Fetal bowel remains challenging to assess antenatally. Ultrasound assessment is limited to its echogenicity and luminal diameter. Although MRI has been used to visualise fetal bowel, uncertainties remain and reference ranges for 2D diameter of large bowel have only recently been reported. Advanced MRI techniques now facilitate motion-corrected 3D analysis of fetal abdominal structures. This study aimed to apply these techniques to fetal large bowel enabling generation of high-resolution datasets for volumetric visualisation and quantification. All participants underwent fetal MRI on a 3T system, with T2-weighted images acquired in multiple orthogonal planes. Motion-correction pipelines were applied to obtain 3D reconstruction of fetal abdomen, and manual segmentation of five large bowel regions was performed to generate a 3D reconstruction of large bowel facilitating volumetric measurements. To assess reproducibility, intra- and inter-observer variability were performed using intraclass correlation coefficient (ICC). Linear regression was used to assess relationship between large bowel volume and gestation. Forty datasets from fetuses between 16 and 38 weeks' gestation were analysed. The whole fetal large bowel was identified in 100% of datasets. Intra- and inter-observer agreement were good to excellent. Volume increased linearly with advancing gestational age in all five large bowel segments. Model-derived estimates of total large bowel volume increased from 1266 cm3 at 18 weeks' gestation to 13,550 cm3 at 38 weeks (p<0.001). This study demonstrates 3D reconstruction and volumetric assessment of fetal large bowel is a feasible and reproducible technique in all large bowel regions. This technique may improve understanding of normal fetal bowel development enabling antenatal identification of pathologies, currently rarely detected antenatally.
The global stillbirth rate is 13.9 stillbirths per 1000 births, with most stillbirths being recorded in developing countries. Most cases of stillbirth are preceded by reduced fetal movement. Early detection of reduced fetal movement is a key element in reducing the number of stillbirths. Therefore, a "FetalkickApp" that is a self-monitoring digital health tool, assists a pregnant woman to count, record, and send her fetal movement count to her health care provider without the use of mobile data or internet. This study is a longitudinal pilot study involving 25 pregnant women with single fetuses between 28 and 38 weeks of gestation. The mobile application monitor was used to record the number of fetal movements for 4 weeks. A 5-point Likert scale questionnaire is used to assess the use of the application, interface experience, satisfaction with the design, and function of the application without internet. The mean age of the women is 31.2 (±4.5) years, and the mean gestational age is 29.5 (±2.4) weeks. The results obtained show that the majority of the women (72%) had good knowledge of fetal movement. About two-thirds (64%) of the women agreed that the FetalkickApp is helpful in counting their fetal movement. Forty-four per cent (44%) of the women strongly agreed that the application is easy to use, and 68% of the women agreed that the FetalkickApp's effectiveness is satisfactory. The FetalkickApp is independent of the internet, which means that it could be used everywhere. The interface and design of the application are simple and could be operated by any individual concerned.
Accurate estimation of fetal weight is a crucial component of pregnancy management and plays a key role in reducing maternal and neonatal complications. Although ultrasonography is considered the gold standard, its limited availability and cost emphasize the need to assess alternative clinical methods. This cross-sectional study included 132 term pregnant women (37to 41 weeks) selected via non-probability sampling. Fetal weight was estimated prior to childbirth using three methods: ultrasonography (performed within the last two weeks of the third trimester to minimize the impact of rapid fetal weight gain closer to term), Johnson's formula, and Insler's formula and was compared with the actual birth weight immediately after childbirth. Data were analyzed using SPSS version 24, with descriptive statistics and regression. The mean ± SD of estimated fetal weights (EFW) obtained via third-trimester ultrasonography and based on the Johnson and Insler formulas were 3164 ± 382.95 g, 3161.27 ± 302.90 g, and 3309.35 ± 374.05 g, respectively. Regarding diagnostic accuracy, the Johnson formula showed a precision of 69.70% for neonates < 3000 g and 71.21% for macrosomia (> 3500 g), the Insler formula showed a precision of 75.76% for neonates < 3000 g and 68.94% for macrosomia (> 3500 g). In the multivariate regression analysis of estimated fetal weight using the Johnson formula, only fundal height remained a significant independent predictor (β = 149.43, P < 0.001). Although ultrasound is the most accurate method for estimating fetal weight, with the smallest mean difference from the actual weight, clinical methods, particularly the Insler method for normal weight pregnancies and the Johnson method for ruling out macrosomia, have acceptable accuracy. Not applicable.
Fetal speckle tracking echocardiography is an ultrasound-based technique used to assess myocardial velocity and deformation of the fetal heart. Despite its potential, the method has not yet been integrated into routine pregnancy care, partly due to concerns about inconsistent reproducibility. This study aimed to evaluate the intra- and inter-observer reproducibility of global longitudinal strain measurements derived from a fixed fetal cardiac cycle, using speckle tracking echocardiography. Healthy women with singleton pregnancies were enrolled during the second trimester. From enrolment until delivery, four-chamber view clips of the fetal heart were acquired every four weeks. For intra-observer reproducibility, a single observer analyzed the same heart cycle in one DICOM clip twice for global longitudinal strain in the left and right ventricles, with a minimum interval of two weeks between assessments in a blinded manner. For inter-observer reproducibility, two independent observers analyzed the same cardiac cycle within one DICOM clip. A total of 124 women were included, yielding 632 ultrasound clips. Intra-observer reproducibility was poor to moderate for global longitudinal strain for the right and left ventricles. Inter-observer reproducibility demonstrated moderate to good reproducibility for global longitudinal strain in both ventricles. The reproducibility was generally higher in the left ventricle than in the right, and the highest reproducibility was observed before 32 weeks of gestation. In conclusion, speckle tracking echocardiography during pregnancy showed variable reproducibility of strain analysis when performed on a fixed cardiac cycle, with more consistent results in the left ventricle. These findings support the potential utility of fetal speckle tracking echocardiography, while highlighting the need for further refinement of reproducibility before clinical implementation.
Maternal infection during pregnancy has been associated with increased risk for adverse neurodevelopmental outcomes, yet the mechanisms linking maternal inflammation to fetal brain vulnerability remain under active investigation. Here, we used a mouse-adapted gestational influenza A virus (IAV; X31) model of maternal immune activation to assess cerebrovascular leakage of fibrinogen, fibrinogen-microglia colocalization, oxidative stress-related responses, and cell death in fetal brains. Maternal IAV infection induced classic sickness symptoms and fetoplacental growth restriction, reflected by reduced fetal weight, crown-to-rump length, and placental weight. In the fetal brain, maternal flu increased fibrinogen accumulation in the subventricular zone (SVZ), while fibrinogen-microglia colocalization increased in the SVZ, thalamus-third ventricle interface, and whole hemisphere, suggesting broad fibrinogen-microglia proximity. These changes were accompanied by increased Iba1⁺/p47 phox⁺ cell density in the same regions, consistent with greater microglial oxidative state. Because these regions contain neurogenic SOX2⁺ progenitors, we assessed whether fibrinogen accumulation and increased oxidation coincided with altered progenitor maintenance or survival. Although fetal SOX2⁺ neural progenitor density was not broadly altered by maternal flu, apoptosis analyses revealed a treatment- and sex-biased vulnerability, with males from IAV-infected dams demonstrating increased cell death, particularly within SOX2⁺ progenitors. Consistent with these in vivo findings, conditioned medium from fibrin-stimulated BV-2 microglia-like cells increased neural progenitor cell death in vitro , including amongst SOX2⁺ populations. Together, these findings support a framework in which maternal IAV-induced inflammation contributes to fibrinogen accumulation, microglial oxidative stress, and male-biased neural progenitor vulnerability in fetal brain regions critical for neurodevelopment.
Cardiac rhabdomyoma, the most common fetal cardiac tumor, is frequently associated with tuberous sclerosis complex (TSC). This study examined pre- and postnatal factors affecting mortality in fetal cardiac rhabdomyoma (FCR) and explored links between TSC and clinical features. A systematic review was conducted in July 2023 using Medline, Web of Science, Embase, and Cochrane Library to identify reported FCR cases. Analyses were performed on two sample groups (A and B). Neonatal mortality was significantly associated with hydrops (p < 0.001), tumor progression (p < 0.001), fetal heart failure (p < 0.001), and fetal growth restriction (FGR) (p = 0.021). Hydrops was the strongest predictor of mortality (Sample A: RR 17.2, p = 0.027; Sample B: RR 12.2, p = 0.006). Among 683 cases, 73% were diagnosed with TSC. Multiple tumors increased the likelihood of TSC (Sample A: RR 4.8, p < 0.0001; Sample B: RR 3, p = 0.015). In postnatal factors, preterm delivery (p < 0.001), cardiac arrhythmia (p = 0.001), and heart failure (p < 0.001) were also linked to mortality. Hydrops is the strongest mortality predictor in FCR. Multiple tumors are associated with TSC. In prenatal factors, tumor progression, fetal heart failure, and FGR were associated with increased mortality.
Maternal immune adaptation during pregnancy is orchestrated by dynamic signals from the uterine microenvironment, including placental extracellular vesicles (pEVs) released into maternal circulation. EVs have emerged as key mediators of this crosstalk; however, their role in sex-specific immune modulation remains incompletely defined. Here, we investigated whether pEVs derived from term placentas induce sex-dependent changes in the phenotype, metabolism, and function of human monocytes. pEVs were isolated from 13 term uncomplicated placentas (six male-derived, M-pEVs, and seven female-derived, F-pEVs) and characterized by complementary approaches, revealing similar size distributions and concentrations, with differences in physicochemical properties and molecular cargo. Circulating monocytes from 17 non-pregnant female donors were exposed to M-pEVs or F-pEVs and analyzed for phenotypic, metabolic, and functional responses. pEVs induced distinct activation profiles depending on fetal sex. F-pEVs reduced CD11b and CD11c expression while increasing CD14, CD39 and IL-10 production. On the other hand, M-pEVs increased CD14 expression and enhanced IL-1β secretion. Both nanovesicles populations increased IL-10 and CXCL8 release and promoted a shift toward classical monocytes (CD14+CD16-) with a reduction in the intermediate subsets. Metabolic analyses revealed divergent immunometabolic programs: M-pEVs promoted lactate and reactive oxygen species production, whereas F-pEVs enhanced lactate production, fatty acid uptake, lipid droplet accumulation, and mitochondrial activity without increasing ROS. Functionally, both pEV populations increased efferocytosis, with a distinct sensitivity to metabolic inhibitors. These findings demonstrate that pEVs differentially modulate circulating monocytes according to fetal sex and support a role for fetal sex in shaping maternal immunometabolic responses.
Prenatal cannabis use is on the rise, and observational studies suggest that such use results in neurodevelopmental deficits in the offspring. Because observational studies can be confounded by unaccounted factors, we studied the neurodevelopmental consequences, at the molecular level, of prenatal cannabis use. We applied an integrated multi-omics approach, combining transcriptomics and global proteomics, to first trimester (T1) and second trimester (T2) human fetal brains from pregnancies with and without documented maternal cannabis exposure and no use of drugs of abuse. Prenatal cannabis exposure produced minimal molecular effects in female T1 fetal brains but induced pronounced system-level disruption in male T2 fetal brains. These disrupted pathways have molecular signatures linked to neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorder, schizophrenia-related pathology, and disorders of cortical connectivity, raising significant concerns of prenatal cannabis use.
暂无摘要（点击查看详情）
Pseudoamniotic band syndrome (PABS) is an iatrogenic amniotic disruption sequence that may occur after invasive fetal procedures, including fetoscopic laser therapy and amniocentesis. Fetoscopic release of the bands has been reported in singleton pregnancies, but it remains rare in twin pregnancies after intrauterine fetal surgery. This study aimed to report two rare cases of PABS occurring after invasive fetal interventions-one for twin-to-twin transfusion syndrome (TTTS) and one for twin reversed arterial perfusion (TRAP) sequence-both of which were successfully managed by fetoscopic band release, and to review the clinical characteristics of PABS in TTTS. We describe one rare case off fetal abdominal constriction caused by amniotic bands following TTTS fetoscopic surgery, and one case of PABS in TRAP sequence after microwave ablation and amniocentesis. Both cases were successfully treated in utero via subsequent fetoscopic band release later. A literature review was conducted on PABS cases after TTTS intervention, comparing cases managed expectantly versus those treated with fetoscopic release. We reported two cases of PABS with constriction of the fetal abdomen and ankle, respectively, treated by fetoscopic band release, and both cases achieved successful outcomes after fetoscopic band release. A literature review identified 50 reported PABS cases after TTTS treatment. PABS occurred predominantly in recipients (78.0%, 39/50 cases), primarily affecting fetal limbs (88.2%, 45/51 fetuses). Antenatal detection was low (20.0%, 10/50 cases), and without intervention, 9.5% (4/42 fetuses) developed fetal limb amputation. Including our case, only 8 PABS cases in TTTS have undergone fetoscopic release, with a median interval of 4.3 weeks post-TTTS fetoscopic laser. The median GA at fetoscopic release surgery was 23.5 (range, 21-27.4) weeks, with a median interval of 5.6 (range, 0.8-11.9) weeks between fetoscopic release and delivery (at 30.7 weeks; range, 24.7-34.9). Of these, 37.5% (3/8) of the newborns required further plastic surgery after birth, but all fully recovered functionally without amputation. Serial ultrasound surveillance after fetal interventions should include PABS assessment, particularly 4 weeks post-procedure. Although antenatal diagnosis remains challenging, fetoscopic band release appears technically feasible in twin pregnancies and potentially beneficial in carefully selected, antenatally diagnosed cases, but the evidence remains limited and vulnerable to publication bias.
 Spontaneous abortion (SAB, miscarriage) affects and may influence outcomes in subsequent pregnancies. This study aimed to assess maternal and fetal outcomes in women with a history of SAB who conceived a subsequent pregnancy.  A hospital‑based observational study was conducted at Mahatma Gandhi Medical College and Research Institute, Puducherry, over 18 months. Ninety‑six women aged 18-35 years with at least one previous SAB were enrolled. Maternal outcomes (gestational hypertension, diabetes mellitus, placental complications, and mode of delivery) and fetal/neonatal outcomes (fetal growth retardation, birth weight, Apgar score, and neonatal intensive care unit (NICU) admission) were recorded. Comparisons were made between single (82, 85.4%) and recurrent (≥2 abortions; 14, 14.6%) subgroups.  A total of 96 pregnant women with a history of SAB were included. The mean maternal age was 27.74 ± 4.81 years, and most participants were aged <30 years (65, 67.7%) and had conceived spontaneously (88, 91.7%). Recurrent SAB was present in 14 (14.6%) women. Gestational diabetes mellitus and gestational hypertension were observed in 17 (17.7%) and 12 (12.5%) women, respectively. Preterm delivery occurred in 12 (12.5%) pregnancies, while 58 (60.4%) women underwent cesarean section. Fetal growth restriction was identified in 12 (12.5%) cases, and NICU admission was required in 18 (18.8%) neonates. Low birth weight, low APGAR score, and meconium aspiration syndrome were each observed in 1 (1.0%) neonate, with no intrauterine deaths recorded. Recurrent abortion was associated with higher rates of preterm birth (21.4% vs. 11.0%; P = 0.375) and NICU admission (28.6% vs. 17.1%; P = 0.291), although these associations were not statistically significant. Preterm delivery was significantly associated with NICU admission (41.7% vs. 15.5%; P = 0.043).  Pregnancy after SAB generally results in favorable outcomes with no intrauterine deaths and high rates of normal birth weight and Apgar scores. However, clinically significant risks of gestational diabetes, hypertension, fetal growth retardation, high cesarean section rates, and NICU admissions persist. Structured antenatal surveillance and individualized care are recommended for this population.
Pulmonary hypoplasia is a rare but clinically significant congenital disorder characterized by impaired fetal lung development, leading to impaired growth and maturation of lung parenchyma and pulmonary vasculature. Stemming from a diverse group of underlying etiologies including congenital diaphragmatic hernia, congenital lung malformations, and prolonged oligohydramnios, the clinical presentation of pulmonary hypoplasia is highly variable. Although many factors affect severity of disease, pulmonary hypoplasia can be life-threatening and accounts for a disproportionately high proportion of neonatal morbidity and mortality. Advances in fetal ultrasonography and fetal magnetic resonance imaging have improved the ability to evaluate the severity of pulmonary hypoplasia before birth and predict clinical outcomes. Prenatal interventions like fetal endoscopic tracheal occlusion or serial amnioinfusions have showed promise in helping alleviate lethal pulmonary hypoplasia, but ongoing research is required to identify techniques that mitigate the associated complications and morbidities. Postnatal management requires multidisciplinary and individualized care, with management tailored toward gentle ventilatory support and surgical management of the underlying cause when applicable. Severe respiratory failure and pulmonary hypertension are hallmarks of severe cases, and extracorporeal membrane oxygenation support is sometimes required. Although advances in care from fetal diagnosis through long-term follow-up have improved survival in some groups, long-term survivors still exhibit persistent impairments in growth, pulmonary function, and neurodevelopment. Infants with pulmonary hypoplasia continue to have high morbidity and mortality, and ongoing research is required to optimize their clinical outcomes.
The management of brain tumors during pregnancy presents a complex clinical challenge, balancing maternal neurological needs with fetal safety. Awake craniotomy (AC) is a potential strategy to maximize tumor resection in eloquent areas while minimizing fetal anesthetic exposure, but the literature remains sparse. The objective of this review is to summarize the current evidence regarding the use of AC for brain tumors during pregnancy. Following PRISMA guidelines, a systematic search was conducted in PubMed, Scopus, Cochrane Library, and ScienceDirect databases for studies reporting on AC in pregnant patients. Data on clinical characteristics, anesthetic techniques, and maternal/fetal outcomes were extracted. Methodological quality was assessed using the Joanna Briggs Institute checklist for case reports. Eleven studies, comprising 11 patients, met the inclusion criteria. All were case reports or a small case series. AC was performed across all trimesters for various tumors, predominantly gliomas. Anesthetic techniques included both "awake throughout" and "asleep-awake-asleep" approaches, with dexmedetomidine and propofol being common agents. All cases reported successful surgical resections with positive fetal outcomes, resulting in the delivery of healthy infants. Short-term maternal neurological outcomes were generally favorable; however, long-term maternal prognosis was variable and dependent on the underlying tumor pathology. A multidisciplinary approach was highlighted as crucial for success. The available evidence, though limited to case reports, suggests that AC is a viable, effective option for carefully selected pregnant patients with brain tumors. However, the high potential for publication bias warrants caution, and larger, prospective studies are needed to establish definitive guidelines.
Anaphylaxis during pregnancy is uncommon but remains one of the most critical emergencies in obstetric medicine because maternal deterioration and fetal hypoxia evolve simultaneously. Despite established treatment recommendations, diagnostic uncertainty and persistent concerns regarding epinephrine use continue to contribute to jeopardize preventable morbidity/mortality. This review examines recent advances in the recognition, management, and prevention of pregnancy-associated anaphylaxis, with emphasis on emerging concepts that may improve maternal-fetal safety. Physiological pregnancy-related cardiovascular and respiratory adaptations can obscure classic manifestations of anaphylaxis, creating important diagnostic blind spots and increasing the risk of delayed recognition. Growing evidence indicates that maternal hypotension and hypoxemia represent the main threats to fetal wellbeing. Epinephrine hesitancy remains common in clinical practice. New insights into mast cell disorders, hereditary alpha-tryptasemia, and MRGPRX2-mediated reactions are refining risk stratification and expanding understanding of severe and perioperative anaphylaxis. Recent epidemiological studies also highlight the predominance of drug-related and cesarean-associated triggers and support the implementation of multidisciplinary care pathways, allergy evaluation, and targeted prevention strategies. Maternal anaphylaxis should be viewed as a time-critical obstetric emergency in which prompt recognition and immediate epinephrine administration are essential to optimize maternal and fetal outcomes. Future progress will depend on pregnancy-adapted diagnostic approaches, improved risk identification, systematic prevention efforts, and coordinated multidisciplinary management across obstetric, anesthetic, emergency, and allergy services.
Early applications of fetal Doppler evaluation drew on parameters derived from adult vascular examination, primarily applied to identifying fetuses at risk for growth restriction and hypoxia. The integration of color Doppler into real-time imaging facilitated a shift toward structural-functional correlation, enabling clinicians to visualize fetal cardiac outflow tracts, valve regurgitant jets, and the complex umbilical-venous connections alongside standard grayscale anatomy. Power Doppler extended these capabilities to slow flow and small caliber vascular structures. Doppler modalities have been crucial in delineating the fetal cardiovascular system, increasingly detecting complex congenital heart disease (CHD) prenatally, and illuminating cardiac and non-cardiac vascular structures that previously posed a challenge to visualization, including cerebral, hepatic, and placental capillary beds. Highly sensitive Doppler technologies such as SlowflowHD as well as MV-Flow and LumiFlow, exemplify the convergence of anatomical and physiological imaging, such as fetal venous sinuses and deep cerebral venous return, to allow brain perfusion assessment at earlier gestational stages. Although SlowflowHD has been shown to have added value for diagnosis, it seems to be an underused modality. Here we show several examples drawn from our experience with SlowflowHD, in both routine scanning and anomalous cases spanning various organ systems and stages of gestation. While there is a learning curve in optimizing image acquisition and interpretation of microvascular anatomy, it should not deter practitioners proficient in Doppler techniques. We recommend incorporation of SlowflowHD and comparable microvascular imaging technologies into the sonographic armamentarium.
Maternal cardiac arrest is a life-threatening event with both obstetric and non-obstetric causes, requiring rapid, pregnancy-specific resuscitation. Physiological changes in pregnancy reduce the effectiveness of standard Cardiopulmonary resuscitation, necessitating modifications to advanced cardiac life support (ACLS). This review aims to highlight key causes, resuscitation adaptations, and the critical role of perimortem cesarean delivery (PMCD) in improving maternal and fetal outcomes. A structured literature search was conducted across PubMed, Scopus, Google Scholar, and Web of Science using relevant keywords. Studies were screened by title/abstract followed by full-text review, and articles focusing on clinical aspects, techniques, outcomes, and guidelines of PMCD were included, with emphasis on recent high-quality evidence. The literature search included peer-reviewed publications from 2000 to 2025, comprising original research articles, case reports, and guideline documents. Resuscitation follows standard American Heart Association (AHA) basic life support (BLS)/ ACLS with key modifications: provide left uterine displacement (LUD) (15-30° tilt) after 20 weeks to relieve aortocaval compression; secure airway early due to difficult airway and rapid desaturation; perform chest compressions slightly higher on the sternum; use upper-extremity/central venous access; and apply standard defibrillation and drug protocols. If PMCD is performed within 5 min of cardiac arrest, it significantly improves maternal return of spontaneous circulation (ROSC) and increases the likelihood of favorable fetal survival and neurological outcomes. Maternal cardiac arrest requires prompt, pregnancy-specific modifications to standard resuscitation to optimize outcomes. Early uterine displacement, effective airway management, and adherence to ACLS protocols are critical, while timely PMCD within 4-5 min significantly improves maternal hemodynamics and enhances both maternal and fetal survival.
Infants conceived via in vitro fertilization (IVF) have been reported to have increased rates of congenital heart disease (CHD), though estimates and associated risk factors remain variable. This study aimed to quantify CHD prevalence by severity sub-type and identify independent predictors of CHD in an IVF-conceived population. A retrospective cohort study of 1890 IVF-conceived infants born to 1783 mothers at a single tertiary academic center from 2020 to 2025 was performed. Maternal demographics, comorbidities, medication exposures, twin gestation, family history, and fetal echocardiography utilization were analyzed. CHD outcomes included: (1) any CHD; (2) persistent CHD (not spontaneously resolved within 3 years); and (3) significant CHD (requiring medical or procedural intervention). Prevalence was compared to the general population baseline (~1%) using Proportion Z testing. Multivariate logistic regression was performed to identify independent predictors. A sensitivity analysis excluded pregnancies with established CHD risk factors to isolate IVF-associated risk. CHD prevalence was 4.76% for any CHD, 3.33% for persistent, and 1.64% for significant. After exclusion of established CHD risk factors, prevalence decreased to 3.1%, 2.1%, and 1.01%, respectively. Fetal echocardiography utilization and diagnostic yield increased with CHD severity. Maternal hypertension, Black race, and Asian race independently predicted any CHD. However, only maternal hypertension predicted persistent CHD and only twin gestation predicted significant CHD. No independent associations were identified for maternal age, geography, median income, other medical conditions (i.e. diabetes, autoimmune), medication exposures, or family history. This IVF-conceived population showed a higher observed prevalence of CHD than global population baseline, though disease burden is driven by less severe heart disease. Distinct predictors varied by CHD severity subtype, supporting risk-stratified fetal echocardiography and individualized counseling in IVF pregnancies.
Fetal hemoglobin (HbF) expression is silenced postnatally in adult erythroid cells. Sufficiently increased expression of HbF has been shown to overcome the pathophysiologic sequelae of both sickle cell disease and beta-thalassemia. As the MBD2a-NuRD chromatin remodeling complex is required for silencing of HbF, the present studies were aimed at exploring a potential therapeutic approach for disrupting this complex. AlphaFold 3 and a recent crystal structure were employed to predict the critical interaction domains linking GATAD2A in the histone deacetylase core subcomplex (HDCC) of NuRD and the CHD4 ATPase which has been shown to be required for silencing of the fetal gamma-globin ( HBG ) genes. The two predicted critical domains, the CR2 helical domain of GATAD2A and the C-terminal domains 1 and 2 (C1b and C2ab) of CHD4, were validated by in vitro biophysical studies. Mutation of two amino acids in the CR2 helical domain of the endogenous GATAD2A gene in HUDEP-2 cells resulted in dissociation of CHD4, loss of repressive chromatin over the HBG promoter and ~40% HbF levels compared to < 1% in control cells. Strikingly, enforced expression of a peptide containing the helical portion of the CR2 domain of GATAD2A in both HUDEP-2 cells and primary adult erythroid cells resulted in high levels of HbF, with up to ~75% HbF compared to mutant peptide control level of ~9% in the latter without perturbing erythroid differentiation. These results suggest that targeting the critical interaction domains of GATAD2A and CHD4 with a macrocyclic peptide or small molecule may lead to much needed small molecule therapeutics for sickle cell disease. Association of CHD4 with the HDCC core of the MBD2-NuRD chromatin remodeling complex is required for silencing of HbF expression in adult human erythroid cellsGenetic alteration or enforced peptide expression of a critical helical domain of GATAD2A results in dissociation of CHD4 from the MBD2-NuRD complex and high-level expression of HbF.
Prenatal cannabis use is increasing in prevalence and associated with potential harm to maternal-fetal health. Pregnant individuals who use cannabis seek information about prenatal cannabis use informally (e.g., online) and adopt practices perceived to reduce harm. However, no evidence-based harm reduction interventions address prenatal cannabis use. Cannabis protective behavioral strategies (PBS) are associated with less cannabis use and fewer cannabis-related negative consequences among non-pregnant populations. There is a lack of research exploring PBS during pregnancy. This study combined two samples of pregnant individuals who use cannabis (N = 48; Mage = 30.33; 2% American Indian or Alaska Native, 2% Asian, 19% Black, 15% multiracial, 58% White). Participants completed the Protective Behavioral Strategies for Marijuana scale (PBSM; Pedersen et al., 2017), adapted for pregnancy, and an open-ended question about prenatal PBS. We examined relationships between prenatal cannabis use, PBS, consequences, and perceived harm of prenatal cannabis use. Participants reported using PBS (M = 4.07, SD = 0.93) and experiencing consequences in the past 30 days (M = 3.77, SD = 3.30). Higher perceived harm of cannabis to fetal health (B = 0.02, p = .010) and use in later trimesters (second: B = 0.69, p = .011; third: B = 0.82, p = .013) were positively associated with PBS. PBS was associated with lower weekly (IRR = 0.79, 95% CI [0.69, 0.90], p < .001) and daily prenatal cannabis use frequency (IRR = 0.41, 95% CI [0.33, 0.51], p = .001) but was not significantly associated with consequences. Open-ended responses revealed pregnancy-specific practices perceived to reduce harm (e.g., "I had a date set to quit and slowly decreased the amount I was smoking"). Results underscore the need for harm reduction research and validation of PBS and consequence measures for prenatal cannabis use to support informed decision-making among pregnant individuals who use cannabis.
Trophoblast migration and invasion are critical processes in the pathogenesis of preeclampsia (PE), with maternal-fetal cellular communication playing a key role in their regulation. Among the immune components at the maternal-fetal interface, M1-like macrophages are known to influence trophoblast behavior, however, the specific underlying mechanisms remain unclear. Here, we reveal a novel pathway through which M1-like macrophages regulate trophoblast function through extracellular vesicle (EV)-mediated communication. We demonstrated that M1-derived extracellular vesicles (M1-EVs) inhibit trophoblast migration and invasion in vitro. miRNA sequencing and validation revealed that miR-515-5p as one of the most significantly upregulated miRNAs in recipient trophoblast cells following M1-EVs treatment. Mechanistically, miR-515-5p is delivered into trophoblasts via M1-EVs, where it directly targets and downregulates Yes-associated protein (YAP), a central regulator of cellular motility. In vivo, the administration of M1-EVs to pregnant mice induced hallmark PE phenotypes, including hypertension and proteinuria. Importantly, mechanistic studies demonstrating the role of miR-515-5p in targeting YAP were conducted in human trophoblast cells, as miR-515-5p is primate specific and not endogenously expressed in mice. Clinically, miR-515-5p expression was significantly upregulated in human PE placental tissues and inversely correlated with YAP levels. Collectively, the results of our study reveal that M1-EVs deliver miR-515-5p to trophoblasts, leading to YAP downregulation and suppression of migration and invasion, thereby providing new insights into immune-mediated regulation of trophoblast function in preeclampsia.