Single-Cell Tracing Dissects Regulation of Maintenance and Inheritance of Transcriptional Reinduction Memory.

Transcriptional memory of gene expression enables adaptation to repeated stimuli across many organisms. However, the regulation and heritability of transcriptional memory in single cells and through divisions remains poorly understood. Here, we combined microfluidics with single-cell live imaging to monitor Saccharomyces cerevisiae galactokinase 1 (GAL1) expression over multiple generations. By applying pedigree analysis, we dissected and quantified the maintenance and inheritance of transcriptional reinduction memory in individual cells through multiple divisions. We systematically screened for loss- and gain-of-memory knockouts to identify memory regulators in thousands of single cells. We identified new loss-of-memory mutants, which affect memory inheritance into progeny. We also unveiled a gain-of-memory mutant, elp6Δ, and suggest that this new phenotype can be mediated through decreased histone occupancy at the GAL1 promoter. Our work uncovers principles of maintenance and inheritance of gene expression states and their regulators at the single-cell level.

Systematic Gene-to-Phenotype Arrays: A High-Throughput Technique for Molecular Phenotyping.

We have developed a highly parallel strategy, systematic gene-to-phenotype arrays (SGPAs), to comprehensively map the genetic landscape driving molecular phenotypes of interest. By this approach, a complete yeast genetic mutant array is crossed with fluorescent reporters and imaged on membranes at high density and contrast. Importantly, SGPA enables quantification of phenotypes that are not readily detectable in ordinary genetic analysis of cell fitness. We benchmark SGPA by examining two fundamental biological phenotypes: first, we explore glucose repression, in which SGPA identifies a requirement for the Mediator complex and a role for the CDK8/kinase module in regulating transcription. Second, we examine selective protein quality control, in which SGPA identifies most known quality control factors along with U34 tRNA modification, which acts independently of proteasomal degradation to limit misfolded protein production. Integration of SGPA with other fluorescent readouts will enable genetic dissection of a wide range of biological pathways and conditions.

One-year anthropometric follow-up of South African preterm infants in kangaroo mother care: Which early-life factors predict malnutrition?

BACKGROUND: Preterm infants often have poor short- and long-term growth. Kangaroo mother care supports short-term growth, but longer-term outcomes are unclear. METHODS: This study analysed longitudinally collected routine clinical data from a South African cohort of preterm infants (born <37 weeks gestation) attending the outpatient follow-up clinic of a tertiary-level hospital (Tshwane District, South Africa) for 1 year between 2012 and 2019. At 1 year, small-for-gestational age (SGA) and appropriate-for-gestational age (AGA) infants were compared with regard to age-corrected anthropometric z-scores (weight-for-age [WAZ], length-for-age [LAZ], weight-for-length [WLZ] and BMI-for-age [BMIZ]) and rates of underweight (WAZ < -2), stunting (LAZ < -2), wasting (WLZ < -2) and overweight (BMIZ> + 2). Multiple regression analysis was used to investigate associations between maternal/infant characteristics and rates of underweight, stunting, wasting and overweight. RESULTS: At 1 year, compared with AGA infants (n = 210), SGA infants (n = 111) had lower WAZ (-1.26 ± 1.32 vs. -0.22 ± 1.24, p < 0.001), LAZ (-1.50 ± 1.11 vs. -0.60 ± 1.06, p < 0.001), WLZ (-0.66 ± 1.31 vs. 0.11 ± 1.24, p < 0.001) and BMIZ (-0.55 ± 1.31 vs. 1.06 ± 1.23, p < 0.001), despite larger WAZ gains from birth (+0.70 ± 1.30 vs. +0.05 ± 1.30, p < 0.001). SGA infants had significantly more stunting (34.2% vs. 9.1%; p < 0.001), underweight (31.2% vs. 7.2%; p < 0.001) and wasting (12.6% vs. 4.3%, p = 0.012), with no difference in overweight (4.5% vs. 7.7%, p = 0.397). In multiple regression analysis, birth weight-for-GA z-score more consistently predicted 1-year malnutrition than SGA. CONCLUSION: Preterm-born SGA infants remain more underweight, stunted and wasted than their preterm-born AGA peers at 1 year, despite greater WAZ gains. Interventions for appropriate catch-up growth especially for SGA preterm infants are needed.

Uses of antiseizure medication among pregnant women with epilepsy and risk of adverse obstetric outcomes: A group-based trajectory analysis.

OBJECTIVE: This study was undertaken to examine the association between different patterns of antiseizure medication (ASM) use during pregnancy and adverse obstetric outcomes (preterm birth, low birth weight [LBW], and small for gestational age [SGA]). METHODS: This retrospective cohort study used the Birth Certificate Application and National Health Insurance data in Taiwan (January 1, 2004 through December 31, 2018). We retrieved weekly ASM among pregnant women with epilepsy who were prepregnancy chronic users and used group-based trajectory modeling to identify distinct patterns of use. Logistic regressions were adopted to examine the association between patterns of ASM use and risk of preterm birth, LBW, and SGA. In addition, we revealed postnatal ASM utilization pattern among these prepregnancy chronic users as an exploratory study. RESULTS: Of 2175 pregnant women with epilepsy, we identified four patterns of ASM use during pregnancy: frequent and continuous (64.87%), frequent but discontinuous (7.08%), intermittent (19.72%), and intermittent and discontinuous users (8.32%). Compared to frequent and continuous users, the adjusted odds ratios for preterm birth in frequent but discontinuous, intermittent, and intermittent and discontinuous users were .83 (95% confidence interval [CI] = .47-1.48), .71 (95% CI = .47-1.05), and .88 (95% CI = .52-1.49), respectively. Similar results were observed for LBW and SGA. In the exploratory study, we found that most of our study subjects maintained the same patterns before and after delivery. SIGNIFICANCE: After considering duration and timing of exposure, our study did not find an association between four distinct patterns of ASM use and adverse obstetric outcomes among women with epilepsy. The findings suggested that optimal seizure control could be received for pregnant women with epilepsy after evaluating the risks and benefits.

Evaluation of screening performance of first-trimester competing-risks prediction model for small-for-gestational age in Asian population.

OBJECTIVE: To examine the external validity of the Fetal Medicine Foundation (FMF) competing-risks model for the prediction of small-for-gestational age (SGA) at 11-14 weeks' gestation in an Asian population. METHODS: This was a secondary analysis of a multicenter prospective cohort study in 10 120 women with a singleton pregnancy undergoing routine assessment at 11-14 weeks' gestation. We applied the FMF competing-risks model for the first-trimester prediction of SGA, combining maternal characteristics and medical history with measurements of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) concentration. We calculated risks for different cut-offs of birth-weight percentile (< 10th , < 5th or < 3rd percentile) and gestational age at delivery (< 37 weeks (preterm SGA) or SGA at any gestational age). Predictive performance was examined in terms of discrimination and calibration. RESULTS: The predictive performance of the competing-risks model for SGA was similar to that reported in the original FMF study. Specifically, the combination of maternal factors with MAP, UtA-PI and PlGF yielded the best performance for the prediction of preterm SGA with birth weight < 10th percentile (SGA < 10th ) and preterm SGA with birth weight < 5th percentile (SGA < 5th ), with areas under the receiver-operating-characteristics curve (AUCs) of 0.765 (95% CI, 0.720-0.809) and 0.789 (95% CI, 0.736-0.841), respectively. Combining maternal factors with MAP and PlGF yielded the best model for predicting preterm SGA with birth weight < 3rd percentile (SGA < 3rd ) (AUC, 0.797 (95% CI, 0.744-0.850)). After excluding cases with pre-eclampsia, the combination of maternal factors with MAP, UtA-PI and PlGF yielded the best performance for the prediction of preterm SGA < 10th and preterm SGA < 5th , with AUCs of 0.743 (95% CI, 0.691-0.795) and 0.762 (95% CI, 0.700-0.824), respectively. However, the best model for predicting preterm SGA < 3rd without pre-eclampsia was the combination of maternal factors and PlGF (AUC, 0.786 (95% CI, 0.723-0.849)). The FMF competing-risks model including maternal factors, MAP, UtA-PI and PlGF achieved detection rates of 42.2%, 47.3% and 48.1%, at a fixed false-positive rate of 10%, for the prediction of preterm SGA < 10th , preterm SGA < 5th and preterm SGA < 3rd , respectively. The calibration of the model was satisfactory. CONCLUSION: The screening performance of the FMF first-trimester competing-risks model for SGA in a large, independent cohort of Asian women is comparable with that reported in the original FMF study in a mixed European population. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Evaluation of angiogenic factors in prediction of growth-related neonatal morbidity at term and comparison with competing-risks model.

OBJECTIVES: First, to describe the distribution of biomarkers of impaired placentation in small-for-gestational-age (SGA) pregnancies with neonatal morbidity; second, to examine the predictive performance for growth-related neonatal morbidity of a high soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio or low PlGF; and, third, to compare the performance of a high sFlt-1/PlGF ratio or low PlGF with that of the competing-risks model for SGA in predicting growth-related neonatal morbidity. METHODS: This was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, an ultrasound scan and measurement of serum PlGF and sFlt-1. The primary outcome was delivery within 4 weeks after assessment and at < 42 weeks' gestation of a SGA neonate with birth weight < 10th or < 3rd percentile, combined with neonatal unit (NNU) admission for ≥ 48 h or a composite of major neonatal morbidity. The detection rates in screening by PlGF < 10th percentile, sFlt-1/PlGF ratio > 90th percentile, sFlt-1/PlGF ratio > 38 and the competing-risks model for SGA, using combinations of maternal risk factors and Z-scores of estimated fetal weight (EFW) with multiples of the median values of uterine artery pulsatility index, PlGF and sFlt-1, were estimated. The detection rates by the different methods of screening were compared using McNemar's test. RESULTS: In the study population of 29 035 women, prediction of growth-related neonatal morbidity at term provided by the competing-risks model was superior to that of screening by low PlGF concentration or a high sFlt-1/PlGF concentration ratio. For example, at a screen-positive rate (SPR) of 13.1%, as defined by the sFlt-1/PlGF ratio > 38, the competing-risks model using maternal risk factors and EFW predicted 77.5% (95% CI, 71.7-83.3%) of SGA < 10th percentile and 89.3% (95% CI, 83.7-94.8%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered within 4 weeks after assessment. The respective values for SGA with major neonatal morbidity were 71.4% (95% CI, 56.5-86.4%) and 90.0% (95% CI, 76.9-100%). These were significantly higher than the respective values of 41.0% (95% CI, 34.2-47.8%) (P < 0.0001), 48.8% (95% CI, 39.9-57.7%) (P < 0.0001), 37.1% (95% CI, 21.1-53.2%) (P = 0.003) and 55.0% (95% CI, 33.2-76.8%) (P = 0.035) achieved by the application of the sFlt-1/PlGF ratio > 38. At a SPR of 10.0%, as defined by PlGF < 10th percentile, the competing-risks model using maternal factors and EFW predicted 71.5% (95% CI, 65.2-77.8%) of SGA < 10th percentile and 84.3% (95% CI, 77.8-90.8%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered within 4 weeks after assessment. The respective values for SGA with major neonatal morbidity were 68.6% (95% CI, 53.1-83.9%) and 85.0% (95% CI, 69.4-100%). These were significantly higher than the respective values of 36.5% (95% CI, 29.8-43.2%) (P < 0.0001), 46.3% (95% CI, 37.4-55.2%) (P < 0.0001), 37.1% (95% CI, 21.1-53.2%) (P = 0.003) and 55.0% (95% CI, 33.2-76.8%) (P = 0.021) achieved by the application of PlGF < 10th percentile. CONCLUSION: At 36 weeks' gestation, the prediction of growth-related neonatal morbidity by the competing-risks model for SGA, using maternal risk factors and EFW, is superior to that of a high sFlt-1/PlGF ratio or low PlGF. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Polish translation, cultural adaptation, and validity confirmation of the Scored Patient-Generated Subjective Global Assessment.

PURPOSE: The Scored Patient-Generated Subjective Global Assessment (PG-SGA©) is a validated nutritional screening, assessment, triage, and monitoring tool. The aim of this study was to perform translation, cultural adaptation, linguistic, and content validation of the translated and culturally adapted version of the PG-SGA for the Polish setting. METHODS: The study was performed in concordance with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Principles. Patients (n = 174) and healthcare professionals (HCPs, n = 188) participated in the study. Comprehensibility and difficulty were assessed by patients for the PG-SGA Short Form, and by HCPs for the professional component. Content validity was assessed for the full PG-SGA by HCPs only. Evaluations were operationalized by a 4-point scale. Item and scale indices were calculated using the average item ratings divided by the number of respondents. Item indices < 0.78 required further analysis of the item, while scale indices ≥ 0.90 were defined as excellent and 0.80-0.89 as acceptable. RESULTS: The PG-SGA Short Form was rated as excellent for content validity (Scale-CVI = 0.90) by HCPs and easy to comprehend (Scale-CI = 0.96) and use (Scale-DI = 0.94) by patients. The professional component of the PG-SGA was perceived as acceptable for content validity (Scale-CVI = 0.80), comprehension (Scale-CI = 0.87), and difficulty (Scale-DI = 0.80). The physical exam was rated the least comprehensible and the most difficult, and with the lowest content validity. We found significant differences in scale indices (p < 0.05 for all) between HCPs with different professions and between those being familiar with PG-SGA and not. CONCLUSION: Translation and cultural adaptation of the PG-SGA for the Polish setting preserved the purpose and conceptual meaning of the original PG-SGA. Validation revealed that the Polish version of PG-SGA is well understood and easy to complete by patients and professionals, and is considered relevant by professionals. However, detailed results indicate the need for appropriate training of the Polish HCPs, especially physicians and nurses, mainly in the worksheets related to the metabolic demand and physical exam.

Association of maternal serum uric acid levels with LBW/SGA: a large retrospective cohort study.

BACKGROUND: Elevated maternal serum uric acid (UA) levels were associated with adverse perinatal outcomes. This study aimed to examine the association between UA and the risk of low birth weight (LBW) / small for gestational age (SGA). METHODS: A cohort study of women delivered in Shanghai maternity hospital was included between 2017 and 2021. Electronic medical records were utilized to extract information and antenatal care records. The cut-off value of UA was 360 µmol/L. The outcome was LBW/SGA, with LBW defined as birth weight below 2500 g and SGA indicating birth weight below the 10th percentile of average weight for gestational age. The assessment of SGA was based on the Chinese standard curve for birth weight at various gestational ages. Univariate, multivariate logistic regression models, restricted cubic spline were used in this study, with adjustments made for confounding factors. RESULTS: Sixty-nine thousand six hundred seventy-four live births and singleton pregnancies were included. The ratio of LBW/SGA was 3.3%/9%. Maternal UA levels were significantly negatively correlated with birth weight. High UA levels were associated with high risk of LBW/SGA, especially in third trimester. In BMI < 25 group, the risk of LBW increased to 2.35-fold (95%CI, 1.66-3.31) in hyperuricemic group (UA > 360 µmol/L). The SGA risk was 1.66-fold (95%CI, 1.37-2.00). Gestational hypertension (GH) with hyperuricemica increased the risk of LBW (aOR = 4.00, 95%CI, 2.01-7.93) and SGA (aOR = 2.63, 95%CI, 1.83-3.78). Preeclampsia (PE) with hyperuricemia increased the risk of LBW (aOR = 1.38, 95%CI, 0.63-3.03) and SGA (aOR = 1.81, 95%CI, 1.18-2.78). In delivery gestational week (DGW) ≥ 37 group, if UA > 360 µmol/L, the incidence of LBW increased to 2.46-fold (95%CI, 1.62, 3.73) and the incidence of SGA increased to 1.52-fold (95%CI, 1.24, 1.87). In DGW < 37 group, if UA > 360 µmol/L, the incidence of LBW increased to 2.70-fold (95%CI, 1.92, 3.80) and the incidence of SGA increased to 2.13-fold(95%CI, 1.50, 3.02). CONCLUSIONS: The study found an inverse correlation between UA levels and birth weight. High UA levels were associated with increased risk of LBW/SGA, particularly in third trimester. GH or PE complicated by hyperuricemia were found to have significantly higher risk of developing LBW/SGA. This relationship also existed in pregnant women with BMI < 25.

Peripartum Prediction of Fetal Weight in Gravidas With Obesity.

OBJECTIVES: Estimated fetal weight (EFW) is an important metric at delivery as neonates with abnormal birthweight and their mothers are at higher risk of birth complications. Data regarding optimal EFW assessment in gravidas with obesity is inconsistent, and with the increasing incidence of obesity, clarification of this question is crucial. We aimed to compare accuracy of ultrasound (US)-derived EFW and clinical assessments of EFW in predicting neonatal birthweight among gravidas with obesity. METHODS: This prospective cohort study enrolled gravidas with obesity and a singleton pregnancy admitted for delivery at term. EFW was determined using either US biometry or clinical assessment (Leopold's maneuvers, Johnson's formula, and Insler's formula) at time of admission. Our primary outcome was accurate EFW, defined as EFW within 500 g of birthweight. Secondary outcomes included ability to predict small-for-gestational age (SGA) and large-for-gestational age (LGA) birthweights. These outcomes were compared between all EFW methods. RESULTS: A total of 250 gravidas with a median body mass index of 36.4 kg/m2 were enrolled. Admission US outperformed Leopold's maneuvers in obtaining accurate EFW (81.6% versus 74.5%, P = .03). When comparing all methods, Johnson's and Insler's formulae performed the worst, accurately predicting EFW in only 27.4% and 14.3% of cases, respectively. Likewise, US-derived EFW outperformed Leopold's maneuvers and fundal height in the prediction of SGA and LGA neonates. CONCLUSIONS: US is more accurate than clinical assessment of EFW in gravidas with obesity both for estimation of actual birthweight and prediction of abnormal birthweight. Universal late third-trimester or peripartum US for EFW should be considered in gravidas with obesity.

Assessment criteria to diagnose malnutrition (undernutrition and overnutrition) in haemodialysis patients.

OBJECTIVE: This study aimed to determine if adapted Global Leadership Initiative on Malnutrition (GLIM) criteria can diagnose overnutrition, in addition to undernutrition, in hemodialysis patients. Additionally, it compared the adapted GLIM criteria with the Subjective Global Assessment (SGA) for diagnosing undernutrition. METHODS: A cross-sectional, descriptive study design with an analytical component was utilized. An interviewer-administered questionnaire (IAQ) was completed with 116 adult participants from two public renal units in Cape Town. Data collection included demographic, medical, and anthropometric information, incorporating the established SGA tool and the adapted GLIM criteria. RESULTS: Of the participants, 58% were female, with a mean age of 41.04 years (SD 10.6). The primary causes of renal failure were hypertension (38%) and glomerular disease (33%). The median weight was 64.74 kg (IQR 16.4) and the mean BMI was 25.44 kg/m2 (SD 4.66). The prevalence of obesity was 20%, and undernutrition was 4% by BMI. Participants from Groote Schuur Hospital (GSH) had a higher mean BMI (26.40, SD 4.9) than those from Tygerberg Hospital (TBH) (p=0.0033). Abdominal obesity prevalence was 51%, with a mean waist circumference of 87.06 cm (SD 11.37). Using SGA parameters, undernutrition prevalence was 26%, all classified as SGA-B, compared to 22% by adapted GLIM. Adapted GLIM classified 69.83% as malnourished (overnutrition 47%, undernutrition 22%). For undernutrition, the adapted GLIM had a sensitivity of 75% (CI 64.04, 85.96), specificity of 77.78% (CI 67.26, 88.3), positive predictive value of 69.23% (CI 57.55, 80.91), and negative predictive value of 82.35% (CI 72.71, 92.00). Among those diagnosed with overnutrition by adapted GLIM, 89% were classified as well-nourished by SGA. CONCLUSION: The adapted GLIM criteria effectively assessed overnutrition as well as undernutrition in hemodialysis patients. It identified a significant proportion of patients misclassified as well-nourished by SGA who were actually overnourished. The adapted GLIM showed good sensitivity and specificity for diagnosing undernutrition in this population.

Swedish translation and cultural adaptation of the scored Patient-Generated Subjective Global Assessment (PG-SGA©)-A validated tool for screening and assessing malnutrition in clinical practice and research.

INTRODUCTION: The scored Patient-Generated Subjective Global Assessment (PG-SGA©) is a validated tool for the screening, assessment and monitoring of malnutrition, and triaging of interventions. It contains a patient-generated component and a healthcare professional (HCP)-generated component. AIM: To translate the PG-SGA into Swedish, assess the linguistic and content validity of the Swedish version, and ensure conceptional, semantic and operational equivalence to the original English PG-SGA. METHODS: In line with the methodology used in previously translated and culturally adapted versions, the standardised 10-step process suggested by the International Society for Health Economics and Outcomes Research (ISPOR) was followed. In step 7, a cross-sectional study targeting patients n = 51 and HCPs n = 52 was performed at a university hospital in Sweden. Using separate questionnaires, patients assessed the patient component and HCPs, the professional component regarding perceived comprehensibility and difficulty (linguistic validity). The HCPs also assessed perceived relevance (content validity) of all items on the PG-SGA. Item indices for comprehensibility (I-CI), difficulty (I-DI) and content validity (I-CVI) were calculated and averaged into scale indices (S-CI, S-DI and S-CVI). Cut-off standards for item and scale indices were used as reference. RESULTS: The Swedish version of the PG-SGA rated excellent for comprehensibility (S-CI 0.96) and difficulty (S-DI 0.93) for the patient component. The professional component rated acceptable for comprehensibility (S-CI 0.89) and below acceptable for difficulty (S-DI 0.70), with the physical examination rated most difficult (I-DI 0.39 to 0.69). Content validity for the full Swedish PG-SGA was rated excellent (S-CVI 0.94). CONCLUSION: The patient component was considered clear and easy to complete. The full Swedish PG-SGA was considered relevant by HCPs for screening and assessment of malnutrition. Due to perceived difficulty with the physical examination, training of Swedish HCPs in using the PG-SGA is essential before implementing the professional component into clinical practice or research.

Correlation of toxoplasmosis with small­for­gestational­age newborns.

BACKGROUND: Toxoplasma gondii infection in pregnant women could lead to significant changes during the pregnancy, affect the outcomes of pregnancy and the timing of labour. Small­for­gestational­age (SGA) newborns are defined by birthweight below the 10th percentile for gestational age. We tested an association between latent toxoplasmosis in pregnant women and deliveries of SGA babies. MATERIAL AND METHODS: For testing, we included 1,647 women who gave birth to a singleton baby at ≥ 37 weeks of gestation. The complement-fixation test (CFT) and enzyme-linked immunosorbent assay (ELISA) tests for IgG and IgM were used. The latent form of toxoplasmosis was defined as a CFT titre of 1:8 or higher, together with index positivity IgG ELISA > 1.1 and negative IgM. RESULTS: There were 406 (24.7 %) women positive, and 1,241 (75.3 %) women negative for latent toxoplasmosis. Of all deliveries. 190 were SGA­positive and 1,457 were SGA­negative. Our study found a statistically significant association between latent toxoplasmosis and SGA foetuses born at term. The Pearson chi-square model was statistically significant (χ2(1) = 7.365, p = .007). The odds ratio was 1.567. CONCLUSION: Pregnant women with latent toxoplasmosis giving birth at ≥ 37 weeks of gestation have a 1.567 times higher risk of delivering an SGA baby (Tab. 2, Fig. 1, Ref. 30).

Malnutrition diagnosed by GLIM criteria better predicts long-term outcomes for patients with non-Hodgkin's lymphoma: A prospective multicenter cohort study.

Since Global Leadership Initiative on Malnutrition (GLIM) method was proposed, few studies have applied these new criteria to hematological tumors. In this study, we explored the prevalence of malnutrition according to the GLIM criteria and scored Patient-Generated Subjective Global Assessment (sPG-SGA) and their association with 1-year, 3-year and 5-year mortality among patients with non-Hodgkin's lymphoma (NHL). Malnutrition of all patients were assessed by GLIM criteria and sPG-SGA. Relationship between the malnutrition based on GLIM criteria or sPG-SGA and mortality was investigated by Cox regression analyses. The performance of GLIM criteria was evaluated by assessing the sensitivity, specificity, k-value, receiver operating characteristic (ROC) curve and time-dependent ROC. Of 963 patients with NHL, the prevalence of malnutrition was 38.8% with GLIM criteria, 65.3% with GLIM-omitted NRS-2002 and 53.2% with sPG-SGA. In comparison with sPG-SGA, the sensitivity of GLIM criteria was 61.7%, the specificity was 84.8%, and the agreement was moderate (k = 0.48, p < 0.001). Malnutrition based on GLIM criteria could also predict 3-year and 5-year mortality after adjusting for confounders, except for sPG-SGA (HR = 1.816, 95%CI = 1.274-2.589, p = 0.001 for 3-year mortality; HR = 1.707, 95%CI = 1.223-2.382, p = 0.002 for 5-year mortality). For patients with NHL, GLIM criteria could be applied as an effective replacement to sPG-SGA for nutrition assessment and mortality prediction, especially for predicting long-term prognostic outcomes.

Endothelial protein C receptor is increased in preterm preeclampsia and fetal growth restriction.

Placental dysfunction is the leading cause of both preeclampsia and fetal growth restriction. This study aimed to characterize endothelial protein C receptor (EPCR) in preterm preeclampsia, term preeclampsia, and fetal growth restriction (defined by delivery of a small for gestational age [SGA] infant [<10% birthweight centile]) and examine its regulation in primary syncytiotrophoblast. Placental EPCR mRNA and protein were significantly increased in patients with preterm preeclampsia (<34 weeks gestation) compared to gestation-matched controls (p < .0001). In the plasma, EPCR was also significantly elevated (p = .01) in established preterm preeclampsia while its substrate, protein C (PC) was significantly reduced (p = .0083). Placentas from preterm small for gestational age (SGA) cases, had elevated EPCR mRNA expression (p < .0001) relative to controls. At 36 weeks, no significant changes in plasma EPCR were detected in samples from patients destined to develop preeclampsia or deliver an SGA infant at term. In terms of syncytiotrophoblast, hypoxia significantly increased EPCR mRNA expression (p = .008), but Tumor Necrosis Factor Alpha (TNF-α) decreased EPCR mRNA. Interleukin-6 (IL-6) had no significant effect on EPCR mRNA expression. When isolated syncytiotrophoblast was treated with metformin under hypoxia (1% O2 ) or normoxia (8% O2 ), EPCR mRNA expression was significantly reduced (p = .008) relative to control. In conclusion, EPCR is markedly elevated in the placenta and the circulation of patients with established preterm preeclampsia and placental increases may be associated with hypoxia. Additionally, fetal growth-restricted pregnancies (as defined by the delivery of an SGA infant) also demonstrated elevated placental EPCR.

Afferent venous perfusion of fetal liver: umbilical and portal blood-flow volumes in fetuses born small-for-gestational age.

OBJECTIVE: To quantify the dynamic changes in the afferent venous flow volume of the liver in low-risk pregnancies with fetuses born small-for-gestational age. METHODS: This was a prospective study of low-risk singleton pregnancies with estimated fetal weight (EFW) and birth weight ≤ 10th centile attending for a routine second- or third-trimester ultrasound examination. Their umbilical and portal blood-flow volumes were compared with those of a control group of fetuses born appropriate-for-gestational age from which normal reference ranges were constructed. Absolute and Z-score differences between the groups were assessed. RESULTS: In total, 133 fetuses were included in the study group and 362 in the control group. The mean umbilical blood-flow volume in the study group, both absolute and normalized per kg of EFW, was below that of the appropriate-for-gestational-age fetuses for most of the period of pregnancy studied (overall mean Z-score, -0.82 and -0.84, respectively). In contrast, the mean portal blood-flow volume, per kg of EFW, showed the opposite trend (overall mean Z-score, +0.86), reaching its maximum level (+1.43) in the late third trimester. This resulted in a steep decrease in the mean placental-to-portal-blood-flow volume ratio, from 14.4 at 24 weeks of gestation (above the 60th centile) to 4.7 at 38 weeks of gestation (15th centile), corresponding to Z-scores of +0.4 and -1.02, respectively. CONCLUSION: In fetuses born small-for-gestational age, the ratio of blood-flow volume in the umbilical vein to that in the portal vein decreases consistently during pregnancy, and to a greater extent compared with those born appropriate-for-gestational age, reaching a lower nadir in the third trimester. This additional redistribution of liver perfusion affects negatively fetal growth even in low-risk pregnancy, and should be taken into account when planning delivery. We suggest considering liver venous perfusion as an ancillary tool for monitoring small-for-gestational-age pregnancies. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Predictive index for adverse perinatal outcome in pregnancies complicated by fetal growth restriction.

OBJECTIVES: To develop and validate an index predictive of adverse perinatal outcome (APO) in pregnancies meeting the consensus-based criteria for fetal growth restriction (FGR) endorsed by the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG). METHODS: This was a retrospective analysis of consecutive singleton non-anomalous gestations meeting the ISUOG-endorsed criteria for FGR at a single tertiary care center from November 2010 to August 2020. The dataset was divided randomly into a development set (two-thirds) and a validation set (one-third). The primary composite APO comprised one or more of: perinatal demise, Grade III-IV intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), seizures, hypoxic ischemic encephalopathy (HIE), necrotizing enterocolitis (NEC), sepsis, bronchopulmonary dysplasia (BPD) and length of stay in the neonatal intensive care unit (NICU) > 7 days. Regression analysis incorporated clinical factors readily available at the time of FGR diagnosis. The sum of ß coefficient-based weights yielded an index score, the performance of which was assessed in the validation set. Score cut-offs were selected to identify 'high-risk' and 'low-risk' ranges for which positive (PPV) and negative (NPV) predictive values and positive (LR+) and negative (LR-) likelihood ratios were calculated. RESULTS: Of the 875 consecutive pregnancies that met the criteria for FGR and were included in the study cohort, 405 (46%) were complicated by one or more components of the composite APO, including 54 (6%) perinatal deaths, 22 (3%) neonates with Grade III-IV IVH and/or PVL, nine (1%) with seizures and/or HIE, 91 (10%) with BPD, 57 (7%) with sepsis, 21 (2%) with NEC, and 361 (41%) who remained in the NICU > 7 days. In addition, 270 (31%) pregnancies were delivered by Cesarean section for non-reassuring fetal status, 43 (5%) were admitted to the NICU for < 7 days, 79 (9%) had 5-min Apgar score < 7, 125/631 (20%) had a cord gas pH ≤ 7.1 and 35/631 (6%) had a base excess ≥ 12 mmol/L. The predictive index we developed included seven factors available at the time of FGR diagnosis: hypertensive disorder of pregnancy (HDP) (+8 points), chronic hypertension without HDP (+4 points), gestational age ≤ 32 weeks (+5 points), absent or reversed end-diastolic flow in the umbilical artery (+8 points), prepregnancy body mass index ≥ 35 kg/m2 (+3 points), isolated abdominal circumference < 3rd percentile (-4 points) and non-Hispanic black race (-2 points). The bias-corrected bootstrapped (1000 replicates) area under the receiver-operating-characteristics curve (AUC) of the predictive index for composite APO in the validation group was 0.88 (95% CI, 0.84-0.92), which was similar to that in the development group (AUC, 0.86 (95% CI, 0.82-0.89); P = 0.34). In the total cohort, 40% of pregnancies had a low-risk index score (≤ 2), associated with a NPV of 85% (95% CI, 81-88%) and a LR- of 0.21 (95% CI, 0.16-0.27), and 23% had a high-risk index score (≥ 10), associated with a PPV of 96% (95% CI, 93-98%) and a LR+ of 27.36 (95% CI, 14.33-52.23). Of the remaining pregnancies that had an intermediate-risk score, 50% were complicated by composite APO. CONCLUSION: An easy-to-use index incorporating seven clinical factors readily available at the time of FGR diagnosis is predictive of APO and may prove useful in counseling and management of pregnancies meeting the ISUOG-endorsed criteria for FGR. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Effect of intrapartum epidural analgesia on rate of emergency delivery for presumed fetal compromise: nationwide registry-based cohort study.

OBJECTIVES: To determine the rate of emergency delivery for presumed fetal compromise after epidural analgesia (EDA) compared with that after alternative analgesia or no analgesia, and to assess whether this rate is increased in pregnancies with reduced placental reserve. METHODS: This was a nationwide registry-based cohort study of 629 951 singleton pregnancies delivered at 36 + 0 to 42 + 0 weeks of gestation that were recorded in the Dutch national birth registry between 2014 and 2018, including 120 426 cases that received EDA, 86 957 that received alternative analgesia and 422 568 that received no analgesia during labor. Pregnancies with congenital anomaly, chromosomal abnormality, fetal demise, planned Cesarean delivery, non-cephalic presentation at delivery and use of multiple forms of analgesia were excluded. The primary outcome was emergency delivery for presumed fetal compromise. Secondary outcomes included delivery characteristics and neonatal outcome. Negative binomial regression analysis was stratified by parity and results are presented according to birth-weight centile, after adjusting for confounding. RESULTS: Among women who received EDA, 13.2% underwent emergency delivery for presumed fetal compromise, compared with 4.1% of women who had no analgesia (relative risk (RR), 3.23 (95% CI, 3.16-3.31)) and 7.0% of women who received alternative analgesia (RR, 1.72 (95% CI, 1.67-1.77)). Independent of birth weight, the RR of presumed fetal compromise after EDA vs no analgesia was higher in parous women (adjusted RR (aRR), 2.15 (95% CI, 2.04-2.27)) compared with nulliparous women (RR, 1.88 (95% CI, 1.84-1.94)). Stratified for parity, the effect of EDA was modified significantly by birth-weight centile (interaction P-value, < 0.001 for nulliparous and 0.004 for parous women). The emergency delivery rate following EDA was highest in those with a birth weight < 5th centile (25.2% of nulliparous and 16.6% of parous women), falling with each increasing birth-weight centile category up to the 91st -95th centile (11.8% of nulliparous and 7.2% of parous women). CONCLUSIONS: Intrapartum EDA is associated with a higher risk of emergency delivery for presumed fetal compromise compared with no analgesia and alternative analgesia, after adjusting for relevant confounding. The highest rate of emergency delivery for presumed fetal compromise was observed at the lowest birth-weight centiles. RRs of emergency delivery for presumed fetal compromise after EDA were modestly but consistently modified by birth-weight centile, supporting the hypothesis that the adverse effects of EDA are exacerbated by reduced placental function. While EDA provides effective pain relief during labor, alternative strategies for pain management may be preferable in pregnancies with a high background risk of fetal compromise. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Predictive value of fetal growth trajectory from 20 weeks of gestation onwards for severe adverse perinatal outcome in low-risk population: secondary analysis of IRIS study.

OBJECTIVES: The placental dysfunction underlying fetal growth restriction (FGR) may result in severe adverse perinatal outcome (SAPO) related to fetal hypoxia. Traditionally, the diagnostic criteria for FGR have been based on fetal size, an approach that is inherently flawed because it often results in either over- or underdiagnosis. The anomaly ultrasound scan at 20 weeks' gestation may be an appropriate time at which to set a benchmark for growth potential of the individual fetus. We hypothesized that the fetal growth trajectory from that point onwards may be informative regarding third-trimester placental dysfunction. The aim of this study was to investigate the predictive value for SAPO of a slow fetal growth trajectory between 18 + 0 to 23 + 6 weeks and 32 + 0 to 36 + 6 weeks' gestation in a large, low-risk population. METHODS: This was a post-hoc data analysis of the IUGR Risk Selection (IRIS) study, a Dutch nationwide cluster-randomized trial assessing the (cost-)effectiveness of routine third-trimester sonography in reducing SAPO. In the current analysis, for the first ultrasound examination we used ultrasound data from the routine anomaly scan at 18 + 0 to 23 + 6 weeks' gestation, and for the second we used data from an ultrasound examination performed between 32 + 0 and 36 + 6 weeks' gestation. Using multilevel logistic regression, we analyzed whether SAPO was predicted by a slow fetal growth trajectory, which was defined as a decline in abdominal circumference (AC) and/or estimated fetal weight (EFW) of more than 20 percentiles or more than 50 percentiles or as an AC growth velocity (ACGV) < 10th percentile (p10). In addition, we analyzed the combination of these indicators of slow fetal growth with small-for-gestational age (SGA) (AC or EFW < p10) and severe SGA (AC/EFW < 3rd percentile) at 32 + 0 to 36 + 6 weeks' gestation. RESULTS: Our sample included the data of 6296 low-risk singleton pregnancies, among which 82 (1.3%) newborns experienced at least one SAPO. Standalone declines in AC or EFW of > 20 or > 50 percentiles or ACGV < p10 were not associated with increased odds of SAPO. EFW < p10 between 32 + 0 and 36 + 6 weeks' gestation combined with a decline in EFW of > 20 percentiles was associated with an increased rate of SAPO. The combination of AC or EFW < p10 between 32 + 0 and 36 + 6 weeks' gestation with ACGV < p10 was also associated with increased odds of SAPO. The odds ratios of these associations were higher if the neonate was SGA at birth. CONCLUSIONS: In a low-risk population, a slow fetal growth trajectory as a standalone criterion does not distinguish adequately between fetuses with FGR and those that are constitutionally small. This absence of association may be a result of diagnostic inaccuracies and/or post-diagnostic (e.g. intervention and selection) biases. We conclude that new approaches to detect placental insufficiency should integrate information from diagnostic tools such as maternal serum biomarkers and Doppler ultrasound measurements. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Characteristics associated with antenatally unidentified small-for-gestational-age fetuses: prospective cohort study nested within DESiGN randomized controlled trial.

OBJECTIVE: To identify the clinical characteristics and patterns of ultrasound use amongst pregnancies with an antenatally unidentified small-for-gestational-age (SGA) fetus, compared with those in which SGA is identified, to understand how to design interventions that improve antenatal SGA identification. METHODS: This was a prospective cohort study of singleton, non-anomalous SGA (birth weight < 10th centile) neonates born after 24 + 0 gestational weeks at 13 UK sites, recruited for the baseline period and control arm of the DESiGN trial. Pregnancy with antenatally unidentified SGA was defined if there was no scan or if the final scan showed estimated fetal weight (EFW) at the 10th centile or above. Identified SGA was defined if EFW was below the 10th centile at the last scan. Maternal and fetal sociodemographic and clinical characteristics were studied for associations with unidentified SGA using unadjusted and adjusted logistic regression models. Ultrasound parameters (gestational age at first growth scan, number and frequency of ultrasound scans) were described, stratified by presence of indication for serial ultrasound. Associations of unidentified SGA with absolute centile and percentage weight difference between the last scan and birth were also studied on unadjusted and adjusted logistic regression, according to time between the last scan and birth. RESULTS: Of the 15 784 SGA babies included, SGA was not identified antenatally in 78.7% of cases. Of pregnancies with unidentified SGA, 47.1% had no recorded growth scan. Amongst 9410 pregnancies with complete data on key maternal comorbidities and antenatal complications, the risk of unidentified SGA was lower for women with any indication for serial scans (adjusted odds ratio (aOR), 0.56 (95% CI, 0.49-0.64)), for Asian compared with white women (aOR, 0.80 (95% CI, 0.69-0.93)) and for those with non-cephalic presentation at birth (aOR, 0.58 (95% CI, 0.46-0.73)). The risk of unidentified SGA was highest among women with a body mass index (BMI) of 25.0-29.9 kg/m2 (aOR, 1.15 (95% CI, 1.01-1.32)) and lowest in those with underweight BMI (aOR, 0.61 (95% CI, 0.48-0.76)) compared to women with BMI of 18.5-24.9 kg/m2 . Compared to women with identified SGA, those with unidentified SGA had fetuses of higher SGA birth-weight centile (adjusted odds for unidentified SGA increased by 1.21 (95% CI, 1.18-1.23) per one-centile increase between the 0th and 10th centiles). Duration between the last scan and birth increased with advancing gestation in pregnancies with unidentified SGA. SGA babies born within a week of the last growth scan had a mean difference between EFW and birth-weight centiles of 19.5 (SD, 13.8) centiles for the unidentified-SGA group and 0.2 (SD, 3.3) centiles for the identified-SGA group (adjusted mean difference between groups, 19.0 (95% CI, 17.8-20.1) centiles). CONCLUSIONS: Unidentified SGA was more common amongst women without an indication for serial ultrasound, and in those with cephalic presentation at birth, BMI of 25.0-29.9 kg/m2 and less severe SGA. Ultrasound EFW was overestimated in women with unidentified SGA. This demonstrates the importance of improving the accuracy of SGA screening strategies in low-risk populations and continuing performance of ultrasound scans for term pregnancies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Epidural analgesia and emergency delivery for presumed fetal compromise: post-hoc analysis of RAVEL multicenter randomized controlled trial.

OBJECTIVE: To investigate the association between epidural analgesia (EDA) vs patient-controlled remifentanil analgesia (PCRA) and emergency delivery for presumed fetal compromise, in relation to birth-weight quintile. METHODS: This was a post-hoc per-protocol analysis of the RAVEL multicenter equivalence randomized controlled trial. Non-anomalous singleton pregnancies between 36 + 0 and 42 + 6 weeks' gestation were randomized at the time of requesting pain relief to receive EDA or PCRA. The primary outcome was emergency delivery for presumed fetal compromise. Secondary outcomes included mode of delivery and neonatal outcomes. Analysis was performed according to birth-weight quintile and was corrected for relevant confounding variables. RESULTS: Of 619 pregnant women, 336 received PCRA and 283 received EDA. Among women receiving EDA, 14.8% had an emergency delivery for presumed fetal compromise, compared with 8.3% of women who received PCRA. After adjusting for parity, women receiving EDA had higher odds of presumed fetal compromise compared to those receiving PCRA (odds ratio, 1.69 (95% CI, 1.01-2.83)). A statistically significant linear-by-linear association was observed between presumed fetal compromise and birth-weight quintile (P = 0.003). The incidence of emergency delivery for presumed fetal compromise was highest in women receiving EDA and delivering a neonate with a birth weight in the lowest quintile. CONCLUSIONS: Intrapartum EDA is associated with a higher rate of emergency delivery for presumed fetal compromise compared to treatment with PCRA. Birth-weight quintile is a strong predictor of this outcome, independent of pain management method. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.