendations completely after counseling including amniocentesis, fetal MRI, targeted ultrasound scans, fetal echocardiography. Seventy-seven declined amniocentesis (group 4—43%). Additional abnormalities were detected postpartum in all groups without statistically difference: 3/52 (10%) in group 1, 9/129 (7%) in group 2, 6/104 (6%) in group 3, and 6/77 (8%) in group 4). GC in the third trimester of pregnancy provided the couple with a sharper more focused picture and assisted them to perceive the significance of new, significant fetal findings which attest to the value of the GC.

Objective To assess diagnostic accuracy, related findings, and outcomes of fetuses with clubfoot. Methods Sonographic characteristics, pregnancy work-up, and postnatal outcomes were evaluated in 109 fetuses with clubfoot. Results Among 40 320 prenatal ultrasound anomaly scans, clubfoot was diagnosed in 150 (0.37%). Analysis included 108 pregnancies (72%) with 109 fetuses. Bilateral clubfoot was diagnosed in 51/109 (46.7%) fetuses and unilateral in 58/109 (53.2%). Clubfoot was diagnosed as an isolated anomaly in 76/109 (69.7%) and complex in 33/109 (30.2%). Amniocentesis or chorionic villus sampling in 48/109 (44%) yielded 6 (12.5%) with abnormalities (5.5% of the entire cohort). Diagnosis was confirmed in 65/91 (71.4%) liveborn infants. In singletons, 7/63 (11.1%) cases considered isolated on ultrasound had additional anomalies postpartum and 8/14 (57.1%) complex cases were verified after birth. Sonographic diagnosis of clubfoot was verified postpartum in more singletons than twins (p = 0.05). Bilateral clubfoot was verified postpartum more often than unilateral [29/33 (87.9%) vs. 29/44 (65.9%), respectively; p = 0.03]. Bilateral clubfoot resulted in additional prenatal testing without increased likelihood of finding additional anomalies and was associated with more surgical interventions postnatally. Conclusions Prenatal ultrasound diagnosis of clubfoot is more accurate in singletons with bilateral findings. Bilateral findings do not increase the likelihood of additional anomalies. Karyotyping should be considered even with isolated clubfoot. © 2017 John Wiley & Sons, Ltd.

Chromosomal microarray analysis (CMA) is preferred for genetic work-up when fetal malformations are detected prenatally.To assess the detection rate of CMA after pregnancy termination due to abnormal ultrasound findings.CMA was successfully performed in 71 pregnancies using fetal DNA (mainly from skin) or placenta. Data regarding clinical background, pregnancy work-up, and CMA were analyzed.Findings were abnormal in 17 cases (23.9%), of which 13 were detectable by karyotype. The incremental yield of CMA was 4/71 (5.6%); 1/32 (3.1%) for cases with an isolated anomaly and 3/39 (7.7%) for cases with nonisolated anomalies.CMA yield from terminated pregnancies was 23.9%. Although most chromosomal abnormalities are detectable by karyotype, CMA does not require viable dividing cells; hence, it is more practical for work-up after termination. In most cases, the diagnosis was followed by consultation regarding the risk of recurrence and recommendations for testing in subsequent pregnancies.

The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.

Objective To explore the risk for abnormal chromosomal microarray analysis (CMA) findings in pregnancies with oligohydramnios. Methods Data from all CMA analyses performed due to oligohydramnios between 2013 and 2017 were retrospectively obtained from the Israeli Ministry of Health database. The rate of clinically significant (pathogenic and likely pathogenic) findings was compared to a local cohort of pregnancies with normal ultrasound, yielding a 1.4% rate of abnormal CMA results. In addition, a search was conducted through the PubMed database addressing the issue. Results Fifty CMA analyses were performed due to oligohydramnios. The 2% risk for clinically significant CMA finding in pregnancies with oligohydramnios did not differ from the control population of 5541 pregnancies with normal ultrasound – relative risk (RR) 1.4 [95% confidence interval (CI) 0.2–10.2]. Literature search yielded 394 titles, of which four relevant articles were selected, all using fetal karyotyping. Conclusion There is yet insufficient evidence to support invasive prenatal testing in pregnancies with isolated oligohydramnios.

Objective The yield of chromosomal microarray analysis (CMA) for prenatally detected congenital heart defects (CHD) is 6.6-19.2%. We evaluated the yield of CMA in cases of prenatally detected CHD in regard to specific clinical characteristics. Methods Data from 192 cases of CHD including type, clinical and familial background, work-up performed during the pregnancy, and pregnancy outcomes were collected. Results Fetal echocardiography was performed in all cases. 61.4% of CHD were suspected by ultrasound. There was a positive family history (FH) in 15.7%. Abnormal nuchal translucency or umbilical cord anomalies were detected in 1.7% and 5.9% respectively and 45.1% were isolated cases. In 11 of 96 cases in which genetic testing was performed, either karyotype and/or CMA were abnormal (11.5%). The detection rate of CMA (performed in 72 cases) was 9.7%. The yield of CMA was similar in simple cases, isolated cases and cases with a positive FH. CMA was abnormal in 7.3% of ventricular septal defect (VSD) cases. Conclusion Most cases of prenatally detected CHD had no additional extra-cardiac, sonographic findings suggesting increased risk for CHD. The yield of CMA testing was significant in all clinical scenarios including simple heart malformations, isolated cases and cases with a positive FH.

Clinical genetics services are time- and labor-intensive. With increasing pressure for cost-effective medical care, the means of providing medical genetics services need to be evaluated in the current era of new genomic technologies. An anonymous online survey regarding activities linked to medical genetics practice was administered to an international cohort of professionals. Among 151 responses, the reported average time required for pediatric, oncogenetic, pregnancy with a malformed fetus, and preamniocentesis counseling sessions was 48, 37, 40, and 18 min, respectively. The time required to prepare a summary letter followed a similar pattern. Professionals with less experience needed more time for specific activities. The time required for the total workup of a pediatric patient ranged from 1 h and 48 min to 4 h, most of which was associated with indirect activities. Professionals performing one type of consultation (74% pediatric geneticists) perform fewer consultations per week. Respondents’ narrative comments reflected the complexity of the work and challenges faced. Clinical genetics is a time-consuming profession with increased demands related to advanced genetic and genomic testing. Further consideration is required to determine how to adapt these changes to the demands of cost-effectiveness without compromising the quality of patient care. Genet Med 18 4, 372–377.

Early-onset preeclampsia (EOPE;34 weeks' gestation) usually has more severe morbidity for the mother and fetus compared to late-onset preeclampsia (LOPE). Telomere homeostasis is disrupted in preeclampsia (PE) and senescence markers are increased. The pathophysiologic differences between early and LOPE are not fully unraveled yet.We studied placental biopsies from 7 pregnancies with EOPE, 6 pregnancies with LOPE, and 13 healthy gestational age-matched controls. Telomere length and aggregate formation were assessed using qualitative fluorescence in situ hybridization and electronic quantitative methods. Senescence markers were evaluated including senescence-associated heterochromatin foci, β-galactosidase (SAβ-Gal), and P16 staining, as was the expression of P16 complementary DNA (cDNA) using real-time quantitative polymerase chain reaction (RT-qPCR).There were no differences in maternal age, gravidity, parity, body mass index, and mode of conception between the study and the control groups. The percentage of trophoblasts with short telomeres was higher in placental samples from EOPE (52.61% [12.27%]) versus LOPE (28.72% [10.14%]); both were higher compared to controls (7.53% [5.14%],Impaired telomere homeostasis and senescence markers are more prominent in EOPE versus LOPE. These findings may contribute to our understanding of the pathophysiology and explain their different clinical presentations and outcomes.

Isolated hand syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover two novel variants, chr11 g.46896373C>G; p.D1403H and chr11 g.46893078G>T; p.Q1564K, in LRP4 in a child with isolated bilateral syndactyly of the third and fourth fingers. Each variant was inherited from a different parent and neither parent was affected. Variants in LRP4 have been previously associated with syndactyly in Cenani-Lenz syndactyly syndrome and Sclerosteosis 2, but have not been reported in individuals with isolated syndactyly. LRP4 inhibits LRP6/LRP5-mediated activation of canonical Wnt signaling and mediates sclerostin-dependent inhibition of bone formation. p.D1403H and p.Q1564K are located within the fourth β-propeller of the extracellular protein domain that has yet to be associated with human disease. Functional analyses of p.D1403H and p.Q1564K show that they significantly decrease LRP4's inhibition of Wnt signaling. These results suggest that variants in the fourth β-propeller of the extracellular protein domain may cause a phenotype distinct from previously characterized LRP4 variants.

The purpose of this study was to analyse the association between free beta hCG (fβhCG) increased levels and pregnancy complications (PC), foetal growth restriction (FGR) and preeclampsia (PE). This connection was evaluated in two stages (i) investigating the association between those PC with first trimester fβhCG and second trimester intact hCG (ihCG), and (ii) studying the association between these two analytes in the same pregnancy. This was a retrospective study in two settings: medical centre that provided data on fβhCG and ihCG levels in pregnancies with FGR and PE, and central laboratory that provided fβhCG and ihCG levels that were compared in the same pregnancy. No association was found between those PC and the hCG analytes, except for elevated ihCG levels and FGR. Elevated fβhCG (3.00 MoM) was found in 570/16,849 (3.4%) women. However, only 14% of whom had elevated second trimester ihCG. A positive correlation was found between the magnitude of first trimester fβhCG levels and the percentage of women who had elevated second trimester ihCG. This association was determined by the magnitude of the elevation of fβhCG levels. Impact statement What is already known on this subject: The two analytes, first trimester fβhCG and second trimester ihCG, are independently produced and parameters of the biochemical screening during pregnancy. What the results of this study add: Referring to 3.00 MoM as cut-off levels, most pregnancies with elevated levels of first trimester fβhCG will have normal ihCG second trimester levels. What the implications are of these findings for clinical practice and/or further research: The risk of developing pregnancy complications, FGR and PE should be associated with second trimester ihCG levels. About 3.5% of women had high fβhCG levels during the first trimester. However, only 14% also had increased ihCG levels, defined as 3.00 MoM; additional studies are needed to explore the association between increased first trimester fβhCG levels and the risk of developing pregnancy complications, independent of ihCG levels in the second trimester.

Introduction The intrauterine environment, including the placenta, is influenced by a variety of factors, among which is diabetes during pregnancy. These factors can affect lifetime morbidity. Senescence is a state of cellular metabolic arrest, known to be correlated with age-related diseases and is usually accompanied by short telomeres. This study evaluated telomere characteristics in placentas and in cord blood from term pregnancies complicated by uncontrolled diabetes mellitus. Methods Placental biopsies and cord blood were collected from 16 pregnancies with poorly controlled diabetes and from 16 healthy controls. Senescence-associated heterochromatin foci (SAHF) and senescence-associated β-galactosidase (SAβ-Gal) staining were evaluated. Apoptosis was evaluated using tunel staining. Telomere length and aggregate formation were assessed in placentas and in cord blood using Q-FISH. Results Increased SAHF (19.28% ± 7.93 vs. 7.78% ± 5.31, P

To evaluate the yield of work-up in intrauterine growth restriction (IUGR) pregnancies and their outcomes.Retrospective data regarding prenatal work-up (serology, genetic testing and imaging), and neonatal outcomes of 198 IUGR pregnancies (estimated fetal weight10th percentile) were analyzed.IUGR was isolated in 72 cases. Work-up performed in 158 (80%) cases was positive in 4 (2.5%). No abnormalities were detected in prenatal genetic testing. Echocardiogram performed in 27 cases was abnormal in 3 (11.1%). Serological testing performed in 150 pregnancies (75.8%) detected 1 case (0.7%) of cytomegalovirus (CMV) infection. Thirteen neonates (6.5%) were diagnosed with significant health problems. A positive work-up and significant postnatal health problems were not correlated with IUGR severity, symmetry or additional concurrent findings.The yield of IUGR work-up is not clear and is probably highest for fetal echocardiography. The rate of significant adverse outcomes after birth is increased in IUGR pregnancies.

Placentas from pregnancies complicated with IUGR (intrauterine growth restriction) express altered telomere homeostasis. In the current study, we examined mechanisms of telomere shortening in these placentas.Placental biopsies from 15 IUGR and 15 healthy control pregnancies were examined. The percentage of trophoblasts with fragmented nuclei: senescence-associated heterochromatin foci (SAHF), was calculated using DAPI staining. The amount of human telomerase reverse transcriptase (hTERT) mRNA was evaluated using RtPCR levels of telomere capture using FISH in those samples were estimated.The percentage of trophoblasts with SAHF was higher in IUGR compared to control samples, (25±13.4% vs. 1.6±1.6%, P0.0001), hTERT mRNA was decreased (0.5±0.2 vs. 0.9±0.1, P0.0001) and telomere capture was increased (13.2±9.7% vs.1.3±2.5%, P0.001).We suggest that IUGR placentas express increased signs of senescence as part of the impaired telomere homeostasis. One factor that mediates telomere shortening in these placentas is decreased hTERT mRNA, leading to decreased protein expression and therefore, reduced telomere elongation. Telomere capture, which is a healing process, is increased in IUGR trophoblasts as a compensatory mechanism.

This study assessed the use and complications of late amniocentesis (AC) and analyzed factors that affect complication rate. A retrospective analysis of 167 genetic AC performed after 24 weeks during a 10-year period in two medical centers was conducted. Data regarding the indications for AC, genetic work-up, and pregnancy outcomes were retrieved from patient medical records and telephone-based questionnaires. Mean gestational age (GA) at the time of AC was 31.7 ± 2.7 weeks; 104 procedures were performed at ≤32 weeks, including 24 at ≤30 weeks. The overall pregnancy complication rate occurring at any time after the procedure was 6.6% (11). Of these, 4.8% (8) occurred within a month after AC, including 2.4% (4) that occurred within a week. An additional three occurred after 30 days. There were no differences in the total complication rate and in the rate of specific complications of procedures performed at ≤32 weeks or at ≤30 weeks. Maternal age did not affect outcomes. Genetic testing was abnormal in five cases (3%). Amniocyte culture failed in 3 cases (2.3%), with no technical failures in 52 chromosomal microarray tests. The complication rate of AC performed after 24 weeks was 4.8%, which is significantly higher than that of second trimester AC. GA and maternal age did not affect the complication rate.

Objective Telomeres are nucleoprotein structures located at the termini of chromosomes, and protect them from fusion and degradation. Telomeres are progressively shortened with each mitotic cycle and by environmental factors. We hypothesized that antepartum stress can lead to accelerated telomere shortening in placental trophoblasts, and plays a role in intrauterine growth restriction (IUGR). Methods Placental biopsies were derived from 16 pregnancies complicated with IUGR and from 13 uncomplicated pregnancies. Fluorescence-in-situ protocol was used to determine telomere length. Immunohistochemistry for hTERT was performed to assess telomerase activity. Clinical and histopathological characteristics were collected to ensure that IUGR was secondary to placental insufficiency. Fluorescence-in-situ-hybridization was used to rule out aneuploidy as a reason for shortened telomeres. Results The number and intensity of telomeres staining and telomerase activity were significantly lower in the IUGR placentas. No aneuploidy was detected for the chromosomes checked in the placental biopsies. Conclusions Telomeres are shorter in trophoblasts of IUGR placentas.

The carrier frequency of spinal muscular atrophy varies from 1:168 to 1:35. We analyzed the carrier rate in a large population in Israel, evaluated the false-negative rate based on the number of alleles with duplication of exon 7, and analyzed the ethnic differences in both parameters. Data were collected from two centers that conduct carrier screening using the multiplex ligation-dependent probe amplification kit. We studied the number of copies of exons 7 and 8 in our population, which we divided into six different ethnic groups. Statistical analysis was conducted using chi-square test. A total of 7308 healthy individuals were tested in an organized community health maintenance organization (HMO) program, and 1729 in a large hospital setup. The carrier rate was 1:62 and was not statistically different between the ethnic groups. Duplication was found in one in nine individuals (false-negative rate 5.5%) with a significant difference in frequency between the ethnic groups: 13.5% among Ashkenazim, 6% among North-African Jews (p0.001). This difference was consistent in both centers and in exon 8 as well. There is, therefore, a higher prevalence of false negative results in some ethnic groups. The discrepancy between the rates of deletions versus duplications can be explained by the genetic disadvantage of deletions.

Telomeres are specific repetitive DNA sequences that cap and stabilize the ends of chromosomes. Functional telomeres are essential for the normal segregation and maintenance of chromosomes during mitotic and meiotic division. Pre-eclampsia, a pregnancy-specific syndrome of increased blood pressure accompanied by proteinuria, is often associated with growth deficiency in the fetus. Oxidative stress is a major component in the pathophysiology of pre-eclampsia. In contrast to the nonoverlapping nature of telomeres in normal nuclei, telomeres of tumor nuclei tend to form aggregates (TAs) in various numbers and sizes. The formation of TAs represents a stress-related process and is independent of telomere length and telomerase activity. The aim of this study was to evaluate TA formation in paraffin-embedded placentas from pregnancies complicated with pre-eclampsia (study group), compared with placentas from normal pregnancies (control group). There were significantly more TAs in the study group (mean, 8.00 TAs per case) than in the control group (mean, 2.36 TAs per case) (P < 0.01). Pre-eclampsia-related stress may accelerate apoptosis and cell death and lead to placental dysfunction. TAs formation, which has been linked to stress and tumorgenesis is increased in placentas of pre-eclamptic patients.

Objective To evaluate the safety of oocyte activation by calcium ionophore in cases of failed fertilization after intracytoplasmic sperm injection (ICSI) procedure with respect to birth defects. Design A retrospective cohort of pregnancies achieved by oocyte activation with calcium ionophore after ICSI (ICSI-Ca) and routine ICSI between the years 2006 and 2014. Setting Not applicable. Patient(s) The cohort included a total of 793 pregnancies: 66 (8%) were lost to follow up and 49 (6%) were ongoing pregnancies at the time of data collection. Out of the 678 available cases for analysis, 595 treatments were ICSI alone (88%) and 83 were ICSI-Ca (12%). Intervention(s) None. Main Outcome Measure(s) Pregnancy and neonatal outcomes including birth defects were compared. Result(s) On the basis of a cohort of 595 ICSI pregnancies and 83 ICSI-Ca pregnancies, we found no difference in birth defects rate for singletons or for twins. Additionally, no significant difference was found between defect type (chromosomal aberration or structural malformations) and malformation type (heart, urogenital, and limb), between the ICSI and ICSI-Ca groups. Moreover, no significant differences were found regarding birth weight, gestational week at time of delivery, and fetal gender for singleton or twin pregnancies. Conclusion(s) Ca ionophore oocyte activation should be considered as a legitimate option for cases of failed or low fertilization by ICSI.

Objective: This prospective cohort study evaluated the relationship between fertility treatments and the prevalence and outcomes of dichorionic discordant twins. This issue has gained importance due to twin gestations resulting from fertility treatments. Study design: Mothers of dichorionic twin pregnancies achieved in a single fertility clinic by assisted reproduction techniques, who had completed the first trimester of the pregnancy, were prospectively enrolled. Pregnancies with major fetal anomalies were excluded. Data regarding concordant and discordant twins based on the fertility treatments given to achieve the pregnancies were analyzed to determine the prevalence of discordance and pregnancy outcomes. Results: A total of 571 dichorionic twin pregnancies were available for evaluation. Fertility treatments modalities, sperm quality and implantation of cultured and thawed embryos did not influence the rate and severity of discordant twins. Increased hospitalization rates were found among discordant (n=108) compared to concordant (n=463) twins (47.2% vs. 31.3%, P Conclusions: Our data suggest that fertility treatments do not play a major role in the pervasiveness and outcome of discordant twin pregnancies.

Background The optimal choice of skin closure at cesarean delivery has not yet been determined. Objective This study compared wound complications and scar healing following cesarean delivery between 2 methods of skin closure: glue (Dermabond; Ethicon, Somerville, NJ) and monofilament (Monocryl; Ethicon) epidermal sutures. Study Design We conducted a randomized controlled trial in which pregnant women undergoing a scheduled cesarean delivery were randomly assigned to skin (epidermis) closure with glue or with a monofilament synthetic suture. The subcutaneous tissue was sutured for all patients. Outcome assessors were blinded to group allocation. Scars were evaluated >8 weeks. Primary outcome measures were Patient and Observer Scar Assessment Scale scores. Secondary outcome measures were surgeon satisfaction, duration of surgery, duration of hospitalization after the cesarean delivery, and complications of surgical site infection or wound disruption (hematoma or seroma). A sample of 104 women was needed to achieve a clinically significant effect with a power of 80%. Results Demographic characteristics, patients' clinical background, prepregnancy body mass index, and subcutaneous thickness were similar in both groups. Length of surgery between the groups (37 ± 10 minutes for glue vs 39 ± 13 minutes for sutures, P = .515) was similar. Scores immediately after the wound closure were similar for both groups regarding surgeons' time estimate of closure ( P = .181) and closure appearance ( P = .082). Surgeons' satisfaction with the technique was significantly higher in the suture group ( P = .003). No significant differences were found between the groups in blood loss, surgical site infection, length of postpartum hospitalization, or wound disruption. Glue and suture skin closure scores using Patient and Observer Scar Assessment Scale were similar 8 weeks after surgery, at P = .710 for patients and P = .568 for a physician observer. Conclusion Skin closure using glue or a monofilament synthetic suture had similar results. Both methods were shown to be safe and successful for skin closure after a scheduled cesarean delivery and, therefore, can be used based on surgeon and patient preferences.

Genomic aneuploidy is a common cause of human genetic disorders. Individuals with aneuploidy tend to develop malignancies. Recent studies correlated aneuploidy with early aging, senescence and organ dysfunction. This study investigated potential explanations for these increased risks by evaluating random aneuploidy and senescence rates in amniocytes from fetuses with aneuploidy.The rates of random aneuploidy in amniocytes from normal pregnancies were evaluated and compared to amniocytes from fetuses with trisomies 21, 18 and 47,XXY using a FISH technique with X+Y, 9 and 18 probes. Senescence was evaluated by calculating the percentage of amniocytes with fragmented nuclei: senescence associated heterochromatin foci (SAHF), using DAPI staining.Significantly increased rates of cells with aneuploidy were observed in trisomies 18 and 21, and 47,XXY (p0.001) compared to the control group for the somatic and sex chromosomes. Increased rates of amniocytes with SAHFs were observed among the trisomy samples compared to the control group.Higher incidence of random aneuploidy and senescence were observed in amniocytes from fetuses with trisomy. These findings might explain the greater lifetime tendency to develop malignancies and diseases related to early aging in these individuals.

Individuals with trisomy 21 have an increased risk of developing leukemia and premature dementia. They also have a higher rate of telomere loss. The aim of the study was to compare telomere length and the hTERC gene copy number, which encodes the telomerase RNA subunit, in amniocytes of trisomy 21 conceptions and normal pregnancies. A quantitative fluorescence-in-situ protocol (Q-FISH) was used to compare telomere length in amniocytes cultured from 11 trisomy 21 conceptions and from 14 normal pregnancies. Quantification was conducted using novel computer software. Fluorescence in situ hybridization (FISH) was used to assess the percentage of cells with additional copies of hTERC. We found that the immunofluorescence intensity, which represents telomere length, was significantly lower in amniocytes from trisomy 21 conceptions compared to the control group. The trisomy 21 group had a higher number of cells with additional copies of hTERC. This observation could be one of the cytogenetic parameters that represent a state of genetic instability and might play a role in the pathomechanism of typical features of Down syndrome, such as dementia and malignancy.

Introduction Intrauterine growth restriction (IUGR) is a significant cause of both short- and long-term morbidity and mortality. IUGR secondary to placental dysfunction is correlated with telomere shortening. Telomerase is an enzyme complex that elongates telomeres. One of its components is encoded by the telomerase RNA component gene (TERC), which serves as the RNA template for the addition of telomeric repeats. We hypothesized decreased TERC gene copy number in IUGR placentas as part of the mechanism of telomere shortening in placental dysfunction. Methods We estimated the gene copy number of the TERC gene at 3q26 by applying FISH to trophoblasts of placental biopsies from five pregnancies with IUGR caused by placental insufficiency and compared them to placentas from five gestational-age matched, uncomplicated pregnancies. Results Significantly lower TERC gene copy number was observed in IUGR trophoblasts on the same chromosome and on other chromosomes, compared to the control samples (p Conclusions The TERC gene copy number is decreased in IUGR trophoblasts. These results support the observations of telomere shortening and decreased telomerase activity in IUGR placentas. We suggest that these findings might play a role in the pathophysiology of IUGR, perhaps by promoting senescence in trophoblasts of IUGR placentas.

Objective Telomeres shorten and aggregate with cellular senescence and oxidative stress. Telomerase and its catalytic component human telomerase reverse-transcriptase regulate telomere length. The pathogenesis of preeclampsia and intrauterine growth restriction involves hypoxic stress. We aimed to assess telomere length in trophoblasts from pregnancies with those complications. Study Design Placental specimens from 4 groups of patients were studied: severe preeclampsia, intrauterine growth restriction, preeclampsia combined with intrauterine growth restriction, and uncomplicated (control). Telomere length and human telomerase reverse-transcriptase expression were assessed by using quantitative fluorescence-in-situ protocol and immunohistochemistry. Results Telomere length was significantly lower in preeclampsia, intrauterine growth restriction, and preeclampsia plus intrauterine growth restriction placentas. More aggregates were found in preeclampsia, but not in intrauterine growth restriction placentas. Human telomerase reverse-transcriptase was significantly higher in the controls compared with the other groups. Conclusion Telomeres are shorter in placentas from preeclampsia and intrauterine growth restriction pregnancies. Increased telomere aggregate formation in preeclampsia but not in intrauterine growth restriction pregnancies, implies different placental stress-related mechanisms in preeclampsia with or without intrauterine growth restriction.

The purpose of this review article is to evaluate the current method of sonographic measurement of ovarian volume as a means of diagnosing ovarian tumors in postmenopausal women, in whom an ovarian volume greater than 10 ml is generally considered abnormal. After reviewing the general medical literature, we propose a nomogram of ovarian volume that may be used to determine whether an ovary is abnormal. Furthermore, on the basis of our previous results, we recommend that a cutoff point for ovarian volume that is adjusted to patient age be used to determine whether an ovary is abnormal. We recommend the use of such nomograms in routine clinical practice to assist physicians in identifying abnormality of the ovaries during sonographic examination.