Clinical exome sequencing uncovers genetic disorders in neonates with suspected hypoxic-ischemic encephalopathy: A retrospective analysis.

Hypoxic-ischemic encephalopathy (HIE) occurs in up to 7 out of 1000 births and accounts for almost a quarter of neonatal deaths worldwide. Despite the name, many newborns with HIE have little evidence of perinatal hypoxia. We hypothesized that some infants with HIE have genetic disorders that resemble encephalopathy. We reviewed genetic results for newborns with HIE undergoing exome or genome sequencing at a clinical laboratory (2014-2022). Neonates were included if they had a diagnosis of HIE and were delivered ≥35 weeks. Neonates were excluded for cardiopulmonary pathology resulting in hypoxemia or if neuroimaging suggested postnatal hypoxic-ischemic injury. Of 24 patients meeting inclusion criteria, six (25%) were diagnosed with a genetic condition. Four neonates had variants at loci linked to conditions with phenotypic features resembling HIE, including KIF1A, GBE1, ACTA1, and a 15q13.3 deletion. Two additional neonates had variants in genes not previously associated with encephalopathy, including DUOX2 and PTPN11. Of the six neonates with a molecular diagnosis, two had isolated HIE without apparent comorbidities to suggest a genetic disorder. Genetic diagnoses were identified among neonates with and without sentinel labor events, abnormal umbilical cord gasses, and low Apgar scores. These results suggest that genetic evaluation is clinically relevant for patients with perinatal HIE.

Insulin requirements during pregnancy in women with type 1 diabetes treated with insulin pump.

INTRODUCTION: Insulin requirement in women with Type 1 diabetes (T1DM) changes throughout pregnancy. The aim of this study was to determine the total change in insulin requirements and the effect of gestational weight gain (GWG) and pre-gestational BMI on insulin requirements during pregnancy in women with T1DM treated with continuous subcutaneous insulin infusion and continuous glucose monitoring. METHODS: This historical cohort study included all consecutive women with T1DM who were monitored during pregnancy at the high-risk pregnancy clinic at a tertiary medical center during April 2011-April 2019. One Way Repeated Measures ANOVA with Bonferroni adjustment was conducted to compare the effects of gestational age on insulin requirements and a Two Way Repeated Measures ANOVA was employed to test for the interaction between gestational age intervals and maternal BMI and GWG. RESULTS: Data regarding insulin requirements of 185 pregnancies were included in the analyses. There was a significant effect of gestational age on total insulin (Wilks' Lambda = 0.34, F(6,14) = 4.52, p = 0.009), basal insulin (Wilks' Lambda = 0.41, F(6,14) = 3.30, p = 0.031) and bolus insulin (Wilks' Lambda = 0.43, F(6,14) = 3.02, p = 0.041). Total insulin/kg requirements increased by 5.5% from 13-20 weeks to 20-26 weeks, 19% from 20-26 weeks to 26-33 weeks, and 17.4% from 26 to 33 weeks to delivery (p for trend = 0.009). Overall, insulin requirements increased by 42.1% from conception to delivery (p < 0.01). There was no significant main effect of maternal BMI or GWG on insulin requirements. CONCLUSIONS: There is a significant increase in insulin requirements per kg during pregnancy in women with T1DM who were treated with an insulin pump.

The relationship between neonatal hypoglycaemia and cord blood C-peptide levels in neonates of birthing individuals with type 1 diabetes.

INTRODUCTION: Neonates of individuals with type 1 diabetes (T1D) are at increased risk of neonatal hypoglycaemia. It is hypothesised that this is a result of birthing-individual hyperglycaemia and subsequent foetal hyperinsulinemia. AIMS: To test for association between clinically significant neonatal hypoglycaemia (requiring intravenous glucose treatment) and cord-blood c-peptide (CBCP) concentrations in birthing-individuals with T1D. MATERIALS AND METHODS: This is a prospective cohort study of individuals with T1D followed at a single tertiary centre. Clinical variables and glucose control during pregnancy were recorded. Cord-blood was collected and CBCP concentrations determined. The correlation between clinically significant neonatal hypoglycaemia and CBCP concentrations was determined. RESULTS: Fifty-four pregnant individuals and their newborns were included in the study. Individuals to neonates who experienced hypoglycaemia had longer diabetes duration (19 vs. 13 years, respectively, p = 0.023), higher HbA1c at conception (7.3 [6.3-8.8] vs. 6.5 [6.0-7.0], respectively, p = 0.042) and higher rates of caesarian section (73.3% vs. 28.2%, respectively, p = 0.005) than individuals to those who did not. CBCP levels were significantly higher in neonates with clinically significant neonatal hypoglycaemia as compared to those who did not experience hypoglycaemia (3.3 mcg/L vs. 1.9 mcg/L, respectively, p = 0.002). After adjustment for possible confounders, every 1 unit higher in CBCP level was associated with a 1.46 (1.02-2.09, p = 0.035)-fold greater risk for neonatal hypoglycaemia. No significant differences were observed in either birthing individual complications or glucose control indices during pregnancy between the two groups. CONCLUSIONS: In neonates of individuals with T1D, higher CBCP levels are an independent risk factor for clinically significant neonatal hypoglycaemia.

Neonatal birth weight percentile following the use of sensor-augmented pump therapy in women with pre-gestational diabetes.

AIMS: To assess the effect of using sensor-augmented pump therapy (SAP) during pregnancy on neonatal birth weight percentile and other neonatal and pregnancy outcomes. METHODS: This retrospective cohort study included consecutive women with pregestational diabetes mellitus (PGDM) treated with an insulin pump and sensor that enabled the SAP feature during pregnancy. SAP use was defined as utilization of either low-glucose suspend (LGS) or predictive LGS technology. Utilization of SAP was according to physician discretion. Differences in neonatal birth weight percentile and in other neonatal and pregnancy outcomes were compared between those who did and not use SAP. OUTCOMES: Of 142 women, 136 had type 1 diabetes, 5 type 2 diabetes and one diabetes due to pancreatectomy. 83 women used SAP and 59 did not. For the neonates of the mothers of the respective groups, the median birth weight percentiles were similar (79 and 80, pV = 0.96), as were the other neonatal outcomes assessed. The rate of cesarean section was higher in the SAP group. However, after adjusting for maternal age, BMI, and a history of severe hypoglycemic events before pregnancy, the relation between mode of delivery and the use of SAP was no longer statistically significant. CONCLUSION: In women with PGDM treated with an insulin pump and sensor, SAP use during pregnancy was not associated with higher neonatal birth weight percentile or the occurrences of other adverse neonatal or pregnancy outcomes.

Prenatal diagnosis and postnatal outcome of closed spinal dysraphism.

OBJECTIVE: To evaluate the prenatal diagnosis of closed dysraphism (CD) and its correlation with postnatal findings and neonatal adverse outcomes. METHODS: A retrospective cohort study including pregnancies diagsnosed with fetal CD by prenatal ultrasound (US) and magnetic resonance imaging (MRI) at a single tertiary center between September 2011 and July 2021. RESULTS: CD was diagnosed prenatally and confirmed postnatally in 12 fetuses. The mean gestational age of prenatal imaging was 24.2 weeks, in 17% the head circumference was ≤fifth percentile and in 25% the cerebellar diameter was ≤fifth percentile. US findings included banana sign in 17%, and lemon sign in 33%. On MRI, posterior fossa anomalies were seen in 33% of cases, with hindbrain herniation below the foramen magnum in two cases. Mean clivus-supraocciput angle (CSA) was 74°. Additional anomalies outside the CNS were observed in 50%. Abnormal foot position was demonstrated prenatally in 17%. Neurogenic bladder was present in 90% of patients after birth. CONCLUSION: Arnold Chiari II malformation and impaired motor function can be present on prenatal imaging of fetuses with CD and may be associated with a specific type of CD. Prenatal distinction of CD can be challenging. Associated extra CNS anomalies are frequent and the rate of neurogenic urinary tract dysfunction is high.

Adipose tissue-derived FABP4 mediates glucagon-stimulated hepatic glucose production in gestational diabetes.

AIMS: One of the most common complications of pregnancy is gestational diabetes mellitus (GDM), which may result in significant health threats of the mother, fetus and the newborn. Fatty acid-binding protein 4 (FABP4) is an adipokine that regulates glucose homeostasis by promoting glucose production and liver insulin resistance in mouse models. FABP4 levels are increased in GDM and correlates with maternal indices of insulin resistance, with a rapid decline post-partum. We therefore aimed to determine the tissue origin of elevated circulating FABP4 levels in GDM and to assess its potential contribution in promoting glucagon-induced hepatic glucose production. MATERIALS AND METHODS: FABP4 protein and gene expression was determined in biopsies from placenta, subcutaneous (sWAT) and visceral (vWAT) white adipose tissues from GDM and normoglycaemic pregnant women. FABP4 differential contribution in glucagon-stimulated hepatic glucose production was tested in conditioned media before and after its immune clearance. RESULTS: We showed that FABP4 is expressed in placenta, sWAT and vWAT of pregnant women at term, with a significant increase in its secretion from vWAT of women with GDM compared with normoglycaemic pregnant women. Neutralizing FABP4 from both normoglycaemic pregnant women and GDM vWAT secretome, resulted in a decrease in glucagon-stimulated hepatic glucose production. CONCLUSIONS: This study provides new insights into the role of adipose tissue-derived FABP4 in GDM, highlighting this adipokine, as a potential co-activator of glucagon-stimulated hepatic glucose production during pregnancy.

SNV/indel hypermutator phenotype in biallelic RAD51C variant: Fanconi anemia.

We previously reported a fetus with Fanconi anemia (FA), complementation group O due to compound heterozygous variants involving RAD51C. Interestingly, the trio exome sequencing analysis also detected eight apparent de novo mosaic variants with variant allele fraction (VAF) ranging between 11.5 and 37%. Here, using whole genome sequencing and a 'home-brew' variant filtering pipeline and DeepMosaic module, we investigated the number and signature of de novo heterozygous and mosaic variants and the hypothesis of a rare phenomenon of hypermutation. Eight-hundred-thirty apparent de novo SNVs and 21 de novo indels had VAFs below 37.41% and were considered postzygotic somatic mosaic variants. The VAFs showed a bimodal distribution, with one component having an average VAF of 25% (range: 18.7-37.41%) (n = 446), representing potential postzygotic first mitotic events, and the other component with an average VAF of 12.5% (range 9.55-18.69%) (n = 384), describing potential second mitotic events. No increased rate of CNV formation was observed. The mutational pattern analysis for somatic single base substitution showed SBS40, SBS5, and SBS3 as the top recognized signatures. SBS3 is a known signature associated with homologous recombination-based DNA damage repair error. Our data demonstrate that biallelic RAD51C variants show evidence for defective genomic DNA damage repair and thereby result in a hypermutator phenotype with the accumulation of postzygotic de novo mutations, at least in the prenatal period. This 'genome hypermutator phenomenon' might contribute to the observed hematological manifestations and the predisposition to tumors in patients with FA. We propose that other FA groups should be investigated for genome-wide de novo variants.

SNV/indel hypermutator phenotype in biallelic RAD51C variant - Fanconi anemia.

We previously reported a fetus with Fanconi anemia (FA), complementation group O due to compound heterozygous variants involving RAD51C . Interestingly, the trio exome sequencing analysis also detected eight apparent de novo mosaic variants with variant allele fraction (VAF) ranging between 11.5%-37%. Here, using whole genome sequencing and a 'home-brew' variant filtering pipeline and DeepMosaic module, we investigated the number and signature of de novo heterozygous and mosaic variants and the rare phenomenon of hypermutation. Eight-hundred-thirty apparent dnSNVs and 21 de novo indels had VAFs below 37.41% and were considered postzygotic somatic mosaic variants. The VAFs showed a bimodal distribution, with one component with an average VAF of 25% (range: 18.7-37.41%) (n=446), representing potential postzygotic first mitotic events, and the other component with an average VAF of 12.5% (range: 9.55-18.69%) (n=384), describing potential second mitotic events. No increased rate of CNV formation was observed. The mutational pattern analysis for somatic single base substitution showed SBS40, SBS5, and SBS3 as the top recognized signatures. SBS3 is a known signature associated with homologous recombination-based DNA damage repair error. Our data demonstrate that biallelic RAD51C variants show evidence for defective genomic DNA damage repair and thereby result in a hypermutator phenotype with the accumulation of postzygotic de novo mutations, at least in the prenatal period. This 'genome hypermutator phenomenon' might contribute to the observed hematological manifestations and the predisposition to tumors in patients with FA, and pregnancy loss in general. We propose that other FA groups should be investigated for genome-wide de novo variants.

Fertility and pregnancy complications following chorioamnionitis.

Acute chorioamnionitis complicates 1-2% of all pregnancies and might increase the prevalence of endometritis that can cause Asherman syndrome or adhesions, but little is known about the direct effects of chorioamnionitis on future fertility. We aimed to evaluate the effect of chorioamnionitis on future fertility and obstetrics complications in patients diagnosed with chorioamnionitis during their pregnancy. We performed an observational, case-control retrospective study of pregnant women aged 18-40 years old, hospitalized with a diagnosis of chorioamnionitis between January 2013 and December 2017. The control group consisted of patients with similar demographic/obstetrics characteristics, matched with a ratio of 1:2 without chorioamnionitis. The prevalence of post gestational diagnostic hysteroscopy was significantly higher in the study group as compared to the control group (22.9% versus 9.0%, respectively; p = 0.005). Moreover, the study group underwent significantly more operative hysteroscopy compared to the control group (10.8% versus 3.6%, respectively; p = 0.04). The patients in the study group had significantly higher prevalence of miscarriages (27% versus 13.2%, respectively; p < 0.01). We conclude that chorioamnionitis may cause endometritis with the consequent impaired fertility, necessitating comprehensive evaluations for secondary infertility, including hysteroscopy aiming to treat intrauterine adhesions that may affect and impair fertility.

Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology.

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care.

Parental mosaicism for apparent de novo genetic variants: Scope, detection, and counseling challenges.

The disease burden of de novo mutations (DNMs) has been evidenced only recently when the common application of next-generation sequencing technologies enabled their reliable and affordable detection through family-based clinical exome or genome sequencing. Implementation of exome sequencing into prenatal diagnostics revealed that up to 63% of pathogenic or likely pathogenic variants associated with fetal structural anomalies are apparently de novo, primarily for autosomal dominant disorders. Apparent DNMs have been considered to primarily occur as germline or zygotic events, with consequently negligible recurrence risks. However, there is now evidence that a considerable proportion of them are in fact inherited from a parent mosaic for the variant. Here, we review the burden of DNMs in prenatal diagnostics and the influence of parental mosaicism on the interpretation of apparent DNMs and discuss the challenges with detecting and quantifying parental mosaicism and its effect on recurrence risk. We also describe new bioinformatic and technological tools developed to assess mosaicism and discuss how they improve the accuracy of reproductive risk counseling when parental mosaicism is detected.

Do fertility treatments affect labor induction success rate? A retrospective cohort study.

PURPOSE: To evaluate labor induction success rate by Foley catheter (FC) on patients who conceived spontaneously, as compared to those who underwent fertility treatments. MATERIALS AND METHODS: This retrospective cohort study included all pregnant women hospitalized at a single tertiary care center between January 2011 and May 2018 for induction of labor with FC. The study groups included patients with a singleton pregnancy who conceived after fertility treatments: controlled ovarian hyperstimulation (COH) or in vitro fertilization (IVF), while control group included patients who conceived spontaneously. Our primary outcome was the rate of cesarean deliveries. Regression analysis was conducted on the following parameters: age, gravidity, parity, the gestational week, and IVF. RESULTS: The study groups included 59, 321, and 3159 patients who conceived following COH, IVF, or spontaneously, respectively. While 72.1% of patients who conceived spontaneously had a vaginal delivery, only 62.7% and 58% of patients who conceived by COH and IVF had successful labor induction (respectively, p < .01). Similarly, significantly higher cesarean section (CS) rates were demonstrated by patients who conceived by COH and IVF (28.8% and 30%, respectively), compared to the control group (18.7%, p < .01). Regression analysis demonstrated that although age, parity, and the gestational week were significantly related to cesarean sections, no statistically significant association was found regarding fertility treatments (p = .050). CONCLUSIONS: The possible association between fertility treatments and cesarean delivery remains an important dilemma for obstetricians and fertility experts. While unadjusted analysis demonstrated such association among patients who undergo labor induction by FC, adjusted analysis has not supported that finding. Further studies focusing on the causes of failed vaginal delivery are needed to further expand our knowledge and to improve patient consultation.

The effect of mode of delivery in twin pregnancies on the latency period between diagnosis of preterm labor and birth.

INTRODUCTION: The optimal mode of delivery in twin pregnancies presenting with preterm labor is controversial. Current literature regarding these cases is based on observational studies, innately prone to bias. A possibly substantial, yet hitherto unexplored, source of bias is an effect of mode of delivery on the timing of delivery. The aim of our study is to examine whether the mode of delivery affects the latency period between preterm labor (PTL) presentation and actual delivery and to assess the possible effect of latency on neonatal outcome. MATERIAL AND METHODS: A retrospective cohort study at a single tertiary center from the year 2011 to 2018. All twin pregnancies (dichorionic or monochorionic-diamniotic) between 24 and 36 weeks of gestation admitted due to PTL were included in the study. RESULTS: A total of 469 twin deliveries met the study criteria, of them, 204 delivered by cesarean section and 265 delivered vaginally. Cesarean delivery significantly decreased the chances of reaching a latency period of 1 or more days (OR = 0.53, 95% CI = 0.33-0.84), 2 or more days (OR = 0.47, 95% CI = 0.27-0.82) and 3 or more days (OR = 0.28, 95% CI = 0.09-0.9). In a regression model adjusting for gestational age at delivery, mode of delivery was not associated with neonatal morbidity or mortality. However, in a regression model adjusting for gestational age at PTL presentation, thereby accounting for differences in the latency period, cesarean delivery was found to significantly increase the risk of respiratory distress syndrome (OR = 1.62, 95% CI = 1.04-2.54). CONCLUSIONS: In PTL of twin pregnancies, the latency period is significantly longer in vaginal deliveries compared to cesarean deliveries. The possibility of longer latency period in vaginal deliveries should be considered when counseling patients on the mode of delivery in preterm twin pregnancies.

Detection of low-level parental somatic mosaicism for clinically relevant SNVs and indels identified in a large exome sequencing dataset.

BACKGROUND: Due to the limitations of the current routine diagnostic methods, low-level somatic mosaicism with variant allele fraction (VAF) < 10% is often undetected in clinical settings. To date, only a few studies have attempted to analyze tissue distribution of low-level parental mosaicism in a large clinical exome sequencing (ES) cohort. METHODS: Using a customized bioinformatics pipeline, we analyzed apparent de novo single-nucleotide variants or indels identified in the affected probands in ES trio data at Baylor Genetics clinical laboratories. Clinically relevant variants with VAFs between 30 and 70% in probands and lower than 10% in one parent were studied. DNA samples extracted from saliva, buccal cells, redrawn peripheral blood, urine, hair follicles, and nail, representing all three germ layers, were tested using PCR amplicon next-generation sequencing (amplicon NGS) and droplet digital PCR (ddPCR). RESULTS: In a cohort of 592 clinical ES trios, we found 61 trios, each with one parent suspected of low-level mosaicism. In 21 parents, the variants were validated using amplicon NGS and seven of them by ddPCR in peripheral blood DNA samples. The parental VAFs in blood samples varied between 0.08 and 9%. The distribution of VAFs in additional tissues ranged from 0.03% in hair follicles to 9% in re-drawn peripheral blood. CONCLUSIONS: Our study illustrates the importance of analyzing ES data using sensitive computational and molecular methods for low-level parental somatic mosaicism for clinically relevant variants previously diagnosed in routine clinical diagnostics as apparent de novo.

Maternal glucose variability during pregnancy & birthweight percentile in women with pre-gestational diabetes.

INTRODUCTION: Pre-gestational diabetes mellitus (PGDM) is a major risk factor for fetal overgrowth. Interestingly, even in relatively well controlled PGDM women, as determined by average glucose indices such HbA1c, there is an increased rate of LGA (large for gestational age). Glucose variability (GV) has emerged as an important independent risk factor for several diabetes complications. The aim of this study was to determine the relationship between maternal GV indices and neonatal birth percentile. METHODS: This was a historical cohort study that included all consecutive PGDM women monitored in a single tertiary care center. Clinical and demographic variables, as well as data regarding glucose control, were prospectively recorded. Mean, standard deviation (SD) and coefficient of variance (CV) of glucose values were calculated. Pearson correlations coefficient was used to determine the correlation between glucose indices and birth percentile. The analysis was repeated after adjustment for several confounders. RESULTS: Mean birthweight and birthweight percentile were 3212 ± 532 g and 66.9%, respectively. There was a statistically significant correlation between birthweight percentile and maternal glucose SD (ß = 0.28, p = .002) and maternal glucose CV (ß = 0.21, p = .019). There was no significant correlation between birthweight percentile and mean glucose values. The association between the maternal glucose SD and birthweight percentile remained statistically significant after adjustment for maternal age, pre-pregnancy BMI and duration of diabetes. CONCLUSION: There is an association between maternal glucose variability indices (SD and CV) during pregnancy and neonatal birth percentile. Larger studies are needed to confirm these results.

Early-onset preeclampsia - The impact of antiphospholipid antibodies on disease severity.

OBJECTIVES: Antiphospholipid antibodies have been associated with various obstetric complications, including recurrent pregnancy loss, preeclampsia, intrauterine growth restriction, placental insufficiency, and late fetal loss. Despite the amassed body of evidence emphasizing the association between antiphospholipid antibodies and preeclampsia, the severity of preeclampsia with regard to antiphospholipid antibodies status has not been elucidated. This study aimed to evaluate whether early-onset preeclampsia with severe features before 34 weeks' gestation is clinically different when associated with antiphospholipid antibodies. STUDY DESIGN: In this retrospective case-control study, we collected data on pregnancy outcomes of 101 women with singleton pregnancies who delivered prior to 34 weeks of gestation due to preeclampsia with severe features. The antiphospholipid antibodies status of 55 of these women was available for analysis. The study group comprised 20 women with positive antiphospholipid antibodies (positive-aPL group), while the control group comprised 35 women without antiphospholipid antibodies (negative-aPL group). Obstetric and neonatal outcomes, laboratory results and pregnancy complications were extracted from medical records. RESULTS: In the clinical setting of early-onset preeclampsia with severe features necessitating delivery before 34 weeks gestation, positive-aPL women were hospitalized earlier (29, IQR 26.3-32, vs. 32, IQR 28-33 weeks gestation, P = 0.05), gave birth at a significantly earlier gestational age (30, IQR 28.3-32.8 vs. 33, IQR 30-34, P = 0.02) with a lower mean birth-weight (1266.7 ±â€¯579.6 vs. 1567.3 ±â€¯539.7 g, P = 0.058) compared with negative-aPL women. Furthermore, platelet nadir was significantly lower for positive-aPL compared with negative-aPL women (97 ±â€¯49×103/µL vs. 141 ±â€¯61×103/µL, P < 0.001) and maximal serum creatinine was higher (1.0 ±â€¯0.3 mg/dL vs. 0.9 ±â€¯0.1 mg/dL, P = 0.03). Rates of neonatal complications were low and comparable between groups, except for higher rates of retinopathy of prematurity requiring treatment in the study group (30.0% vs. 5.7%, p = 0.02), and there was a trend for higher perinatal mortality among study group infants. CONCLUSIONS: The presence of antiphospholipid antibodies in women with early-onset preeclampsia with severe features is associated with earlier, more severe disease course. Expedited screening for antiphospholipid antibodies in cases of early-onset severe preeclampsia may be considered, along with close monitoring for pregnant women with positive antibodies.

Overview and recent developments in cell-based noninvasive prenatal testing.

Investigators have long been interested in the natural phenomenon of fetal and placental cell trafficking into the maternal circulation. The scarcity of these circulating cells makes their detection and isolation technically challenging. However, as a DNA source of fetal origin not mixed with maternal DNA, they have the potential of considerable benefit over circulating cell-free DNA-based noninvasive prenatal genetic testing (NIPT). Endocervical trophoblasts, which are less rare but more challenging to recover are also being investigated as an approach for cell-based NIPT. We review published studies from around the world describing both forms of cell-based NIPT and highlight the different approaches' advantages and drawbacks. We also offer guidance for developing a sound cell-based NIPT protocol.

The association between level of physical activity and pregnancy rate after embryo transfer: a prospective study.

RESEARCH QUESTION: Is physical activity after embryo transfer, as assessed by a smart band activity tracker, associated with decreased pregnancy rates? DESIGN: Prospective observational cohort study comprising infertile women aged < 38 years, who had undergone fewer than three previous embryo transfers, achieved a good ovarian response and were undergoing frozen-thawed embryo transfer in a tertiary-referral centre. A validated smart band activity tracker was used to assess physical activity level immediately after the embryo transfer and until the pregnancy test. No specific recommendations were given to participants on level or intensity of physical activity. Physicians and patients were blinded to the data stored in the pedometer. Primary outcome was ongoing pregnancy rate. RESULTS: Fifty women met the inclusion criteria. Ongoing pregnancy rate was 30%. In a pooled analysis, participants walked significantly fewer steps per day on the day of embryo transfer compared with the first 2 days after embryo transfer (4075, interquatile range [IQR] 2932-5592 versus 5204, IQR4203-8584, P = 0.01). No significant difference was observed between pregnant women and non-pregnant women in the median steps per day after embryo transfer until serum beta-HCG was measured (7569, IQR 6008-10884 versus 6572.5, IQR 5299-8786, P = 0.43). No significant difference was observed in the median number of steps on the day of embryo transfer or the first 2 days after embryo transfer between pregnant and non-pregnant women. CONCLUSIONS: A quantitative objective assessment of the association between physical activity and pregnancy rates after frozen-thawed embryo transfer was conducted. Ambulation after embryo transfer has no adverse effect on pregnancy rates and, therefore, women should resume regular activity immediately after embryo transfer.

Evolution of colorectal cancer screening research in the past 25 years: text-mining analysis of publication trends and topics.

BACKGROUND: There is a growing research effort in the field of colorectal cancer (CRC) screening, with varying topics and shifting research foci over the years. The aim of this study was to apply a text-mining technique to evaluate trends in publications for CRC screening in the last 25 years. METHODS: We retrieved MEDLINE/PubMed datasets from 1992-2017. We selected keywords from Medical Subject Headings to include CRC screening related publications. For each article, we extracted the following data: title, journal, publication date, abstract, article type, citation frequency, and country of origin. Articles were categorized into topics using word combination and title match technique. RESULTS: In 1992-2017, 14,119 CRC screening related papers were published. The US had the highest number of papers (n = 4824) and China had the highest growth rate in publications. Overall, the most researched topic was "screening and surveillance programs" (38%). The topics of "quality assurance" (r = 0.87) and "racial disparities" (r = 0.91) have gained increased research attention over the years. In total, 11 of the 20 most cited articles in the field were published in The New England Journal of Medicine. CONCLUSION: The number of publications devoted to CRC screening has grown, with high-quality research reaching top-tier journals. A surge in the number of publications has been increasing in countries previously less involved in research in the field. Screening programs remain the most researched topic, and quality indicators is attracting a growing attention. Text-mining analysis of CRC screening research contributes to an understanding of publication trends and topics and can point to the need for potential future investigations.

Towards Implementation of the Saint Vincent Declaration: Outcomes of Women with Pregestational Diabetes.

BACKGROUND: Pregestational diabetes mellitus (PGDM) carries a significantly elevated risk of adverse maternal and fetal outcomes. There is evidence that certain interventions reduce the risk for adverse outcomes. Studies have shown that a multi-disciplinary approach improves pregnancy outcomes in women with PGDM. OBJECTIVES: To determine pregnancy outcomes in women with PGDM using a multi-disciplinary approach. METHODS: We retrospectively reviewed consecutive women with pregestational type 1 and type 2 diabetes who were monitored at a high-risk pregnancy clinic at the Sheba Medical Center. Clinical data were obtained from the medical records. All data related to maternal glucose control and insulin pump function were prospectively recorded on Medtronic CareLink® pro software (Medtronic MiniMed, Northridge, CA). RESULTS: This study comprised 121 neonates from 116 pregnancies of 94 women. In 83% of the pregnancies continuous glucose monitoring (CGM) sensors were applied during a part or all of the pregnancy. Pregnancy outcomes among women who were followed by a multi-disciplinary team before and during pregnancy, and during labor and puerperium resulted in better glucose control (hemoglobin A1c 6.4% vs. 7.8%), lower risk for pregnancy induced hypertension/preeclampsia (7.7% vs. 15.6%), lower birth weight (3212 g vs. 3684 g), and lower rate of large size for gestational age and macrosomia (23.1% vs. 54.2% and 3.3% vs. 28.4%, respectively), compared to data from European cohorts. CONCLUSIONS: The multi-disciplinary approach for treating women with PGDM practiced in the high-risk pregnancy clinic at the Sheba Medical Center resulted in lower rates of macrosomia, LGA, and pregnancy induced hypertension compared to rates reported in the literature.