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Background: Fetal growth monitoring is important for twin pregnancies. However, there has been no clinically validated tool for monitoring fetal growth of twin pregnancies in China. This study aims to develop and validate a chorionicity-specific growth chart of ultrasound estimated fetal weight (EFW) for Chinese twin pregnancies. Methods: This retrospective cohort study included all twin pregnancies who delivered two live fetuses with gestational age ≥ 34 weeks without severe obstetric complications at a tertiary hospital from January 2007 to March 2021. The participants were divided into a development set (delivered in or before December 2017) and a validation set (delivered in or after January 2018). Chorionicity-specific growth charts were created using the generalized additive models for location, scale, and shape (GAMLSS) based on the development set. The fetuses from the validation set were classified into three groups based on the last EFW: small-for-gestational-age (SGA) indicated by both the newly established twin charts and the Hadlock singleton chart currently used for twin pregnancies in China, suspected SGA indicated by only the singleton chart, and no SGA indicated by either chart. The incidence of neonatal outcomes among the three groups was then compared accordingly, including intensive care unit (NICU) stay length, respiratory diseases, and neurological disorders. Results: The development set included 883 twin pregnancies and a total of 6374 EFW measurements between 16 and 38 weeks of gestation, and the validation set included 801 twin pregnancies and 7630 EFW measurements. In the development set, monochorionic diamniotic (MCDA) twins had a significantly lower EFW compared to dichorionic diamniotic (DCDA) twins beginning at 26 weeks, with the difference gradually increasing thereafter, supporting the establishment of chorionicity-specific growth charts. Of the 1,602 twin neonates in the validation set, 103 (6.4%) were classified into the SGA group, 164 (10.2%) into the suspected SGA group, and 1335 (83.3%) into the no SGA group. The incidence of respiratory diseases and neurological disorders was comparable between the suspected SGA group and the no SGA group, but apparently higher in the SGA group. Meanwhile, NICU stay lengths were consistently longer for twins in the SGA group compared to the no SGA group (difference: 0.57, 95% CI: 0.31–0.83), with no significant differences observed between the suspected SGA and no SGA groups. Conclusions: The fetal growth trajectories differed by chorionicity, with a lower EFW for MCDA twins beginning at 26 weeks. The establishment of chorionicity-specific growth chart could reduce overdiagnosis of SGA and improve fetal growth monitoring of twin pregnancies. [ABSTRACT FROM AUTHOR]

Objectives: In a cohort of patients with estimated fetal weights (EFWs) <10th centile, we aimed 1) to compare the prevalence of abnormalities of fetal 4‐chamber view (4CV) cardiac size, shape, and ventricular contractility in fetal growth restricted (FGR) and small‐for‐gestational‐age (SGA) fetuses and 2) to compare umbilical vein flow (UVF) measurements to standard Doppler surveillance in predicting abnormalities of cardiac function. Methods: Prospective observational cohort study of fetuses with EFW <10th percentile. Measurements of size and shape used were 4CV transverse width, 4CV cardiac area, 4CV global sphericity index, and right‐to‐left ventricular mid‐chamber width ratio. Variables of contractility used were fractional shortening change at the mid‐ventricle chamber, global longitudinal strain, fractional area change, and left ventricular cardiac output. The UVF and standard Doppler surveillance including umbilical artery (UA), middle cerebral artery, and cerebroplacental ratio (CPR) were collected. Control data were from previously published studies. Results: A total of 95 fetuses with EFWs <10th centile were included in the study. The rates of abnormalities of cardiac size and shape and ventricular contractility were all significantly elevated compared with normally grown control fetuses but similar between FGR and SGA fetuses. In a subset of 76 patients with UVF data, evaluation UVF identified more patients with any abnormality of contractility compared with UA (37.9 vs 17.2%, P =.02). Conclusions: The addition of UVF doubled the detection rate of ventricular contractility abnormalities. The addition of UVF should be considered in the surveillance of FGR and SGA fetuses to further stratify the severity of hypoxemia and to identify those at greater risk for future cardiovascular dysfunction. [ABSTRACT FROM AUTHOR]

Background: Maternal undernutrition is the most common cause of fetal growth restriction (FGR) worldwide. FGR increases morbidity and mortality during infancy, as well as contributes to adult-onset diseases including obesity and type 2 diabetes. The role of the maternal or offspring microbiome in growth outcomes following FGR is not well understood. Methods: FGR was induced by 30% maternal calorie restriction (CR) during the second half of gestation in C57BL/6 mice. Pup weights were obtained on day of life 0, 1, and 7 and ages 3, 4 and 16 weeks. Fecal pellets were collected from pregnant dams at gestational day 18.5 and from offspring at ages 3 and 4 weeks of age. Bacterial genomic DNA was used for amplification of the V4 variable region of the 16S rRNA gene. Multivariable associations between maternal CR and taxonomic abundance were assessed using the MaAsLin2 package. Associations between microbial taxa and offspring outcomes were performed using distance-based redundancy analysis and Pearson correlations. Results: FGR pups weighed about 20% less than controls. Beta but not alpha diversity differed between control and CR dam microbiomes. CR dams had lower relative abundance of Turicibacter, Flexispira, and Rikenella, and increased relative abundance of Parabacteroides and Prevotella. Control and FGR offspring microbiota differed by beta diversity at ages 3 and 4 weeks. At 3 weeks, FGR offspring had decreased relative abundance of Akkermansia and Sutterella and increased relative abundance of Anaerostipes and Paraprevotella. At 4 weeks, FGR animals had decreased relative abundance of Allobaculum, Sutterella, Bifidobacterium, and Lactobacillus, among others, and increased relative abundance of Turcibacter, Dorea, and Roseburia. Maternal Helicobacter abundance was positively associated with offspring weight. Akkermansia abundance at age 3 and 4 weeks was negatively associated with adult weight. Conclusions: We demonstrate gut microbial dysbiosis in pregnant dams and offspring at two timepoints following maternal calorie restriction. Additional research is needed to test for functional roles of the microbiome in offspring growth outcomes. [ABSTRACT FROM AUTHOR]

Arcuate uterus does not impact the success of infertility treatments, but there is no consensus on whether it influences perinatal outcomes. The objective of the present study was to investigate whether minor congenital uterine anomalies such as an arcuate uterus contribute to perinatal complications. This was a retrospective cohort study at a single institution. The study included 1097 deliveries after 22 weeks of gestation. Transvaginal ultrasound, with three‐dimensional functionality, assessed uterine morphology based on American Society for Reproductive Medicine criteria. We compared maternal backgrounds and perinatal complications between arcuate uterus and normal uterus groups. Statistical analyses, including multivariate analysis, aimed to identify independent risk factors. A total of 69 patients (7.5%) with diagnosed arcuate uterus were included. Maternal background factors showed no significant differences between groups. In perinatal complications, an arcuate uterus was associated with a significantly higher incidence of preterm delivery (13% versus 4.7%, P = 0.01), preterm premature rupture of membranes (7.2% versus 1.6%, P = 0.01), fetal growth restriction (FGR; 16% versus 6.7%, P = 0.01), and abnormal placental cord insertion (33% versus 7.6%, P < 0.01). After multivariate analysis, arcuate uterus emerged as an independent risk factor for preterm delivery (adjusted odds ratio [aOR], 4.0 [95% confidence interval (CI), 1.6–9.9], P < 0.01), FGR (aOR, 2.6 [95% CI, 1.2–5.6], P = 0.02), and abnormal placental cord insertion (aOR, 6.0 [95% CI, 3.4–10.6], P < 0.01). Arcuate uterus stands as an independent risk factor for preterm delivery, FGR, and abnormal placental cord insertion. The findings emphasize the importance of recognizing even minor uterine morphological abnormalities in assessing and managing perinatal complications. [ABSTRACT FROM AUTHOR]

To investigate the effect of the combination of uterine artery (UtA) Doppler and vitamin D levels on perinatal outcomes in second trimester pregnants was aimed.UtA Dopplers and vitamin D levels of 226 pregnant women in the second trimester were measured. Patients were followed for adverse pregnancy outcomes. The relationship of this combination with these pregnancy outcomes was evaluated.Sensitivity and specificity values ​​are respectively; Left UtA-S/D ratio for preeclampsia was 85.29 and 81.77 %, left UtA-RI was 90.62 and 43.30 % for preterm birth, and 76.19 and 66.34 % for the development of fetal distress had the best predictive effect. Vitamin D values ​​had no predictive value for any parameter (p>0.005).UtA Doppler has a good predictive value for many adverse pregnancy outcomes. However, in order to correlate these results with second trimester vitamin D levels, more homogeneous and specific groups are needed. [ABSTRACT FROM AUTHOR]

Introduction Material and Methods Results Conclusions Cesarean delivery has been shown to increase the risk of preterm delivery in future pregnancies. The association could be a direct result of the procedure, or because the indications that led to the cesarean delivery also increase the risk of preterm delivery in later pregnancies.298 901 mothers with first and second singleton deliveries from 1999 to 2020 were investigated using data from the Medical Birth Registry of Norway linked with Statistics Norway. The mothers were categorized by mode of cesarean delivery (total, emergency and planned) and vaginal delivery at term in the first pregnancy. We used log‐binomial regression models to estimate relative risks with 95% confidence intervals (CI) of iatrogenic and spontaneous preterm delivery <37 gestational weeks in the second pregnancy. Second, we explored the role of recurrent placental disease in preterm delivery by comparing estimates in mothers with placental disease in neither or both pregnancies.8243 mothers (2.8%) had a preterm delivery in the second pregnancy. The adjusted relative risk (aRR) of preterm delivery was 1.24 (95% CI 1.17–1.32) after cesarean compared with vaginal delivery in the first pregnancy. The association was stronger in previous planned compared with emergency cesarean delivery (aRR 1.52, 95% CI 1.30–1.77 and aRR 1.21, 95% CI 1.14–1.29, respectively). Spontaneous preterm delivery was not associated with the previous mode of delivery; the risk was confined to iatrogenic preterm delivery after both emergency and planned cesarean delivery (aRR 1.69, 95% CI 1.52–1.87 and aRR 2.65, 95% CI 2.12–3.30, respectively). Mothers with placental disease in both pregnancies had a sixfold increased risk of preterm delivery in the second pregnancy compared with mothers with no placental disease, however, the association between mode of delivery and subsequent preterm delivery was similar in mothers with and without placental disease in the pregnancies.Compared with vaginal term delivery in the first pregnancy, cesarean delivery increases the risk of iatrogenic, but not spontaneous preterm delivery in the next pregnancy. Although strongly associated with preterm delivery, placental disease had limited influence on the estimates. [ABSTRACT FROM AUTHOR]

We evaluated fetal growth and birthweight in pregnancies with placenta previa with and without placenta accreta spectrum (PAS).We retrospectively studied pregnant patients with placenta previa with or without PAS diagnosed at 20–37 weeks’ gestation. Estimated fetal weight (EFW) percentile and fetal growth rate were calculated based on ultrasound at two timepoints: 20–24 and 30–34-weeks’ gestation. Fetuses were small (SGA) or large for gestational age (LGA) when EFW or abdominal circumference was <10th or >90th percentile for gestational age, respectively. Fetal growth rate was estimated by subtracting EFW percentiles from the two ultrasounds. Birthweight in grams and percentiles were estimated via Anderson and INTERGROWTH-21 standards adjusted for neonatal sex. EFW percentiles, fetal growth rate, birth weight and birthweight percentiles were compared between patients with placenta previa with and without PAS.We studied 171 patients with and 146 patients without PAS. SGA rates did not differ between groups on first (PAS n=3, no-PAS n=3, p=0.8) or second ultrasound (PAS n=10, no-PAS n=8, p=0.8). LGA rates were similar between groups on first (PAS n=11, no-PAS n=9, p=0.8) and second ultrasound (PAS n=20, no-PAS n=12, p=0.6). The growth rate was higher in fetuses with PAS than placenta previa (1.22 ± 22.3 vs. −4.1 ± 18.1, p=0.07), but not significantly. The birthweight percentile was higher in the PAS than the placenta previa group (74 vs. 67, p=0.01). On multi-linear regression, birthweight percentile remained higher in the PAS group, but not significantly.Placenta previa with or without PAS is not associated with SGA, LGA or lower birthweight. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia (PE) is a condition in pregnancy characterized by hypertension and proteinuria, thus leading to severe complications for both mother and fetus, including fetal growth restriction (FGR). However, there are still unclear aspects regarding the pathogenesis, prevention, and treatments. This study aimed to elucidate the characteristics of lipid metabolism in maternal and umbilical cord plasma complicated with PE using liquid chromatography-mass spectrometry (LC-MS). Method: The study included singleton pregnant women at Osaka Metropolitan University Hospital from March 2023 to February 2024. PE was diagnosed based on new-onset hypertension after 20 weeks of gestation and other symptoms such as proteinuria and organ dysfunction. FGR was defined by ultrasound measurements below -1.5 standard deviation (SD). Plasma samples were collected from maternal and umbilical cord blood within 24 hours before delivery. Lipid metabolites were comprehensively analyzed using LC-MS, and the lipokine 12,13-diHOME, identified as elevated in the comprehensive analysis, was quantified. Immunohistochemistry was conducted on placental samples to assess soluble epoxide hydrolase (sEH) expression. Results: The study involved 31 participants, with 20 in the control group and 11 in the PE group. A comprehensive analysis of maternal plasma samples identified a significant increase in 12,13-diHOME levels in the PE group compared to the control group. Quantification of 12,13-diHOME showed a significant increase in maternal plasma, umbilical venous plasma, and umbilical arterial plasma in the PE group compared to the control group (p = 0.007, p = 0.008, p = 0.005). PE with FGR showed significantly higher 12,13-diHOME concentrations in the umbilical arterial/venous ratio compared to the PE without FGR group (p = 0.03). Negative correlations were observed between 12,13-diHOME levels and birth weight in the PE group. Immunohistochemistry did not show significant differences in the sEH expression between the groups. Conclusion: This study demonstrated that 12,13-diHOME levels were significantly elevated in maternal and umbilical cord blood in PE patients, particularly in PE with FGR. Elevated 12,13-diHOME may reflect the progression of placental ischemia due to PE pathogenesis. This lipid metabolite could serve as a marker for the severity of preeclampsia, thus providing new insights into perinatal lipidomics and the potential role of 12,13-diHOME in PE. [ABSTRACT FROM AUTHOR]

Objective The Italian Association of Preeclampsia (AIPE) and the Italian Society of Perinatal Medicine (SIMP) developed clinical questions on maternal hemodynamics state of the art. Study Design AIPE and SIMP experts were divided in small groups and were invited to propose an overview of the existing literature on specific topics related to the clinical questions proposed, developing, wherever possible, clinical and/or research recommendations based on available evidence, expert opinion, and clinical importance. Draft recommendations with a clinical rationale were submitted to 8th AIPE and SIMP Consensus Expert Panel for consideration and approval, with at least 75% agreement required for individual recommendations to be included in the final version. Results More and more evidence in literature underlines the relationship between maternal and fetal hemodynamics, as well as the relationship between maternal cardiovascular profile and fetal-maternal adverse outcomes such as fetal growth restriction and hypertensive disorders of pregnancy. Experts agreed on proposing a classification of pregnancy hypertension, complications, and cardiovascular states based on three different hemodynamic profiles depending on total peripheral vascular resistance values: hypodynamic (>1,300 dynes·s·cm −5), normo-dynamic, and hyperdynamic (<800 dynes·s·cm −5) circulation. This differentiation implies different therapeutical strategies, based drugs' characteristics, and maternal cardiovascular profile. Finally, the cardiovascular characteristics of the women may be useful for a rational approach to an appropriate follow-up, due to the increased cardiovascular risk later in life. Conclusion Although the evidence might not be conclusive, given the lack of large randomized trials, maternal hemodynamics might have great importance in helping clinicians in understanding the pathophysiology and chose a rational treatment of patients with or at risk for pregnancy complications. Key Points Altered maternal hemodynamics is associated to fetal growth restriction. Altered maternal hemodynamics is associated to complicated hypertensive disorders of pregnancy. Maternal hemodynamics might help choosing a rational treatment during hypertensive disorders. [ABSTRACT FROM AUTHOR]

Gestational metabolic diseases adversely impact the health of pregnant persons and their offspring. Pregnant persons of color are impacted disproportionately by gestational metabolic disease, highlighting the need to identify additional risk factors contributing to racial-ethnic pregnancy-related health disparities. Trauma exposure and posttraumatic stress disorder (PTSD) are associated with increased risk for cardiometabolic disorders in nonpregnant persons, making them important factors to consider when identifying contributors to gestational metabolic morbidity and mortality health disparities. Here, we review current literature investigating trauma exposure and posttraumatic stress disorder as psychosocial risk factors for gestational metabolic disorders, inclusive of gestational diabetes, low birth weight and fetal growth restriction, gestational hypertension, and preeclampsia. We also discuss the physiological mechanisms by which trauma and PTSD may contribute to gestational metabolic disorders. Ultimately, understanding the biological underpinnings of how trauma and PTSD, which disproportionately impact people of color, influence risk for gestational metabolic dysfunction is critical to developing therapeutic interventions that reduce complications arising from gestational metabolic disease. Key Points Gestational metabolic diseases disproportionately impact the health of pregnant persons of color. Trauma and PTSD are associated with increased risk for cardiometabolic disorders in nonpregnant per. Trauma and PTSD impact physiological cardiometabolic mechanisms implicated in gestational metabolic. [ABSTRACT FROM AUTHOR]

Background: This study investigates the role of Delta Neutrophil Index (DNI), an inflammation marker, in late-onset fetal growth restriction (LO-FGR) and its prediction of composite adverse neonatal outcomes. Methods: A retrospective study was conducted on 684 pregnant women (456 with normal fetal development and 228 with LO-FGR) who delivered at Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital between January 1, 2015, and June 30, 2018. Composite adverse neonatal outcomes were defined as at least one of the following: 5th minute APGAR score < 7, respiratory distress syndrome (RDS), or neonatal intensive care unit (NICU) admission. Results: The FGR group had significantly higher levels of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), and DNI compared to controls (p < 0.05, for all). For FGR diagnosis, the DNI demonstrated the highest area under the curve (AUC = 0.677, 95% CI: 0.642–0.711) with a cut-off value of > -2.9, yielding a sensitivity of 78.41%, a specificity of 52.97%, a positive likelihood ratio (+ LR) of 1.68, and a negative likelihood ratio (-LR) of 0.37 (p < 0.001). For predicting composite adverse neonatal outcomes in the FGR group, DNI again demonstrated superior performance with an AUC of 0.635 (95% CI: 0.598–0.670), a cut-off value of > -2.2, a sensitivity of 69.90%, a specificity of 55.36%, a + LR of 1.56, and a -LR of 0.51 (p < 0.001). NLR, PLR, and MLR had AUCs below 0.55, indicating poor discriminative ability, with none reaching statistical significance. Conclusion: This study highlights the potential role of DNI as a promising biomarker for detecting inflammatory processes associated with LO-FGR and its complications. [ABSTRACT FROM AUTHOR]

Objective To investigate the predictive value of placental microvascular index combined with serum matrix metalloproteinase inhibitor 2 (TIMP-2) levels in fetal growth restriction (FGR) in pregnant women with preeclampsia (PE). Methods A total of 139 PE pregnant women (observation group), including 41 with FGR, 98 without FGR, and meanwhile, 50 normal pregnant women (control group) were selected. On the day after admission in the observation group and on the day of physical examination in the control group, the placental microvascular examination was performed by three-dimensional ultrasonic diagnostic instrument, and the placental microvascular index, including vascularization index (VI), blood flow index (FI) and vascularization-flow index (VFI), was recorded. Fasting peripheral venous blood was collected, serum was retained by centrifugation, and serum TIMP-2 was detected by double antibody enzyme-linked immunosorbent assay. The risk factors of FGR in PE pregnant women were analyzed, and the predictive value of placental microvascular index and serum TIMP-2 level for FGR in PE pregnant women was analyzed by receiver operating characteristic (ROC) curve. Results The placental microvascular indexes VI, FI and VFI levels in the observation group were lower than those in the control group, and the serum TIMP-2 level was higher than that in the control group (all P<0. 05). Univariate analysis showed that the placental microvascular indexes VI, FI and VFI of the PE pregnant women with FGR were lower than those in PE pregnant women without FGR, while the serum TIMP-2 level was higher (all P<0. 05). Multivariate Logistic regression analysis showed that the decreased placental microvascular indexes VI, FI and VFI and the increased serum TIMP-2 were independent risk factors for FGR in PE pregnant women (all P<0. 05). ROC curve analysis showed that the area under the curve (AUC) of placental microvascular indexes VI, FI, VFI and serum TIMP-2 in predicting the occurrence of FGR in PE pregnant women was 0. 792, 0. 797, 0. 821 and 0. 696, respectively, and the AUC of the four combined in predicting the occurrence of FGR in PE pregnant women was 0. 949. The AUC of the combination of placental microvascular indexes VI, FI, VFI and serum TIMP-2 in predicting FGR in PE pregnant women was higher than that of the four alone (all P<0. 05) . Conclusions The decreased placental microvascular indexes VI, FI and VFI and the increased serum TIMP-2 level are independent risk factors for FGR in PE pregnant women. The placental microvascular indexes VI, FI, VFI and serum TIMP-2 have certain predictive value for the occurrence of FGR in PE pregnant women, and the predictive value of the four combined is higher. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluates the association of novel inflammatory markers and Doppler parameters in late‐onset FGR (fetal growth restriction), utilizing a machine‐learning approach to enhance predictive accuracy. Materials and Methods: A retrospective case–control study was conducted at the Department of Perinatology, Ministry of Health Etlik City Hospital, Ankara, from 2023 to 2024. The study included 240 patients between 32 and 37 weeks of gestation, divided equally between patients diagnosed with late‐onset FGR and a control group. We focused on novel inflammatory markers—systemic immune‐inflammation index (SII), systemic inflammatory response index (SIRI), and neutrophil‐percentage‐to‐albumin ratio (NPAR)—and their correlation with Doppler parameters of umbilical and uterine arteries. Machine‐learning algorithms were employed to analyze the data collected, including demographic, neonatal, and clinical parameters, to develop a predictive model for FGR. Results: The machine‐learning model, specifically the Random Forest algorithm, effectively integrated the inflammatory markers with Doppler parameters to predict FGR. NPAR showed a significant correlation with FGR presence, providing a robust tool in the predictive model (Accuracy 77%, area under the curve [AUC] 0.851). In contrast, SII and SIRI, while useful, did not achieve the same level of predictive accuracy (Accuracy 75% AUC 0.818 and Accuracy 73% AUC 0.793, respectively). The model highlighted the potential of combining ultrasound measurements with inflammatory markers to improve diagnostic accuracy for late‐onset FGR. Conclusions: This study illustrates the efficacy of integrating machines with traditional diagnostic methods to enhance the prediction of late‐onset FGR. Further research with a larger cohort is recommended to validate these findings and refine the predictive model, which could lead to improved clinical outcomes for affected pregnancies. Trial Registration: ClinicalTrials.gov identifier: NCT06372938 [ABSTRACT FROM AUTHOR]

Background: Routine Doppler study is a common tool for early diagnosis of Fetal Growth Restriction (FGR) and Small for Gestational Age (SGA) patients. It aimed to determine the role of the Foramen Ovale Pulsatility Index (FOPI) study beside routine Doppler study among patients with FGR and SGA fetuses. Methods: This prospective study was conducted on 35 FGR, 32 SGA, and 33 Appropriate for Gestational Age (AGA) fetuses. Demographic data, amniotic fluid index, neonatal outcome, and Doppler velocimetry, including Umbilical Artery Pulsatility Index (UMAPI), Uterine Artery Pulsatility Index (UTAPI), Middle Cerebral Artery Pulsatility Index (MCAPI), Ductus Venosus Pulsatility Index (DVPI), and FOPI were documented. Kolmogorov-Smirnov normality test, one-way ANOVA, Mann-Whitney U, Kruskal-Wallis, non-parametric pairwise comparisons adjusted for Bonferroni correction, Pearson correlation test, Chi square, Fisher's exact test, and Receiver Operating Characteristic Curve (ROC) analysis with Youden's Index (sensitivity+specificity-1) to estimate cut-off point were used to analyze the data at significance level <0.05 for all tests. Results: FOPI cut-off points were 2.24 (sensitivity=77%, specificity=94%) and 1.15 (sensitivity=90%, specificity=20%) to predict FGR and SGA, respectively. FOPI showed a positive correlation with UMAPI and UTAPI (r=0.52 and r=0.30, P<0.001 and P=0.006, respectively), but not with MCAPI and DVPI (r=0.08 and r=0.12, P=0.50 and P=0.30, respectively). Besides, UMAPI, UTAPI, and FOPI were altered among patients with stages I and II FGR. Umbilical cord potential hydrogen (umbilical cord pH), 1- and 5-min Apgar score significantly increased by Birth weight centile; however, UMAPI, FOPI, and UTAPI significantly decreased. Conclusion: UMAPI is recommended to predict short-term neonatal morbidities and demonstrate the early or late onset FGR. Besides, FOPI is suggested as the first-line Doppler study to detect abnormal growth velocity. More studies are warranted, especially considering long-term neonatal morbidities. [ABSTRACT FROM AUTHOR]

Objective: To identify which components of maternal vascular malperfusion (MVM) pathology are associated with adverse pregnancy outcomes and to investigate the morphological phenotypes of MVM placental pathology and their relationship with distinct clinical presentations of pre‐eclampsia and/or fetal growth restriction (FGR). Design: Retrospective cohort study. Setting: Tertiary care hospital in Toronto, Canada. Population: Pregnant individuals with low circulating maternal placental growth factor (PlGF) levels (<100 pg/mL) and placental pathology analysis between March 2017 and December 2019. Methods: Association between each pathological finding and the outcomes of interest were calculated using the chi‐square test. Cluster analysis and logistic regression was used to identify phenotypic clusters, and their association with adverse pregnancy outcomes. Cluster analysis was performed using the K‐modes unsupervised clustering algorithm. Main outcome measures: Preterm delivery <34+0 weeks of gestation, early onset pre‐eclampsia with delivery <34+0 weeks of gestation, birthweight <10th percentile (small for gestational age, SGA) and stillbirth. Results: The diagnostic features of MVM most strongly associated with delivery <34+0 weeks of gestation were: infarction, accelerated villous maturation, distal villous hypoplasia and decidual vasculopathy. Two dominant phenotypic clusters of MVM pathology were identified. The largest cluster (n = 104) was characterised by both reduced placental mass and hypoxic ischaemic injury (infarction and accelerated villous maturation), and was associated with combined pre‐eclampsia and SGA. The second dominant cluster (n = 59) was characterised by infarction and accelerated villous maturation alone, and was associated with pre‐eclampsia and average birthweight for gestational age. Conclusions: Patients with placental MVM disease are at high risk of pre‐eclampsia and FGR, and distinct pathological findings correlate with different clinical phenotypes, suggestive of distinct subtypes of MVM disease. [ABSTRACT FROM AUTHOR]

High-altitude (HA) hypoxia lowers uterine artery (UtA) blood flow during pregnancy and birth weight. Adenosine monophosphate kinase (AMPK) activation has selective, uteroplacental vasodilator effects that lessen hypoxia-associated birth weight reductions. In this study, we determined the relationship between AMPK-pathway gene expression and metabolites in the maternal circulation during HA pregnancy as well as with the maintenance of UtA blood flow and birth weight at HA. Residents at HA (2,793 m) versus low altitude (LA; 1,640 m) had smaller UtA diameters at weeks 20 and 34, lower UtA blood flow at week 20, and lower birth weight babies. At week 34, women residing at HA versus women residing at LA had decreased expression of upstream and downstream AMPK-pathway genes. Expression of the α1-AMPK catalytic subunit, PRKAA1, correlated positively with UtA diameter and blood flow at weeks 20 (HA) and 34 (LA). Downstream AMPK-pathway gene expression positively correlated with week 20 fetal biometry at both altitudes and with UtA diameter and birth weight at LA. Reduced gene expression of AMPK activators and downstream targets in women residing at HA versus women residing at LA, together with positive correlations between PRKAA1 gene expression, UtA diameter, and blood flow suggest that greater sensitivity to AMPK activation at midgestation at HA may help offset later depressant effects of hypoxia on fetal growth. NEW & NOTEWORTHY: Fetal growth restriction (FGR) is increased and uterine artery (UtA) blood flow is lower at high altitudes (HA) but not all HA pregnancies have FGR. Here we show that greater UtA diameter and blood flow at week 20 are positively correlated with higher expression of the gene encoding the α1-catalytic subunit of AMP protein kinase, PRKAA1, suggesting that increased AMPK activation may help to prevent the detrimental effects of chronic hypoxia on fetal growth. [ABSTRACT FROM AUTHOR]

AbstractObjective: To determine the role of sortilin in the pathogenesis of fetal growth restriction (FGR) by examining serum sortilin levels in fetal cord blood. Methods: This prospective case-control study was conducted at Ankara Etlik City Hospital between July 2023 and January 2024. Group 1 included 44 pregnant women with late FGR; Group 2 included 44 healthy pregnant women as controls. Results: Umbilical cord blood sortilin levels were significantly higher in the FGR group [2.96 (2.43–4.01)] compared to the control group [2.12 (1.74–3.18)] (p = 0.001). Sortilin levels negatively correlated with APGAR scores at 1 min (r=-0.281, p = 0.008) and 5 min (r=-0.292, p = 0.006). A sortilin threshold of 2.58 ng/ml predicted composite adverse neonatal outcomes with 66.7% sensitivity, 53.1% specificity, and an AUC of 0.652 (95% CI: 0.529–0.775, p = 0.031). Conclusion: This study showed that sortilin levels, which are indicators of oxidation, were higher in the cord blood of newborns with late FGR. [ABSTRACT FROM AUTHOR]

Atenolol is a commonly used beta bloscker in non-pregnant women. Many providers are hesitant in prescribing atenolol in pregnancy because of a possible association with poor fetal growth. We aimed to assess the association between atenolol and the occurrence of small for gestational age neonates compared to other beta blockers, as described in the existing literature. We used the meta-analytic method to generate a forest plot for risk ratios (RR) of small for gestational age in patients who used atenolol vs. other beta blockers. Statistical heterogeneity was assessed with the I2 statistic. Two studies were included, with a resultant RR of 1.94 [95 % confidence interval (CI) 1.60; 2.35]. A study by Duan et al. in 2018 noted the following rate of small for gestational age for each beta blocker use: 112/638 atenolol, 590/3,357 labetalol, 35/324 metoprolol, and 50/489 propranolol. A study by Tanaka et al. in 2016 noted the following rate of small for gestational age: 8/22 for propranolol, 2/12 for metoprolol, 2/6 for atenolol, 0/5 for bisoprolol. Heterogeneity (I2) was 0 %. Our results suggested an elevated risk of small for gestational age associated with atenolol use in comparison to other beta blockers, specifically labetalol, propranolol, bisoprolol, and metoprolol. [ABSTRACT FROM AUTHOR]

Customized birthweight centiles have improved the detection of small for gestational age (SGA) and large for gestational age (LGA) babies compared to existing population standards. This study used perinatal registry data to derive coefficients for developing customized growth charts for Qatar. The PEARL registry data on women delivering in Qatar (2017–2018) was used to develop a multivariable linear regression model predicting optimal birthweight. Physiological variables included gestational age, maternal height, weight, ethnicity, parity, and sex of the baby. Pathological variables such as hypertension, preexisting and gestational diabetes and smoking were calculated and excluded to derive the optimal weight at term. The regression model found a term optimal birthweight of 3,235 g for a Qatari nationality mother with median height (159 cm), booking weight (72 kg), parity (1) and gestation at birth (276 days) at the end of an uncomplicated pregnancy. Constitutional coefficients significantly affecting birthweight were gestational age, height, weight, and parity. The main pathological factors were preexisting diabetes (increase by +175.7 g) and smoking (decrease by −190.9 g). The SGA and LGA rates in the entire cohort after applying the population-specific customized centiles were 11.1 and 12.2 %, respectively (contrasting with the Hadlock standard: SGA-26.3 % and LGA-1.8 %, and Fenton standard: SGA-12.9 % and LGA-4.0 %). Constitutional and pathological variations in fetal growth and birthweight apply in the maternity population in Qatar and have been quantified to allow the generation of customised charts for better identification of pregnancies with abnormal growth. Currently in-use population standards may misdiagnose many SGA and LGA babies. [ABSTRACT FROM AUTHOR]

Objectives: Twin pregnancies are at higher risk of stillbirth compared to singletons. Fetal growth restriction (FGR) is a major cause of perinatal mortality, but its impact on twins vs singletons remains unclear. The primary objective of this study was to investigate the association of FGR and small‐for‐gestational age (SGA) with stillbirth in twin compared with singleton pregnancies. A secondary objective was to assess these associations stratified by gestational age at delivery. Furthermore, we aimed to compare the associations of FGR and SGA with stillbirth in twin pregnancies using twin‐specific vs singleton birth‐weight charts, stratified by chorionicity. Methods: This was a retrospective cross‐sectional study of pregnancies receiving obstetric care and giving birth between 1999 and 2022 at St George's Hospital, London, UK. The exclusion criteria included triplet and higher‐order pregnancies, those resulting in miscarriage or live birth at ≤ 23 + 6 weeks, termination of pregnancy and missing data regarding birth weight or gestational age at birth. Birth‐weight data were collected and FGR and SGA were defined as birth weight <5th and <10th centiles, respectively. While standard logistic regression was used for singleton pregnancies, the association of FGR and SGA with stillbirth in twin pregnancies was investigated using mixed‐effects logistic regression models. For twin pregnancies, intercepts were allowed to vary for twin pairs to account for intertwin dependency. Analyses were stratified by gestational age at delivery and chorionicity. Statistical significance was set at P ≤ 0.001. Results: The study included 95 342 singleton and 3576 twin pregnancies. There were 494 (0.52%) stillbirths in singleton and 41 (1.15%) stillbirths in twin pregnancies (17 dichorionic and 24 monochorionic). SGA and FGR were associated significantly with stillbirth in singleton pregnancies across all gestational ages at delivery: the odds ratios (ORs) for SGA and FGR were 2.36 ((95% CI, 1.78–3.13), P < 0.001) and 2.67 ((95% CI, 2.02–3.55), P < 0.001), respectively, for delivery before 32 weeks; 2.70 ((95% CI, 1.71–4.31), P < 0.001) and 2.82 ((95% CI, 1.78–4.47), P < 0.001), respectively, for delivery between 32 and 36 weeks; and 3.85 ((95% CI, 2.83–5.21), P < 0.001) and 4.43 ((95% CI, 3.16–6.12), P < 0.001), respectively, for delivery after 36 weeks. In twin pregnancies, when stratified by gestational age at delivery, both SGA and FGR determined by twin‐specific birth‐weight charts were associated with increased odds of stillbirth for those delivered before 32 weeks (SGA: OR, 3.87 (95% CI, 1.56–9.50), P = 0.003 and FGR: OR, 5.26 (95% CI, 2.11–13.01), P = 0.001), those delivered between 32 and 36 weeks (SGA: OR, 6.67 (95% CI, 2.11–20.41), P = 0.001 and FGR: OR, 9.54 (95% CI, 3.01–29.40), P < 0.001) and those delivered beyond 36 weeks (SGA: OR, 12.68 (95% CI, 2.47–58.15), P = 0.001 and FGR: OR, 23.84 (95% CI, 4.62–110.25), P < 0.001). However, the association of stillbirth with SGA and FGR in twin pregnancies was non‐significant when diagnosis was based on singleton charts (before 32 weeks: SGA, P = 0.014 and FGR, P = 0.005; 32–36 weeks: SGA, P = 0.036 and FGR, P = 0.008; after 36 weeks: SGA, P = 0.080 and FGR, P = 0.063). Conclusion: Our study demonstrates that SGA and, especially, FGR are associated significantly with an increased risk of stillbirth across all gestational ages in singleton pregnancies, and in twin pregnancies when twin‐specific birth‐weight charts are used. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. Linked article: There is a comment on this article by Nicolaides et al. Click here to view the Correspondence. [ABSTRACT FROM AUTHOR]

Dysregulated progenitor cell populations may contribute to poor placental development and placental insufficiency pathogenesis. Side-population cells possess progenitor properties. Recent human trophoblast side-population isolation identified enrichment of 8 specific genes (CXCL8, ELL2, GATA6, HK2, HLA-DPB1, INTS6, SERPINE3 and UPP1) (Gamage et al. 2020, Stem Cell Rev Rep). We characterised these trophoblast side-population markers in human placenta and in placental insufficiency disorders: preeclampsia and fetal growth restriction (FGR). Trophoblast side-population markers localised to mononuclear trophoblasts lining the placental villous basement membrane in preterm control, preeclamptic and FGR placental sections (n = 3, panel of 3 markers/serial section). Analysis of single-cell transcriptomics of an organoid human trophoblast stem cell (hTSC) to extravillous trophoblast (EVT) differentiation model (Shannon et al. 2022, Development) identified that all side-population genes were enriched in mononuclear trophoblast and trophoblasts committed to differentiation under hTSC culture conditions. In vitro validation via 96 h time course hTSC differentiation to EVTs or syncytiotrophoblasts (n = 5) demonstrated ELL2 and HK2 increased with differentiation (p < 0.0024, p < 0.0039 respectively). CXCL8 and HLA-DPB1 were downregulated (p < 0.030, p < 0.011 respectively). GATA6 and INTS6 increased with EVT differentiation only, and UPP1 reduced with syncytialisation. SERPINE3 was undetectable. Trophoblast side-population marker mRNA was measured in human placentas (< 34-weeks' gestation; n = 78 preeclampsia, n = 30 FGR, and n = 18 gestation-matched controls). ELL2, HK2 and CXCL8 were elevated in preeclamptic (p = 0.0006, p < 0.0001, p = 0.0335 respectively) and FGR placentas (p = 0.0065, p < 0.0001, p = 0.0001 respectively) versus controls. Placental GATA6 was reduced in pregnancies with preeclampsia and FGR (p = 0.0014, p = 0.0146 respectively). Placental INTS6 was reduced with FGR only (p < 0.0001). This study identified the localisation of a unique trophoblast subset enriched for side-population markers. Aberrant expression of some side-population markers may indicate disruptions to unique trophoblast subtypes in placental insufficiency. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the potential of immunonutritional markers, specifically the hemoglobin, albumin, lymphocyte, and platelet (HALP) score and the prognostic nutritional index (PNI), in predicting late-onset fetal growth restriction (LO-FGR) during the first trimester. Materials and methods: This retrospective study was conducted at a tertiary care center between October 2022 and August 2023. The study included a total of 213 singleton pregnancies, with 99 women in the LO-FGR group and 114 in the healthy control group, matched by maternal age and gestational age at delivery. All blood samples were collected between 11 and 14 weeks of gestation (during the first-trimester screening test). We analyzed first-trimester laboratory parameters, specifically focusing on hemoglobin levels, white blood cells (WBCs), lymphocytes, platelets, and albumin levels. Afterwards, we calculated the HALP score and PNI, and then compared the values of both groups. Results: Both HALP score (3.58 ± 1.31 vs. 4.19 ± 1.8, p = 0.012) and PNI (36.75 ± 2.9 vs. 39.37 ± 3.96, p < 0.001) were significantly lower in the FGR group than in the control group. The HALP score cut-off value of < 3.43 in predicting FGR had a sensitivity of 62.3% and specificity of 54.5% (AUC = 0.600, 95% CI: 0.528–0.672, p = 0.012). The PNI cut-off value of < 37.9 in predicting FGR had a sensitivity of 65.8% and specificity of 62.9% (AUC = 0.707, 95% CI: 0.632–0.778, p < 0.001). While the HALP score was not a significant predictor of composite adverse neonatal outcomes in the FGR group, PNI showed a cut-off value of < 37.7 with a sensitivity of 60.9% and specificity of 59.7% (AUC = 0.657, 95% CI: 0.581–0.733, p < 0.001). Conclusion: The HALP score and PNI are valuable prognostic tools for predicting the risk of FGR in the first trimester. Low PNI values are also associated with composite adverse neonatal outcomes in pregnancies complicated by FGR. [ABSTRACT FROM AUTHOR]

Relative uteroplacental insufficiency of labor (RUPI‐L) is a clinical condition that refers to alterations in the fetal oxygen "demand–supply" equation caused by the onset of regular uterine activity. The term RUPI‐L indicates a condition of "relative" uteroplacental insufficiency which is relative to a specific stressful circumstance, such as the onset of regular uterine activity. RUPI‐L may be more prevalent in fetuses in which the ratio between the fetal oxygen supply and demand is already slightly reduced, such as in cases of subclinical placental insufficiency, post‐term pregnancies, gestational diabetes, and other similar conditions. Prior to the onset of regular uterine activity, fetuses with a RUPI‐L may present with normal features on the cardiotocography. However, with the onset of uterine contractions, these fetuses start to manifest abnormal fetal heart rate patterns which reflect the attempt to maintain adequate perfusion to essential central organs during episodes of transient reduction in oxygenation. If labor is allowed to continue without an appropriate intervention, progressively more frequent, and stronger uterine contractions may result in a rapid deterioration of the fetal oxygenation leading to hypoxia and acidosis. In this Commentary, we introduce the term relative uteroplacental insufficiency of labor and highlight the pathophysiology, as well as the common features observed in the fetal heart rate tracing and clinical implications. [ABSTRACT FROM AUTHOR]

Introduction: The IMPACT BCN trial—a parallel‐group randomized clinical trial where 1221 pregnant women at high risk for small‐for‐gestational age (SGA) newborns were randomly allocated at 19‐ to 23‐week gestation into three groups: Mediterranean diet, Mindfulness‐based Stress reduction or non‐intervention—has demonstrated a positive effect of Mediterranean diet and Stress reduction in the prevention of SGA. However, the mechanism of action of these interventions remains still unclear. The aim of this study is to investigate the effect of Mediterranean diet and Stress reduction on placental volume and perfusion. Material and Methods: Participants in the Mediterranean diet group received monthly individual and group educational sessions, and free provision of extra‐virgin olive oil and walnuts. Women in the Stress reduction group underwent an 8‐week Stress reduction program adapted for pregnancy, consisting of weekly 2.5‐h and one full‐day sessions. Non‐intervention group was based on usual care. Placental volume and perfusion were assessed in a subgroup of randomly selected women (n = 165) using magnetic resonance (MR) at 36‐week gestation. Small placental volume was defined as MR estimated volume <10th centile. Perfusion was assessed by intravoxel incoherent motion. Results: While mean MR placental volume was similar among the study groups, both interventions were associated with a lower prevalence of small placental volume (3.9% Mediterranean diet and 5% stress reduction vs. 17% non‐intervention; p = 0.03 and p = 0.04, respectively). Logistic regression showed that small placental volume was significantly associated with higher risk of SGA in both study groups (OR 7.48 [1.99–28.09] in Mediterranean diet and 20.44 [5.13–81.4] in Stress reduction). Mediation analysis showed that the effect of Mediterranean diet on SGA can be decomposed by a direct effect and an indirect effect (56.6%) mediated by a small placental volume. Similarly, the effect of Stress reduction on SGA is partially mediated (45.3%) by a small placental volume. Results on placental intravoxel incoherent motion perfusion fraction and diffusion coefficient were similar among the study groups. Conclusions: Structured interventions during pregnancy based on Mediterranean diet or Stress reduction are associated with a lower proportion of small placentas, which is consistent with the previously observed beneficial effects of these interventions on fetal growth. [ABSTRACT FROM AUTHOR]

Aim This article determines the compliance rates with low-dose aspirin (LDA) and outcomes in a group of pregnant women identified at high risk for preeclampsia (PE) and fetal growth restriction (FGR) at 11 to 14 gestational weeks (GWs) in a rural district of central India. Methods A single, experienced fetal radiologist assessed all enrolled pregnant women using trimester-specific antenatal screening protocols that included mean arterial blood pressure assessment, and fetal ultrasound and Doppler studies. A trimester-specific individualized risk for preterm PE and FGR was estimated for each woman. Pregnant women categorized as high risk for preterm PE or FGR based on a 1 in 150 criteria at 11 to 14 GW were recommended LDA 150 mg once daily at bedtime. Outcome measures included compliance with LDA assessed, incidence of PE and FGR, preterm delivery (<37 GW), birth weight, stillbirths, and perinatal mortality. Results The data of 488 pregnant women with longitudinal trimester-specific assessments from 11 to 14 GW till childbirth was analyzed. At the third trimester assessment, 215 (80.83%) of the high-risk women were compliant with LDA. The incidence of PE, FGR, and preterm births was significantly higher in LDA noncompliant women, and the mean birth weight was significantly higher in LDA-compliant high-risk women. Conclusion Good compliance for LDA is possible in rural populations with adequate counseling. Starting LDA at 11 to 14 GW for high-risk pregnant women lowered the incidence of PE, FGR, and preterm birth rates and improved birth weight in the study population. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the association between placental abnormalities, placental biomarkers, and fetoplacental Dopplers in a cohort of pregnancies complicated by fetal growth restriction (FGR). We also ascertained the risk of perinatal mortality, severe neurological morbidity, and severe non-neurological morbidity by type of placental abnormality. This was a prospective cohort study. Multivariable logistic regression was used to evaluate the effect of early vs. late FGR, placental biomarkers and fetoplacental Dopplers on Maternal Vascular Malperfusion (MVM) which was the commonest placental abnormality identified. There were 161 (53.5 %) early FGR and 140 (46.5 %) late FGR cases. MVM abnormalities were present in 154 (51.2 %), VUE in 45 (14.6 %), FVM in 16 (5.3 %), DVM in 14 (4.7 %) and CHI in 4 (1.3 %) cases. The odds of MVM were higher in early compared to late FGR cohort (OR 1.89, 95%CI 1.14, 3.14, p = 0.01). Low maternal PlGF levels <100 ng/L (OR 2.34, 95%CI 1.27,4.31, p = 0.01), high sFlt-1 level (OR 2.13, 95%CI 1.35, 3.36, p = 0.001) or elevated sFlt-1/PlGF ratio (OR 3.48, 95%CI 1.36, 8.91, p = 0.01) were all associated with MVM. Increased UA PI > 95th centile (OR 2.91, 95%CI 1.71, 4.95, p=<0.001) and mean UtA PI z-score (OR 1.74, 95%CI 1.15, 2.64, p = 0.01) were associated with higher odds of MVM. Rates of severe non-neurological morbidity were highest in the MVM, FVM, and CHI cohorts (44.8 %, 50 %, and 50 % respectively). MVM was the commonest placental abnormality in FGR, particularly in early-onset disease. Low maternal PlGF levels, high sFlt-1 levels, elevated sFlt-1/PlGF ratio, and abnormal fetoplacental Dopplers were also significantly associated with MVM. MVM, FVM, and CHI abnormalities were associated with lower median birthweight, higher rates of preterm birth, operative birth for non-reassuring fetal status, and severe neonatal non-neurological morbidity. • MVM is the commonest placental abnormality in pregnancies complicated by FGR. • Early-onset FGR is more likely to have MVM abnormalities than late-onset disease. • MVM changes are associated with abnormal placental biomarkers and fetoplacental Dopplers. • Higher rates of hypertension and pre-eclampsia were seen in MVM, FVM, and CHI. • MVM, FVM, and CHI are strongly associated with adverse perinatal and pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Preeclampsia and fetal growth restriction (PE/FGR) are pregnancy complications known to be associated with poor utero-placental function due to abnormal "physiological" remodeling of spiral arteries and unfavorable maternal cardiovascular health. However, the prevalence and degree of impaired spiral artery remodeling has not been clearly established. Prospective, multi-center observational cohort study to assess the prevalence of lesions associated with abnormal development of spiral arteries in placental bed biopsies systematically obtained from 121 women undergoing Caesarian section for PE/FGR compared with a reference group of 149 healthy controls. PE/FGR was associated with a high prevalence of impaired spiral artery remodeling compared with controls (63.6 vs 10.1 %, p < 0.001), and a higher prevalence of non-remodeled spiral arteries without the presence of intramural trophoblast (45.5 vs 6.7 %, p < 0.001), despite abundant interstitial trophoblast invasion in surrounding decidua and myometrium. Normal remodeling was associated with circumferential presence of intramural trophoblast and hardly any trophoblast in surrounding tissue. Acute atherosis (28.9 vs 3.4 %, p < 0.001) and thrombosis (16.5 vs 5.4 %, p = 0.003) lesions were significantly more prevalent in PE/FGR. Impaired remodeling, acute atherosis and thrombosis lesions were equally present in both decidual and myometrial segments of the spiral arteries in both groups. Impaired remodeling was most prominent in the groups with FGR (with or without PE) and thrombosis was most often seen in the group with PE and FGR. PE/FGR is associated with a high prevalence of impaired physiological remodeling and vascular lesions of the uterine spiral arteries in the placental bed. [Display omitted] • Preeclampsia and fetal growth restriction are associated with inefficient trophoblast invasion. • Acute atherosis and thrombosis are more prevalent in spiral arteries of women with preeclampsia and/or FGR. • Normal remodeling is associated with circumferential intramural trophoblast. • Abnormal remodeling is associated with abundant extravascular trophoblast invasion. • Spiral artery lesions are more severe in the FGR group than in the preeclampsia alone group. [ABSTRACT FROM AUTHOR]

Placental insufficiency and gestational diabetes, which are both serious pregnancy complications, are linked to altered fetal growth, whether restricted or excessive, and result in metabolic dysfunction, hypoxic/oxidative injury, and adverse perinatal outcomes. Although much research has been carried out in this field, the underlying pathogenetic mechanisms have not as yet been fully elucidated. Particularly because of the role it plays in cardiovascular performance, glucose metabolism, inflammation, and oxidative stress, the adipokine apelin was recently shown to be a potential regulator of fetal growth and metabolic programming. This review investigated the numerous biological actions of apelin in utero and aimed to shed more light on its role in fetal growth and metabolic programming. The expression of the apelinergic system in a number of tissues indicates its involvement in many physiological mechanisms, including angiogenesis, cell proliferation, energy metabolism, inflammation, and oxidative stress. Moreover, it appears that apelin has a major function in disorders such as diabetes mellitus, fetal growth abnormalities, fetal hypoxia, and preeclampsia. We herein describe in detail the regulatory effects exerted by the adipokine apelin on fetal growth and metabolic programming while stressing the necessity for additional research into the therapeutic potential of apelin and its mechanisms of action in pregnancy-related disorders. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is a common complication of pregnancy, associated with major perinatal mortality and morbidity, and with an increased risk to develop cardiometabolic diseases later in life. There is currently no effective approach to prevent or treat FGR, despite numerous animal and human studies assessing substances likely to improve fetal growth. Phosphodiesterase (PDE) inhibitors appeared as promising drugs to improve FGR management. However, to date, studies have led to somewhat disappointing or controversial results. In this Opinion article, we would like to draw attention to the need to consider the biological sex and the relative reactivity of human umbilical vein and arteries when developing therapeutic interventions to improve human umbilical circulation using PDE inhibitors. Indeed, we suspect that fetal sex, vessel type and the presence of FGR may influence subcellular compartmentation, which could jeopardize beneficial effects of PDE inhibitors. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is a relatively common complication of pregnancy, and insufficient syncytialization in the placenta may play an important role in the pathogenesis of FGR. However, the mechanism of impaired formation of the syncytiotrophoblast layer in FGR patients requires further exploration. In the present study, we demonstrated that the level of syncytialization was decreased in FGR patient placentas, while the expression of connective tissue growth factor (CTGF) was significantly upregulated. CTGF was found to inhibit trophoblast fusion via regulating cell cycle progress of BeWo cells. Furthermore, we found that CTGF negatively regulates cell cycle arrest in a p21-dependent manner as overexpression of p21 could rescue the impaired syncytialization induced by CTGF-overexpression. Besides, we also identified that CTGF inhibits the expression of p21 through ITGB4/PI3K/AKT signaling pathway. Our study provided a new insight for elucidating the pathogenic mechanism of FGR and a novel idea for the clinical therapy of FGR. [ABSTRACT FROM AUTHOR]

Objective: To evaluate amniotic fluid volume with Doppler parameters and its association with composite adverse perinatal outcomes (CAPOs) in fetal growth restriction (FGR). Materials and Methods: This study was conducted prospectively in a tertiary referral center between 2023 and 2024 on pregnant women diagnosed with early‐ and late‐onset FGR. Fetal ultrasonographic measurements, including deepest vertical pocket (DVP) for amniotic fluid, and Doppler parameters including uterine artery (UtA) systolic/diastolic (S/D) and pulsatility index (PI), middle cerebral artery (MCA) S/D and PI, and umbilical artery (UA) S/D and PI, were conducted following fetal biometry. The cerebroplacental ratio (CPR), cerebral ratio, cerebro‐placental‐uterine ratio (CPUR), and amniotic‐umbilical‐to‐cerebral ratio (AUCR) were all calculated. Pregnant women diagnosed with FGR were planned to give birth after 37 weeks' gestation, unless a pregnancy complication requiring earlier delivery occurred. We assessed perinatal outcomes subsequent to delivery, with CAPOs defined as the presence of at least one adverse outcome: 5th minute APGAR score <7, respiratory distress syndrome (RDS), umbilical cord blood pH <7.2, and neonatal intensive care unit (NICU) admission. Results: The study included 132 participants, divided into early‐ (n = 32) and late‐onset FGR (n = 100) groups. AUCR was significantly lower in fetuses with late‐onset FGR who experienced CAPOs. Multivariate analysis showed gestational age at birth and birth weight were significant predictors of CAPOs in early‐onset FGR, while gestational age, birth weight, and AUCR were significant predictors in late‐onset FGR. CPR, UCR, and CPUR did not show significance in predicting CAPOs in both early‐ and late‐onset FGR on multivariate analysis. Conclusions: AUCR is a potential reliable marker for predicting adverse perinatal outcomes in late‐onset FGR. [ABSTRACT FROM AUTHOR]

Purpose: Fetal growth restriction (FGR) is a common pregnancy complication that can be associated with several adverse perinatal outcomes. One of these negative outcomes is ductus arteriosus, especially in preterm babies. In this study, intrauterine heart function and ductus diameter were evaluated in babies with FGR. Methods: Thirty‐seven fetuses with FGR were compared with 37 normal‐weight fetuses at the same gestational week. In our study, ventricular diameters, aorta, pulmonary artery, ductus arteriosus (DA), aortic arch diameter, and flow traces were examined. In addition, the aorta and aortic isthmus diameters were proportioned to the ductus diameter, and the left ventricular myocardial performance index (MPI) [(ICT + IRT)/ET] was evaluated. Results: There was no difference in DA diameters between the patient and control groups. The intragroup comparison of the cases with early‐ and late‐onset FGR revealed no statistically significant difference between DA diameters. However, the ratios of the aortic annulus diameter/ductus diameter (AOD/DAD) and aortic isthmus diameter/ductus diameter (AID/DAD) were significantly lower in early‐onset FGR because the diameter of the DA was greater. In addition, the mod‐MPI values were higher in the patient group. Conclusions: In our study, although the ductal diameters did not change significantly in the patient group, the ductal diameter was greater in the early‐onset intrauterine growth restriction (FGR) group compared with other cardiac measurements. The mod‐MPI value, a cardiac function indicator, was higher in fetuses with FGR. These findings may be useful for evaluating postnatal cardiac functions in FGR. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Design Setting Population Methods Main Outcome Measure Results Conclusion To identify whether maternal and pregnancy characteristics associated with stillbirth differ between preterm and term stillbirth.Secondary cohort analysis of the DESiGN RCT.Thirteen UK maternity units.Singleton pregnant women and their babies.Multiple logistic regression was used to assess whether the 12 factors explored were associated with stillbirth. Interaction tests assessed for a difference in these associations between the preterm and term periods.Stillbirth stratified by preterm (<37+0 weeks') and term (37+0–42+6 weeks') births.A total of 195 344 pregnancies were included. Six hundred and sixty‐seven were stillborn (3.4 per 1000 births), of which 431 (65%) were preterm. Significant interactions were observed for maternal age, ethnicity, IMD, BMI, parity, smoking, PAPP‐A, gestational hypertension, pre‐eclampsia and gestational diabetes but not for chronic hypertension and pre‐existing diabetes. Stronger associations with term stillbirth were observed in women with obesity compared to BMI 18.5–24.9 kg/m2 (BMI 30.0–34.9 kg/m2 term adjusted OR 2.1 [95% CI 1.4–3.0] vs. preterm aOR 1.1 [0.8–1.7]; BMI ≥ 35.0 kg/m2 term aOR 2.2 [1.4–3.4] vs. preterm aOR 1.5 [1.2–1.8]; p‐interaction < 0.01), nulliparity compared to parity 1 (term aOR 1.7 [1.1–2.7] vs. preterm aOR 1.2 [0.9–1.6]; p‐interaction < 0.01) and Asian ethnicity compared with White (p‐interaction < 0.01). A weaker or lack of association with term, compared to preterm, stillbirth was observed for older maternal age, smoking and pre‐eclampsia.Differences in association exist between mothers experiencing preterm and term stillbirth. These differences could contribute to design of timely surveillance and interventions to further mitigate the risk of stillbirth. [ABSTRACT FROM AUTHOR]

Background: Fetal growth restriction (FGR) occurs in 10% of pregnancies worldwide. Placenta dysfunction, as one of the most common causes of FGR, is associated with various poor perinatal outcomes. The main objectives of this study were to screen potential diagnostic biomarkers for FGR and to evaluate the function of immune cell infiltration in the process of FGR. Methods: Firstly, differential expression genes (DEGs) were identified in two Gene Expression Omnibus (GEO) datasets, and gene set enrichment analysis was performed. Diagnosis-related key genes were identified by using three machine learning algorithms (least absolute shrinkage and selection operator, random forest, and support vector machine model), and the nomogram was then developed. The receiver operating characteristic curve, calibration curve, and decision curve analysis curve were used to verify the validity of the diagnostic model. Using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), the characteristics of immune cell infiltration in placental tissue of FGR were evaluated and the candidate key immune cells of FGR were screened. In addition, this study also validated the diagnostic efficacy of TREM1 in the real world and explored associations between TREM1 and various clinical features. Results: By overlapping the genes selected by three machine learning algorithms, four key genes were identified from 290 DEGs, and the diagnostic model based on the key genes showed good predictive performance (AUC = 0.971). The analysis of immune cell infiltration indicated that a variety of immune cells may be involved in the development of FGR, and nine candidate key immune cells of FGR were screened. Results from real-world data further validated TREM1 as an effective diagnostic biomarker (AUC = 0.894) and TREM1 expression was associated with increased uterine artery PI (UtA-PI) (pvalue = 0.029). Conclusion: Four candidate hub genes (SCD, SPINK1, TREM1, and HIST1H2BB) were identified, and the nomogram was constructed for FGR diagnosis. TREM1 was not only associated with a variety of key immune cells but also correlated with increased UtA-PI. The results of this study could provide some new clues for future research on the prediction and treatment of FGR. [ABSTRACT FROM AUTHOR]

In the last three decades, gene therapy has demonstrated significant progress. Over 700 active investigational new drug (IND) applications have been reported. Research on in utero gene therapy has advanced, but ethical and safety concerns persist. A novel approach under investigation is placental gene therapy, which holds promise for targeting diseases associated with placental dysfunction, such as fetal growth restriction (FGR) and preeclampsia. One of the underlying causes of placental insufficiency in these conditions is reduced placental growth factor-driven angiogenesis and endothelial cell dysfunction during fetal development. Studies have explored the overexpression of growth factor transgenes like IGF-1 to address FGR, yielding promising outcomes in animal models. Furthermore, intra-placental gene transfer, instead of systemic delivery of gene therapy vectors, has the potential to treat and cure these disorders. However, challenges and limitations akin to in utero gene therapy persist, including the risk of in utero infection, potential impairment of the mother's future fertility, the risk of germline integration, and possible off-target effects of gene transfer in the fetus or the mother. Consequently, additional research and deliberation within the scientific and medical communities are warranted to fully comprehend the potential benefits and risks of placental gene therapy. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Design Setting Sample Methods Main Outcome Measures Results Conclusions To investigate longitudinal trends in fetal and offspring cardiovascular adaptation in fetal growth restriction (FGR).Prospective longitudinal study.Fetal Medicine Unit.Thirty‐five FGR pregnancies and 37 healthy controls assessed as term fetuses (mean age 37 ± 1 weeks) and again in infancy (mean age 8 ± 2 months).Conventional echocardiographic techniques, tissue Doppler imaging and speckle tracking echocardiography.Left ventricular (LV) and right ventricular (RV) geometry and function. Echocardiographic parameters were normalised by ventricular size adjusting for differences in body weight between groups.Compared to healthy controls, late FGR fetuses showed significant alterations in cardiac geometry with more globular LV chamber (LV sphericity index, 0.56 vs. 0.52), increase in biventricular global longitudinal systolic contractility (MAPSE, 0.29 vs. 0.25 mm; TAPSE, 0.42 vs. 0.37 mm) and elevated cardiac output (combined CO: 592 vs. 497 mL/min/kg, p < 0.01 for all). Indices of LV diastolic function in FGR fetuses were significantly impaired with myocardial diastolic velocities (LV A', 0.30 vs. 0.26 cm/s; IVS E', 0.19 vs. 0.16 cm/s) and LV torsion (1.2 vs. 3.5 deg./cm, p < 0.01 for all). At postnatal assessment, FGR offspring revealed persistently increased SAPSE (0.27 vs. 0.24 mm), LV longitudinal strain (−19.0 vs. −16.0%), reduced LV torsion (1.6 vs. 2.1 deg./cm) and elevated CO (791 vs. 574 mL/min/kg, p < 0.01 for all).Perinatal cardiac remodelling and myocardial dysfunction in late FGR fetuses is most likely due to chronic placental hypoxaemia. Persistent changes in cardiac geometry and function in FGR offspring may reflect fetal cardiovascular maladaptation that could predispose to long‐term cardiovascular complications in later life. [ABSTRACT FROM AUTHOR]

Poor placental angiogenesis is associated with several pregnancy complications including fetal growth restriction (FGR), which causes low birth weight (LBW) babies to have a high risk of growth disorders and metabolic disorders in adulthood. Recent research using syncytin knock-out mice showed significant disruption in the growth of placental vascularization. Syncytin-1 which encoded by ERVW-1 gene, is proposed to have a role in placental angiogenesis, but its relationship with other proangiogenic factors such as vascular endothelial growth factor (VEGF) in the placenta of LBW babies has not yet been determined. By knowing the mechanisms of FGR, more proactive preventive and therapeutic measures can be taken in the future. This study aimed to determine the expression of ERVW-1 , proangiogenic gene VEGF and its receptor (FLT-1), and hypoxia inducible factor-1 (HIF-1) in LBW placentas, and investigate the relationship between these genes' expression in the placenta of LBW babies. Total RNA was extracted from placental tissue. Total RNA is used as a cDNA synthesis template, followed by qRT-PCR. Correlations of ERVW-1, VEGF, FLT-1 and HIF-1 genes' expression were analyzed by linear regression. The age and body mass index of mothers with LBW and normal birth weight (NBW) babies were not significantly different. ERVW-1 expression in LBW placentas was lower than in NBW placentas, but VEGF, FLT-1 and HIF-1 expressions were higher. ERVW-1 was negatively correlated with HIF-1 and VEGF. Low expression of ERVW-1 in the placenta of LBW babies may result in impaired placental angiogenesis and possibly lead to hypoxia. • Lower expression of ERVW-1 was found in the placenta of Low Birth Weight babies. • Low ERVW-1 expression leads to hypoxia, as indicated by high HIF-1 expression. • Hypoxic conditions are compensated by upregulation of VEGF and its receptor, FLT-1. [ABSTRACT FROM AUTHOR]

Fetal growth restriction and underlying placental insufficiency are associated with increased oxidative stress. Current diagnostics fail to identify all growth restricted fetuses and newborns, due to focus on small size. This scoping review aims to summarize the available evidence on usefulness of cord blood oxidative stress biomarkers for identification of growth restricted newborns in need of monitoring and support because of associated health risks. MEDLINE and EMBASE were searched from inception to May 2024. Studies were included if oxidative stress biomarkers were measured in cord blood collected immediately after delivery in newborns suspected to be growth restricted. Biomarkers were categorized based on the origin and/or biological function and their interrelationships. Oxidative stress was determined for each individual biomarker and category. Literature search identified 78 studies on 39 different biomarkers, with a total of 2707 newborns with suspected growth restriction, and 4568 controls. Total oxidant/antioxidant status, catalase, glutathione, ischemia-modified albumin, and nucleated red blood cells were most consistently associated with suspected growth restriction. Reactive oxygen species/reactive nitrogen species, factors in their production, antioxidant enzymes, non-enzymatic antioxidants, and products of oxidative stress were not consistently associated. This review collates the evidence of associations between cord blood oxidative stress biomarkers and growth restriction. Total oxidant/antioxidant status, catalase, glutathione, ischemia-modified albumin, and nucleated red blood cells could potentially be candidates for developing a cord blood diagnostic tool for future clinical use. • Oxidative stress cord blood biomarkers useful to identify growth restricted newborns. • (Anti)oxidant status, CAT, GSH, IMA, NRBC most associated with growth restriction. • Offering possibilities for development of cord blood diagnostic tool for clinical use. [ABSTRACT FROM AUTHOR]

A high frequency of single nucleotide somatic mutations in the placenta has been recently described, but its relationship to placental dysfunction is unknown. We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction. Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111–870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381–779), 582 (450–735), and 338 (245–441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. −34, −351 to +419), and with no association with placental dysfunction (p = 0.7). We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency. • Somatic mutation is highly prevalent in the human placenta. • 95 % of comatic variants were present in just one of four biopsies in each placenta. • Somatic mutation estimates were driven by sequencing depth and gestational age. • Two variant calling algorithms yield very different somatic variation estimates. • We found no association between somatic variant burden and clinical outcome. [ABSTRACT FROM AUTHOR]

The congenital condition gastroschisis is associated with delayed villous development and placental malperfusion, suggesting placental involvement. This study uses RNA sequencing to compare the placental transcriptome in pregnancies with and without gastroschisis. 180 coding genes were differentially expressed, mapping to multiple gene ontology pathways. Altered placental gene expression may represent fetal signalling to the placenta, and these changes could contribute to the pathogenesis of gastroschisis and associated morbidities, including fetal growth restriction. • Gastroschisis is a congenital condition where the infant's intestines extend outside the abdomen. • Developmental and vascular defects are associated with Gastroschisis. • Gastroschisis associated changes in the placental transcriptome were observed. • These changes may reflect altered fetal to placental signalling. [ABSTRACT FROM AUTHOR]

A 31‐year‐old primiparous woman underwent non‐invasive prenatal testing. The result was trisomy 13 (T13) positive. The chromosome 13 t‐statistics (Z‐score) was significantly high. The result of amniocentesis was normal karyotype (46,XX). Detailed ultrasound showed no fetal structural abnormalities. We suspected T13 confined placental mosaicism (CPM) and observed the course naturally. From the late second trimester, severe fetal growth restriction manifested followed by proteinuria and hypertension, diagnosing her with preeclampsia (PE). At 35 + 5 weeks, emergent cesarean section was required, yielding a 1480 g female infant. We sampled five locations of chorionic villi in the placenta. T13 cells dominated cells with normal karyotypes in all parts and the rate of trisomic cells ranged from 57% to 96%, which were generally high rate. None developed PE in reported T13 CPM cases and this is the first case of PE. The dominancy of T13 cells can be associated with PE development. [ABSTRACT FROM AUTHOR]

Umbilical vascular thromboembolism is a rare condition that can lead to serious consequences such as fetal hypoxia, fetal growth restriction, and even stillbirth. However, there is currently a lack of research on the pathology, pathogenesis, clinical management, and prognosis of this condition. Therefore, the purpose of this article is to analyze this condition's high-risk factors, clinical characteristics, pregnancy management, and discuss its corresponding pregnancy outcomes. Databases such as PubMed are searched using the relevant keywords of umbilical vascular thromboembolism in worldwide. And related information is analyzed such as maternal risk factors, fetal risk factors, umbilical cord and placental risk factors, and pregnancy outcomes. The literature search yields 113 articles, 64 of which meet the inclusion criteria for umbilical vascular thromboembolism. There are 4 retrospective cohort studies and 8 case series, the rest are all case reports. A total of 262 cases of umbilical vascular thromboembolism are found. The most common maternal complications and fetal related risk factors are diabetes (25 cases, 9.5%) and stillbirths (106 cases, 40.5%), respectively. Among these 262 cases, 98 (37.4%) cases are found by prenatal ultrasound to have umbilical vascular thromboembolism and the fetus is in a viable state with complete clinical information. In addition, considering the effectiveness and safety of low molecular weight heparin in thromboembolic conditions, twenty-four patients of umbilical artery thromboembolism attempted to use low molecular weight heparin during observation. Maternal diabetes was the highest risk factor for this condition. When umbilical artery thromboembolism occurs, the incidence of stillbirth increases. Premature patients with this condition can continue their pregnancy under close external monitoring. However, due to the small sample size, further research is needed. [ABSTRACT FROM AUTHOR]

Introduction: Three-dimensional fractional moving blood volume (3D-FMBV) may provide superior noninvasive measurement of feto-placental perfusion compared to current methods. This study investigated the feasibility and repeatability of producing 3D-FMBV measurements of the placenta, fetal liver, kidney, and brain in a single ultrasound consultation. Methods: The placenta, fetal liver, kidney, and brain were scanned in triplicate using 3D power Doppler ultrasound (3D-PDU) in 48 women ≥22 weeks of gestation with healthy fetuses. 3D-FMBV was calculated by two analyzers. Feasibility was assessed as the percentage of cases where 3D-FMBV could be evaluated; repeatability (intraobserver and interobserver) using two-way mixed measure intraclass correlation coefficients (ICCs). Results: 3D-FMBV was calculated for 100% of scanned organs. Intraobserver ICCs (95% CI) were good to excellent; 0.93 (0.88–0.96) and 0.87 (0.78–0.92) for placenta, 0.95 (0.92–0.97) and 0.98 (0.96–0.99) for fetal liver, 0.96 (0.94–0.98) and 0.91 (0.85–0.95) for fetal kidney, and 0.98 (0.97–0.99) and 0.97 (0.95–0.98) for fetal brain. Interobserver ICCs (95% CI) were 0.50 (0.08–0.73), 0.92 (0.85–0.96), 0.89 (0.78–0.94), and 0.71 (0.46–0.85) for placenta, fetal liver, kidney, and brain. Conclusion: Feto-placental perfusion assessment with 3D-FMBV is highly reliable in healthy pregnancies ≥22 weeks of gestation and can be feasibly calculated in four feto-placental vascular beds in a single ultrasound consultation. Plain Language Summary: Throughout pregnancy the placenta provides the fetus with nutrients and oxygen. If blood flow to the fetus is impaired (i.e., in placental disease), the fetus adapts by directing more blood to its brain and less to peripheral organs, called "brain-sparing." This has consequences including impaired growth, stillbirth, and chronic adulthood disease. Brain-sparing is currently detected by measuring how pulsatile blood flow is in the fetal brain and placental vessels. However, in many cases, brain-sparing is detected too late for interventions to be implemented, or not at all. Three-dimensional fractional moving blood volume (3D-FMBV) is a new noninvasive technique that may be able to earlier detect brain-sparing by measuring blood flow in whole fetal organs. If successful, this technique could be used to define normal blood flow ranges in different organs throughout pregnancy, allowing for early detection, intervention, and optimization of fetal outcomes. To do this, it must first be practical to take 3D-FMBV measurements in a single ultrasound consultation (and not be too time intensive) and produce reliable measurements between patients. Our study found that it is practical to measure blood flow in four organs; placenta, fetal liver, kidney, and brain, in a single ultrasound consult, taking a median 10 min and 12 s for scanning and 41 min and 59 s for offline analysis. We were able to calculate 3D-FMBV for all organs scanned. Following our proposed protocol for scanning and analysis, 3D-FMBV measurements can be reliably calculated to a good to excellent degree by the same observer and between observers. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction (IUGR) is a pregnancy complication impairing fetal growth and development. The compromised development is often attributed to disruptions of oxygen and nutrient supply from the placenta, resulting in a number of unfavourable physiological outcomes with impaired brain and organ growth. IUGR is associated with compromised development of both grey and white matter, predisposing the infant to adverse neurodevelopmental outcomes, including long‐lasting cognitive and motor difficulties. Cerebral thyroid hormone (TH) signalling, which plays a crucial role in regulating white and grey matter development, is dysregulated in IUGR, potentially contributing to the neurodevelopmental delays associated with this condition. Notably, one of the major TH transporters, monocarboxylate transporter‐8 (MCT8), is deficient in the fetal IUGR brain. Currently, no effective treatment to prevent or reverse IUGR exists. Management strategies involve close antenatal monitoring, management of maternal risk factors if present and early delivery if IUGR is found to be severe or worsening in utero. The overall goal is to determine the most appropriate time for delivery, balancing the risks of preterm birth with further fetal compromise due to IUGR. Drug candidates have shown either adverse effects or little to no benefits in this vulnerable population, urging further preclinical and clinical investigation to establish effective therapies. In this review, we discuss the major neuropathology of IUGR driven by uteroplacental insufficiency and the concomitant long‐term neurobehavioural impairments in individuals born IUGR. Importantly, we review the existing clinical and preclinical literature on cerebral TH signalling deficits, particularly the impaired expression of MCT8 and their correlation with IUGR. Lastly, we discuss the current evidence on MCT8‐independent TH analogues which mimic the brain actions of THs by being metabolised in a similar manner as promising, albeit underappreciated approaches to promote grey and white matter development and improve the neurobehavioural outcomes following IUGR. [ABSTRACT FROM AUTHOR]

Problem: Accelerated placental aging is linked to abnormal fetal growth, preeclampsia (PE), and preterm birth (PTB). NANOG, a transcription factor, is known for its role in cellular reprogramming, self‐renewal, and clonogenic growth. Its expression is regulated by Kruppel‐like factor 4 (KLF4), which functions as both a transcriptional activator and repressor. This study evaluated the KLF4‐NANOG pathway in placental samples from normal pregnancies (NP) as well as those with PE, fetal growth restriction (FGR), and PTB. Method of Study: Placental samples from NP pregnancies and those with PE, FGR, and PTB were analyzed for NANOG and KLF4 expression using western blotting and immunohistochemistry. Results: NANOG protein expression was significantly increased in placentas from PE, FGR, and PTB compared to NP (fold changes vs. NP: PE 2.48 ± 0.3, p = 0.002; FGR 1.64 ± 0.16, p = 0.03; PTB 6.03 ± 3.35, p = 0.01). Similarly, KLF4 protein expression was elevated in PE, FGR, and PTB placentas compared to NP (fold changes vs. NP: PE 5.78 ± 0.73, p = 0.001; FGR 2.61 ± 0.43, p = 0.02; PTB 11.42 ± 2.76, p = 0.0006). Immunohistochemistry revealed strong NANOG staining in the syncytiotrophoblast tissue of PE, FGR, and PTB samples, especially in extravillous trophoblasts, compared to NP placentas. Conclusions: The elevated expression of NANOG and KLF4 in abnormal placental tissues suggests their potential role as markers of enhanced placental aging and dysfunction. These findings underscore the importance of the KLF4‐NANOG pathway in the pathology of PE, FGR, and PTB, providing a basis for future research into therapeutic targets for these conditions. [ABSTRACT FROM AUTHOR]

Objectives: Pregnancies in women with Fontan circulation are on the rise, and they are known to imply high maternal and fetal complication rates. The altered hemodynamic profile of univentricular circulation affects placental development and function. This study describes placental sonomorphologic appearance and Doppler examinations and correlates these to histopathologic findings and pregnancy outcomes in women with Fontan circulation. Methods: A single-center retrospective analysis of pregnancies in women with Fontan circulation was conducted between 2018 and 2023. Maternal characteristics and obstetric and neonatal outcomes were recorded. Serial ultrasound examinations including placental sonomorphologic appearance and Doppler studies were assessed. Macroscopic and histopathologic findings of the placentas were reviewed. Results: Six live births from six women with Fontan physiology were available for analysis. Prematurity occurred in 83% (5/6 cases) and fetal growth restriction and bleeding events in 66% (4/6 cases) each. All but one placenta showed similar sonomorphologic abnormalities starting during the late second trimester, such as thickened globular shape, inhomogeneous echotexture, and hypoechoic lakes, resulting in a jelly-like appearance. Uteroplacental blood flow indices were within normal range in all women. The corresponding histopathologic findings were non-specific and consisted of intervillous and subchorionic fibrin deposition, villous atrophy, hypoplasia, or fibrosis. Conclusions: Obstetric and perinatal complication rates in pregnancies of women with Fontan circulation are high. Thus, predictors are urgently needed. Our results suggest that serial ultrasound examinations with increased awareness of the placental appearance and its development, linked to the Doppler sonographic results of the uteroplacental and fetomaternal circulation, may be suitable for the early identification of cases prone to complications. [ABSTRACT FROM AUTHOR]

Dexamethasone is frequently prescribed for preterm infants to wean from respiratory support and/or to facilitate extubation. This pre-/postintervention prospective study ascertained the impact on clinical (respiratory support) and echocardiographic parameters after dexamethasone therapy in preterm fetal growth restriction (FGR) infants compared with appropriate for gestational age (AGA) infants. Echocardiography was performed within 24 h before the start and after completion of 10-day therapy. Parameters assessed included those reflecting pulmonary vascular resistance and right ventricular output. Seventeen FGR infants (birth gestation and birth weight, 25.2 ± 1.1 wk and 497 ± 92 g, respectively) were compared with 22 AGA infants (gestation and birth weight, 24.5 ± 0.8 and 663 ± 100 g, respectively). Baseline respiratory severity score (mean airway pressure × fractional inspired oxygen) was comparable between the groups, (median [interquartile range] FGR, 10 [6, 13] vs. AGA, 8 ± 2.8, P = 0.08). Pre-dexamethasone parameters of pulmonary vascular resistance (FGR, 0.19 ± 0.03 vs. AGA, 0.2 ± 0.03, P = 0.16) and right ventricular output (FGR, 171 ± 20 vs. 174 ± 17 mL/kg/min, P = 0.6) were statistically comparable. At post-dexamethasone assessments, the decrease in the respiratory severity score was significantly greater in AGA infants (median [interquartile range] FGR, 10 [6, 13] to 9 [2.6, 13.5], P = 0.009 vs. AGA, 8 ± 2.8 to 3 ± 1, P < 0.0001). Improvement in measures of pulmonary vascular resistance (ratio of time to peak velocity to right ventricular ejection time) was greater in AGA infants (FGR, 0.19 ± 0.03 to 0.2 ± 0.03, P = 0.13 vs. AGA 0.2 ± 0.03 to 0.25 ± 0.03, P < 0.0001). The improvement in right ventricular output was significantly greater in AGA infants (171 ± 20 to 190 ± 21, P = 0.014 vs. 174 ± 17 to 203 ± 22, P < 0.0001). This highlights differential cardiorespiratory responsiveness to dexamethasone in extremely preterm FGR infants, which may reflect the in utero maladaptive state. NEW & NOTEWORTHY: Dexamethasone (DEX) is frequently used in preterm infants dependent on ventilator support. Differences in vascular structure and function that may have developed prenatally arising from the chronic intrauterine hypoxemia in FGR infants may adversely affect responsiveness. The clinical efficacy of DEX was significantly less in FGR (birth weight < 10th centile) infants, compared with appropriate for gestational age (AGA) infants. Echocardiography showed significantly less improvement in pulmonary vascular resistance in FGR, compared with AGA infants. [ABSTRACT FROM AUTHOR]

Fetal hypoxia due to placental dysfunction is the hallmark of fetal growth restriction (FGR). Preferential perfusion of the brain (brain-sparing effect), as a part of physiological placental cardiovascular compensatory mechanisms to hypoxia, in FGR was reported. Therefore, the correlation between vascular endothelial growth factor A (VEGF-A) protein expression in the FGR placentas and newborns' early neurological outcome was examined. This study included 50 women with FGR complicated pregnancies and 30 uneventful pregnancies. Fetal hemodynamic parameters, neonatal acid–base status after delivery, placental pathohistology and VEGF-A expression were followed. Early neonatal morphological brain evaluation by ultrasound and functional evaluation of neurological status by Amiel – Tison Neurological Assessment at Term (ATNAT) were performed. VEGF-A protein expression level was significantly higher in the FGR placentas than normal term placentas (Fisher–Freeman–Halton's test, p≤0.001). No statistically significant correlation between placental VEGF-A expression and different prenatal and postnatal parameters was noticed. Whereas the alteration of an early neurological status assessed by ATNAT was found in 58 % of FGR newborns, morphological brain changes evaluated by UZV was noticed in 48 % of cases. No association between the level of placental VEGF-A expression and the early neurological deficits was found. As far as we know this is the first study of a possible connection between VEGF-A protein expression in the FGR placentas and neonates' early neurological outcomes. The lack of correlation between the FGR placental VEGF-A expression and neonates' neurological outcome could indicate that optimal early neurodevelopment may take place due to compensatory mechanism not related to placental VEGF-A expression. [ABSTRACT FROM AUTHOR]

Objectives: Small for gestational age (SGA) singletons are at increased risk for neurodevelopmental abnormalities. Scarce data exist regarding the long-term implications of SGA in twins. We opted to study the association between SGA of one twin and long-term neurologic related morbidity in dichorionic diamniotic twins. Study design: A population-based retrospective cohort study including consecutive dichorionic diamniotic twins, born between the years 1991 and 2021 at a tertiary medical center was conducted. Total and subtypes of neurologic related pediatric hospitalizations among SGA versus non-SGA twins were compared. A Kaplan–Meier survival curve was used to compare the cumulative neurologic morbidity incidence, and a Cox proportional hazards model was constructed to adjust for confounders. Results: The study population included 4222 newborns; 180 (4.3%) were SGA. Rate of long-term neurologic related hospitalizations was comparable between the two groups (8.7 vs. 8.0%, p = 0.755; Kaplan–Meier survival curve Log-rank p = 0.652). Using a Cox proportional hazards model, controlling for gender and birth order, no association was found between SGA and the risk for subsequent neurologic pediatric morbidity of the offspring (Adjusted HR = 1.0, 95% CI 0.6–1.8, p = 0.973). Conclusions: SGA is not associated with an increased risk for long-term pediatric neurologic morbidity in dichorionic diamniotic twins. [ABSTRACT FROM AUTHOR]

Purpose: Fetal movements are crucial indicators of fetal well-being, with reduced fetal movements (RFM) suggesting potential fetal compromise. Fetal growth restriction (FGR), often linked to placental insufficiency, is a major cause of perinatal morbidity and mortality. This study aimed to investigate the neonatal, labor, and placental outcomes of FGR pregnancies with and without RFM at term. Methods: In this retrospective study, data from all term, singleton deliveries with FGR and concomitant RFM were obtained and compared to an equal control group of FGR without RFM. Maternal characteristics, pregnancy and neonatal outcomes, and placental histology were compared. The primary outcome was a composite of adverse neonatal outcomes. A multivariable regression analysis was performed to identify independent associations with adverse neonatal outcomes. Results: During the study period, 250 FGR neonates with concomitant RFM and an equal control group were identified. The groups did not differ in maternal demographics aside from significantly higher rates of maternal smoking in the RFM group (p < 0.001). Polyhydramnios and oligohydramnios (p = 0.032 and p = 0.007, respectively) and meconium-stained amniotic fluid (p < 0.001) were more prevalent in the FGR+RFM group. Additionally, the RFM group showed higher rates of adverse neonatal outcomes despite having larger neonates (p = 0.047 and p < 0.001, respectively). No significant differences were observed in placental findings. Logistic regression identified RFM as an independent predictor of adverse neonatal outcomes (aOR 2.45, 95% CI 1.27–4.73, p = 0.008). Conclusion: Reduced fetal movements are significant and independent predictors of worse neonatal outcomes in FGR pregnancies, suggesting an additional acute insult on top of underlying placental insufficiency. [ABSTRACT FROM AUTHOR]