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Objective: To compare morbidity, as measured by length of stay in the neonatal intensive care unit (NICU), in twin and singleton gestations classified as small‐for‐gestational age (SGA) according to estimated fetal weight < 10th percentile on twin or singleton growth charts. Methods: NICU length of stay was compared in 1150 twins and 29 035 singletons that underwent ultrasound assessment between 35 + 0 and 36 + 6 weeks' gestation. Estimated fetal weight was obtained from measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Gestational age was derived from the first‐trimester crown–rump length measurement, using the larger of the two twins. Singletons and twins were compared in terms of NICU admission rate and length of stay according to classification as SGA by the Fetal Medicine Foundation singleton and twin reference distributions. Results: The overall proportions of twins and singletons admitted to NICU were similar (7.3% vs 7.4%), but twins tended to have longer lengths of stay in NICU (≥ 7 days: 2.4% vs 0.8%; relative risk (RR), 3.0 (95% CI, 1.6–4.4)). Using the singleton chart, a higher proportion of twins were classified as SGA compared with singletons (37.6% vs 7.0%). However, the proportion of SGA neonates entering NICU was similar (10.2% for twins and 10.1% for singletons) and the proportion of SGA neonates spending ≥ 7 days in NICU was substantially higher for twins compared with singletons (3.7% vs 1.4%; RR, 2.6 (95% CI, 1.4–4.7)). Conclusions: When singleton charts are used to define SGA in twins and in singletons, there is a greater degree of growth‐related neonatal morbidity amongst SGA twins compared with SGA singletons. Consequently, singleton charts do not inappropriately overdiagnose fetal growth restriction in twins and they should be used for monitoring fetal growth in both twins and singletons. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) seriously threatens perinatal health. The main cause of FGR is placental malperfusion, but the specific mechanism is still unclear, and there is no effective treatment for FGR. We constructed a FGR mouse model by adding exogenous asymmetric dimethylarginine (ADMA) through in vivo experiments and found that ADMA could cause placental dysplasia and induce the occurrence of FGR. Compared with the control group, reactive oxygen species (ROS) production in the placenta was increased in mice with FGR, and the expression of autophagy-related proteins p-AKT/AKT, p-mTOR/mTOR, and P62 was significantly decreased, while the expression of Beclin-1 and LC3-II was significantly increased in the FGR group. Furthermore, ADMA had a favorable effect in promoting the formation of autophagosomes. Hydroxychloroquine (HCQ) and N-acetylcysteine (NAC) improved ADMA-induced disorders of placental development and alleviated ADMA-induced FGR. This study found that ADMA could cause excessive autophagy of trophoblasts by increasing the level of oxidative stress, ultimately leading to the occurrence of FGR, and HCQ and NAC had therapeutic effects on ADMA-induced FGR. [ABSTRACT FROM AUTHOR]

MIRAGE syndrome is a recently described congenital condition characterized genetically by heterozygous gain-of-function missense mutations in the growth repressor sterile alpha domain containing 9 (SAMD9) located on the arm of chromosome 7 (7q21.2). The syndrome is rare and is usually diagnosed in newborns and children with myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy, hence the acronym MIRAGE. The aims of this paper are (1) to present fetal ultrasound features in a case where MIRAGE syndrome was diagnosed prenatally and (2) to review the existing literature records on prenatal manifestations of MIRAGE syndrome. In our case, the fetus had severe early fetal growth restriction (FGR) with normal Doppler studies, atypical genitalia, oligohydramnios, and hyperechogenic bowel at the routine mid-gestation anomaly scan. Amniocentesis excluded infections and numeric or structural chromosomal abnormalities while whole exome sequencing (WES) of the fetal genetic material identified the specific mutation. Targeted testing in parents was negative, suggesting the "de novo" mutation in the fetus. We could not identify other specific case reports in the literature on the prenatal diagnosis of MIRAGE syndrome. In cases reported in the literature where the diagnosis of MIRAGE syndrome was achieved postnatally, there are mentions related to the marked FGR on prenatal ultrasound. Severe early-onset FGR with no other apparent cause seems to be a central prenatal feature in these babies, and WES should be offered, especially if there are other structural abnormalities. Prenatal diagnosis of MIRAGE syndrome is possible, allowing for reproductive choices, improved counseling of parents, and better preparation of neonatal care. [ABSTRACT FROM AUTHOR]

This article examines the limitations of using "small for gestational age" (SGA) as a measure for fetal growth restriction (FGR). The authors argue that SGA does not accurately represent the prevalence or severity of FGR, and it fails to distinguish between high-risk and low-risk infants. They propose alternative approaches, such as incorporating new clinical markers and using unsupervised learning methods, to better define and understand FGR. The authors suggest that abandoning SGA as a criterion for FGR in research could lead to improved insights into the causes and treatment of pathological growth restriction. [Extracted from the article]

Fetal growth restriction (FGR) and small for gestational age (SGA) infants have increased risk of mortality and morbidity. Although both FGR and SGA infants have low birthweights for gestational age, a diagnosis of FGR also requires assessments of umbilical artery Doppler, physiological determinants, neonatal features of malnutrition, and in utero growth retardation. Both FGR and SGA are associated with adverse neurodevelopmental outcomes ranging from learning and behavioral difficulties to cerebral palsy. Up to 50% of FGR, newborns are not diagnosed until around the time of birth, yet this diagnosis lacks further indication of the risk of brain injury or adverse neurodevelopmental outcomes. Blood biomarkers may be a promising tool. Defining blood biomarkers indicating an infant's risk of brain injury would provide the opportunity for early detection and therefore earlier support. The aim of this review was to summarize the current literature to assist in guiding the future direction for the early detection of adverse brain outcomes in FGR and SGA neonates. The studies investigated potential diagnostic blood biomarkers from cord and neonatal blood or serum from FGR and SGA human neonates. Results were often conflicting with heterogeneity common in the biomarkers examined, timepoints, gestational age, and definitions of FGR and SGA used. Due to these variations, it was difficult to draw strong conclusions from the results. The search for blood biomarkers of brain injury in FGR and SGA neonates should continue as early detection and intervention is critical to improve outcomes for these neonates. [ABSTRACT FROM AUTHOR]

Background Fetal growth restriction is associated with perinatal morbidity and mortality. Early identification of women having at-risk fetuses can reduce perinatal adverse outcomes. Objectives To assess the predictive performance of existing models predicting fetal growth restriction and birthweight, and if needed, to develop and validate new multivariable models using individual participant data. Design Individual participant data meta-analyses of cohorts in International Prediction of Pregnancy Complications network, decision curve analysis and health economics analysis. Participants Pregnant women at booking. External validation of existing models (9 cohorts, 441,415 pregnancies); International Prediction of Pregnancy Complications model development and validation (4 cohorts, 237,228 pregnancies). Predictors Maternal clinical characteristics, biochemical and ultrasound markers. Primary outcomes fetal growth restriction defined as birthweight 32 weeks). To assess if the performance of the prediction models is generalisable for various definitions of FGR, and assess the association between various birthweight centiles calculated using customised and population-based standards and perinatal morbidity and mortality. To estimate the net benefit (clinical utility) of the developed prediction models using decision curve analysis (DCA). To assess the costs and outcomes and the potential impact of resource use of the prediction models. Methods We followed existing recommendations for prediction model development and validation and reported in line with guidelines for prognostic research and IPD meta-analysis. Our meta-analysis utilised IPD within the IPPIC Network database. IPPIC is a living data repository of cleaned and harmonised data of pregnant women from large birth or population-based cohorts, study cohort data, registries or unpublished data from hospital records. The primary outcomes were (1) FGR defined as birthweight

BackgroundSmall-for-gestational-age (SGA) fetuses are at increased risk of mortality and morbidity, and less than 30% will be detected by any ultrasound scan within 4 weeks before delivery. Our aim was to evaluate the relationship between neutrophil/lymphocyte ratio (NLR) in the first trimester of pregnancy and SGA fetuses.MethodWe performed a prospective study between June 2021 and August 2022, to evaluate the relationship between the neutrophil to lymphocyte ratio in maternal blood in the first trimester of pregnancy, with the birth of an SGA fetus. One hundred ninety-four participants with singleton pregnancies between 11 + 1 and 13 + 6 weeks of gestation were recruited. Pregnancies affected with diagnosed fetal chromosomal abnormalities, or chronic pathologies were excluded. SGA was defined as birthweight less than the 10th centile (N = 42) and severe SGA as birthweight less than the 3rd centile for gestation (N = 10) according to a locally derived descriptive charts. The NLR value measured in the first trimester was compared between these two groups and controls.ResultsWe found no statistically significant difference in NLR, (3.5 +/−1.2 vs. 3.4+/−1.2, p-value of 0.78) when comparing the SGA less than the 10th centile group to the control group. NLR was also not different between severe SGA and controls (3.6+/−1.4 vs. 3.4+/−1.2 p-value of 0.78).ConclusionWe found no association between first-trimester NLR ratio and SGA.

Introduction: Fetal growth restriction (FGR) is associated with a higher risk of perinatal morbidity and mortality, as well as long-term health issues in newborns. Currently, there is no effective medicine for FGR. Phosphodiesterase-5 (PDE-5) inhibitors have been shown in pre-clinical studies to improve FGR. This study aimed to evaluate the latest evidence about the clinical outcomes and safety of PDE-5 inhibitors for the management of FGR.Methods: Eight databases (PubMed, Embase, Medline, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Database and WangFang Database) were searched for English and Chinese articles published from the database inception to December 2023. Randomized controlled trials (RCTs) reporting the use of PDE-5 inhibitors in FGR were included. The quality of the RCTs was assessed using the Cochrane Risk of Bias Tool. Odds ratio and mean difference (MD) (95% confidence intervals) were pooled for meta-analysis.Results: From 253 retrieved publications, 16 studies involving 1,492 pregnant women met the inclusion criteria. Only sildenafil (15 RCTs) and tadalafil (1 RCT) were studied for FGR. Compared with the control group (placebo, no treatment, or other medication therapies), sildenafil increased birth weight, pregnancy prolongation and umbilical artery pulsatility indices. However, it also increased the risk of pulmonary hypertension in newborns, as well as headache and flushing/rash in mothers. There were no significant differences in gestation age, perinatal mortality or major neonatal morbidity, stillbirth, neonate death, infants admitted to neonatal intensive care unit, intraventricular hemorrhage and necrotizing enterocolitis in infants, as well as pregnancy hypertension and gastrointestinal side effects in mothers between the treatment and the control groups.Discussion: Sildenafil was the most investigated PDE-5 inhibitors for FGR. Current evidence suggests that sildenafil can improve birth weight and duration of pregnancy but at the same time increase the risk of neonatal pulmonary hypertension. It remains uncertain whether the benefits of sildenafil in FGR outweigh the risks and further high-quality RCTs are warranted.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=325909

Placental function plays a crucial role in fetal development, as it serves as the primary interface for delivery of nutrients and oxygen from the mother to fetus. Magnetic resonance imaging (MRI) has significantly improved our ability to visualize and understand the placenta's complex structure and function. This review provides an up-to-date examination of the most common and novel placental MRI techniques. It will also discuss the clinical applications of MRI in diagnosing and monitoring placental insufficiency, as well as its implications for fetal growth restriction (FGR) and congenital heart disease (CHD). Ongoing research using multi-parametric MRI techniques aims to develop novel biomarkers and uncover the relationships between placental parameters and pre-onset diseased states, ultimately contributing to better maternal and fetal health outcomes, which is essential to better guide clinical judgement.

BackgroundPreterm birth and fetal growth restriction are the main determinants of perinatal mortality. In the absence of therapeutic interventions, management is restricted to the observation of fetal growth and fetoplacental perfusion to determine the timing of delivery. Fetal circulatory redistribution, known as “brain sparing,” represents a sign of fetal hypoxia and has been implemented in algorithms for when to deliver. In the absence of any other option, the nitric oxide donor pentaerythrityl tetranitrate (PETN), which has been shown to improve fetoplacental flow and reduce preterm birth in high-risk patients, is offered to patients as a personal therapy attempt. The aim of this study was to evaluate determinants related to pregnancy, including PETN intake during pregnancy, on immediate neonatal outcomes in a cohort of growth-restricted infants born before 32 completed weeks of gestation.MethodsWe performed a retrospective cohort study of 98 infants born with a birth weight below the 10th percentile before 32 completed weeks of gestation at our tertiary care center between 2010 and 2019. PETN was offered to all mothers with a history of severe adverse pregnancy outcomes who were at high risk of developing fetal growth restriction as an individual therapy attempt.ResultsThe mean gestational age at birth was 188.5 days, and the mean birth weight was 549 g, corresponding to a median percentile of three. In 73 (79.3%) cases, brain sparing occurred during pregnancy. A total of 22 (22.4%) neonates were stillborn, 20 died postnatally, and 37.3% developed a severe complication. Multivariable analysis revealed birth weight percentile, gestational age at birth, and gestational age when brain sparing first occurred to be robust predictors of mortality or severe neonatal morbidity. In 39 neonates of mothers taking PETN, this impact of brain sparing was not observed.ConclusionOur study is the first to demonstrate a significant association between the early occurrence of brain-sparing and severe neonatal outcomes in a cohort of very early preterm, growth-restricted newborns. The data suggest that PETN intake may ameliorate the effect of brain sparing in the affected neonates.

Placental macrophages, which include maternal decidual macrophages and fetal Hofbauer cells, display a high degree of phenotypical and functional plasticity. This provides these macrophages with a key role in immunologically driven events in pregnancy like host defense, establishing and maintaining maternal-fetal tolerance. Moreover, placental macrophages have an important role in placental development, including implantation of the conceptus and remodeling of the intrauterine vasculature. To facilitate these processes, it is crucial that placental macrophages adapt accordingly to the needs of each phase of pregnancy. Dysregulated functionalities of placental macrophages are related to placental malfunctioning and have been associated with several adverse pregnancy outcomes. Although fetal growth restriction is specifically associated with placental insufficiency, knowledge on the role of macrophages in fetal growth restriction remains limited. This review provides an overview of the distinct functionalities of decidual macrophages and Hofbauer cells in each trimester of a healthy pregnancy and aims to elucidate the mechanisms by which placental macrophages could be involved in the pathogenesis of fetal growth restriction. Additionally, potential immune targeted therapies for fetal growth restriction are discussed.

Background: The relationship between genetic immune dysregulation and the occurrence of preeclampsia (PE) or PE with fetal growth restriction (PE with FGR) has yielded inconsistent findings, and the underlying mediators of this association remain elusive. We aimed to explore the causal impact of genetic immune dysregulation on the risk of PE or PE with FGR and to elucidate the role of specific transcriptomes in mediating this relationship. Methods: A two-step Mendelian randomization (MR) analysis was performed to explore the link between immune dysregulation and PE or PE with FGR, as well as to identify potential inflammatory biomarkers that act as mediators. GWAS summary data for outcomes were obtained from the FinnGen dataset. The analyses encompassed five systemic immune-associated diseases, four chronic genital inflammatory diseases, and thirty-one inflammatory biomarkers. Summary-data-based MR (SMR) and HEIDI analysis were conducted to test whether the effect size of single nucleotide polymorphisms (SNPs) on outcomes was mediated by the expression of immune-associated genes. Results: The primary univariable analysis revealed a significant positive correlation between systemic lupus erythematosus (SLE), type 1 diabetes (T1D), type 2 diabetes (T2D), and rheumatoid arthritis (RA) with the risk of PE or PE with FGR. Surprisingly, a counterintuitive finding showed a significant negative association between endometriosis of pelvic peritoneum (EMoP) and the risk of PE with FGR. None of the inflammatory factors had a causal relationship with PE or PE with FGR. However, there was a significant association between lymphocyte count and the risk of PE with FGR. Within the lymphocyte subset, both the proportion of Natural Killer (NK) cells and absolute counts of naïve CD4+ T cells demonstrated significant effects on the risk of PE with FGR. Two-step MR analysis underscored the genetically predicted lymphocyte count as a significant mediator between T1D and PE with FGR. Additionally, SMR analysis indicated the potential involvement of SH2B3 in the occurrence of PE with FGR. Conclusions: Our findings provided substantial evidence of the underlying causal relationship between immune dysregulation and PE or PE with FGR and some of these diseases proved to accelerate immune cells disorders and then contribute to the risk of incident PE or PE with FGR.

IntroductionFetuses with growth abnormalities are at an increased risk of adverse neonatal outcomes. The aim of this study was to investigate if placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), or the sFlt-1/PlGF ratio were efficient predictive factors of adverse neonatal outcomes in small-for-gestational-age (SGA) newborns.MethodsA prospective observational multicenter cohort study was performed between 2020 and 2023. At the time of the SGA fetus diagnosis, serum angiogenic biomarker measurements were performed. The primary outcome was an adverse neonatal outcome, diagnosed in the case of any of the following:

Objective: Substance use disorder is a growing concern in the USA, especially among pregnant women. This study was undertaken to assess the impact of substance use disorder on adverse pregnancy outcomes using a nationwide sample of inpatient pregnancy hospitalizations in the USA, and to elucidate the influence on each type of adverse pregnancy outcome. Study design: A cross-sectional analysis of inpatient pregnancy hospitalizations in the USA from the Healthcare Cost and Utilization Project National Inpatient Sample from 2016 to 2020 was conducted. International Classification of Diseases – 10th revision and diagnosis-related group codes were used to identify inpatient pregnancy-related delivery hospitalizations with a substance use disorder and/or adverse pregnancy outcomes. Propensity score matching and multiple logistic regression analyses were undertaken to predict the likelihood of adverse pregnancy outcomes among pregnancy hospitalizations with and without substance use disorder. Subgroup analyses were performed to estimate the impact of substance use disorder on each adverse pregnancy outcome. Results: From 3,238,558 hospitalizations, the prevalence of adverse pregnancy outcomes was substantially higher among pregnancy hospitalizations with substance use disorder (35.6 %) compared with pregnancy hospitalizations without substance use disorder (25.1 %, p

Abstract Background Bisphenol A (BPA) is an environmental contaminant with endocrine-disrupting properties that induce fetal growth restriction (FGR). Previous studies on pregnant ewes revealed that BPA exposure causes placental apoptosis and oxidative stress (OS) and decreases placental efficiency, consequently leading to FGR. Nonetheless, the response of gut microbiota to BPA exposure and its role in aggravating BPA-mediated apoptosis, autophagy, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and OS of the maternal placenta and intestine are unclear in an ovine model of gestation. Results Two pregnant ewe groups (n = 8/group) were given either a subcutaneous (sc) injection of corn oil (CON group) or BPA (5 mg/kg/day) dissolved in corn oil (BPA group) once daily, from day 40 to day 110 of gestation. The maternal colonic digesta and the ileum and placental tissue samples were collected to measure the biomarkers of autophagy, apoptosis, mitochondrial dysfunction, ERS, and OS. To investigate the link between gut microbiota and the BPA-induced FGR in pregnant ewes, gut microbiota transplantation (GMT) was conducted in two pregnant mice groups (n = 10/group) from day 0 to day 18 of gestation after removing their intestinal microbiota by antibiotics. The results indicated that BPA aggravates apoptosis, ERS and autophagy, mitochondrial function injury of the placenta and ileum, and gut microbiota dysbiosis in pregnant ewes. GMT indicated that BPA-induced ERS, autophagy, and apoptosis in the ileum and placenta are attributed to gut microbiota dysbiosis resulting from BPA exposure. Conclusions Our findings indicate the underlying role of gut microbiota dysbiosis and gut-placental axis behind the BPA-mediated maternal intestinal and placental apoptosis, OS, and FGR. The findings further provide novel insights into modulating the balance of gut microbiota through medication or probiotics, functioning via the gut-placental axis, to alleviate gut-derived placental impairment or FGR. Video Abstract

Background. Gestational diabetes mellitus is the most frequent metabolic disorder during pregnancy. Its prevalence is steadily increasing worldwide. In the setting of hyperinsulinism, this pathology may cause various structural and functional changes in the placenta, as well as a reduction in oxygen supply to the fetus. This may result in fetal hypoxia and increased risk of fetal growth restriction. Therefore, research into the specific features of gestation course in patients with gestational diabetes mellitus in order to prevent its complications appears relevant. Objective. To study the specific features of gestation, delivery, and perinatal outcomes in patients with non-insulin dependent gestational diabetes mellitus. Methods. We conducted an observational cohort study of the case histories of 120 women with singleton pregnancies of the second and third trimesters with diagnosed non-insulin dependent gestational diabetes mellitus, their labor and delivery records, and the medical records of the newborns. All the patients were managed at the Ural Research Institute of Maternity and Child Care during 2021–2023. The main group comprised 70 patients whose pregnancy was complicated by sub- and decompensated forms of placental insufficiency. The comparison group comprised 50 pregnant women without pathologies of the fetoplacental complex. The obstetric history, gestation course of the present pregnancy and its outcomes, as well as the condition of the newborns, were analyzed. The obtained data were processed by the methods of variation statistics using Microsoft Excel spreadsheets (Microsoft, USA) and Statistica 13 (DellInc., USA) and MedCalc 15.8 (MedCalcSoftware, Belgium) applications. The null hypothesis was rejected at p > 0.05. Results. Gestational diabetes mellitus in previous pregnancies was statistically significantly less frequent in the main group (2.9% (n = 2)) than in the comparison group (18.0% (n = 9)) ( p > 0.05). Placental insufficiency in the main group was characterized by fetal growth restriction, which was associated with impaired uteroplacental blood flow in 58.6% (n = 41) of the cases. In the main group, the pregnancy ended in preterm delivery in 21.4% (n = 15) of the cases; in 78.6% (n = 55) of the cases, the delivery was at term. There were no preterm births in the comparison group, p > 0.05. Cesarean section was performed in 62.9% (n = 44) of patients in the main group, compared to 20.0% (n = 10) in the comparison group ( p > 0.05). Newborns of the main group required respiratory support more often (p > 0.05). Conclusion. The mechanism of placental insufficiency in patients with non-insulin dependent gestational disorders of carbohydrate metabolism remains to be elucidated. Further research should investigate the predictors of fetoplacental complex pathologies in this group of patients in order to reduce the number of perinatal complications.

The aim of the work is to determine the frequency and impact of prenatal identification of fetal growth restriction (FGR) on obstetric and perinatal outcomes based on a retrospective analysis. Materials and methods. In total, 618 birth histories in singleton normal pregnancies complicated by FGR in the city of Zaporizhzhia were analyzed. Of these, in 546 cases of FGR, women gave birth to live infants (group I), and in 72 such cases, pregnancies ended up in a stillbirth (group II). The mean age of pregnant women in the studied groups was 28.7 ± 3.1 and 31.7 ± 3.1 years and it was significantly greater in group II (p < 0.0001). In all the cases, the gestational age was ≥22 weeks, and the fetal weight was less than the 10th percentile for the relevant gestational age according to the current Order of the Ministry of Health of Ukraine No. 1718 dated 02.10.2023. Growth restriction in newborns was determined according to the criteria of the Consensus Definition (2018) including birth weight the

Background: To investigate the effect and correlation of serum SIRT1 combined with uterine hemodynamic parameters on disease severity and fetal uterine growth restriction in the progression of preeclampsia, and to evaluate its clinical value as potential markers. Methods: A total of 100 patients with preeclampsia who were hospitalized in Qufu Normal University Hospital from June 2017 to June 2021 were selected as the research objects. According to the severity, they were divided into Mild group (62 cases) and Severe group (38 cases), and according to whether the fetal growth restriction was combined or not, they were divided into the Combined fetal growth restriction group (56 cases) and the Uncomplicated fetal growth restriction group (44 cases). Serum SIRT1 levels and uterine artery hemodynamic parameters were detected, and spearman analysis was used to evaluate the association of serum SIRT1 levels and uterine artery hemodynamic parameters (peak-to-trough ratio of arterial blood velocity, pulsatility index, resistance index) with disease severity (systolic blood pressure, diastolic blood pressure, and random urinary protein levels) and fetal growth restriction (femoral length, biparietal diameter, head circumference and neonatal weight); unsupervised PCA analysis, supervised PLS-DA analysis, Cluster heat map analysis, ROC curve and AUC analysis were used to evaluate the diagnostic value of serum SIRT1 levels combined with uterine artery hemodynamic parameters in the severity of disease and fetal growth restriction in patients with preeclampsia. Results: Serum SIRT1 levels was decreased in patients with severe preeclampsia (p < 0.0001), arterial blood flow velocity peak-to-trough ratio, pulsatility index and resistance index were increased (p < 0.001; p < 0.0001), and serum SIRT1 levels and uterine artery hemodynamic parameters were closely related to disease severity (p < 0.001; p < 0.0001). In addition, the levels of serum SIRT1 in patients with preeclampsia combined with fetal growth restriction was decreased (p < 0.0001), the peak-to-trough ratio of arterial blood flow velocity, pulsatility index and resistance index were increased (p < 0.0001), and serum SIRT1 levels and uterine artery hemodynamics were closely related to fetal growth restriction (p < 0.0001). Unsupervised PCA analysis and supervised PLS-DA analysis showed that patients with different severity of disease and patients with or without fetal growth restriction were similar within groups, and there were significant differences between groups; cluster heat map analysis showed that mild and severe groups were stratified clustering, the combined fetal growth restriction group and the uncombined group were hierarchically clustered; ROC curve and AUC analysis showed that serum SIRT1 levels combined with uterine artery hemodynamic parameters had a significant effect on the severity of preeclampsia and whether combined with fetal growth restriction high diagnostic value. Conclusions: Serum SIRT1 combined with uterine hemodynamic parameters in preeclampsia is closely related to disease severity and fetal growth restriction, and is expected to become potential biomarkers for early clinical intervention in patients.

Intrauterine restriction of fetal growth is one of the most interestings and nowadays intensively studied problems of modern obstetrics. Fetal growth restriction can lead to significant obstetric complications, as well as consequences after delivery. For the obstetricians the fetal growth means iatrogenic prematurity, fetal distress, perinatal morbidity but also long term consequences as metabolic disease, cardiovascular pathology and Alzhaimer disease. There was considerable controversy as to how fetal growth restriction should be defined and diagnosed. Biometric and biophysical tests have been proposed to diagnose growth restriction, but until recently there were no unanimously accepted standards for the diagnosis of this pathology. This definition was reached in 2021 by the FIGO publication. Under the condition of intrauterine hypoxia adaptation mechanisms are activated. Understanding the ongoing pathophysiological process of adaptation in a hypoxic media helps to better understand proposed diagnosis criteria and the classification.

Objectives: The objective of the study is to study the fetomaternal outcome associated with folic acid deficiency in pregnancy. Materials and Methods: This hospital-based observational study was conducted in the Department of Obstetrics and Gynaecology at Base Hospital, Delhi Cantt, and a total of 351 participants were enrolled who were fulfilling the inclusion criteria. The plasma folic acid level of the selected patients was measured in the booking visit by automated chemiluminescence assay. The cutoff levels of folic acid were taken at 8.6 ng/mL. Based on these values, the study population was divided into two groups, one with folic acid values

Fetal growth restriction (FGR) is one of the most studied topics in the medicine of the mother and fetus. However, not identified antenatally FGR can have an increased risk of both perinatal morbidity and mortality, as well as adverse long-term consequences. The identification of FGR during pregnancy will contribute to the reduction of both perinatal morbidity and perinatal mortality. Aim. Based on a retrospective analysis, assess the obstetric and perinatal consequences of childbirth in women with antenatally undiagnosed fetal growth restriction. Materials and methods. An analysis of 488 cases of childbirth in women with singleton pregnancy, who gave birth to a live child, was conducted. In all cases, the gestational age was ≥22 weeks with a fetal weight less than the 10th percentile for the corresponding gestational age. Depending on the antenatally established diagnosis of FGR, two study groups were formed: group I consisted of 204 (41.8 %) cases with antenatally diagnosed FGR, group II – 284 (58.2 %) cases in which signs of FGR were identified after the birth of the child. Maternal characteristics, neonatal outcomes, and evaluation of short-term infant outcomes were analyzed. Results. Both groups were dominated by women with first births, the number of which was almost the same. Somatic pathology was almost 2 times more common in women of group I, 17.2 %, compared to 9.2 % of women in group II (p < 0.01), this indicates that the majority of women who were not diagnosed with FGR during pregnancy belong to the low-risk group. Fetuses with impaired blood flow in the umbilical cord arteries were twice as common in group I, 49.5 % versus 23.9 % in group II (p < 0.0001), and the frequency of absent/reversible end flow in the umbilical arteries in group I compared to group II, prevailed 3 times (p < 0.0001), indicating more serious lesions of the placenta and, as a result, early manifestation of the fetal condition disorder. The frequency of premature abdominal delivery was 3.75 times higher in group I compared to group II. The most frequent indication for cesarean delivery in both groups was signs of fetal distress syndrome. Analysis of neonatal outcomes showed that the average birth weight was significantly lower in group I and was 2180 ± 55 g against 2420 ± 61 g in group II (p < 0.0001). The need for hospitalization of newborns in the intensive care unit had no statistical difference between the groups (p > 0.05). However, the complications of the early neonatal period and the total length of stay in the hospital were greater in children of the I group, compared to the II group (p < 0.0001). Conclusions. The results of the conducted research indicate a low level of prenatal diagnosis of fetal growth restriction. Most pregnant women with antenatally undiagnosed fetal growth restriction belong to the group of low perinatal risk. The most frequent indication for cesarean section operation, regardless of the date of delivery, in both groups were signs of fetal distress, the frequency of which was 1.5 times higher in the antenatally diagnosed fetal growth retardation group. Newborns with an undetected growth anomaly before delivery have an increased risk of fetal distress, the severity of which is determined by the degree of deterioration of fetal oxygenation, and not by weight percentile, which requires more careful observation of fetuses with signs of growth restriction.

A Breus’ mole is a massive subchorionic thrombohematoma that arises below the chorionic plate on the fetal side of the placenta. It requires careful perinatal management because of the associated high incidence of severe fetal growth restriction and intrauterine fetal demise. However, the mechanism of its development remains unclear, and there are no reports examining the continuous changes in the hematomas. Herein, we report a case of a Breus’ mole in which ultrasonographic massive subchorionic thrombohematoma changes were observed during pregnancy. A 40-year-old pregnant patient presented with fetal growth restriction, a hematoma with a highly echoic lesion, and an extremely thickened placenta. The clinical picture of massive subchorionic thrombohematoma gradually changed from a high-echoic phase with a 7-cm thick placenta to a high- and low-echoic mixed phase to a completely low-echoic phase with a prominent atrophic placenta (placental thickness = 3.5 cm) in almost 8 weeks. At 34 weeks of gestation, a male infant was delivered via cesarean section due to its nonreassuring fetal status with extremely low birth weight (1230 g). Postpartum histological findings revealed the presence of a Breus’ mole. In conclusion, we observed the ultrasonographic changes of the massive subchorionic thrombohematoma that were detected as a placental hemorrhagic infarction by magnetic resonance imaging, from a high- to low-echoic area. The clinical course from massive subchorionic thrombohematoma to Breus’ mole may be a prominent atrophic change in the placental tissue during pregnancy. These sequential ultrasonographic findings could be a key factor in understanding the pathophysiology of Breus’ moles.

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.

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.

Background During pregnancy, the placenta is an extremely important organ as it secretes its own hormones, e.g. insulin-like growth factor 1 (IGF-1), to ensure proper intrauterine fetal growth and development. Ethanol, an addictive and widely used drug, has numerous adverse effects during pregnancy, including fetal growth restriction (FGR). To date, the molecular mechanisms by which ethanol triggers its toxic effects during pregnancy, particularly in the placenta, are not entirely known. For this reason, a murine model of partial IGF-1 deficiency was used to determine ethanol alterations in placental morphology and AAH expression. Methods Heterozygous (HZ, Igf1 +/- ) female mice were given 10% ethanol during 14 days as an acclimation period and throughout pregnancy. HZ female mice given water were used as controls. At gestational day 19, pregnant dams were sacrificed, placentas were collected and genotyped for subsequent studies. Results IGF-1 deficiency and ethanol consumption during pregnancy altered placental morphology, and decreased placental efficiency and aspartyl/asparaginyl β-hydroxylase (AAH) expression in placentas from all genotypes. No differences were found in Igf1, Igf2, Igf1r and Igf2r mRNA expression in placentas from all groups. Conclusions IGF-1 deficiency and ethanol consumption throughout gestation altered placental development, suggesting the crucial role of IGF-1 in the establishment of an adequate intrauterine environment that allows fetal growth. However, more studies are needed to study the precise mechanism to stablish the relation between both insults.

Introduction: With the aim of optimizing the balance of maintaining a safe oxygen saturation and reducing the risk of retinopathy of prematurity in human neonates with fetal growth restriction (FGR), the present study investigated the distinct effects of oxygen supplementation on the retinal neovasculature using a murine premature neonatal oxygen-induced retinopathy (OIR) model with or without fetal growth restriction. Methods: For comparisonwith normal birth-weight neonates, maternal low-protein diet-induced FGR neonates were subjected to fluctuating oxygen levels to generate oxygen-induced retinopathy. The retinal neovasculature was histologically evaluated, and comprehensive transcriptome analysis was conducted. Results: Compared to OIR neonates with normal birth weight, significant amelioration of the neovasculature, as indicated by decreases in the number of branch junctions, vascular distribution,maximal vascular radius andmicroaneurysmlike tufts, was observed in OIR mice with FGR. The results of retinal RNA-sequencing revealed downregulation of angiogenic factors that trigger pathological retinal neovascularization, such as the mitogen-activated protein kinase pathway and corresponding upstream signaling pathways in OIR mice with FGR. Conclusion: Our findings demonstrated that FGR neonates have a higher capacity for retinal oxygen stress, and the risk of OIR development is attenuated compared to that in mature neonates with normal birth weight. [ABSTRACT FROM AUTHOR]

Background: Bisphenol A (BPA) is an environmental contaminant with endocrine-disrupting properties that induce fetal growth restriction (FGR). Previous studies on pregnant ewes revealed that BPA exposure causes placental apoptosis and oxidative stress (OS) and decreases placental efficiency, consequently leading to FGR. Nonetheless, the response of gut microbiota to BPA exposure and its role in aggravating BPA-mediated apoptosis, autophagy, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and OS of the maternal placenta and intestine are unclear in an ovine model of gestation. Results: Two pregnant ewe groups (n = 8/group) were given either a subcutaneous (sc) injection of corn oil (CON group) or BPA (5 mg/kg/day) dissolved in corn oil (BPA group) once daily, from day 40 to day 110 of gestation. The maternal colonic digesta and the ileum and placental tissue samples were collected to measure the biomarkers of autophagy, apoptosis, mitochondrial dysfunction, ERS, and OS. To investigate the link between gut microbiota and the BPA-induced FGR in pregnant ewes, gut microbiota transplantation (GMT) was conducted in two pregnant mice groups (n = 10/group) from day 0 to day 18 of gestation after removing their intestinal microbiota by antibiotics. The results indicated that BPA aggravates apoptosis, ERS and autophagy, mitochondrial function injury of the placenta and ileum, and gut microbiota dysbiosis in pregnant ewes. GMT indicated that BPA-induced ERS, autophagy, and apoptosis in the ileum and placenta are attributed to gut microbiota dysbiosis resulting from BPA exposure. Conclusions: Our findings indicate the underlying role of gut microbiota dysbiosis and gut-placental axis behind the BPA-mediated maternal intestinal and placental apoptosis, OS, and FGR. The findings further provide novel insights into modulating the balance of gut microbiota through medication or probiotics, functioning via the gut-placental axis, to alleviate gut-derived placental impairment or FGR. DorkkcsjvJM4thb48aSHyr Video Abstract [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a gestational disorder characterized by hyperglycemia, that can lead to dysfunction of diverse cells in the body, especially the immune cells. It has been reported that immune cells, specifically natural killer (NK) cells, play a crucial role in normal pregnancy. However, it remains unknown how hyperglycemia affects NK cell dysfunction thus participates in the development of GDM. In this experiment, GDM mice were induced by an intraperitoneal injection of streptozotocin (STZ) after pregnancy and it has been found that the intrauterine growth restriction occurred in mice with STZ-induced GDM, accompanied by the changed proportion and function of NK cells. The percentage of cytotoxic CD27-CD11b+ NK cells was significantly increased, while the proportion of nourished CD27-CD11b- NK cells was significantly reduced in the decidua of GDM mice. Likewise, the same trend appeared in the peripheral blood NK cell subsets of GDM patients. What's more, after intrauterine reinfusion of NK cells to GDM mice, the fetal growth restriction was alleviated and the proportion of NK cells was restored. Our findings provide a theoretical and experimental basis for further exploring the pathogenesis of GDM. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is characterized by maternal hypertension and placental dysfunction, often leading to fetal growth restriction (FGR). It is associated with an overexpression of the anti-angiogenic sFLT1 protein, which originates from the placenta and serves as a clinical biomarker to predict PE. To analyze the impact of sFLT1 on placental function and fetal growth, we generated transgenic mice with placenta-specific human sFLT1 (hsFLT1) overexpression. Immunohistochemical, morphometrical, and molecular analyses of the placentas on 14.5 dpc and 18.5 dpc were performed with a focus on angiogenesis, nutrient transport, and inflammation. Additionally, fetal development upon placental hsFLT1 overexpression was investigated. Dams exhibited a mild increase in serum hsFLT1 levels upon placental hsFLT1 expression and revealed growth restriction of the fetuses in a sex-specific manner. Male FGR fetuses expressed higher amounts of placental hsFLT1 mRNA compared to females. FGR placentas displayed an altered morphology, hallmarked by an increase in the spongiotrophoblast layer and changes in labyrinthine vascularization. Further, FGR placentas showed a significant reduction in placental glycogen storage and nutrient transporter expression. Moreover, signs of hypoxia and inflammation were observed in FGR placentas. The transgenic spongiotrophoblast-specific hsFLT1 mouse line demonstrates that low hsFLT1 serum levels are sufficient to induce significant alterations in fetal and placental development in a sex-specific manner. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether different grades of subchorionic hematoma (SCH) are involved in the timing of birth and the development of adverse pregnancy outcomes in singleton pregnant women. Methods: A total of 171 women with singleton pregnancies, 72 of whom had SCH before 20 weeks and between 12 and 20 weeks of gestational age (GA), were included in this study conducted between January 2018 and December 2021. These patients were divided into three subgroups based on the size of the subchorionic hematoma on ultrasound imaging. Baseline demographic data, obstetric outcomes, and risk factors for subchorionic hematoma were compared for the two groups. Results: A higher number of pregnancies from the SCH group resulted in miscarriage (30.56% versus 2.02%, p < 0.0001), early preterm birth (8.33% versus 1.01%, p = 0.0035), premature rupture of membranes (15.28% versus 4.04%, p = 0.0103), fetal growth restriction (9.72% versus 0%, p = 0.0015), and delivery 13.18 days earlier (274.34 ± 11.25 versus 261.16 ± 29.80, p = 0.0013) than those from the control group. Compared with SCH detected before 12 weeks of GA, the rate of miscarriage increased, and the live birth rate decreased significantly in patients with SCH caught between 12 and 20 weeks of GA. With the increase in hematoma size, the likelihood of miscarriage increased significantly. Further analysis found that delivery occurred earlier in the medium/large SCH group (271.49 ± 23.61 versus 253.28 ± 40.68/261.77 ± 22.11, p = 0.0004/0.0073) but not in the small SCH group (274.34 ± 11.25 versus 267.85 ± 21.01, p = 0.2681) compared to the control group. Our results also showed that the anterior placenta (52.04% versus 33.33%, p = 0.0005, OR = 0.3137, 95% CI [0.1585, 0.601]) is a protective factor for subchorionic hematoma. Conclusion: Our study shows that women with SCH are at a higher risk of adverse pregnancy outcomes and are independently associated with miscarriage, early preterm birth, premature rupture of membranes, and fetal growth restriction. A subchorionic hematoma, especially detected between 12 and 20 weeks of GA, is very likely to cause miscarriage or preterm birth in women with a medium or large subchorionic hematoma. [ABSTRACT FROM AUTHOR]

Objective: To compare the femoral artery and other ultrasonographic Doppler measurements between fetuses with late-onset fetal growth restriction and uncomplicated fetuses. Material and Method: This prospective cohort study was conducted with 168 patients, including 83 pregnancies presenting with late-onset fetal growth restriction and 85 uncomplicated control pregnancies at similar gestational weeks. The study group was further divided into two according to the neonatal intensive care unit requirements. Demographic characteristics, obstetric characteristics, femoral artery and other ultrasonographic Doppler measurements, and pregnancy outcomes were compared between the groups. Results: Uterine artery pulsatility index, umbilical artery systolic/diastolic ratio, and peak systolic velocity of the middle cerebral artery were similar between the study and control groups. However, while the middle cerebral artery pulsatility index was significantly lower in the study group, the femoral artery pulsatility index value was significantly higher (p<0.001 and p=0.002, respectively). When the two subgroups of the study group were compared according to the neonatal intensive care unit requirements, their femoral artery and other Doppler measurements were similar. Estimated fetal weight was statistically lower in the group requiring neonatal intensive care unit (p=0.033). Conclusion: The femoral artery pulsatility index measurement was higher in the late-onset fetal growth restriction cases than in the healthy controls. The Doppler examination of the femoral artery was not found to be effective in demonstrating adverse perinatal outcomes. [ABSTRACT FROM AUTHOR]

Background: During the early stages of human fetal development, the fetal skeleton system is chiefly made up of cartilage, which is gradually replaced by bone. Fetal bone development is mainly regulated by the parathyroid hormone parathormone (PTH) and PTH-related protein, with specific calprotectin playing a substantial role in cell adhesion and chemotaxis while exhibiting antimicrobial activity during the inflammatory osteogenesis process. The aim of our study was to measure the levels of PTH and calprotectin in early second trimester amniotic fluid and to carry out a comparison between the levels observed among normal full-term pregnancies (control group) and those of the groups of embryos exhibiting impaired or enhanced growth. Methods: For the present prospective study, we collected amniotic fluid samples from pregnancies that underwent amniocentesis at 15 to 22 weeks of gestational age during the period 2021–2023. Subsequently, we followed up on all pregnancies closely until delivery. Having recorded fetal birthweights, we then divided the neonates into three groups: small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). Results: In total, 64 pregnancies, including 14 SGA, 10 LGA, and 40 AGA fetuses, were included in our study. Both substances were detected in early second trimester amniotic fluid in both groups. Concentrations of calprotectin differed significantly among the three groups (p = 0.033). AGA fetuses had a lower mean value of 4.195 (2.415–6.425) IU/mL, whereas LGA fetuses had a higher mean value of 6.055 (4.887–13.950) IU/mL, while SGA fetuses had a mean value of 5.475 (3.400–9.177) IU/mL. Further analysis revealed that only LGA fetuses had significantly higher calprotectin concentrations compared to AGA fetuses (p = 0.018). PTH concentration was similar between the groups, with LGA fetuses having a mean value of 13.18 (9.51–15.52) IU/mL, while SGA fetuses had a mean value of 14.18 (9.02–16.00) IU/mL, and AGA fetuses had similar concentrations of 13.35 (9.05–15.81) IU/mL. The differences in PTH concentration among the three groups were not statistically significant (p = 0.513). Conclusions: Calprotectin values in the amniotic fluid in the early second trimester were higher in LGA fetuses compared to those in the SGA and AGA categories. LGA fetuses can possibly be in a state of low-grade chronic inflammation due to excessive fat deposition, causing oxidative stress in LGA fetuses and, eventually, the release of calprotectin. Moreover, PTH concentrations in the amniotic fluid of early second trimester pregnancies were not found to be statistically correlated with fetal growth abnormalities in either LGA or SGA fetuses. However, the early time of collection and the small number of patients in our study should be taken into account. [ABSTRACT FROM AUTHOR]

Objective To investigate the clinical significance of combining matemal serum placental growth factor (PLGF) levels with maternal and fetal vascular parameters in predicting fetal growth restriction (FGR). Methods Sixty pregnant women diagnosed with FGR (FGR group) and 60 pregnant women with routine prenatal examinations (Healthy group) were selected. Maternal serum PLGF levels were measured using enzyme linked immunosorbent assay. Ultra-sonography was performed on pregnant women at gestational weeks 20-24 to assess parameters including uterine artery (UtA), middle cerebral artery (MCA), and umbilical artery (UA) resistance index (RI), pulsatility index (PI), and systolic/diastolic blood flow ratio (S/D). ROC curves were plotted to evaluate the predictive value of maternal serum PL-GF levels combined with maternal and fetal vascular parameters for FGR. Multiple logistic regression analysis was conduc- ted to identify factors influencing the occurrence of FGR. Results The FGR group showed significantly higher RI, PI, and S/D in UtA and UA, while serum PLGF levels, as well as RI, PI, and S/D in MCA, were significantly lower com- pared to the Healthy group (P<0.05). ROC curve analysis indicated that UtA-S/D, MCA-PI, UA-RI, and UA- PI had high sensitivity, while PLGF, UA-S/D, and MCA - S/D exhibited high specificity, all exceeding 90%. Multiple logistic regression analysis revealed that UtA - RI, UA-PI, UtA-S/D, MCAPI, MCA-S/D, UA-RI, UA-PI, UA-S/D, and PLGF were factors influencing the occurrence of FGR (P<0.05). Conclusion Lower maternal serum PLGF levels and abnormal maternal fetal vascular parameters can serve as potential indicators for predicting the occurrence of FGR in pregnant women. [ABSTRACT FROM AUTHOR]

Objective The relationship between FMF and pregnancy outcomes remains unclear. This systematic review and meta-analysis aimed to clarify this association. Methods Electronic databases—PubMed, Web of Science, Cochrane, and EMBASE—were searched on 20 December 2022, using specific search terms. Case–control, cohort, and randomized clinical trial studies comparing patients with FMF and healthy controls were considered eligible. We excluded systematic reviews, meta-analyses, case series with fewer than five cases, republished articles without new findings on pregnancy outcomes, studies targeting paternal FMF, and those not published in English. The results were summarized in the form of odds ratios (ORs) and 95% CIs, using a random-effects model. This study was registered in the University hospital Medical Information Network Clinical Trials Registry (Japan) as UMIN000049827. Results The initial electronic search identified 611 records, of which 9 were included in this meta-analysis (177 735 pregnancies, 1242 with FMF, and 176 493 healthy controls). FMF was significantly associated with increased odds of preterm deliveries (OR, 1.67; 95% CI, 1.05–2.67; I 2 = 22%) and insignificantly associated with increased odds of fetal growth restriction (OR, 1.45; 95% CI, 0.90–2.34; I 2 = 0%) and hypertensive disorders during pregnancy (OR, 1.28; 95% CI, 0.87–1.87; I 2 = 0%). Conclusion FMF was significantly associated with preterm delivery and insignificantly associated with fetal growth restriction and hypertensive disorders. All of the included studies were observational studies. Treatment characteristics were not fully collected from the articles, and further analysis of treatments for FMF in pregnancy is still warranted. [ABSTRACT FROM AUTHOR]

Introduction: Cerebroplacental ratio (CPR) has been shown to be an independent predictor of adverse perinatal outcome at term and a marker of failure to reach the growth potential (FRGP) regardless of fetal size, being abnormal in compromised fetuses with birthweight above the 10th centile. The main aim of this study was to propose a risk‐based approach for the management of pregnancies with normal estimated fetal weight (EFW) and abnormal CPR near term. Material and methods: This was a retrospective study of 943 pregnancies, that underwent an ultrasound evaluation of EFW and CPR at or beyond 34 weeks. CPR values were converted into multiples of the median (MoM) and EFW into centiles according to local references. Pregnancies were then divided into four groups: normal fetuses (defined as EFW ≥10th centile and CPR ≥0.6765 MoM), small for gestational age (EFW <10th centile and CPR ≥0.6765 MoM), fetal growth restriction (EFW <10th centile and CPR <0.6765 MoM), and fetuses with apparent normal growth (EFW ≥10th centile) and abnormal CPR (<0.6765 MoM), that present FRGP. Intrapartum fetal compromise (IFC) was defined as an abnormal intrapartum cardiotocogram or pH requiring cesarean delivery. Risk comparisons were performed among the four groups, based on the different frequencies of IFC. The risks of IFC were subsequently extrapolated into a gestational age scale, defining the optimal gestation to plan the birth for each of the four groups. Results: Fetal growth restriction was the group with the highest frequency of IFC followed by FRGP, small for gestational age, and normal groups. The "a priori" risks of the fetal growth restriction and normal groups were used to determine the limits of two scales. One defining the IFC risk and the other defining the appropriate gestational age for delivery. Extrapolation of the risk between both scales placed the optimal gestational age for delivery at 39 weeks of gestation in the case of FRGP and at 40 weeks in the case of small for gestational age. Conclusions: Fetuses near term may be evaluated according to the CPR and EFW defining four groups that present a progressive risk of IFC. Fetuses in pregnancies complicated by FRGP are likely to benefit from being delivered at 39 weeks of gestation. [ABSTRACT FROM AUTHOR]

We report the case of a four-year-old male patient with a complex medical history born prematurely as the result of intrauterine growth restriction due to placental insufficiency. His clinical manifestations included severe neurodevelopmental deficits, global developmental delay, Pierre-Robin sequence, and intractable epilepsy with both generalized and focal features. The proband's low levels of citrulline and lactic acidosis provoked by administration of Depakoke were evocative of a mitochondrial etiology. The proband's genotype–phenotype correlation remained undefined in the absence of nuclear and mitochondrial pathogenic variants detected by deep sequencing of both genomes. However, live-cell mitochondrial metabolic investigations provided evidence of a deficient oxidative-phosphorylation pathway responsible for adenosine triphosphate (ATP) synthesis, leading to chronic energy crisis in the proband. In addition, our metabolic analysis revealed metabolic plasticity in favor of glycolysis for ATP synthesis. Our mitochondrial morphometric analysis by transmission electron microscopy confirmed the suspected mitochondrial etiology, as the proband's mitochondria exhibited an immature morphology with poorly developed and rare cristae. Thus, our results support the concept that suboptimal levels of intrauterine oxygen and nutrients alter fetal mitochondrial metabolic reprogramming toward oxidative phosphorylation (OXPHOS) leading to a deficient postnatal mitochondrial energy metabolism. In conclusion, our collective studies shed light on the long-term postnatal mitochondrial pathophysiology caused by intrauterine growth restriction due to idiopathic placental insufficiency and its negative impact on the energy-demanding development of the fetal and postnatal brain. [ABSTRACT FROM AUTHOR]

Objective: To derive reference distributions of estimated fetal weight (EFW) in twins relative to singletons. Methods: Gestational‐age‐ and chorionicity‐specific reference distributions for singleton percentiles and EFW were fitted to data on 4391 twin pregnancies with two liveborn fetuses from four European centers, including 3323 dichorionic (DC) and 1068 monochorionic diamniotic (MCDA) twin pregnancies. Gestational age was derived using the larger of the two crown–rump length measurements obtained during the first trimester of pregnancy. EFW was obtained from ultrasound measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Singleton percentiles were obtained using the Fetal Medicine Foundation population weight charts for singleton pregnancies. Hierarchical models were fitted to singleton Z‐scores with autoregressive terms for serial correlations within the same fetus and between twins from the same pregnancy. Separate models were fitted for DC and MCDA twins. Results: Fetuses from twin pregnancies tended to be smaller than singletons at the earliest gestational ages (16 weeks for MCDA and 20 weeks for DC twins). This was followed by a period of catch‐up growth until around 24 weeks. After that, both DC and MCDA twins showed reduced growth. In DC twins, the EFW corresponding to the 50th percentile was at the 50th percentile of singleton pregnancies at 23 weeks, the 43rd percentile at 28 weeks, the 32nd percentile at 32 weeks and the 22nd percentile at 36 weeks. In MCDA twins, the EFW corresponding to the 50th percentile was at the 36th percentile of singleton pregnancies at 24 weeks, the 29th percentile at 28 weeks, the 19th percentile at 32 weeks and the 12th percentile at 36 weeks. Conclusions: In DC and, to a greater extent, MCDA twin pregnancies, fetal growth is reduced compared with that observed in singleton pregnancies. Furthermore, after 24 weeks, the divergence in growth trajectories between twin and singleton pregnancies becomes more pronounced as gestational age increases. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: Most of the published literature on selective fetal growth restriction (sFGR) has focused on monochorionic twin pregnancies. The aim of this systematic review was to report on the outcome of dichorionic diamniotic (DCDA) twin pregnancies complicated by sFGR. Methods: MEDLINE, EMBASE and The Cochrane Library databases were searched. The inclusion criteria were DCDA twin pregnancies complicated by sFGR. The outcomes explored were intrauterine death (IUD), neonatal death and perinatal death (PND), survival of at least one and both twins, preterm birth (PTB) (either spontaneous or iatrogenic) prior to 37, 34, 32 and 28 weeks' gestation, pre‐eclampsia (PE) or gestational hypertension, neurological, respiratory and infectious morbidity, Apgar score < 7 at 5 min, necrotizing enterocolitis, retinopathy of prematurity and admission to the neonatal intensive care unit (NICU). A composite outcome of neonatal morbidity, defined as the occurrence of respiratory, neurological or infectious morbidity, was also evaluated. Random‐effects meta‐analysis was used to analyze the data, and results are reported as pooled proportion or odds ratio (OR) with 95% CI. Results: Thirteen studies reporting on 1339 pregnancies with sFGR and 6316 pregnancies without sFGR were included. IUD occurred in 2.6% (95% CI, 1.1–4.7%) of fetuses from DCDA pregnancies with sFGR and 0.6% (95% CI, 0.3–9.7%) of those from DCDA pregnancies without sFGR, while the respective values for PND were 5.2% (95% CI, 3.5–7.3%) and 1.7% (95% CI, 0.1–5.7%). Spontaneous or iatrogenic PTB before 37 weeks complicated 84.1% (95% CI, 55.6–99.2%) of pregnancies with sFGR and 69.1% (95% CI, 45.4–88.4%) of those without sFGR. The respective values for PTB before 34, 32 and 28 weeks were 18.4% (95% CI, 4.4–38.9%), 13.0% (95% CI, 9.5–17.1%) and 1.5% (95% CI, 0.6–2.3%) in pregnancies with sFGR and 10.2% (95% CI, 3.1–20.7%), 7.8% (95% CI, 6.8–9.0%) and 1.8% (95% CI, 1.3–2.4%) in those without sFGR. PE or gestational hypertension complicated 19.9% (95% CI, 12.4–28.6%) of pregnancies with sFGR and 12.8% (95% CI, 10.4–15.4%) of those without sFGR. Composite morbidity occurred in 28.2% (95% CI, 7.8–55.1%) of fetuses from pregnancies with sFGR and 13.9% (95% CI, 6.5–23.5%) of those from pregnancies without sFGR. When stratified according to the sFGR status within a twin pair, composite morbidity occurred in 39.0% (95% CI, 11.1–71.5%) of growth‐restricted fetuses and 29.9% (95% CI, 3.5–65.0%) of appropriately grown fetuses (OR, 1.9 (95% CI, 1.7–3.1)), while the respective values for PND were 3.0% (95% CI, 1.8–4.5%) and 1.6% (95% CI, 0.9–2.6%) (OR, 2.1 (95% CI, 1.0–4.1)). On risk analysis, DCDA pregnancies complicated by sFGR had a significantly higher risk of IUD (OR, 5.2 (95% CI, 3.2–8.6)) and composite morbidity or admission to the NICU (OR, 3.2 (95% CI, 1.9–5.6)) compared to those without sFGR, while there was no difference in the risk of PTB before 34 weeks (P = 0.220) or PE/gestational hypertension (P = 0.210). Conclusions: DCDA twin pregnancies complicated by sFGR are at high risk of perinatal morbidity and mortality. The findings of this systematic review are relevant for counseling and management of complicated DCDA twin pregnancies, in which twin‐specific, rather than singleton, outcome data should be used. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) can lead to fetal mental development abnormalities, malformations, and even intrauterine death. Defects in the trophoblasts at the maternal-fetal interface may contribute to FGR. However, the impact of trophoblasts on FGR is still not well understood. Therefore, the objective of this study is to characterize the heterogeneity of placental cells at the single-cell level and investigate the role of trophoblast subtypes in the pathogenesis of FGR at the cellular and molecular levels. Single-cell RNA sequencing was performed on the maternal side of placentas from two normal pregnant women and two pregnant women with FGR. Lentivirus transfection was used to establish a FN1 knockout model in trophoblast HTR-8-Svneo cells. The effect of FN1 knockout on cell migration and invasion of HTR-8-Svneo cells was assessed through wound healing and transwell assays. Nine cell types were annotated in 39,161 cells derived from single-cell RNA sequencing. The FGR group exhibited a decrease in the percentage of trophoblasts, especially in subtype of extravillous trophoblasts (EVTs). The expression of FN1 was reduced in trophoblasts and EVTs. Furthermore, the protein expression levels of FN1 in the placentas of FGR patients were significantly lower than those of normal pregnant women. The cell migration and invasion ability of HTR-8-Svneo cells were inhibited after the knockdown of FN1. The dysregulation of the trophoblast subtype-EVTs is involved in placental dysplasia related to FGR. The association between aberrant placental trophoblasts and reduced FN1 expression may contribute to insufficient remodeling of spiral arteries and the formation of FGR. • The cell composition and gene expression profile in trophoblasts were remodeled in FGR. • FN1 expression in the placentas of FGR patients is lower than that in normal. • The reduced FN1 induces FGR through attenuating cell invasion of trophoblasts. [ABSTRACT FROM AUTHOR]

We aimed to examine the effect of uterine arterial (UtA) blood flow changes after tadalafil treatment for fetal growth restriction (FGR) using two-dimensional (2D) phase-contrast magnetic resonance imaging (PC-MRI). We recruited 14 pregnant women with FGR aged 20–44 years, at ≥20 weeks' gestation, between May 2019 and July 2020. They underwent 2D PC-MRI for UtA blood flow measurement 3 days (interquartile range: 2–4) after diagnosis. This group (FGR group) was compared with 14 gestational age (GA)-matched healthy pregnant women (control group). Six patients in the FGR group received treatment with tadalafil administered at 20 mg twice daily after the first MRI until delivery. They underwent a second MRI a week later. The median total UtA blood/body surface area was 420 mL/min/m2 (290–494) in the FGR group and 547 mL/min/m2 (433–681) in the control group (p = 0.01). Percent increase in blood flow were significantly different between the FGR cases treated with tadalafil and control at 15.8 % (14.3–21.3) and 4.2 % (3.6–8.7), respectively (p = 0.03). UtA blood flow in pregnant women with FGR was significantly lower than that in healthy pregnant women. Tadalafil is expected to improve UtA blood flow, thereby improving placental function in pregnant patients with FGR. • Two-dimensional PC-MRI can accurately measure uterine arterial blood flow. • Tadalafil may improve UtA blood flow and placental function in patients with FGR. • Pregnant women with FGR had much less UtA blood flow than healthy pregnant women. • Estimated fetal body weight was greater in the tadalafil-treated FGR group. [ABSTRACT FROM AUTHOR]

Pregnant individuals with sickle cell disease have an increased risk of maternal and perinatal morbidity and mortality. However, prepregnancy counseling and multidisciplinary care can lead to favorable maternal and neonatal outcomes. In this consult series, we summarize what is known about sickle cell disease and provide guidance for sickle cell disease management during pregnancy. The following are Society for Maternal-Fetal Medicine recommendations: 1. We recommend that patients with sickle cell disease be managed by a multidisciplinary team that includes maternal-fetal medicine, hematology (ideally a hematologist specializing in sickle cell disease), genetics, pain management, and social work or behavioral health (as appropriate) starting in early pregnancy (best practice). 2. We recommend that pregnant patients with sickle cell disease receive all routinely recommended antenatal vaccinations in addition to meningococcal and pneumococcal vaccinations if due (GRADE 1A). 3. We recommend prenatal vitamins without iron unless iron deficiency is confirmed and initiation of 4 mg of folic acid for pregnant patients with sickle cell disease (GRADE 1B). 4. We recommend fetal growth surveillance every 4 weeks beginning in the 28th week of gestation (GRADE 1C). 5. For patients with uncomplicated sickle cell disease and a normally grown fetus, we suggest weekly or twice-weekly antenatal testing beginning at 32 to 34 weeks of gestation. For patients with complicated sickle cell disease (i.e., maternal hypertension, vaso-occlusive crises, fetal growth restriction, or other coexisting complication), we suggest initiating individualized antenatal testing at diagnosis or at a gestational age when delivery would be considered if results are abnormal (GRADE 2B). 6. We recommend following evidence-based guidelines for the management of chronic and acute pain during pregnancy (best practice). 7. We suggest the use of prophylactic transfusions be individualized for high-risk patients with sickle cell disease in accordance with American Society of Hematology guidelines and directed by a hematologist and maternal-fetal medicine subspecialist in shared decision-making with the patient (GRADE 2B). 8. We recommend shared decision-making occur regarding the use of hydroxyurea in pregnancy, in conjunction with a sickle cell disease specialist and maternal-fetal medicine subspecialist, accounting for the timing of use and individual disease severity (GRADE 1C). 9. We recommend that reliable contraception be offered to patients with sickle cell disease to decrease the risk of an unintended pregnancy and associated maternal and perinatal risks (GRADE 1B). [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is a common complication of pregnancy and can have significant impact on obstetric and neonatal outcomes. Increasing evidence has shown that the inhibited mechanistic target of rapamycin (mTOR) signaling in placenta is associated with FGR. However, interpretation of existing research is limited due to inconsistent methodologies and varying understanding of the mechanism by which mTOR activity contributes to FGR. Hereby, we have demonstrated that different anatomic regions of human and mouse placentas exhibited different levels of mTOR activity in normal compared to FGR pregnancies. When using the rapamycin-induced FGR mouse model, we found that placentas of FGR pregnancies exhibited abnormal morphological changes and reduced mTOR activity in the decidual-junctional layer. Using transcriptomics and lipidomics, we revealed that lipid and energy metabolism was significantly disrupted in the placentas of FGR mice. Finally, we demonstrated that maternal physical exercise during gestation in our FGR mouse model was associated with increased fetal and placental weight as well as increased placental mTOR activity and lipid metabolism. Collectively, our data indicate that the inhibited placental mTOR signaling contributes to FGR with altered lipid metabolism in mouse placentas, and maternal exercise could be an effective method to reduce the occurrence of FGR or alleviate the adverse outcomes associated with FGR. Human and mouse placentas have different mTOR signaling activities in different anatomic regions in normal and FGR pregnancies. Pregnant mice with FGR induced by rapamycin show smaller placentas, decreased mTOR activity in DJ layer of placenta and altered lipid metabolism. Maternal exercise partially alleviates the abnormal outcomes of FGR model. [ABSTRACT FROM AUTHOR]