Neuroprotective effects of maternal melatonin administration in early-onset placental insufficiency and fetal growth restriction.

BACKGROUND: Early-onset fetal growth restriction (FGR) is associated with adverse outcomes. We hypothesised that maternal melatonin administration will improve fetal brain structure in FGR. METHODS: Surgery was performed on twin-bearing ewes at 88 days (0.6 gestation), and FGR induced in one twin via single umbilical artery ligation. Melatonin was administered intravenously (6 mg/day) to a group of ewes commencing on day of surgery until 127 days (0.85 gestation), when the ewe/fetuses were euthanized, and fetal brains collected. RESULTS: Study groups were control (n = 5), FGR (n = 5), control+melatonin (control+MLT; n = 6) and FGR+melatonin (FGR + MLT; n = 6). Melatonin administration did not significantly alter fetal body or brain weights. Myelin (CNPase+) fibre density was reduced in FGR vs. control animals in most brain regions examined (p < 0.05) and melatonin treatment restored CNPase fibre density. Similar but less pronounced effect was seen with mature myelin (MBP+) staining. Significant differences in activated microglia (Iba-1) activity were seen between lamb groups (MLT mitigated FGR effect) in periventricular white matter, subventricular zone and external capsule (p < 0.05). Similar effects were seen in astrogliosis (GFAP) in intragyral white matter and cortex. CONCLUSIONS: Maternal melatonin administration in early onset FGR led to improved myelination of white matter brain regions, possibly mediated by decreased inflammation. IMPACT: Maternal melatonin administration might lead to neuroprotection in the growth-restricted fetus, possibly via dampening neuroinflammation and enhancing myelination. This preclinical study adds to the body of work on this topic, and informs clinical translation. Neuroprotection likely to improve long-term outcomes of this vulnerable infant group.

N-acetylcysteine and Hydroxychloroquine Ameliorate ADMA-Induced Fetal Growth Restriction in Mice via Regulating Oxidative Stress and Autophagy.

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.

Two-dimensional phase-contrast MRI reveals changes in uterine arterial blood flow in pregnant women administered tadalafil for fetal growth restriction.

INTRODUCTION: 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). METHODS: 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. RESULTS: 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). DISCUSSION: 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.

Effects of dietary epidermal growth factor supplementation on liver antioxidant capacity of piglets with intrauterine growth retardation.

The present experiment was conducted to study the effects of dietary epidermal growth factor (EGF) supplementation on the liver antioxidant capacity of piglets with intrauterine growth retardation (IUGR). The present study consists of two experiments. In experiment 1, six normal-birth-weight (NBW) and six IUGR newborn piglets were slaughtered within 2 to 4 h after birth to compare the effects of IUGR on the liver antioxidant capacity of newborn piglets. The results showed that compared with NBW piglets, IUGR piglets had a lower birth weight and liver relative weight; IUGR piglets had a higher serum malondialdehyde (MDA) level, liver MDA level and hydrogen peroxide (H2O2) level, and had a lower liver total antioxidant capacity (T-AOC) level and glutathione peroxidase (GSH-Px) activity; IUGR trended to increase serum alanine aminotransferase activity, aspartate aminotransferase activity, and H2O2 level, and trended to decrease liver total superoxide dismutase activity. In experiment 2, six NBW piglets, and 12 IUGR piglets weaned at 21 d of age were randomly divided into the NC group (NBW piglets fed with basal diet); IC group (IUGR piglets fed with basal diet), and IE group (IUGR piglets fed with basal diet plus 2 mg/kg EGF), and feeding for 14 d. Organ index, serum parameters, liver antioxidant capacity, and liver antioxidant-related genes expression were measured. The results showed that compared to the IC group, dietary EGF supplementation (IE group) significantly reduced serum malondialdehyde level and H2O2 level, and liver protein carbonyl (PC) level and 8-hydroxydeoxyguanosine level of piglets with IUGR; dietary EGF supplementation (IE group) significantly increased serum T-AOC level, liver T-AOC level and GSH-Px activity; dietary supplemented with EGF (IE group) enhanced liver Nrf2, NQO1, HO1, and GPX1 mRNA expression compared to IC group. Pearson's correlation analysis further showed that EGF can alleviate liver oxidative injury caused by IUGR and improve the performance of IUGR piglets. In conclusion, EGF exhibited potent protective effects on IUGR-induced liver oxidative injury, by activating the Nrf2 signaling pathway to mediate the expression of downstream antioxidant enzymes and phase II detoxification enzymes (NQO1 and HO1), thereby alleviating liver oxidative damage and promoting the growth performance of IUGR piglets.

The liver is an important metabolic and secretory organ in vertebrates, which plays an important role in the overall health of animals. Studies have shown that intrauterine growth retardation (IUGR) can cause liver injury in piglets, which is unfavorable to the growth and development of piglets. Epidermal growth factor (EGF) has antioxidant properties, but its effect on liver oxidative damage caused by IUGR remains uncertain. In the present study, we chose newborn piglets with low birth weight as the IUGR models to investigate whether IUGR could cause oxidative damage in the liver. Then, the diet supplemented with EGF was fed to IUGR piglets to study the effects of EGF supplementation on the liver antioxidant function of IUGR-weaned piglets. Results showed that IUGR caused serious damage to the liver of piglets, while dietary EGF supplementation could reverse the oxidative injury induced by IUGR to some extent. Therefore, this study confirmed that EGF has positive effects on the liver health of piglets with IUGR.

Antenatal Neuroprotective Magnesium Sulfate in Very Preterm Infants and Its Association With Feeding Intolerance.

INTRODUCTION/OBJECTIVE: Magnesium sulfate (MgSO 4 ) treatment is widely used for fetal neuroprotection despite the controversy concerning the side effects. There is limited data regarding the impact of various cumulative maternal doses and neonatal serum magnesium (Mg) levels on short-term neonatal morbidity and mortality. We opted to carry out a study to determine the impact of neonatal serum Mg levels on neonatal outcomes. METHOD: We conducted this prospective observational study between 2017 and 2021. Antenatal MgSO 4 was used for neuroprotective purpose only during the study period. Inborn preterm infants delivered between 23 and 31 6/7 weeks of gestation were enrolled consecutively. Babies who underwent advanced resuscitation in the delivery room, inotropic treatment due to hemodynamic instability in the first 7 days of life, >12 hours since the discontinuation of maternal MgSO 4 treatment, severe anemia, and major congenital/chromosomal anomalies were excluded from the study. The subgroup of babies with serum Mg level at the 6th hour of life underwent an analysis. A neonatal Mg concentration of 2.5 mg/dL was used to classify MgSO 4 -exposed patients into 2 groups (<2.5 mg/dL and ≥2.5 mg/dL). Another analysis was performed between babies whose mothers were exposed to MgSO 4 and those not exposed. Finally, the groups' neonatal outcomes were compared. RESULTS: Of the 584 babies, 310 received antenatal MgSO 4 . The birth weights were significantly lower in the MgSO 4 exposed group (1113 ± 361 g vs 1202 ± 388 g, P = 0.005). Antenatal corticosteroid usage and intrauterine growth restriction were also noted to be higher. The MgSO 4 group was more likely to have bronchopulmonary dysplasia, prolonged invasive ventilation, necrotizing enterocolitis, delayed enteral nutrition, and feeding intolerance ( P < 0.05). MgSO 4 treatment was shown as an independent risk factor for feeding intolerance when corrected for confounders (odds ratio 2.13, 95% confidence interval: 1.4-3.1, P = 0.001). Furthermore, serum Mg level significantly correlated with feeding intolerance ( r = 0.21, P = 0.002). CONCLUSION: This study highlighted the effect of MgSO 4 treatment and the potential superiority of serum Mg level as a predictor of immediate neonatal outcomes, particularly delayed enteral nutrition and feeding intolerance. Further studies are warranted to ascertain the optimal serum Mg concentration of preterm infants in early life to provide maximum benefit with minimal side effects.

[Prenatal rescue dose of betamethasone in the preterm infant with intrauterine growth restriction]. / Dosis prenatal de rescate de betametasona en el prematuro con restricción del crecimiento intrauterino.

Antenatal corticosteroids reduce mortality and respiratory distress syndrome (RDS) in preterm newborns. These benefits decrease after a week of administration, recommending a rescue therapy if there is a new threat of premature delivery. Repeated administration of antenatal corticosteroids may have deleterious effects and their benefits are controversial in intrauterine growth restriction (IUGR). OBJECTIVE: to verify the effects in the IUGR population of antenatal betamethasone rescue therapy on neonatal morbidity and mortality, RDS, and neurodevelopment at 2 years. PATIENTS AND METHOD: Retrospective study including ≤ 34 weeks and ≤ 1,500g preterm newborns divided according to antenatal betamethasone exposure: Single-cycle (2 doses) vs Rescue therapy (3 doses). Subgroups were created for those ≥ 30 weeks. Both cohorts were followed up to 24 months of corrected age. The Ages & Stages Questionnaires (ASQ)® was administered to assess neurodevelopment. RESULTS: 62 preterm infants with a diagnosis of IUGR were included. The rescue therapy group compared with the single-dose group showed no differences in morbidity and mortality and less intubation rate at birth (p = 0.02), with no differences in respiratory support at 7 days of life. Preterm newborns ≥ 30 weeks exposed to rescue therapy showed higher morbidity and mortality (p = 0.03) and bronchopulmonary dysplasia (BPD) (p = 0.02), showing no differences in RDS. The rescue therapy group showed worse mean scores on the ASQ-3 scale, with no significant differences in cerebral palsy or sensory deficits. CONCLUSIONS: Rescue therapy reduces intubation at birth but does not reduce morbidity and mortality. However, at > 30 weeks, this benefit is not observed and the IUGR population exposed to rescue therapy presented more BPD and lower scores on the ASQ-3 scale at 2 years. Future studies should be aimed at the individualization of antenatal corticosteroid therapy.

Dietary ferulic acid supplementation improves antioxidant capacity and lipid metabolism in liver of piglets with intrauterine growth retardation.

Intrauterine growth retardation (IUGR) can result in early liver oxidative damage and abnormal lipid metabolism in neonatal piglets. Ferulic acid (FA), a phenolic compound widely found in plants, has many biological functions, such as anti-inflammation and anti-oxidation. Thus, we explored the effects of dietary FA supplementation on antioxidant capacity and lipid metabolism in newborn piglets with IUGR. In the study, 24 7-day-old piglets were divided into three groups: normal birth weight (NBW), IUGR, and IUGR + FA. The NBW and IUGR groups were fed formula milk as a basal diet, while the IUGR + FA group was fed a basal diet supplemented with 100 mg/kg FA. The trial lasted 21 days. The results showed that IUGR decreased absolute liver weight, increased transaminase activity, reduced antioxidant capacity, and disrupted lipid metabolism in piglets. Dietary FA supplementation enhanced absolute liver weight, reduced serum MDA level and ROS concentrations in serum and liver, markedly increased serum and liver GSH-PX and T-SOD activities, decreased serum HDL-C and LDL-C and liver NEFA, and increased TG content and HL activity in the liver. The mRNA expression related to the Nrf2-Keap1 signaling pathway and lipid metabolism in liver were affected by IUGR. Supplementing FA improved the antioxidant capacity of liver by down-regulating Keap1 and up-regulating the mRNA expression of SOD1 and CAT, and regulated lipid metabolism by increasing the mRNA expression level of Fasn, Pparα, LPL, and CD36. In conclusion, the study suggests that FA supplementation can improve antioxidant capacity and alleviate lipid metabolism disorders in IUGR piglets.

Association Between Enteral Supplementation With High-Dose Docosahexaenoic Acid and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-analysis.

Importance: High-dose docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid, may affect the risk of bronchopulmonary dysplasia (BPD). However, high-level summative evidence supporting such clinical association in very preterm infants is lacking. Objective: To examine the association between enteral supplementation with high-dose DHA during the neonatal period and the risk of BPD in preterm infants born at less than 29 weeks' gestation. Data Sources: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, medRxiv, and ClinicalTrials.gov were searched from inception to August 1, 2022, for eligible articles with no language restrictions. Study Selection: Randomized clinical trials (RCTs) were eligible for inclusion (1) if their interventions involved direct administration of a minimum DHA supplementation of 40 mg/kg/d or breast milk or formula feeding of at least 0.4% of total fatty acids, and (2) if they reported data on either BPD, death, BPD severity, or a combined outcome of BPD and death. Data Extraction and Synthesis: Two investigators completed independent review of titles and abstracts, full text screening, data extraction, and quality assessment using the Cochrane Risk of Bias 2.0. Risk ratios (RRs) with 95% CIs were pooled using random-effect meta-analyses. Main Outcomes and Measures: Primary outcome was BPD using trial-specific definitions, which was further stratified for RCTs that used a more stringent BPD definition based on systematic pulse oximetry assessment at 36 weeks' postmenstrual age. Other outcomes were BPD, death, BPD severity, or combined BPD and death. Results: Among the 2760 studies screened, 4 RCTs were included, which involved 2304 infants (1223 boys [53.1%]; mean [SD] gestational age, 26.5 [1.6] weeks). Enteral supplementation with high-dose DHA was associated with neither BPD (4 studies [n = 2186 infants]; RR, 1.07 [95% CI, 0.86-1.34]; P = .53; I2 = 72%) nor BPD or death (4 studies [n = 2299 infants]; RR, 1.04 [95% CI, 0.91-1.18]; P = .59; I2 = 61%). However, an inverse association with BPD was found in RCTs that used a more stringent BPD definition (2 studies [n = 1686 infants]; RR, 1.20 [95% CI, 1.01-1.42]; P = .04; I2 = 48%). Additionally, DHA was inversely associated with moderate-to-severe BPD (3 studies [n = 1892 infants]; RR, 1.16 [95% CI, 1.04-1.29]; P = .008; I2 = 0%). Conclusions and Relevance: Results of this study showed that enteral supplementation with high-dose DHA in the neonatal period was not associated overall with BPD, but an inverse association was found in the included RCTs that used a more stringent BPD definition. These findings suggest that high-dose DHA supplementation should not be recommended to prevent BPD in very preterm infants.

Management of patent ductus arteriosus in very preterm infants in England and Wales: a retrospective cohort study.

OBJECTIVE: To describe the diagnosis and treatment of patent ductus arteriosus (PDA) in infants born at <32 weeks' gestational age (GA) in England and Wales between 2010 and 2017. STUDY DESIGN: Retrospective cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks admitted to neonatal units in England and Wales from 2010 to 2017. RESULTS: Among 58 108 infants born at <32 weeks' GA, 28.3% (n=16 440) had a PDA diagnosed clinically or with echocardiographic confirmation. Of these, 34.8% (n=5721; 9.8% of total <32 weeks' infants included) had PDA treatment including 7.6% (n=1255) with indomethacin, 23.5% (n=3857) with ibuprofen and 5.6% (n=916) with surgical closure. The highest incidence of PDA was among infants born at 24 and 25 weeks' GA (70.2% and 70.8%, respectively), decreasing to 6.1% among infants born at 31 weeks' GA. The percentage of infants with a PDA increased over the study period (25.5% in 2010 to 28.5% in 2017). The percentage of infants who received ibuprofen or indomethacin or had PDA surgery decreased from 41.3% in 2010 to 33.7% in 2017, with an increase in use of ibuprofen from 20.2% to 27.3% while use of indomethacin decreased from 20.0% to 8.8%. Surgical closure of PDA decreased from 9.1% to 3.0%. Indomethacin was used for median (IQR) 3 (2-5) days while ibuprofen was given for 3 (2-4) days, at a median of 8 and 10 days after birth, respectively; surgical treatment was used later at 33 (24-45) days after birth. CONCLUSIONS: Ibuprofen is the preferred drug and surgical interventions are becoming less frequent for PDA closure among very preterm infants in England and Wales. TRIAL REGISTRATION NUMBER: NCT03773289.

Comparison of Low Molecular Weight Heparin Used alone or Combined with Aspirin in the Treatment of Fetal Growth Restriction.

The objective of the study was to compare the efficacy of low-molecular weight heparin (LMWH) alone and use in the combination with aspirin in the treatment of fetal growth restriction (FGR) patients. Ninety-six FGR patients were divided into the LMWH group (n=48) and the combined group (n=48), according to the different treatments. This research showed after treatment, values of PI, RI and S/D, serum IL-6 and TNF-α in the combined group were lower than those in the LMWH group (all p <0.001). The frequency of pregnancy complications and adverse neonatal outcomes in the combined group were 2 (4.2%) lower than the LMWH group (p=0.045, 0.025). Combination of LMWH with aspirin in FGR patients effectively reduced levels of IL-6 and TNF-α within the mother, improved fetal developmental parameters, and reduced the frequency of pregnancy complications and adverse neonatal outcomes compared with LMWH treatment alone. Key Words: Fetal growth restriction (FGR), Low-molecular weight heparin (LMWH), Aspirin, Pregnancy, Newborn.

Effects of ferulic acid on the growth performance, antioxidant capacity, and intestinal development of piglets with intrauterine growth retardation.

Neonates with intrauterine growth retardation (IUGR) are prone to suffer from delayed postnatal growth and development during the early stages of life. Ferulic acid (FA) is a phenolic compound that is abundantly present in fruits and vegetables and has various health benefits. Hence, we explored whether FA supplementation could favorably affect the growth performance, antioxidant capacity, and intestinal development of piglets with IUGR. In total, eight normal-birth-weight (NBW) piglets and 16 piglets with IUGR (age, 7 d) were assigned to be fed either basic formula milk (NBW and IUGR groups, respectively) or basic formula milk supplemented with 100 mg/kg FA (IUGR + FA group) for 21 d. At necropsy, the serum and intestinal tissues were collected. FA supplementation increased (P < 0.05) the feed conversion ratio and serum total superoxide dismutase and catalase activities in piglets with IUGR. Moreover, FA supplementation elevated (P < 0.05) the duodenal lactase and maltase activities, jejunal villus height and jejunal maltase activity but reduced (P < 0.05) the duodenal crypt depth and duodenal and jejunal cell apoptosis, cleaved cysteinyl aspartic acid protease-3 (caspase-3) content and cleaved caspase-9 content in piglets with IUGR. In summary, FA supplementation could elevate antioxidant capacity and facilitate intestinal development, thus resulting in increased feed efficiency in piglets with IUGR.

Intrauterine growth retardation (IUGR) impairs postnatal growth and development in neonatal piglets. Ferulic acid (FA) is a ubiquitous phenolic compound that is present in numerous fruits and vegetables and possesses various biological activities. However, little is known about whether FA supplementation has beneficial effects on the growth performance, antioxidant capacity, and intestinal development of piglets with IUGR. Our findings provide important implications for treating piglets with IUGR after birth by stimulating intestinal development with FA supplementation.

Sildenafil como tratamiento de la restricción de crecimiento intrauterino, revisión sistemática de la literatura / Sildenafil as a treatment for blood restriction fetal growth, systematic review of the literature

INTRODUCCIÓN Y OBJETIVO: La restricción del crecimiento intrauterino (RCIU), expresión insuficiente del potencial genético de crecimiento fetal, complica el 5-8% de los embarazos, con unas altas tasas de morbimortalidad perinatal. De origen multifactorial, puede ser causada por patologías maternas, fetales o placentarias. El tratamiento es limitado, optándose por un seguimiento riguroso con eventual interrupción del embarazo según la evolución. Se han utilizado diferentes estrategias terapéuticas para su prevención y manejo, surgiendo el citrato de sildenafil (CS), inhibidor de la fosfodiesterasa tipo 5, como fármaco que podría mejorar el flujo sanguíneo uteroplacentario y ofrecer mejores resultados perinatales en fetos con RCIU. Se propone realizar una revisión de la literatura disponible en relación al CS como tratamiento del RCIU. MÉTODO: Se realizó una búsqueda de literatura en inglés y español. De 105 artículos seleccionados, se excluyeron 94. La información obtenida fue clasificada y utilizada como soporte para la realización de esta revisión, siguiendo el modelo PRISMA. RESULTADOS: Se encontraron 11 estudios que contrastan el uso de placebo y CS en pacientes con RCIU. Respecto al aumento de peso al nacimiento, solo dos estudios demostraron evidencia significativa. Se reportaron 40 casos de muerte fetal/neonatal asociada al tratamiento con CS. CONCLUSIONES: No se encontró evidencia suficiente que justifique el uso sistemático de CS en casos de RCIU. Aún es necesario realizar estudios con muestras de mayor tamaño y posterior metaanálisis para confirmar el beneficio farmacológico en cuanto al aumento de peso de nacimiento, la prolongación del embarazo y los posibles efectos adversos a largo plazo.

INTRODUCTION AND OBJECTIVE: Intrauterine growth restriction (IUGR) is an insufficient expression of the genetic potential for fetal growth, complicates 5-8% of pregnancies and represents high rates of perinatal morbidity and mortality. Of multifactorial origin, it can be caused by pathologies at the maternal, fetal or placental level. The treatment is limited, opting for a rigorous follow-up with eventual interruption of the pregnancy according to evolution. Different therapeutic strategies have been used for its prevention and management, emerging sildenafil citrate (CS), inhibitor of phosphodiesterase type 5, as a drug that could improve the uteroplacental blood flow and offer better perinatal results in fetuses with IUGR. A review of the available literature on CS as a treatment for IUGR is proposed. METHOD: A search was conducted for literature in English and Spanish. Out of 105 selected articles, 94 were excluded. The information obtained was classified and used as support for this review, following the PRISMA model. RESULTS: We found 11 studies that contrast the use of placebo and CS in patients with IGR. Regarding birth weight gain, only two studies showed significant evidence. Forty cases of fetal/neonatal death associated with CS treatment were reported. CONCLUSIONS: Not enough evidence was found to justify the routine use of CS in IUGR cases. Studies with larger samples and subsequent meta-analysis are still necessary to confirm the benefit of this drug in terms of birth weight gain, prolongation of pregnancy and possible long-term adverse effects.

Nano-selenium and Macleaya cordata Extracts Improved Immune Function and Reduced Oxidative Damage of Sows and IUGR Piglets After Heat Stress of Sows in Late Gestation.

To investigate the effects of nano-selenium (nano-Se) and Macleaya cordata extracts (MCE) on immune function and oxidative damage of sows and intrauterine growth retardation (IUGR) piglets exposed to heat stress (HS) in large-scale farms, a 2 × 2 factorial design was adopted in this test, and the two factors were nano-Se (0, 0.50 mg/kg) and MCE (0, 500 mg/kg). A total of 80 sows ([Landrace × Yorkshire] × Duroc, parity 2) were used in a 25-day trial from day 90 of gestation to delivery with 20 replications per group and 1 sow per replication. The dietary treatments of sows were as follows: (1) CON group, basic diet (0.30 mg/kg added Se, sodium selenite); (2) Nano-Se group, basic diet (0.00 mg/kg added Se) + 0.50 mg/kg added nano-Se; (3) MCE group, basic diet (0.00 mg/kg added Se) + 500 mg/kg added MCE; and (4) Combined group, basic diet (0.00 mg/kg added Se) + 0.50 mg/kg added nano-Se and 500 mg/kg added MCE. The activities of serum SOD, CAT, and GSH-Px of sows and IUGR piglets were significantly increased in MCE group and combined group, and the MDA content was extremely decreased. There were extreme differences in serum IgG level of sows and IUGR piglets, colostrum, and serum IgM level of IUGR piglets in MCE group and combined group compared with CON group. Maternal combined diets increased greatly the levels of serum IL-10 and IFN-γ of sows and IUGR piglets, and decreased extremely the contents of serum IL-1ß and TNF-α. MCE alone or combination with nano-Se in sow diets decreased greatly mRNA level of Hsp70 and increased mRNA level of Hsp27 in sows and IUGR piglets. In conclusion, nano-Se and/or MCE can be added to sow diets for the amelioration of HS-induced oxidative damage through improving immune function.

The effect of ultrasound-guided intraperitoneal injection of ulinastatin on lung development in intrauterine growth-restricted fetal rabbits.

OBJECTIVES: To investigate the effect and mechanism of ulinastatin (UTI) on development of lungs in fetal rabbits with intrauterine growth retardation (IUGR). METHODS: Twenty pregnant rabbits were equally divided into normal, IUGR, UTI, and LY groups. The normal group was only injected with saline and marked with tattoo ink. IUGR models were established by injecting N-nitro-L-arginine methyl ester in the rabbits of IUGR, UTI, and LY groups. The three groups were injected with saline, UTI, or UTI + LY294002 (PI3K inhibitor) respectively, and then marked with tattoo ink. After cesarean section, neonatal weights, and levels of dipalmitoyl phosphatidylcholine (DPPC), nitric oxide (NO), P-Akt, P-eNOS, and pulmonary surfactant-associated protein A (SP-A) were determined in tissues of the lungs. Radial alveoli count (RAC), pulmonary interstitial ratio, and ultrastructural changes in type II alveolar epithelial cells (AEC II) were also determined through light and electron microscopy. RESULTS: Compared with control, the IUGR group showed significantly decreased weight, RAC, lamellar bodies in AEC II, and levels of P-Akt, P-eNOS, DPPC, NO, and SP-A, and increased pulmonary interstitial ratio (p < .05). The UTI treatment did not affect the weight; however, all other parameters were opposite to those observed in the IUGR group (p < .05). Furthermore, these UTI-mediated changes were inhibited by LY294002. CONCLUSIONS: Intraperitoneal UTI injection can promote the development of lungs and increase pulmonary surfactant production in IUGR fetal rabbits, potentially by activating PI3K/Akt/eNOS/NO signaling.

Assessment of the value of measuring soluble fms-like tyrosine kinase-1 and placental growth factor levels following administration of tadalafil to treat fetal growth restriction.

PURPOSE: The aim of this study was to measure the blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) before and after tadalafil treatment in patients with fetal growth restriction. MATERIALS AND METHODS: Maternal blood was collected from 13 women before and 2 weeks after tadalafil administration in the TADAFER II trial. The tadalafil treatment was conducted in addition to the conventional FGR treatment. As a control, maternal blood was also collected from 11 women before and 2 weeks after conventional treatment for fetal growth restriction. Blood sFlt-1 and PlGF were measured and the sFlt-1/PlGF ratio was calculated. Student's t-test was used to statistically analyze differences in the sFlt-1 and PlGF levels, and in the sFlt-1/PlGF ratios. RESULTS: In both treatment groups, the levels of sFlt-1 and PlGF before and after treatment were not significantly different from each other. The sFlt-1/PlGF ratio was 2.0 ± 1.0 before and 17.6 ± 11.3 after treatment in the control group (p=.04). The sFlt-1/PlGF ratio was 2.2 ± 1.1 before and 22.2 ± 10.6 after tadalafil treatment in the tadalafil group (p=.06). The sFlt-1/PlGF ratios before and after tadalafil treatment were significantly increased in the control group. In both treatment groups, the sFlt-1/PlGF ratios before and after treatment were less than 38. CONCLUSIONS: We conclude that the levels of sFlt-1 and PlGF were not significantly different as a result of tadalafil treatment. Further studies are needed to understand the mechanism of action of tadalafil in the treatment of fetal growth restriction.

Nebulized curcumin protects neonatal lungs from antenatal insult in rats.

Intrauterine growth restriction (IUGR) increases the risk of bronchopulmonary dysplasia (BPD), one of the major complications of prematurity. Antenatal low-protein diet (LPD) exposure in rats induces IUGR and mimics BPD-related alveolarization disorders. Peroxisome proliferator-activated receptor-γ (PPARγ) plays a key role in normal lung development and was found deregulated following LPD exposure. The objective of this article was to investigate the effects of nebulized curcumin, a natural PPARγ agonist, to prevent IUGR-related abnormal lung development. We studied rat pups antenatally exposed to an LPD or control diet (CTL) and treated with nebulized curcumin (50 mg/kg) or vehicle from postnatal (P) days 1 to 5. The primary readouts were lung morphometric analyses at P21. Immunohistochemistry (P21) and microarrays (P6 and P11) were compared within animals exposed to LPD versus controls, with and without curcumin treatment. Quantitative morphometric analyses revealed that LPD induced abnormal alveolarization as evidenced by a significant increase in mean linear intercept (MLI) observed in P21 LPD-exposed animals. Early curcumin treatment prevented this effect, and two-way ANOVA analysis demonstrated significant interaction between diet and curcumin both for MLI [F(1,39) = 12.67, P = 0.001] and radial alveolar count at P21 [F(1,40) = 6.065, P = 0.0182]. Immunohistochemistry for fatty acid binding protein 4 (FABP4), a major regulator of PPARγ pathway, showed a decreased FABP4+ alveolar cell density in LPD-exposed animals treated by curcumin. Transcriptomic analysis showed that early curcumin significantly prevented the activation of profibrotic pathways observed at P11 in LPD-exposed animals. Nebulized curcumin appears to be a promising strategy to prevent alveolarization disorders in IUGR rat pups, targeting pathways involved in lung development.

Maternal antioxidant treatment protects adult offspring against memory loss and hippocampal atrophy in a rodent model of developmental hypoxia.

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long-term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention. Pregnant rats were randomly chosen for normoxic or hypoxic (13% oxygen) pregnancy with or without maternal supplementation with vitamin C in their drinking water. In one cohort, the placenta and fetal tissues were collected at the end of gestation. In another, dams were allowed to deliver naturally, and offspring were reared under normoxic conditions until 4 months of age (young adult). Between 3.5 and 4 months, the behavior, cognition and brains of the adult offspring were studied. We demonstrated that prenatal hypoxia reduced neuronal number, as well as vascular and synaptic density, in the hippocampus, significantly impairing memory function in the adult offspring. These adverse effects of prenatal hypoxia were independent of the hypoxic pregnancy inducing fetal growth restriction or elevations in maternal or fetal plasma glucocorticoid levels. Maternal vitamin C supplementation during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring. Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress, and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy.

Evaluating the Effect of Pravastatin in Early-Onset Fetal Growth Restriction: A Nonrandomized and Historically Controlled Pilot Study.

OBJECTIVE: This study aimed to analyze the effect of pravastatin on angiogenic factors, feto-maternal Doppler findings and pregnancy outcomes in women with early-onset fetal growth restriction (FGR) treated with pravastatin compared with nontreated controls. STUDY DESIGN: This was a pilot study conducted between March 2016 and September 2017. Women with single pregnancies and FGR diagnosed at ≤ 28 weeks of gestation were offered 40 mg of pravastatin daily. Doppler progression, soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) values, and pregnancy outcomes were assessed and compared with consecutive historical controls. Controls were matched to treated women for gestational age, maternal characteristics, maternal and obstetric history, Doppler severity classification, and angiogenic factors at diagnosis. The sFlt-1/PlGF was measured in maternal serum at two different times: before pravastatin was started (ratio M0) and during pravastatin treatment (ratio M1). Doppler severity was classified into four categories: normal, mild, moderate, and severe. RESULTS: A total of 38 women were enrolled in this study. No differences were observed in baseline characteristics between groups. However, when compared with the ratio M0, M1 was increased by a median (interquartile range) of 67.0 (-34.8 to 197.3) in the control group but decreased by a median (interquartile range) of -10.1 (-53.1 to -0.07) in the pravastatin treated group (p < 0.001). No significant differences were observed in Doppler progression throughout pregnancy. Median interval from diagnosis to delivery was extended by 16.5 days, the median newborn birthweight was increased from 1,040 to 1,300 g, and the number of women with preeclampsia decreased from 9 (47.4%) to 6 (31.6%) in treated women; however, these trends were not statistically significant. CONCLUSION: In women with early-onset FGR, treatment with pravastatin 40 mg daily was associated with significant improvement in the angiogenic profile. Additionally, median pregnancy duration and median birthweight increased and the incidence of PE was reduced in treated women. Nevertheless, since this pilot study was underpowered, none of these differences were statistically significant. KEY POINTS: · Pravastatin improves sFlt-1/PlGF in FGR.. · Pregnancy duration tended to be greater in treated women.. · Birthweight tended to be greater in treated women..

Antenatal antioxidants to avert autism?

Paternally derived de novo mutations (DNMs) caused by oxidative stress (OS) have been implicated in the development of autism spectrum disorders (ASDs). Whether preconception antioxidant supplementation can reduce the incidence of ASDs by reducing OS is an area of uncertainty and potentially important future scientific investigation.

Male preconception antioxidant supplementation may lower autism risk: a call for studies.

Current research indicates that a sizable number of autism spectrum disorder (ASD) cases arise from de novo mutations (DNMs) occurring within the paternal germline, usually in an age-dependent manner. Andrologists have reported that somatic cells and gametes share the same pathologies that generate these DNMs-specifically, DNA hypomethylation caused by oxidative nucleoside base damage. Because many ASD researchers seek to identify genetic risk factors, teams are developing methods of assessing aberrant DNA patterns, such as parental gonadal mosaicism. Several studies propose antioxidant supplementation as a strategy to lower autism risk, and/or suggest connections between childhood neurodevelopmental disorders such as autism and paternally-derived DNMs. Actual data, however, are currently not available to determine whether male preconception antioxidant supplementation effectively lowers autism risk. The purpose of this paper is to (1) explore the mechanisms causing DNMs, specifically DNA hypomethylation; (2) explain how antioxidant supplementation may lower the risk of having a child with ASD; and, (3) advocate for the implementation of large prospective studies testing (2). These studies may very well find that male preconception supplementation with antioxidants prevents neurodevelopmental disorders in offspring, in much the same way that female prenatal consumption of folate was found to decrease the risk of birth defects. If this is indeed the case, the alarming rise in autism prevalence rates of the past few decades will slow-or even cease-upon the initiation of public awareness campaigns.