Early Vitamin A Supplementation for Prevention of Short-Term Morbidity and Mortality in Very-Low-Birth-Weight Infants: A Systematic Review and Meta-Analysis.

Background: Vitamin A plays an important role in the development and maintenance of the normal function of organs and systems. Premature infants have low levels of vitamin A, which may be associated with an increased risk of developing disease. This study aimed to evaluate the effects of vitamin A supplementation on short-term morbidity and mortality in very-low-birth-weight (VLBW) infants. Methods: We used PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and Web of Science to conduct a literature search of studies published before January 1, 2022, to be included in our meta-analysis. The analysis included randomized controlled trials that compared the effects of vitamin A supplementation on VLBW infants (birth weight <1,500 g) and controls given a placebo or no treatment. The certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines. Results: Twelve randomized controlled trials were included in the meta-analysis, and 2,111 infants were pooled and analyzed. The overall risk of bias was not serious in the included studies. Vitamin A supplementation for reducing the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age seems to be limited [risk ratio (RR):0.85; 95% confidence intervals (CI): 0.70-1.04; 8 studies, 1,595 infants, very-low-certainty evidence], which is different from the previous systematic review. Length of hospital stay (mean difference: -12.67, 95% CI: -23.55 to -1.79; 6 studies, 739 infants, low-certainty evidence), and the incidence of vitamin A deficiency at 28 days postnatal age (RR: 0.08; 95% CI: 0.02-0.38; 3 studies, 358 infants, low-certainty evidence) were reduced in the vitamin A group. Besides, vitamin A supplementation seems to reduce the incidence of periventricular leukomalacia (RR: 0.68; 95% CI: 0.47-0.97; 4 studies, 1,224 infants, low-certainty evidence) and retinopathy of prematurity of any grade (RR: 0.61; 95% CI: 0.48-0.76; 4 studies, 463 infants, moderate-certainty evidence). Conclusions: There is no sufficient evidence regarding vitamin A supplementation preventing BPD in VLBW infants. Vitamin A supplementation can reduce the incidence of vitamin A deficiency and retinopathy of prematurity of any grade, and may exert an effect of preventing periventricular leukomalacia. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42020211070.

Intensive phototherapy vs. exchange transfusion for the treatment of neonatal hyperbilirubinemia: a multicenter retrospective cohort study.

BACKGROUND: Intensive phototherapy (IPT) and exchange transfusion (ET) are the main treatments for extreme hyperbilirubinemia. However, there is no reliable evidence on determining the thresholds for these treatments. This multicenter study compared the effectiveness and complications of IPT and ET in the treatment of extreme hyperbilirubinemia. METHODS: This retrospective cohort study was conducted in seven centers from January 2015 to January 2018. Patients with extreme hyperbilirubinemia that met the criteria of ET were included. Patients were divided into three subgroups (low-, medium-, and high- risk) according to gestational week and risk factors. Propensity score matching (PSM) was performed to balance the data before treatment. Study outcomes included the development of bilirubin encephalopathy, duration of hospitalization, expenses, and complications. Mortality, auditory complications, seizures, enamel dysplasia, ocular motility disorders, athetosis, motor, and language development were evaluated during follow-up at age of 3 years. RESULTS: A total of 1164 patients were included in this study. After PSM, 296 patients in the IPT only group and 296 patients in the IPT plus ET group were further divided into the low-, medium-, and high-risk subgroups with 188, 364, and 40 matched patients, respectively. No significant differences were found between the IPT only and IPT plus ET groups in terms of morbidity, complications, and sequelae. Hospitalization duration and expenses were lower in the low- and medium-risk subgroups in the IPT only group. CONCLUSIONS: In this study, our results suggest that IPT is a safe and effective treatment for extreme hyperbilirubinemia. The indication of ET for patients with hyperbilirubinemia could be stricter. However, it is necessary to have a contingency plan for emergency ET as soon as IPT is commenced especially for infants with risk factors. If IPT can be guaranteed and proved to be therapeutic, ET should be avoided as much as possible.

New-generation intravenous fat emulsions and bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis.

BACKGROUND: Fat emulsion is an important component of parenteral nutrition in premature infants. However, intravenous fat emulsions (IVFE) was reported to be associated with some serious complications, such as bronchopulmonary dysplasia (BPD). Compared to conventional soybean oil-based IVFE, new-generation IVFE may protect against BPD but the results are conflicting. METHODS: Relevant literatures search was conducted and the summary effect estimates of odds ratio (OR) and 95% confidence interval (CI) were calculated with fixed-effects models. RESULTS: Of 22 studies involving 3781 infants were selected in this study and BPD was reported as part of the included studies. The pooled estimate for 13 studies, comparing administration of new-generation IVFE with conventional IVFE, indicated that new-generation IVFE was not associated with a reduced risk of BPD in preterm infants, compared with conventional IVFE (OR 0.96; 95% CI 0.80-1.14); the pooled estimate for 18 studies, comparing administration of fish oil-containing IVFE with non-fish oil IVFE, indicated that fish oil-containing IVFE has no protective effect against the occurrence of BPD in preterm infants (OR 0.88; 95% CI 0.71-1.08). CONCLUSIONS: There is no evidence to support that the new-generation IVFEs could prevent the incidence of BPD or fish oil-containing IVFEs could show a beneficial effect to BPD in premature infants.

First-year growth of 834 preterm infants in a Chinese population: a single-center study.

BACKGROUND: The aim of this study was to follow the growth and hematological indicators of preterm infants during their first year. METHODS: Neonates below 37 gestational weeks had routine follow-ups up through 1 year from January 2012 to December 2015 at West China 2nd University Hospital, Sichuan University. Weight, length and head circumference (HC) were measured monthly during the first 6 months, followed by monitoring every second month until 12 months. The catch-up growth defined as a gain of Z-score > 0.67 according to previous study. All preterm infants were prescribed iron prophylaxis based on national guideline. The hemoglobin concentration was examined at 6 and 12 months. RESULTS: Altogether, 132 very-low-birth-weight (VLBW), 504 low-birth-weight (LBW) and 198 normal-birth-weight (NBW) infants were followed. The rates of catch-up growth for weight, length and HC 12 months of corrected age (CA) were 22.6, 29.1 and 14.6%, respectively. SGA and VLBW infants showed higher catch-up growth rates. The overall prevalence of anemia was 6.8% at 6 months and 7.8% at 12 months. The Z-scores for weight-for-length, length and HC were lower in the VLBW and SGA preterm infant groups than in the other preterm groups throughout the first year of life. The incidences of stunting, microcephaly and wasting changed from 5, 1.3 and 3.7% to 2, 1.1, 0.9 and 2.4%, respectively, during the first year. However, the incidences of wasting and stunting were higher for the VLBW infants than for the LBW and NBW infants at 12 months (9.3% vs. 1.4%, p < 0.01; 9.3% vs. 1%, p < 0.01,respectively; 4.7% vs. 0.8%, p < 0.01, 4.7% vs. 0%, p < 0.01,respectively). Similar results were observed between SGA and AGA infants (8.7% vs. 1.5%, p < 0.01; 5.8% vs. 0.4%, p < 0.01). Logistic regression revealed SGA and VLBW as risk factors for poor growth (WLZ < -2SD) at 12 months (OR = 5.5, 95% CI: 2.1-14.8, p < 0.01: OR = 4.8, 95% CI: 1.8-12.8, p < 0.01, respectively). CONCLUSION: The VLBW and SGA preterm infants showed significant catch-up growth during their first year of life. However, SGA and VLBW were risk factors for poor growth during the preterm infants' first year of life. Prophylactic iron supplementation in preterm infants appears to reduce the prevalence of anemia.

Proton Magnetic Resonance Spectroscopy Biomarkers in Neonates With Hypoxic-Ischemic Encephalopathy: A Systematic Review and Meta-Analysis.

Background: Hypoxic-ischemic encephalopathy (HIE) is a major contributor to child mortality and morbidity. Reliable prognostication for HIE is of key importance. Proton magnetic resonance spectroscopy (1H-MRS) is a quantitative, non-invasive method that has been demonstrated to be a suitable complementary tool for prediction. The aim of this study was to investigate the prognostic capability of 1H-MRS in the era of therapeutic hypothermia (TH). Methods: Databases, namely MEDLINE, Embase, Web of Science, and the Cochrane library (Cochrane Center Register of Controlled Trials), were searched for studies published before July 17, 2017. Study selection and data extraction were performed by two independent reviewers. The mean difference (MD) or standardized MD (SMD) and 95% confidence interval (CI) were calculated using random-effects models. Subgroup analyses were conducted based on the use of TH. Results: Among the 1,150 relevant studies, seven were included for meta-analysis, but only two small studies were conducted under TH. For 1H-MRS measurement, three peak area ratios revealed predictive values for adverse outcomes in TH subgroup and the combined results (with and without TH): N-acetylaspartate (NAA)/creatine in basal ganglia/thalamus (BG/T) in TH (MD -0.31, 95%CI -0.55 to -0.07) and combined results (MD -0.37, 95% CI -0.49 to -0.25); NAA/choline in BG/T in TH (MD -0.89, 95%CI -1.43 to -0.35) and combined results (MD -0.25, 95%CI -0.42 to -0.07); and myo-inositol/choline in cerebral cortex in TH (MD -1.94, 95%CI -3.69 to -0.19) and combined results (MD -1.64, 95%CI -2.64 to -0.64). Moreover, NAA relative concentration is associated with adverse outcomes: in TH (MD -0.04, 95%CI -0.06 to -0.02) and combined results (MD -0.06, 95%CI -0.11 to -0.01) in white matter; in TH (MD -0.04, 95%CI -0.07 to -0.01) and combined results (MD -0.05, 95%CI -0.07 to -0.02) in gray matter. Conclusions: NAA may be a potential marker in outcome prediction for all HIE subjects. It seems that MDs for the ratios including NAA are larger than for its relative concentration, and therefore are more likely to be measurable in a clinical context. Larger prospective multicenter studies with a standardized protocol for both measurement protocols and analysis methods are required in future studies.

Iron Status in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children. However, the pathogenesis of ADHD remains unclear. Iron, an important trace element, is implicated in brain function and dopaminergic activity. Recent studies have investigated the association between iron deficiency and ADHD, but the results are inconsistent. METHODS: A systemic search of MEDLINE, EMBASE, Web of Science and Cochrane Library databases was supplemented by manual searches of references of key retrieved articles. Study quality was evaluated using the Newcastle-Ottawa Scale. The standardised mean difference (SMD) and 95% confidence intervals (CIs) were calculated using a random-effects model. H2 and I2 were used to evaluate the heterogeneity, and sensitivity, subgroup and meta-regression analyses were conducted to explore the reason of heterogeneity. RESULTS: The search yielded 11 studies published before July 25, 2016. Of these, 10 studies, comprising 2191 participants and 1196 ADHD cases, reported serum ferritin levels, and six studies, comprising 617 participants and 369 ADHD cases, reported serum iron levels. Serum ferritin levels were lower in ADHD cases (SMD = -0.40, 95% CI = -0.66 to -0.14). However, we found no correlation between serum iron levels and ADHD (SMD = -0.026, 95% CI = -0.29 to 0.24). Meta-regression analysis indicated that publication year, age, gender, sample size, and Hb levels did not significantly influence the pooled estimates of serum ferritin. CONCLUSION: Lower serum ferritin rather than serum iron is associated with ADHD in children.

Hyperbaric oxygen therapy for people with autism spectrum disorder (ASD).

BACKGROUND: The rising prevalence of autism spectrum disorder (ASD) has increased the need for evidence-based treatments to lessen the impact of symptoms. Presently, no therapies are available to effectively treat individuals with all of the symptoms of this disorder. It has been suggested that hyperbaric oxygen therapy may alleviate the biochemical dysfunction and clinical symptoms of ASD. OBJECTIVES: To determine whether treatment with hyperbaric oxygen:1. improves core symptoms of ASD, including social communication problems and stereotypical and repetitive behaviors;2. improves noncore symptoms of ASD, such as challenging behaviors;3. improves comorbid states, such as depression and anxiety; and4. causes adverse effects. SEARCH METHODS: On 10 December 2015, we searched CENTRAL, Ovid MEDLINE, Embase, and 15 other databases, four of which were Chinese language databases. We also searched multiple trial and research registers. SELECTION CRITERIA: We selected randomized controlled trials (RCTs) and quasi-RCTs of any dose, duration, and frequency for hyperbaric oxygen therapy compared with no treatment or sham treatment for children and adults with ASD. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration, in that three review authors independently selected studies, assessed them for risk of bias, and extracted relevant data. We also assessed the quality of the evidence by using the GRADE approach. MAIN RESULTS: We included one trial with a total of 60 children with a diagnosis of ASD who randomly received hyperbaric oxygen therapy or a sham treatment. Using GRADE criteria, we rated the quality of the evidence as low because of the small sample size and wide confidence intervals (CIs). Other problems included selection bias and short duration or follow-up.Overall, study authors reported no improvement in social interaction and communication, behavioral problems, communication and linguistic abilities, or cognitive function. With regard to the safety of hyperbaric oxygen therapy (adverse events), they reported minor-grade ear barotrauma events. Investigators found significant differences between groups in total number of side effect events (Peto odds ratio (OR) 3.87, 95% CI 1.53 to 9.82) and in the number of children who experienced side effects (Peto OR 4.40, 95% CI 1.33 to 14.48). AUTHORS' CONCLUSIONS: To date, there is no evidence that hyperbaric oxygen therapy improves core symptoms and associated symptoms of ASD. It is important to note that adverse effects (minor-grade ear barotrauma events) can occur. Given the absence of evidence of effectiveness and the limited biological plausibility and possible adverse effects, the need for future RCTs of hyperbaric oxygen therapy must be carefully considered.

Antithetical regulation of α-myosin heavy chain between fetal and adult heart failure though shuttling of HDAC5 regulating YY-1 function.

Molecular switches of myosin isoforms are known to occur in various conditions. Here, we demonstrated the result from fetal heart failure and its potential mechanisms. Fetal and adult heart failure rat models were induced by injections of isoproterenol as previously described, and Go6976 was given to heart failing fetuses. Real-time PCR and Western blot were adopted to measure the expressions of α-MHC, ß-MHC and YY-1. Co-immunoprecipitation was performed to analysis whether YY-1 interacts with HDAC5. Besides, histological immunofluorescence assessment was carried out to identify the location of HDAC5. α-MHC was recorded elevated in fetal heart failure which was decreased in adult heart failure. Besides, YY-1 was observed elevated both in fetal and adult failing hearts, but YY-1 could co-immunoprecipitation with HDAC5 only in adult hearts. Nuclear localization of HDAC5 was identified in adult cardiomyocytes, while cytoplasmic localization was identified in fetuses. After Go6976 supplied, HDAC5 shuttled into nucleuses interacted with YY-1. The myosin molecular switches were reversed with worsening cardiac functions and higher mortalities. Regulation of MHC in fetal heart failure was different from adult which provided a better compensation with increased α-MHC. This kind of transition was involved with shuttling of HDAC5 regulating YY-1 function.

Evaluation of oxidative stress in placenta of fetal cardiac dysfunction rat model and antioxidant defenses of maternal vitamin C supplementation with the impacts on P-glycoprotein.

AIM: The oxidative stress of placenta during fetal heart dysfunction (FHD) is lack of evaluation. So, we carried out an experiment to explore whether vitamin C (VitC) can be supplied for placental protection under FHD and its impacts on P-glycoprotein expression. METHODS: Fetal heart dysfunction was induced by two intra-amniotic injections of isoproterenol, then (VitC) was supplied. Hematoxylin-eosin (HE) staining was used to evaluate placental histology, and oxidative stress was measured by total antioxidant capacity, total superoxide dismutase and level of advanced oxidation protein products (AOPP), as well as apoptosis rate. Real-time polymerase chain reaction was adopted to measure the expressions of superoxide dismutase-1 (Sod-1), glutathione peroxidase-1 (Gpx-1) and endothelial nitric oxide synthase (eNOS) in placenta. Finally, western blot was performed to detect P-glycoprotein expression. RESULTS: All isoproterenol twice-treated fetuses exhibited significant (P < 0.05) contractile dysfunction by fetal echocardiography compared to others. The HE staining showed severe placental hydrops in the FHD group, and that hydrops could be reduced by VitC treatment. Total antioxidant capacity and total Sod-1 decreased in FHD and elevated after VitC supplementation. Also, level of AOPP increased in FHD and dropped after VitC supplementation. Analysis of apoptosis demonstrated that there was a mild increase in apoptosis rate of FHD. Reductions of Sod-1 and eNOS mRNA expression were confirmed in FHD, but these could recovered after VitC supplementation, with the same tendency of the P-glycoprotein. CONCLUSION: Severe oxidative injuries were identified in placentas of FHD with P-glycoprotein repression. VitC administration can reduce the oxidative stress and rebuild the protective mechanism of placenta.

The association between periconceptional folic acid supplementation and congenital heart defects: a case-control study in China.

OBJECTIVE: This study aims to evaluate the association between folic acid (FA) supplementation and congenital heart defects (CHDs). METHODS: This hospital-based case-control study initiated in 2010 in China analyzed 358 cases and 422 controls. The adjusted odds ratio (AOR) calculated using a logistic model was used to assess the association between FA supplementation and CHDs. RESULTS: Compared with a mother who reported no FA supplementation, mothers who reported FA supplementation were less likely to have offspring with isolated CHD(s) (AOR=0.52, 0.34-0.78) and multiple complex conditions (AOR=0.27, 0.14-0.55). However, mothers who reported FA supplementation for less than 1 month regardless of the start time of supplementation, did not have a significantly lower risk of having an offspring with isolated or multiple complex conditions. Mothers who reported FA supplementation for ≧3 months beginning before conception had a significantly lower risk of having children with isolated CHD(s) (AOR=0.31, 0.18-0.54). CONCLUSION: FA-supplementation is associated with reduced risk of CHDs. The earlier FA supplementation begins before pregnancy and the longer supplementation lasts, the lower the risk of CHDs is.

[Side effects of phototherapy for neonatal hyperbilirubinemia].

Blue light has been widely used for the treatment of neonatal hyperbilirubinemia since the 1950s. Neonatal phototherapy can decrease plasma unconjugated bilirubin level, thus preventing bilirubin encephalopathy, and greatly reduces the exchange transfusion rate. Generally, it is accepted that the side effects of neonatal phototherapy are not serious and seem to be well controlled, however recent research has provided new evidence. The short-term side effects of phototherapy include interference with maternal-infant interaction, imbalance of thermal environment and water loss, electrolyte disturbance, bronze baby syndrome and circadian rhythm disorder. In addition, phototherapy may be associated with some long-term side effects such as melanocytic nevi and skin cancer, allergic diseases, patent ductus arteriosus and retinal damage. Therefore, it is necessary to develop evidence-based guidelines, new light devices and alternative agents, as well as individualized treatments, to minimize the side effects of phototherapy.

Clofibrate for unconjugated hyperbilirubinemia in neonates: a systematic review.

OBJECTIVE: To evaluate the effect of clofibrate for unconjugated hyperbilirubinemia in neonates. METHODS: A systematic review with meta-analysis of randomized controlled trials or quasi-randomized controlled trials was conducted to evaluate the clofibrate treatment in neonates with unconjugated hyperbilirubinemia. We followed the guidelines from the Cochrane review group and the PRISMA statement. RESULTS: Of 148 studies identified, a total of 13 studies on 867 infants were included. A single oral administration of clofibrate was associated with decreased need of phototherapy (RR:.38, 95% CI: 0.21 to 0.68), shortened duration of phototherapy (mean duration: 23.88 h, 95% CI: 33.03 to -14.72 h) and reduced peak total serum bilirubin (mean duration: -1.62 mg/dL, 95% CI: 2.13 to -1.11 mg/dL). These effects were especially obvious in term infants and infants without hemolytic diseases. Data regarding mortality or kernicterus were not available from included studies. CONCLUSIONS: Clofibrate may have short-term benefits for the infants with hyperbilirubinaemia, especially for population of term infants and infants without hemolytic diseases. Large RCTs with long-term followup are required to verify the safety of clofibrate and assess its long-term effects.

The side effects of phototherapy for neonatal jaundice: what do we know? What should we do?

Neonatal phototherapy (NNPT), a noninvasive, easily available therapy, has been widely used for the treatment of neonatal jaundice for more than half a century. Its efficiency in decreasing plasma bilirubin concentration is well documented, and NNPT leads to greatly reduced exchange transfusion rates for neonates with hyperbilirubinemia. It is generally accepted that the side effects of NNPT are not serious and seem to be well controlled. This review will focus on these possible side effects as well as the approaches to minimize them.

Targeting hypoxia inducible factor-1α: a novel mechanism of ginsenoside Rg1 for brain repair after hypoxia/ischemia brain damage.

Hypoxia/ischemia brain damage (HIBD) is one of the most common central nervous system insults in newborns. Brain repair following HIBD is closely associated with cellular processes such as cell survival, angiogenesis, and neurogenesis. In recent years, many studies have suggested that ginsenoside Rg1, one of the major active ingredients of ginseng, may increase neural viability, promote angiogenesis, and induce neurogenesis. However, there are few reports on roles of Rg1 in HIBD repair, and the mechanisms involved are unclear. Recently, a Chinese drug consisting of Rg1 has been shown to be a potential regulator of hypoxia-inducible factor-1α expression in HIBD. Since it has been shown that HIF-1α is a key transcription factor involved in the neuroprotective response to HIBD, it is possible that Rg1 could facilitate the process of brain repair, possibly modulating cell survival, angiogenesis, and neurogenesis after HIBD by targeting HIF-1α.

Neonatal community-acquired pneumonia: pathogens and treatment.

AIM: To analyse the bacterial pathogens and drug sensitivities for neonatal community-acquired pneumonia. METHODS: Seven hundred sixty sputum samples from newborns with community-acquired pneumonia were cultured to determine microbial organisms present and their drug sensitivities. RESULTS: Of the 760 specimens, 425 grew pathogens for a 55.9% positive rate. Among the 425 positive cultures, 278 grew gram-negative organisms (65.4%), 142 grew gram-positive organisms (33.3%), while 5 grew fungus (1.3%). The most common gram-negative organisms were Escherichia coli, Klebsiella pneumoniae and Hemophilus influenzae, while the most common gram-positive organisms were Staphylococcus aureus, Staphylococcus epidermidis and Staphylococcus haemolyticus. To the gram-negative organisms, the most sensitive drugs were meropenem, imipenem and amikacin, while to the gram-positive ones were vancomycin, teicoplanin and quinupristin/dalfopristin. CONCLUSIONS: The most common causative bacteria were gram-negative organisms, which were highly sensitive to Meropenem, Imipenem and Amikacin, yet often treatable with more focused antibiotic coverage, which depended on the bacterium identified.