Intrauterine Growth Restriction Fetuses Research Articles

Thyroid hormone analogues: Promising therapeutic avenues to improve the neurodevelopmental outcomes of intrauterine growth restriction.

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

Regulation of placental amino acid transport in health and disease.

Abnormal fetal growth, i.e., intrauterine growth restriction (IUGR) or fetal growth restriction (FGR) and fetal overgrowth, is associated with increased perinatal morbidity and mortality and is strongly linked to the development of metabolic and cardiovascular disease in childhood and later in life. Emerging evidence suggests that changes in placental amino acid transport may contribute to abnormal fetal growth. This review is focused on amino acid transport in the human placenta, however, relevant animal models will be discussed to add mechanistic insights. At least 25 distinct amino acid transporters with different characteristics and substrate preferences have been identified in the human placenta. Of these, System A, transporting neutral nonessential amino acids, and System L, mediating the transport of essential amino acids, have been studied in some detail. Importantly, decreased placental Systems A and L transporter activity is strongly associated with IUGR and increased placental activity of these two amino acid transporters has been linked to fetal overgrowth in human pregnancy. An array of factors in the maternal circulation, including insulin, IGF-1, and adiponectin, and placental signaling pathways such as mTOR, have been identified as key regulators of placental Systems A and L. Studies using trophoblast-specific gene targeting in mice have provided compelling evidence that changes in placental Systems A and L are mechanistically linked to altered fetal growth. It is possible that targeting specific placental amino acid transporters or their upstream regulators represents a novel intervention to alleviate the short- and long-term consequences of abnormal fetal growth in the future.

Imaging and video of late preterm delivery by midline laparotomy due to incarcerated uterus: A case report and literature review of a rare but morbid condition.

Incarcerated gravid uterus (IGU) is a rare and serious obstetric complication. IGU is defined as the entrapment of the gravid uterus between the pubic symphysis and the sacral promontory. The incidence of IGU is 1 in 3000-10 000 cases. IGU is associated with significant obstetric complications, including preterm labor, intrauterine fetal death, growth restriction, renal failure, uterine ischemia/rupture and thrombosis. Here, we present the case of a primigravida with urinary retention at 14 weeks. On transabdominal ultrasound at 19+5/7 weeks the cervix was difficult to visualize, and the anterior uterine wall appeared thickened. The bladder was elongated superior to the uterus and the placenta was low-lying. Initially the patient was managed with intermittent self-catheterization, and subsequently indwelling catheterization was required from 22 weeks. At 30 weeks, the patient was transferred to a tertiary center and magnetic resonance imaging (MRI) was preformed due to challenging visualization of the cervix on ultrasound and the patient's continued symptoms of constipation and recurrent urinary infections. The MRI found a retroflexed gravid uterus, with vagina and endocervix displaced anteriorly and compressed by the gravid uterus. The findings were consistent with an incarcerated uterus. The patient subsequently had positive urinary cultures for Pseudomonas and rising creatinine. Given the obstructive uropathy and associated morbidity and mortality, a plan for elective pre-term delivery at 33+6/7 weeks was made. Delivery was by midline laparotomy, normal anatomy was restored after manual evacuation of the fundus from below the sacral promontory, and an uncomplicated lower segment transverse uterine cesarean section was performed.

Causal Pathways Between the Acute Experience of Violence During Pregnancy and Fetal Intrauterine Growth Restriction: A Cohort Study.

Introduction: Violence during pregnancy (VDP) is a prevalent global issue with dire consequences for the mother and the developing fetus. These consequences include prematurity, low birthweight, and intrauterine growth restriction (IUGR), but its pathways remain elusive. This study investigated the causal pathways between VDP and IUGR using mediation analysis. Methods: A prospective population-based birth cohort was followed from the beginning of the third gestational trimester to the second year of life. IUGR was defined by the Kramer index, and information on VDP was collected using the WHO-Violence Against Women (WHO VAW) questionnaire. Cases were considered positive only when no other life episodes were reported. Ten different mediators were analyzed as possible pathways based on previous research. Path analysis was conducted to evaluate these relationships. Results: The path analysis model included 755 dyads and presented an adequate fit. Violence during pregnancy showed a direct effect (β = -0.195, p = 0.041) and a total effect (β = -0.276, p = 0.003) on IUGR. Violence was associated with gestational depression or anxiety, tobacco and alcohol consumption, changes in blood pressure, and the need for emergency care, but these did not constitute mediators of its effect on IUGR. The sum of the indirect effects, however, showed a significant association with IUGR (β = -0.081, p = 0.011). Conclusion: The acute experience of violence during pregnancy was associated with IUGR, primarily via a direct pathway. An indirect effect was also present but not mediated through the variables analyzed in this study. The robust strength of these associations underscores the negative health consequences of violence against women for the succeeding generation.

Anatomical and functional changes of the fetal adrenal gland in intrauterine growth restriction.

The aim of this study was to demonstrate the establishment of adrenal sparing in intrauterine growth restricted (IUGR) human fetuses. IUGR fetuses are a subgroup of small for gestational age (SGA) fetuses that are unable to reach their own growth potential because of chronic hypoxia and undernutrition. We hypothesized that in IUGR fetuses the adrenal gland is relatively larger and secretion of noradrenaline (NA), adrenaline (A), and cortisol is increased. This is a prospective observational study including 65 singleton pregnancies (42 IUGR and 23 controls). Using two-dimensional ultrasound, we measured fetal adrenal diameters and adrenal/abdominal circumference (AD/AC) ratio between 25 and 37 weeks. We considered only one measurement per fetus. In 21 pregnancies we also measured NA, A, and cortisol levels in arterial and venous fetal cord blood collected at the time of delivery. The AD/AC ratio was significantly higher in IUGR fetuses than in controls. Cord NA and A levels were significantly higher in IUGR fetuses than in controls. An increase in cortisol secretion in IUGR fetuses was observed but the difference was not statistically significant. Adrenal sparing correlates with a relative increase in adrenal measurements and function.

Isolated fetal umbilical vein varix and the association with intrauterine fetal death and fetal growth restriction: A systematic review, meta-analysis, and nested retrospective cohort study.

To assess the risk of intrauterine fetal death (IUFD) and fetal growth restriction (FGR) in fetuses with an isolated fetal intra-abdominal umbilical vein varix (i-FIUVV). A retrospective cohort study combined with a systematic review and meta-analysis of the literature was performed. In the retrospective cohort study, all singleton fetuses with an i-FIUVV in the fetal medicine units of the Amsterdam UMC (between 2007 and 2023) were analyzed. The primary outcome measures were IUFD and FGR. The sample proportions of IUFD and FGR were depicted as risk percentages. The IUFD proportion was compared to the regional reference population and the FGR proportion was compared to the reported proportions in Europe. The secondary outcome measures were gestational age at diagnosis, initial and maximal FIUVV diameter, fetal monitoring in pregnancy, turbulent flow in the varix, thrombus formation in the varix, induction of labor, gestational age at birth, and birthweight centile. The proportion of fetuses with a birthweight below the 10th centile was compared with that of the regional reference population. The systematic review included all cases from eligible literature published between 2007 and 2023 supplemented by the data of our retrospective cohort study. In the systematic review and meta-analysis, the pooled proportions of IUFD and FGR were assessed in fetuses with i-FIUVV. The retrospective cohort included 43 singletons with an i-FIUVV. The IUFD risk was 0% [Confidence Interval, CI: 0%-8.2%], which did not differ significantly from 0.3% in the reference population, p=1.0. The risk of FGR was 16.3% [CI: 6.8%-30.7%] in the studied population, which is higher than the reported incidence of FGR in Europe ranging from 5%-10%. The proportion of fetuses with birthweights below the 10th centile was higher in our cohort compared with the reference population (23.3 vs. 9.9%, p<0.01). The systematic review included 12 articles, three abstracts, and our current cohort. In total, 513 cases with an i-FIUVV were included. The pooled risk was 0.4% [CI: 0.1%-1.7%] for IUFD and 5.2% [CI: 1.1%-21.3%] for FGR. The mean gestational age at birth did not exceed 39weeks in neither the cohort (38.7weeks) nor the pooled literature (37.6weeks). An i-FIUVV in singletons is not associated with an increased IUFD risk up to 39weeks of gestation but is possibly associated with FGR. The incidence of FGR in our cohort was higher than in the pooled literature (16.3% vs. 5%) but FGR definitions in the included studies varied. The proportion of birthweights below the 10th percentile in our cohort was significantly higher than in the reference group. Thus, based on these findings, we suggest conducting sonographic growth assessments while simultaneously assessing the i-FIUVV. No further monitoring and follow-up are indicated up to 39weeks of gestation. After 39weeks of gestation, data on fetuses with i-FIUVV and their outcomes are lacking.

Quantifying Brain Myelin Water Fraction in a Guinea Pig Model of Spontaneous Intrauterine Growth Restriction.

Intrauterine growth restriction (IUGR) is an obstetrical condition where a fetus has not achieved its genetic potential. A consequence of IUGR is a decrease in brain myelin content. Myelin water imaging (MWI) has been used to assess fetal myelin water fraction (MWF) and might potentially assess myelination changes associated with IUGR. To quantify and compare the MWF of non-IUGR and IUGR fetal guinea pigs (GPs) in late gestation. Prospective animal model. Dunkin-Hartley GP model of spontaneous IUGR (mean ± SD: 60 ± 1.2 days gestation; 19 IUGR, 52 control). Eight spoiled gradient-recalled (SPGR) gradient echo volumes (flip angles [α]: 2°-16°), and two sets of eight balanced steady-state free precession (bSSFP) gradient echo volumes (α: 8° - 64°), at 0° and 180° phase increments, at 3.0 T. MWF maps were generated for each fetal GP brain using multicomponent driven equilibrium single pulse observation of T1 /T2 (mcDESPOT). MWF was quantified in the fetal corpus callosum (CC), fornix (FOR), parasagittal white matter (PSW), and whole fetal brain. Linear regression was performed between five fetal IUGR markers (body volume, body-to-pregnancy volume ratio, brain-to-liver volume ratio, brain-to-placenta volume ratio, and brain-to-body volume ratio) and MWF (coefficient of determination, R2 ). A t-test with a linear mixed model compared the MWF of non-IUGR and IUGR fetal GPs (significance was determined at α < 0.05). The MWF of the control fetuses are (mean ± SD): 0.23 ± 0.02 (CC), 0.31 ± 0.02 (FOR), 0.28 ± 0.02 (PSW), and 0.20 ± 0.01 (whole brain). The MWF of the IUGR fetuses are (mean ± SD): 0.19 ± 0.02 (CC), 0.27 ± 0.01 (FOR), 0.24 ± 0.03 (PSW), and 0.16 ± 0.01 (whole brain). Significant differences in MWF were found between the non-IUGR and IUGR fetuses in every comparison. The mean MWF of IUGR fetal GPs is significantly lower than non-IUGR fetal GPs. 2 TECHNICAL EFFICACY: Stage 1.

Exosomal small RNA profiling in first-trimester maternal blood explores early molecular pathways of preterm preeclampsia.

Preeclampsia (PE) is a severe obstetrical syndrome characterized by new-onset hypertension and proteinuria and it is often associated with fetal intrauterine growth restriction (IUGR). PE leads to long-term health complications, so early diagnosis would be crucial for timely prevention. There are multiple etiologies and subtypes of PE, and this heterogeneity has hindered accurate identification in the presymptomatic phase. Recent investigations have pointed to the potential role of small regulatory RNAs in PE, and these species, which travel in extracellular vesicles (EVs) in the circulation, have raised the possibility of non-invasive diagnostics. The aim of this study was to investigate the behavior of exosomal regulatory small RNAs in the most severe subtype of PE with IUGR. We isolated exosomal EVs from first-trimester peripheral blood plasma samples of women who later developed preterm PE with IUGR (n=6) and gestational age-matched healthy controls (n=14). The small RNA content of EVs and their differential expression were determined by next-generation sequencing and further validated by quantitative real-time PCR. We also applied the rigorous exceRpt bioinformatics pipeline for small RNA identification, followed by target verification and Gene Ontology analysis. Overall, >2700 small RNAs were identified in all samples and, of interest, the majority belonged to the RNA interference (RNAi) pathways. Among the RNAi species, 16 differentially expressed microRNAs were up-regulated in PE, whereas up-regulated and down-regulated members were equally found among the six identified Piwi-associated RNAs. Gene ontology analysis of the predicted small RNA targets showed enrichment of genes in pathways related to immune processes involved in decidualization, placentation and embryonic development, indicating that dysregulation of the induced small RNAs is connected to the impairment of immune pathways in preeclampsia development. Finally, the subsequent validation experiments revealed that the hsa_piR_016658 piRNA is a promising biomarker candidate for preterm PE associated with IUGR. Our rigorously designed study in a homogeneous group of patients unraveled small RNAs in circulating maternal exosomes that act on physiological pathways dysregulated in preterm PE with IUGR. Therefore, our small RNA hits are not only suitable biomarker candidates, but the revealed biological pathways may further inform us about the complex pathology of this severe PE subtype.

Postpartum Depression and Inflammatory Biomarkers of Neutrophil-Lymphocyte Ratio, Platelet-Lymphocyte Ratio, and Monocyte-Lymphocyte Ratio: A Prospective Observational Study

Objectives: Postpartum depression (PPD) is a severe mental health disorder affecting a significant proportion of mothers, often undiagnosed and untreated, with potential long-term effects. While numerous studies have identified risk factors for PPD, the relationship between inflammatory markers and PPD remains unknown. This study aimed to investigate the potential correlation between indirect inflammatory markers, specifically neutrophil-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR), and the risk of developing PPD, assessed by the Edinburgh Postnatal Depression Scale (EPDS). Design: This was a prospective observational study conducted in a second-level university hospital, from December 2019 to February 2021. Participants: A total of 211 full-term pregnant women were enrolled. Exclusion criteria included specific psychiatric diagnoses, such as severe intellectual disability, schizophrenia, schizoaffective disorder, delusional disorder, bipolar or other unspecified psychotic spectrum disorders. Additionally, pregnancies affected by gestational and pregestational diabetes, chronic hypertension, gestational hypertension, preeclampsia/eclampsia, intrauterine fetal growth restriction, preterm delivery, multiple pregnancies, and fetal abnormalities detected prenatally were excluded. Methods: Socio-demographic and clinical data were recorded. Blood samples for complete blood count were obtained at hospital admission, focusing on NLR, PLR, and MLR. Analyses were conducted in our laboratory using standard techniques. The postpartum PPD evaluation was conducted 3 days after delivery, with the EPDS Italian version. Statistical analyses included descriptive statistics, group comparisons using t tests or Wilcoxon rank-sum tests for continuous variables, and Pearson χ2 or Fisher’s exact tests for categorical variables. Correlation analyses employed Pearson correlation or Spearman’s rank correlation tests. Simple logistic regression models, adjusted for various baseline patient characteristics, explored the correlation between inflammatory markers (PLR, NLR, MLR) and postpartum depressive symptoms. Version 4.1.3 of RStudio statistical software was utilized. Results: Overall, 211 pregnant women enrolled were categorized into two groups based on the EPDS scores: Limitations: Our evaluation was restricted to the postpartum period, and data for the first and second trimesters of pregnancy are lacking. Conclusions: Our findings did not evidence a correlation between indirect inflammatory markers (NLR, PLR, and MPL) and PPD. This novel finding prompts further evaluation of the role of indirect inflammatory markers in PPD, highlighting the need for additional research to clarify the complex relationship between inflammation and psychological health in the postpartum period.

Effect of L-Arginine Supplementation in treatment of Intrauterine Fetal Growth Restriction

Effect of L-Arginine Supplementation in treatment of Intrauterine Fetal Growth Restriction

Comparative study of pluripotency-related gene expression in Umbilical Cord Mesenchymal Stem Cells (UC-MSC) from IUGR, SGA and normally grown fetuses

Background and Objectives: Intrauterine growth restriction (IUGR) is worldwide a public health problem. IUGR-born individuals acquire epigenetic “thrifty-phenotype” gene adaptations, according to the “Barker hypothesis” and are more susceptible to develop metabolic related diseases. Small for Gestational Age (SGA) fetuses consist of a transitional group between IUGR and normally grown fetuses (Appropriate for Gestational Age, AGA). Currently, there is limited information in the literature whether IUGR or SGA status affects the pluripotency of the Umbilical Cord Mesenchymal Stem Cell (UC-MSC) with respect to gene expression at various stages of cell culture. Materials and Methods: In this study, we investigated stemness marker expression in UC-MSCs derived from twenty-one AGA, IUGR, and SGA fetuses. The relative expression of key genes involved in stemness, pluripotency, and cell proliferation, namely IGF2BP1, CMYC, GLI1, P21, NANOG, OCT4, and SOX2, was assessed in UC-MSCs at passages P0 and P1 using flow cytometry and quantitative PCR. Results: We found lower median expression levels of IGF2BP1 in IUGR group (P=0.044) and P21 in SGA group (P=0.024) at P0 compared to control group. GLI1 and OCT4 exhibited reduced expression at P1 in the IUGR group (P=0.0434 and P=0.0343 respectively) compared to AGA. NANOG median expression differed statistically between CONTROL and IUGR group in P0 (P=0.034) and P1 (P=0.0205). No significant changes were noted for SOX2 and CMYC median expression among the various groups in P0 and P1. Conclusion: The comparative analysis of stemness marker expression among UC-MSCs from these three different sources is a novel descriptive aspect of our study, adding a new perspective to the existing literature.

Heat Stress-Induced Fetal Intrauterine Growth Restriction Is Associated with Elevated LPS Levels Along the Maternal Intestine-Placenta-Fetus Axis in Pregnant Mice.

The exacerbation of the greenhouse effect has made heat stress (HS) an important risk factor for the occurrence of intrauterine growth restriction (IUGR). The experiment aims to uncover the effects of maternal HS on IUGR and its mechanisms. The results showed that HS leads to decreased maternal and fetal birth weights, accompanied by increased serum oxidative stress and cortisol levels. Moreover, HS inflicted significant damage to both the intestinal and placental barriers, altering maternal gut microbiota and increasing intestinal LPS levels. As a result, LPS levels increased in maternal serum, placenta, and fetus. Furthermore, HS damaged the intestinal structure, intensifying inflammation and disrupting the redox balance. The placenta exposed to HS exhibited changes in the placental structure along with disrupted angiogenesis and decreased levels of nutritional transporters. Additionally, the leakage of LPS triggered placental JNK and ERK phosphorylation, ultimately inducing severe placental inflammation and oxidative stress. This study suggests that LPS translocation from the maternal intestine to the fetus, due to a disrupted gut microbiota balance and compromised intestinal and placental barrier integrity, may be the primary cause of HS-induced IUGR. Furthermore, increased LPS leakage leads to placental inflammation, redox imbalance, and impaired nutrient transport, further restricting fetal growth.

Association between intrauterine fetal growth restriction and ABO blood groups at King Abdulaziz University Hospital, Saudi Arabia: Retrospective study.

To investigate the potential association between ABO blood groups and intrauterine fetal growth restriction (IUGR) among pregnant women who delivered at King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia. This is a retrospective cohort study analyzed the medical records of pregnant women who delivered at KAUH and had postnatal follow-up visits. Missing data were completed by conducting phone interviews with patients. A total of 436 patients with a mean age of 31.2±5.5 years were included in the study. 50.7% of the women had blood type O, 28.4% had blood type A, 16.5% had blood type B, and 4.4% had blood type AB. The majority (94.7%) tested positive for the Rhesus antigen. Although statistically significant, women with blood groups AB and B exhibited higher rates of IUGR (31.6%, and 27.8%, respectively) compared to those with blood groups A and O, who had lower rates of IUGR (26.6%, and 24%, respectively). Our study results showed that women with blood groups AB and B had slightly higher rates of IUGR than those with A and O, who had lower rates of IUGR. A larger study comparing blood group O to other groups may provide more insight into the relationship between ABO blood groups and IUGR.

Maternal and Neonatal Outcomes of Gestational Thrombocytopenia in Pregnant Women from Kirkuk City, Iraq: A Case-Control Study

Background: Thrombocytopenia is the most common hematological disorder in pregnant women, second only to anemia. A platelet count of less than 150x109/L is regarded as low. It is the most common cause of thrombocytopenia during pregnancy when the platelet count does not fall below 70x109\L. Methods: A case-control study was carried out in the department of obstetrics and gynecology at Azadi Teaching Hospital, Kirkuk, Iraq. Two hundred pregnant women were enrolled in the study; they were divided into 100 cases and 100 controls. All participants were in labor at the time of admission. The cases were pregnant women with gestational thrombocytopenia, while the controls were pregnant women with a normal platelet count. A platelet count was performed for all participants using the Swelab Alfa Plus system. Results: mean gestational age and platelet count were significantly lower in patients than controls, while there was no statistically significant difference in age or parity between the study groups. Preterm labor, postpartum hemorrhage (PPH), intrauterine fetal growth restriction (IUGR), and intrapartum fetal distress were significantly higher in the patients than in the controls, and the mean APGAR score at 5 minutes was significantly lower in the patients compared to the controls. Conclusions: Pregnant women with gestational thrombocytopenia may be at higher risk of preterm labor, postpartum hemorrhage, IUGR, intrapartum fetal distress and a low neonatal APGAR score.

239 Impaired Myoblast Function and Poor Muscle Growth in Intrauterine Growth-Restricted Fetal Sheep Is Improved By the Anti-Inflammatory Nutraceutical, Eicosapentaenoic Acid

Abstract Chronic heat stress during pregnancy causes low birthweight due to intrauterine growth restriction (IUGR) of the fetus. Recent findings indicate that IUGR fetal programming includes enhanced inflammatory sensitivity that disproportionally affects skeletal muscle. Thus, our objective was to determine if 5-d intravenous fetal infusion of the anti-inflammatory ω-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA) improved growth metrics and ex vivo myoblast (i.e., muscle stem cell) function in heat stress-induced IUGR fetal sheep. Maternal heat stress (40°C, 35% humidity, THI = 85) from d 40 to 95 of gestation was used to produce IUGR fetuses. Saline or EPA (25 mg/d) was infused via fetal femoral catheter from d 118 to 122 of gestation. At 122 d gestation, IUGR fetuses (n = 10; 2.31 ± 0.16 kg) were 26% lighter (P &amp;lt; 0.05) than control fetuses (n = 10; 3.10 ± 0.15 kg). Body mass of EPA-infused IUGR fetuses (n = 9; 2.70 ± 0.16 kg) were intermediate between controls and IUGR fetuses. Likewise, IUGR fetuses had lighter (P &amp;lt; 0.05) hindlimbs (28%), semitendinosus (30%), longissimus muscle (28%), flexor digitorum superficialis (30%), and soleus (31%) than controls. EPA infusion partially recovered (P &amp;lt; 0.05) hindlimb and longissimus muscle mass and fully recovered (P &amp;lt; 0.05) flexor digitorum superficialis and soleus mass but did not improve semitendinosus mass. Primary myoblasts were isolated at necropsy and incubated in proliferation media (DMEM + 20% fetal bovine serum) for 2 h or differentiation media (DMEM + 2% fetal bovine serum) for 96 h. Proliferation rates (determined by EdU incorporation over 2 h) were less (P &amp;lt; 0.05) for myoblasts from IUGR fetuses (38 ± 2% EdU+) and EPA-infused IUGR fetuses (39 ± 2% EdU+) than controls (44 ± 1% EdU+). Differentiation rates (determined by myogenin expression after 96 h) were less (P &amp;lt; 0.05) for myoblasts from IUGR fetuses (9 ± 1% myogenin+) but not EPA-infused IUGR fetuses (13±1% myogenin+) compared with controls (12 ± 1% myogenin+). IUGR fetuses had lighter (P &amp;lt; 0.05) heart (19%) and brain (11%) mass than controls, but heart/fetal mass and brain/fetal mass were greater (P &amp;lt; 0.05) than controls, which indicates tissue sparing for these organs. EPA infusion did not affect heart or brain mass but reduced (P &amp;lt; 0.05) heart/fetal mass and brain/fetal mass. Together, these findings demonstrate that skeletal muscle growth is disproportionately restricted compared with whole-body, brain, heart, or liver growth, and that this is facilitated by intrinsic impairment of myoblast function. Moreover, prolonged fetal infusion of the anti-inflammatory nutraceutical, EPA, partially recovered myoblast function and muscle growth in IUGR fetal sheep.

240 Prolonged Maternofetal Inflammation in the Pregnant Ewe at Mid-Gestation Increases Subsequent Fetal Inflammatory Tone and Disrupts Skeletal Muscle Growth and Glucose Metabolism Near Term

Abstract Chronic maternofetal inflammation in late gestation (i.e., peak fetal growth) causes fetal intrauterine growth restriction (IUGR) in sheep, which was associated with deficits in growth, body composition, and metabolic function before and after birth. However, the impact of sustained maternofetal inflammation during mid-gestation (i.e., peak placental growth and development) has not been explored. Therefore, our objective was to determine the effects of sustained maternofetal inflammation during this critical window on subsequent fetal inflammatory tone, metabolism, and myoblast (i.e., muscle stem cell) function. Pregnant ewes were injected every 3rd day from the 50th to 65th d of gestational age (dGA; term = 150 dGA) with saline (control; n = 12) or bacterial lipopolysaccharide endotoxin to induce maternofetal inflammation and IUGR (MI-IUGR; n = 12). Fetuses were surgically catheterized on dGA 118 to collect blood samples, and a hyperinsulinemic-euglycemic clamp (HEC) was performed on dGA 123. Fetuses were necropsied on dGA 125 to collect semitendinosus muscle samples. Fetal plasma TNFα concentrations tended to be greater (P = 0.07) for MI-IUGR fetuses (440 ± 45 pg/m l) than for controls (348 ± 24 pg/mL). Fetal blood O2 partial pressures were 12% less (P &amp;lt; 0.05) and maternofetal O2 gradients tended to be 11% greater (P = 0.08) for MI-IUGR fetuses than for controls. Hindlimb-specific glucose uptake rates did not differ between fetal groups, but hindlimb-specific glucose oxidation rates were reduced (P &amp;lt; 0.05) by 15% under basal conditions and by 27% under hyperinsulinemic conditions for MI-IUGR fetuses compared with controls. Semitendinosus glycogen content and β2 adrenoceptor content did not differ between fetal groups, but semitendinosus content of the TNFα receptor, TNFR1, was 41% greater (P &amp;lt; 0.05) for MI-IUGR fetuses than for controls. Immunohistochemistry revealed 18% fewer (P &amp;lt; 0.05) proliferating myoblasts (pax7+/Ki67+) and 38% fewer (P &amp;lt; 0.05) differentiated myoblasts (myogenin+) in semitendinosus from MI-IUGR fetuses compared with controls, which coincided with 13% smaller (P &amp;lt; 0.05) muscle fibers. From these findings, we conclude that sustained maternofetal inflammation during peak placental development at mid-gestation resulted in enhanced fetal inflammatory tone near term, which in turn impaired myoblast function, muscle fiber hypertrophy, and muscle glucose metabolism.

241 Increased Inflammatory Tone and Impaired Skeletal Muscle Growth in Intrauterine Growth-Restricted Neonatal Lambs Is Improved By Daily Supplementation of ω-3 Polyunsaturated Fatty Acid Ca2+ Salts

Abstract Low birthweight due to fetal intrauterine growth restriction (IUGR) often results from maternofetal heat stress. IUGR fetuses exhibit enhanced inflammatory tone, which persists after birth and impacts body composition, skeletal muscle growth, and metabolic function. Therefore, our objective was to determine whether daily oral supplementation of Ca2+ salts of ω-3 polyunsaturated fatty acids (ω-3 PUFA) to IUGR-born neonatal lambs improved inflammatory tone, body composition, and growth metrics. Pregnant ewes were exposed to heat stress (40°C, 35% humidity, THI = 85) from d 40 to 95 of gestation to induce IUGR. Lambs were weaned at birth and hand-reared on milk replacer. Daily oral boluses of 0.5 mL molasses containing 0 or 0.42 g/kg bodyweight of ω-3 PUFA (Virtus Nutrition) were administered. Femoral catheters were placed at d 24 and lambs were necropsied at d 30. At birth, IUGR lambs (n = 8; 3.12 ± 0.34 kg) and IUGR+ω-3 lambs (n = 7; 3.67 ± 0.32 kg) were lighter (P &amp;lt; 0.05) than controls (n = 12; 4.28 ± 0.15 kg). Plasma TNFα concentrations were greater (P &amp;lt; 0.05) at birth for IUGR (557 ± 121 pg/mL) and IUGR+ω-3 lambs (437 ± 82 pg/mL) than for controls (213 ± 78 pg/mL). Plasma TNFα concentrations remained increased (P &amp;lt; 0.05) for IUGR lambs but not for IUGR+ω-3 compared with controls at 2, 3, and 4 wk of age. Adjusted 30-d bodyweights were lighter (P &amp;lt; 0.05) for IUGR lambs (9.83 ± 0.6 kg) but not for IUGR+ω-3 lambs (11.59 ± 0.4 kg) than for controls (12.35 ± 0.2 kg). Heart and brain weights were 17% and 6% lighter (P &amp;lt; 0.05), respectively, for IUGR lambs than for controls. Brain weight deficits were resolved in IUGR+ω3 lambs, but heart weights did not differ between IUGR and IUGR+ω-3 IUGR lambs. Crown circumference/ bodyweight, abdominal circumference/ bodyweight, and cannon bone length/ bodyweight (indicators of asymmetric body composition) were 11% to 15% greater (P &amp;lt; 0.05) for IUGR lambs than for IUGR+ω-3 lambs or controls. At necropsy, IUGR lambs had lighter (P &amp;lt; 0.05) whole hindlimbs (29%) and flexor digitorum superficialis (24%), soleus (36%), biceps femoris (25%), semitendinosus (24%), gastrocnemius (29%), and longissimus dorsi (26%) muscles compared with controls. Weight deficits were partially or fully resolved in IUGR+ω-3 lambs for whole hindlimbs and for all muscles but the soleus, which did not differ from IUGR lambs. These findings demonstrate that daily oral supplementation of Ca2+ salts of ω-3 PUFA reduced the enhanced inflammatory tone observed in IUGR-born offspring, which coincided with improved skeletal muscle growth and indicators of symmetrical body composition.

PSVIII-30 Impaired Glucose-Stimulated Insulin Secretion in Intrauterine Growth-Restricted Neonatal Lambs Is Improved By Daily Supplementation of ω-3 Polyunsaturated Fatty Acid Ca2+ Salts

Abstract Maternofetal heat stress during placental development induces fetal intrauterine growth restriction (IUGR), which in turn reduces birthweight. IUGR-born livestock exhibit deficits in insulin stimulus-secretion coupling and glucose metabolism that contribute to poor growth efficiency. Thus, our objective was to determine whether daily oral supplementation of Ca2+ salts of ω-3 polyunsaturated fatty acids (ω-3 PUFA) to IUGR-born neonatal lambs improves glucose-stimulated insulin secretion and other indicators of metabolic efficiency. Maternal heat stress (40°C, 35% humidity, THI = 85) from d 40 to 95 of gestation was used to induce IUGR. Lambs were weaned at birth and hand-reared on milk replacer. Beginning at birth, lambs received daily oral boluses of 0.5 mL molasses containing 0 or 0.42 g/kg bodyweight of ω-3 PUFA (Virtus Nutrition). All lambs were fitted with femoral catheters at d 24 and a square-wave hyperglycemic clamp study was performed on d 28 to assess basal (i.e., resting) and glucose-stimulated insulin secretion (GSIS). Blood glucose concentrations did not differ among IUGR lambs (n = 8), IUGR+ω-3 lambs (n = 7), and controls (n = 12), but by study design were increased (P &amp;lt; 0.05) 205% from basal during hyperglycemic periods. Basal plasma insulin concentrations did not differ among groups, but basal glucose-to-insulin ratios were greater (P &amp;lt; 0.05) for IUGR+ω-3 lambs than for controls or IUGR lambs. During hyperglycemia, plasma insulin concentrations were 53% less (P &amp;lt; 0.05) for IUGR lambs but only 30% less (P &amp;lt; 0.05) for IUGR+ω-3 lambs compared with controls. Hyperglycemic glucose-to-insulin ratios were greater (P &amp;lt; 0.05) for IUGR lambs (3.24 ± 0.59) compared with controls (1.10 ± 0.29) and were intermediate for IUGR+ω-3 lambs (2.08 ± 0.86). Blood lactate concentrations did not differ among groups or between periods, but blood pH was was greater (P &amp;lt; 0.05) for IUGR (7.448 ± 0.006) and IUGR+ω-3 lambs (7.439 ± 0.003) compared with controls (7.422 ± 0.004). Blood partial pressure of CO2 was less (P &amp;lt; 0.05) for IUGR lambs (43.0 ± 0.3 mmHg) than for controls (46.7 ± 0.9 mmHg) and was intermediate for IUGR+ω-3 lambs (44.0 ± 0.4 mmHg). Blood HCO3 concentrations and O2-bound hemoglobin were greater (P &amp;lt; 0.05) for IUGR and IUGR+ω-3 lambs than for controls. Blood Na+ tended to be less (P = 0.07) and blood K+ was less (P &amp;lt; 0.05) for IUGR and IUGR+ω-3 lambs than for controls. Blood Ca2+ was less (P &amp;lt; 0.05) for IUGR lambs but not for IUGR+ω-3 lambs than for controls. These findings demonstrate that daily oral supplementation of Ca2+ salts of ω-3 PUFA improved deficits in insulin stimulus-secretion coupling and several other metabolic indicators observed in IUGR-born offspring. However, it did not improve all electrolyte concentrations or acid-base balance of the blood.

286 Evaluation of Serotonin as a Vasorelaxant in Ovine Saphenous Artery and Vein

Abstract Herbivores that consume ergot alkaloids frequently suffer from vasoconstriction that can result in a myriad of symptoms that can range from necrosis of peripheral tissues to fetal intra-uterine growth restriction. As part of a larger study screening compounds that may mitigate the vasoconstrictive effects of ergot alkaloids, the objective of this experiment was to evaluate serotonin (5-HT) as vasorelaxant in the ovine saphenous artery and vein. Blood vessels were collected from a total mixed breed market rams (n = 16; approximate BW = 58 kg) at slaughter, cleaned of surrounding adipose and connective tissue, sliced into 2-mm cross-sections, and mounted in a multimyograph. Artery and vein cross-sections were equilibrated to 1 g tension in continuously gassed (95% O2/5% CO2) Krebs-Henseleit buffer (pH 7.4; 37.5 °C) for 90 min, precontracted with 0.0001 M phenylephrine for 15 min, exposed to concentrations of 5-HT that ranged from 1 x 10-9 to 1 x 10-4 M for a 5-min interval. Response data were normalized to the 0.0001 M phenylephrine response and were analyzed as a completely randomized design in SAS. The lateral saphenous vein (n = 5 lambs) relaxed to increasing concentrations of 5-HT (P &amp;lt; 0.05) with 65 to 75 % relaxation occurring at 1 x 10-7 M through 1 x 10-4 5-HT. Conversely, the lateral saphenous artery (n = 6 lambs) contracted in response to increasing concentrations of 5-HT (P &amp;lt; 0.05) resulting in a 255% increase from the phenylephrine response by the 1 x 10-4 M addition. In a subsequent experiment, saphenous veins from the remaining lambs (n = 5) were treated the same, but in place of increasing concentrations of 5-HT, saphenous veins were exposed to increasing concentrations of selective 5-HT receptor agonists to determine the receptor subtypes involved in the previously observed vasorelaxation. Agonists for receptors 5-HT2B (BW 723C86; α-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine hydrochloride), 5-HT4 (BIMU-8; 2,3-Dihydro-N-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride), and 5-HT7 (LP44; 4-[2-(methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-piperazinehexanamide, monohydrochloride) were used. These 5-HT receptor subtypes were selected based on their association with vascular smooth muscle relaxation. While all three 5-HT receptor subtypes resulted in vasorelaxation (P &amp;lt; 0.05), the 5-HT2B agonist only stimulated a maximal relaxation of 32% compared with the agonists for 5-HT4 and 5-HT7 that resulted in maximal relaxation of 68% and 50%, respectively. The agonist for 5-HT4 produced the greatest relaxation in the ovine lateral saphenous vein and should be targeted in subsequent research. It is likely that the combined effect of binding multiple receptor subtypes contributes to the overall effect of 5-HT. The focus on development of ergot alkaloid mitigation strategies should consider the divergent responses of arteries and veins to serotonin in peripheral tissues.

Folic acid: The key to a healthy pregnancy - A prospective study on fetomaternal outcome.

The objective of the study is to study the fetomaternal outcome associated with folic acid deficiency in pregnancy. 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 <8.6 ng/mL and the other with values ≥8.6 ng/mL. Plasma Vitamin B12 levels were measured to check for any concurrent deficiencies. Obstetric outcomes included first- and second-trimester miscarriages, development of anemia, gestational hypertension/preeclampsia, gestational diabetes mellitus, hypothyroidism, placental abruption, and intrauterine fetal growth restriction (FGR). Furthermore, the period of gestation at delivery, fetal weights, APGAR scores at 5 min were documented. The study also considered fetal neural tube defects, intrauterine fetal demise for data collection. Collected data were analyzed statistically to find the association of the above-mentioned outcomes with levels of folic acid. The rate of preterm deliveries was significantly higher in the folic acid group with levels <8.6 ng/mL (16.94%). The incidence of small for gestational age/FGR was higher in the folic acid group with levels <8.6 ng/mL (27.11%) compared to the high folic acid group with levels ≥8.6 ng/mL (13.38%). The differences in the incidence of anemia, gestational hypertension, gestational diabetes, and preeclampsia between the two groups were not statistically significant and no cases of intrauterine fetal demise or placental abruption were observed in either group. Moreover, there was no significant difference in the relative risk of low Apgar scores at 5 min between the two groups. The present study suggests that low folic acid levels during pregnancy are associated with a higher risk of adverse pregnancy outcomes such as anemia, miscarriages, preterm delivery, and FGR. Therefore, adherence to nutritional recommendation of folic acid supplementation during pregnancy is essential to prevent these adverse outcomes.