Preterm birth showed the least omega-3 concentrations, with significantly low omega-6 derivates (LA (p = 0.014) and AA (p = 0.025)) compared to control. LCPUFA parameters have shown to increase the risk in both conditions, particularly ALA ≤ 53 µmol/L in preeclampsia with OR 5.44, 95%CI 1.16–25.42 and preterm birth with OR 4.68, 95%CI 1.52–14.38. These findings suggest that severe preeclampsia and preterm birth have an imbalance in LCPUFA status.Long-Chain Polyunsaturated Fatty Acid (LCPUFA) is essential throughout pregnancy, since deficiency of LPUFA may linked to obstetrical complications. This study aimed to investigate LCPUFA status in severe preeclampsia and preterm birth. A cross sectional study was conducted in 104 pregnant women, which divided into normal pregnancy, severe preeclampsia and preterm birth groups. Serum percentage and concentration of total LCPUFA, omega-3, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), omega-6, linoleic acid (LA), and arachidonic acid (AA) were measured using gas chromatography/mass spectrometry. Receiver operating characteristic (ROC), bivariate and multivariate analysis were performed. Severe preeclampsia showed the highest concentration of total PUFA and the lowest DHA percentage, with significantly higher Omega-6/Omega-3 ratio ( Adequate intake on LCPUFA in periconception and during pregnancy is important to support adequate fetal growth and development, specifically brain development3. LCPUFA has a role in maternal health as dietary omega-3 has been correlated with reduced risk in poor maternal outcome associated with inflammation process4.Long-chain polyunsaturated fatty acid (LCPUFA) is essential in pregnancy. It is advised to take at least 200 mg/day of DHA in pregnancy which should be given earlier than 16 weeks6. In preterm birth, oxidative stress and inflammation initiating an environment suitable for labor such as uterine contractility, cervical ripening, and membrane ruptures by releasing proinflammatory cytokines which normally initiated in term labor8.Obstetrical complication such as preeclampsia and preterm birth have been reported to associated with inflammation process. Pathogenesis of preeclampsia is hallmarked by abnormal placental development by placental ischemia which lead to inflammatory response and further widespread maternal endothelial dysfunction9. Particularly in Indonesia, hypertension disorders of pregnancy impacted 3.3% of population and become a major cause of maternal death10. With regard of preterm birth, Indonesia was accounted for the top five countries with the highest rate of preterm birth worldwide in 201411. In addition, nutrient deficiencies are also a major problem among pregnant women in Indonesia. Our study showed most of first trimester pregnant women has low level of iron, zinc, and vitamin D12. Also, a study about LCPUFA status in first trimester of pregnancy showed that most of pregnant women in Indonesia had low intake and blood concentrations of LCPUFA, including LA, AA, ALA, EPA, and DHA13.Preeclampsia and preterm birth are still a major worldwide burden for maternal–fetal health. Hypertensive disorder may occur in about 10% of pregnanciesWith numbers of researchers showing the benefits of LCPUFA in maternal and fetal health, there is no study in LCPUFA status in obstetric complication in pregnant women in Indonesia, particularly in preeclampsia and preterm birth. Therefore, this study aimed to evaluate LCPUFA blood concentration status in preeclampsia and preterm population in Indonesia.14. From previous studies, we found that mean ± SD for EPA + DHA percentage in preterm birth was 1.41 ± 0.8115 and in preeclampsia was 2.69 ± 2.5616, which results in calculated effect size (Cohen’s D) 0.67 and minimum sample requirement was 25. Accounting for dropout, minimum 30 samples for each group were used in this study.This was a cross sectional study of total 104 pregnant women. Normal pregnancy (n = 44) was compared to pregnancy with severe preeclampsia (n = 30) and preterm birth (n = 30). The analysis of variance sample size estimation was used among 3 groups to obtain type I error at least 5% and power as high as 80%Data were obtained in Cipto Mangunkusumo National Referral Hospital, Budi Kemuliaan Hospital, and Koja Regional Hospital, in Jakarta from January to December 2019. This study has been approved by Ethical Committee for Research in Human from the Faculty of Medicine, Universitas Indonesia (KET-628/UN2.F1/ETIK/PPM.00.02/2019). All of the participants have given their informed consent prior to their inclusion to the study. The study confirmed to the principles set out in the World Medical Association Declaration of Helsinki.17. Spontaneous preterm birth group were deliveries in ≥ 26 weeks to < 37 weeks with no maternal morbidities during pregnancy. The exclusion criteria in this study include multiple pregnancy, congenital anomalies, preterm premature rupture of membrane, diabetes mellitus, infection, autoimmune diseases.Preeclampsia with severe feature was defined by any of the findings of severe features based on American College of Obstetricians and Gynecologists (ACOG) 2013 criteria; blood pressure ≥ 160/110 mmHg (on two occasions at least 4 h apart), thrombocytopenia (platelet count less than 100.000/microliter), progressive renal insufficiency , new onset cerebral or visual disturbances, and pulmonary edemaBasic characteristics of subjects were descripted, including maternal age, maternal blood pressure, gestational age, mode of delivery, pre-pregnancy body mass index (BMI), and birth weight. Term gestational age defined for ≥ 37 weeks. Birth weight < 2500 classified as low and ≥ 2500 as normal to high. The calculated BMI was the pre-pregnancy BMI, and categorized based on Asia–Pacific BMI criteria which includes underweight (< 18.5), normal (18.5–22.9), overweight (23–24.9), and obese (≥ 25).Non-fasting maternal blood samples were obtained soon after delivery, and excluded if the delivery had been more than 1 h. Samples were collected using venous puncture into 5-mL tubes . The serum was directly separated out from the whole blood, then frozen at − 80 °C until further analysis.22.For fatty acids measurement, serum was firstly thawed at room temperature for about 30 min, then extracted using . 150 uL of Methanol  was added to 100 uL serum for protein precipitation and homogenized thoroughly and then added with 300 uL Chloroform  contained Nonadecanoic Acid Methyl Ester (Supelco) as internal standard and vortexed. The mixture then centrifuged at 2500 g in 5 min and the chloroform layer which contain fatty acids was transferred to different tubes. The chloroform phase was then dried with gentle nitrogen stream and then reconstituted with n-hexane . Tetramethyl Ammonium Hydroxide (TMAH) in methanol (Sigma) was added and incubated 2 h in room temperature for trans-esterification while vortexed, upper phase then transferred to Gas Chromatography (GC) vials22.Fatty Acid calibration curve prepared by diluting stock of FAME Mix, C4-C24,  with n-Hexane  to obtained 50 mg/mL in concentration. Concentration of every fatty acids then converted to umol/L based on their molecular weight. Further dilution was done to obtain working stock and the serial diluted with h-Hexane to make 9 levels of calibration. FAME Mix standard contained Myristic (C14:0), Palmitic (C16:0), Palmitoleic (C16:1 w7), Stearic (C18:0), Oleic (C18:1 w9), Linoleic (C18:2 w6), y-linolenic (C18:3 w6), α-Linolenic (C18:3 w3), AA (C20:4 w6), DGLA (C20:3 w6), EPA (C20:5 w3), DHA (C22:6 w3). Mass spectrometer was set to Selected Ion Monitoring (SIM) Mode and the ions monitored for every fatty acids as follows: C14:0 for 199 m/z, C16:0 for 199 m/z, C16:1 for 194 m/z, C18:0 for 298 m/z, C18:1 for 296 m/z, C18:2 for 294 m/z, C18:3 w6 for 292 m/z, C18:3 w3 for 292 m/z, C20:4 w6 for 203 m/z, C20:3 w6 for 222 m/z, C20:5 w3 for 201 m/z, and C22:6 w3 for 199 m/z. The quality control of samples showed the intra- and interassay coefficients of variations (CV) range for all fatty acids were 1.0–16.1%. Based on CLSI, maximum CV within the calibration rate was 15%, and if it near the detection limit was 20%22.Standards and samples were injected to 7890 Gas Chromatography (GC) System  coupled with 5977 Mass Selective Detector (MSD)  with Electron Impact (EI) source. Fatty Acids separated through HP-88 column (30 m × 0.25 mm × 0.25 um film thickness) . GC oven temperature was set to ramping from 50 to 180 °C with 7.07 °C rate per minute and 180 °C to 230 °C with 7.07 °C rate per minute. MSD was set in SIM mode. The quality control substance was a pooled serum 2 level based on triglyceride concentration. The accuracy of the measurement was performed as much as 3 levels, with 103–115% recovery rateThe extracted data for the characteristics of subject including maternal age, blood pressure, gestational age, mode of delivery, body mass index, and birth weight. The serum LCPUFA was measured both percentage and concentration, including total LCPUFA, omega-3, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), omega-6, linoleic acid (LA) and arachidonic acid (AA).Data were analysed using Statistical Package for Social Sciences (SPSS) version 25.0 . The numeric data were firstly checked for normal distribution using Kolmogorov Smirnov test, then presented as mean ± SD if normally distributed and as median (IQR) if not normally distributed. One-way ANOVA and Kruskal Wallis test were used to identify significances among groups. Post hoc tests were performed to locate those specific differences in each group, using Bonferroni and Games-Howell test after One-way ANOVA and Mann Whitney test after Kruskal Wallis.p-values < 0.05 (5%) were described as significant and reported.The Receiver Operating Characteristic (ROC) curve analyses were used to analyse corresponding cut-off values, sensitivity and specificity of each LCPUFA concentration variables. The overall performance of each parameter for predicting either preeclampsia or preterm birth were assessed by estimating the area under the curve (AUC). The cut off values for parameters with high overall performance were determined at the point on the curve with the highest value of sensitivity and specificity. Bivariate analysis was performed using Chi-Square test, followed by multivariate association between each LCPUFA serum variables and each pregnancy outcomes in separate logistic regression models after adjusting maternal age, gestational age (only available for preeclampsia), and pre-pregnancy BMI. All results corresponding to p < 0.05), systolic blood pressure (p < 0.05), diastolic blood pressure (p < 0.05), gestational age (p < 0.05), mode of delivery (p < 0.05), BMI (p < 0.05), and birth weight (p < 0.05). Patients with preeclampsia had highest maternal age 32.37 ± 6.41 years old, and highest BMI 26.80 ± 5.76. In contrast, preterm birth had the smallest BMI 21.78 ± 4.43 and lightest birth weight with 1937.5 g (1360.0–2370.0).All of the samples were included in this study. The characteristics of subjects are shown in Table p < 0.05). In addition, preeclampsia group had the highest level of total omega-6 (median 5605 (4587.0–6976.25) µmol/L), LA (median 4725.5 (3882.0–5678.75) µmol/L), and AA (mean 607.5 ± 194.82 µmol/L). Also, having the highest ratio for omega-6/omega-3 (mean 17.40 ± 4.32) and AA/EPA (mean 66.5 ± 30.15) compared to other groups.Details of serum PUFA percentage and concentrations in control, preeclampsia and preterm birth are shown in Table p < 0.05) compared to control group.In contrast, preterm birth had the lowest total PUFA status (median 4405.0 (3748.0–5308.5) µmol/L) compared to other groups. It also had a low level of all of omega-3 and omega-6 parameters, particularly in total omega-3 (median 331.5 (253.5–410.50) µmol/L), ALA (median 47 (29.75–55.50) µmol/L), total omega-6 (median 4089 (3488.0–4836.75) µmol/L), LA (median 3382 (2868.5–4115.75) µmol/L), and AA , ALA (p = 0.033), Omega-3 index (p = 0.002), total omega-6 (p = 0.018), LA (p = 0.030), Omega-6/omega-3 (p = 0.004) and AA/EPA (p < 0.001) were found to be significant in between preeclampsia and control. The overall high omega-6 and low omega-3 content in preeclampsia were shown as the risk increase with high Omega-6/Omega-3 ratio , along with low omega-3 index   found to be significant compared to control. Accompanied by the increase risk in low omega-3  and low omega-6 .For the analysis showing preterm birth risk Table , an overIn comparing 2 variable outcomes, serum concentration of ALA ≤ 53 µmol/L have shown to increase the risk of preeclampsia by OR 5.44, 95%CI 1.16–25.42, with sensitivity 63% and specificity 63.6%, and the risk of preterm birth by OR 4.68, 95%CI 1.52–14.38, with sensitivity 66% and specificity 63.6%.12. We also found that preterm birth group had the lightest mean of BMI. This data was supported by reviews and meta-analysis, which suggested that low maternal BMI is associated with preterm birth23.This research was dominated by overweight to obese participants. This findings was in conjunction with previous study in Indonesia, where 49.1% of 234 first trimester pregnant women were also found to have BMI ≥ 2326, studies have also suggested that low total omega-3 had increased the risk of preterm birth < 34 weeks, which can be reduced through LCPUFA supplementation28. In addition, gestational age seems not affecting total LCPUFA content in preeclampsia, as being the highest level among others. This was thought to influenced by numerous amounts of omega-6 serum concentration.In comparing LCPUFA concentrations of those 3 groups, preterm birth group had the lowest total LCPUFA, total omega-3, and omega-6. Even though studies have shown that there is an increasing trend of LCPUFA level in serum, erythrocyte and plasma throughout pregnancyp < 0.05). This is consistent with other findings, where low number of both omega-3 and omega-6 PUFA in preeclampsia and preterm were found29. Omega-3 fatty acids, including EPA and DHA, have a proangiogenic effect in extra villous trophoblast cell lines, hence increase the development of capillary sprouts30. Studies have shown that supplementation of omega-3 fatty acids during pregnancy may improve birth weight as well as decrease preterm birth rate31. Therefore, a good counselling to encourage pregnant women in improving omega-3 dietary intake and supplementation are required.Preeclampsia and preterm birth group found to have lower amount of omega-3 PUFA than control group, with preterm and control group showed a significant difference (p < 0.001), followed by ALA maternal serum concentration ≤ 53 µmol/L have shown to increase the risk of both pregnancy complications . These findings were consistent with other studies where low ALA and EPA were associated with higher preeclampsia risk32. Moreover, a study by Stewart et al. showed lower ALA was found in patients with earlier gestational age as ALA is expected to increase along pregnancy and become the precursor for omega-3 metabolites, which are EPA and DHA26. Even though the conversion process is not efficient in human and depend on epigenetic, genetic process, as well as sex34, another study suggest that the level of maternal ALA is associated with DHA concentration in blood cord35. A nutrition study about dairy product with ALA, LA, and DHA found to reduce the rate of early preterm birth and improve the length of gestation33. Thus, pregnant women are advised take sufficient amount of ALA and EPA on early terms, using supplementations or omega 3 rich food such as soybean oil, canola oil, green vegetables, and seafood37.ALA and EPA are essential omega-3 fatty acids which have anti-inflammatory properties and vascular benefit. In our study, we found that both preeclampsia and preterm birth have lower ALA and EPA serum concentration compared to control. These were shown by EPA concentrations ≤ 16 µmol/L was significantly associated with preeclampsia (p > 0.05) and preterm birth (p < 0.05). A study have shown that DHA may decrease oxidative stress in deep placentation disorders, including preeclampsia and preterm birth30. Another study also showed DHA supplementation during pregnancy significantly reduce the risk of preeclampsia and severe preeclampsia38. In addition, preterm subjects showed the least of DHA concentrations result among groups and EPA result was lower compared to control group. Studies have shown that DHA promotes longer gestation period by acting as prostaglandin inhibition for ripening cervix and slowing uterine contraction in last week pregnancy39. Trial by Carlson et al. showed supplementation of 600 mg DHA daily given at early pregnancy resulted in significant longer pregnancy (p = 0.041) and higher birthweight (p = 0.004)40. Other study supported this result by showing a decreased preterm birth rates in patients taking Omega-3 PUFA levels up to ~ 600 mg daily41.Furthermore, DHA percentage was found to be significantly low for preeclampsia compared to control , LA (p < 0.05), and AA (p < 0.05) in preeclampsia compared to others. These findings were accompanied with lower total omega-3 level along with its derivates  in preeclampsia compared to control group. The result also showed significantly higher ratio (p < 0.05) of omega-6/omega-3 in preeclampsia group compared to control group. This study showed an altered condition of fatty acid level that occur in preeclampsia patient as shown in previous studies before43.In addition, we found significantly higher level of total omega-6 PUFA . Meanwhile, preterm birth had the lowest mean of omega-6/omega-3 ratio. This might be resulted by relatively low total of omega-3 with relatively normal omega-6 level and lower in its derivates such as AA in preterm group.Our data did not show causality LCPUFA status on preeclampsia, however our result on high total omega-6 level and concordance to high ratio of omega-6/omega-3 may play role in inflammatory reaction in preeclampsia pathogenesis, thus further study is required48, particularly due to AA eicosanoid metabolites49. On the other hand, AA is also found to generate lipoxins, particularly lipoxin (LXA4), which acts as an anti-inflammatory properties that related to obstetrical complications such as preterm and preeclampsia51. Here we showed that the value of ≥ 35 AA/EPA has increased the risk for preeclampsia with sensitivity 83.3% and 84.1%, with significant differences compared to control (p < 0.001) and high adjusted odds ratio (OR 24.78). However, the wide 95%CI (4.25–144.27) found in our study suggesting that this optimal value of AA/EPA should be further elaborated, followed by other metabolites analysis.Our study found that there was a significantly high level of AA/EPA ratio in preeclampsia compared to other groups. Previous studies have suggested that AA/EPA have positive correlation with inflammatory rate of eicosanoidsCertain limitations need to be considered to interpret our study. We did not asses daily intake of PUFA, as well as other biomarkers which responsible in pathological mechanism related to obstetrical outcomes. We also unable to analyse non-fasting blood samples as preeclampsia and preterm birth maternal condition which required highly nutrient intake. Suggesting that mothers who are in labor, especially with vaginal delivery method, should be energized enough to undergo the process. In addition, triglyceride elimination before trans-esterification was unable to performed. Thus, the calculated fatty acids were both free fatty acids and fatty acids which might still bind to triglycerides and phospholipid. Nevertheless, this initial research throughout this topic could represent an overview of maternal LCPUFA status in pregnant women with preeclampsia and preterm birth, as well as a beginning for further research. Detail evaluation of nutritional intake, LCPUFA supplementation, other metabolites as well as sample processing with wider range of population are required in order to gain better understanding regarding LCPUFA effect on obstetrical outcome.Our study proposed that both severe preeclampsia and preterm birth have an imbalance in fatty acid metabolism. LCPUFA plays a great role in those pathological conditions, thus dietary balanced intake of omega-3 and omega-6 enriched functional food or supplementation in pregnant women should be highly considered.


Since energy efficiency in comminution of ores is as small as 1% using a mechanical crushing process, it is highly demanded to improve its efficiency. Using electrical impulses to selectively liberate valuable minerals from ores can be a solution of this problem. In this work, we developed a simulation method using equivalent circuits of granite to better understand the crushing process with high-voltage (HV) electrical pulses. From our simulation works, we calculated the electric field distributions in granite when an electrical pulse was applied. We also calculated other associated electrical phenomena such as produced heat and temperature changes from the simulation results. A decrease in the electric field was observed in the plagioclase with high electrical conductivity and void space. This suggests that the void volume in each mineral is important in calculating the electrical properties. Our equivalent circuit models considering both the electrical conductivity and dielectric constant of a granite can more accurately represent the electrical properties of granite under HV electric pulse application. These results will help us better understand the liberation of minerals from granite by electric pulse application. Minerals are familiar to us in our daily lives and are used in various fields  . In ordeThere are two types of electrical disintegration methods, and they are (1) Electro Hydraulic Disintegration (EHD) and (2) Electrical Disintegration (ED). I-V properties of granite changed under HV applications with different types of electrode spacing. However, the effects of electric pulses on rocks are still largely empirical, and our work is the very first study that considered both conductivity and dielectric constant as far as the authors are aware of.The ED method has been applied to the separation of precious minerals such as diamonds and emeralds . In addiThe purpose of this study is to obtain better knowledge of granite comminution and selective liberation under high voltage pulses. Granite was selected as an example of hard rock. For this purpose, we developed an equivalent circuit model of granite based on both conductivity and dielectric constant, considering the minerals and voids in the granite, and applied a high electric field to the granite model to simulate electrical characteristics under HV applications. Specifically, our equivalent circuit model was created using a C# program, and the electric field distribution in granite was calculated using the circuit simulation software LTspice. Since rocks consist mostly of dielectric materials, our simulation works can be significantly helpful to understand the behavior of rocks  under HV electric pulse, as the circuit models were proposed considering both electric and dielectric properties of granite.R is the resistance, L and S represent the length of the segmented mineral (0.1 mm) and the surface area of the segmented mineral (0.01 mm2), respectively. Capacitance is expressed by the following equation:C is capacitance and ε is dielectric constant. The equivalent circuit was created by assigning the minerals contained in the granite to the divided cubes, calculating the resistance and capacitor values for each mineral, and constructing the circuit. As an example, The simulation was performed for a well-known hard rock, i.e., granite composed of quartz, plagioclase, k-feldspar, and biotite . In thisThe mineral composition of a typical granite is referred to the information available in , as showJ per unit area flowing through a rock is expressed by Ohm’s law:E is the electric field, and ε is the dielectric constant ..19].Walsh et al. (2020) described simulation results with a 10-cm wide granite model with thickness of 2 cm. We used the same mineral composition in the granite as they did. They performed electric pulse crushing simulation using the ED method with needle electrodes placed at the center of the granite model for both the upper/HV and ground electrodes in 2D . In addiAn application example of the ED method was described in the literature where it was applied on several minerals  which were embedded in cement and their selective liberation behavior was observed . The siz(1)The electric field of the granite confirmed that the electric field dropped near the plagioclase;(2)The electrical conductivity of the plagioclase was higher than that of the other minerals due to its higher void volume, which has a significant effect on the electric field distribution;(3)The temperature change in the granite observed a very high temperature change near the upper/HV electrode, but it was very small as away from that electrode.In this study, we investigated the electrical and thermal characteristics of granite under the application of electric pulses. An equivalent circuit model of a granite in 3D (1 mm × 1 mm × 1 mm) was developed. The electric field in the circuit was then calculated considering an electric pulse application. The heat and temperature changes generated in the minerals with the granite were calculated from that result. Until now, existing studies used either electrical conductivity or dielectric constant, but there has been no model that considers both. In this study, however, we used both parameters in the equivalent circuit model, calculated the values of the electric field distribution, and then, the heat distribution, and created the temperature change distribution from the heat distribution. This has not been performed before, and can lead to more detailed data under relatively low applied voltage by considering both parameters; so, the findings of this study can be useful for energy efficient rock crushing. The results of this study are summarized as follows:


Background: Studies have shown that the prevalence of children born with high birth weight or large for gestational age (LGA) is increasing. This is true for spontaneous pregnancies; however, children born after frozen embryo transfer (FET) as part of assisted reproductive technology (ART) also have an elevated risk. In recent years, the practice of FET has increased rapidly and while the perinatal and obstetric risks are well-studied, less is known about the long-term health consequences.Objective: The aim of this systematic review was to describe the association between high birth weight and LGA on long-term child outcomes.Data Sources: PubMed, Scopus, and Web of Science were searched up to January 2021. Exposure included high birth weight and LGA. Long-term outcome variables included malignancies, psychiatric disorders, cardiovascular disease, and diabetes.Study Selection: Original studies published in English or Scandinavian languages were included. Studies with a control group were included while studies published as abstracts and case reports were excluded.Data Extraction: The methodological quality, in terms of risk of bias, was assessed by pairs of reviewers. Robins-I (www.methods.cochrane.org) was used for risk of bias assessment in original articles. For systematic reviews, AMSTAR (www.amstar.ca) was used. For certainty of evidence, we used the GRADE system. The systematic review followed PRISMA guidelines. When possible, meta-analyses were performed.Results: The search included 11,767 articles out of which 173 met the inclusion criteria and were included in the qualitative analysis, while 63 were included in quantitative synthesis . High birth weight and/or LGA was associated with low to moderately elevated risks for certain malignancies in childhood, breast cancer, several psychiatric disorders, hypertension in childhood, and type 1 and 2 diabetes.Conclusions: Although the increased risks for adverse outcome in offspring associated with high birth weight and LGA represent serious health effects in childhood and in adulthood, the size of these effects seems moderate. The identified risk association should, however, be taken into account in decisions concerning fresh and frozen ART cycles and is of general importance in view of the increasing prevalence in high birthweight babies. The association between preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA) and neonatal and long-term outcomes is well-described and suggests higher risks for cardiovascular diseases, diabetes, hypertension, and stroke later in life according to the Barker hypothesis . Less atThe aim of this systematic review and meta-analysis is to summarize the present knowledge on long-term outcomes for children born with a high birth weight or being LGA.We searched PubMed, Scopus, and Web of Science databases up to January 2021. Exposures were large for gestational age and high birth weight. Long-term morbidity outcomes studied were cancer, metabolic disease, cardiovascular disease, and psychiatric disorders. Cancer was focused on breast cancer, child malignancies in the central nervous system (CNS), hematological malignancies, and Wilm's tumor. Metabolic diseases were focused on diabetes type 1 and type 2. Cardiovascular disease was focused on hypertension and other cardiovascular disorders. Psychiatric disorders were focused on schizophrenia/psychosis and cognitive disorders. Some of these outcomes, when appropriate, were used for meta-analysis.The terms used in the searches are listed below:*[tiab] OR higher birth weight*[tiab] OR highest birth weight*[tiab] OR high birthweight*[tiab] OR higher birthweight*[tiab] OR highest birthweight*[tiab] OR macrosomia[tiab]. Because of large heterogenecity in the nomenclature of diseases and to avoid missing any important morbidity, we decided not to include any specific disease or morbidity terms in the search.LGA[tiab] OR large for gestational age[tiab] OR large-for-gestational age[tiab] OR HBW[tiab] OR high birth weightWe also manually searched reference lists of identified articles for additional references. Guidelines for meta-analysis and systematic reviews (SR) of observational studies were followed . The litThe last literature search was performed January 14, 2021.Original studies published in English or Scandinavian languages were included. In the case of double publication, the latest study was included. Studies with a control group were included. Studies published only as abstracts and case reports were excluded.High birth weight was defined by each author but usually ≥4,000 or ≥4,500 or occasionally >5 g. LGA was defined by each author.http://www.methods.cochrane.org). For systematic reviews, we used AMSTAR (http://www.amstar.ca). For certainty of evidence, we used the GRADE system , adjusted odds ratio (AOR), hazard ratio (HR), adjusted hazard ratio (AHR), relative risk (RR), adjusted relative risk (ARR), incidence rate ratio (IRR), adjusted incidence rate ratio (AIRR), standardized incidence ratio (SIR), or random-effects odds ratio (REOR) with 95% CIs. Meta-analyses were performed despite significant heterogeneity in reference groups and despite the fact that outcomes were given in AOR, ARR, or ROR. However, studies reporting estimates as HR, AHR, AIRR, and SIR were not mixed with the RR- and OR-based outcomes. The HR- and IR-based outcomes were also too few to be included in a separate meta-analysis. A random-effects meta-analysis using the Der Simonian and Laird method, with the estimate of heterogeneity being taken from the Mantel–Haenszel model, was used in the analysis (command metan in Stata 15).The search strategy identified a total of 11,767 abstracts, of which 173 were selected for inclusion in the systematic review and 63 for inclusion in quantitative synthesis  . No papeAmong the studies included were 19 meta-analyses, 73 cohort studies, 74 case–control studies, and seven cross-sectional studies .Four SR/meta-analyses, three cohort studies, 14 case–control studies, and one cross-sectional study reported on the association between high birth weight and CNS tumors. Two SRs, of medium and high quality, found an association between birth weight >4,000 g and astrocytoma [OR 1.38 (95% CI 1.07–1.79) and REOR 1.60 (95% CI 1.23–2.09)] and medulloblastoma [OR 1.27 (95% CI 1.02–1.60) and REOR 1.31(95% CI 1.08–1.58)] compared with <4,000 g , 45. A mOur meta-analysis, including 15 original studies, showed a pooled AOR of 1.15 (95% CI 1.05–1.27) for development of CNS tumors, when comparing birth weight >4,000 or >4,500 g vs. birth weight of <4,000 g . For LGAConclusion: High birth weight is probably associated with a slight increase of CNS tumors, moderate certainty of evidence (GRADE ⊕⊕⊕O).Two systematic reviews , 55, fouBoth SR, of high and low quality, respectively, reported an association between birth weight >4,000 g and leukemia [OR 1.25 (95% CI 1.17–1.37) and AOR 1.35 (95% CI 1.24–1.48)] , 55. TwoOne cohort and seven case–control studies reported on lymphoma. The cohort study by Petridou et al.  low ris, 78, comConclusion: High birth weight is probably associated with a moderate increase in leukemia, moderate certainty of evidence (GRADE ⊕⊕⊕O). LGA may be associated with a moderate increase in non-Hodgkin lymphoma, low certainty of evidence (GRADE ⊕⊕OO).One SR , two cohOne out of two cohort studies with low-moderate risk of bias , 83 showConclusion: High birth weight and/or LGA is probably associated with a moderate increase in Wilm's tumor, moderate certainty of evidence (GRADE ⊕⊕⊕O).Outcomes are listed in Four out of six cohort studies, with low to moderate risk of bias, found an association between high birth weight and/or LGA and schizophrenia , 93–95. Two cohort studies, one with low and one with moderate risk of bias reported on depression. In these studies, women born with high birth weight had increased risk for new-onset depression  and currAccording to a recent systematic review and meta-analysis, high birth weight >4,000 g was a protective factor for different types of psychotic disorders  . In our Conclusion: High birth weight and/or LGA may be associated with a moderate increase in schizophrenia and an increase in depression, low certainty of evidence (GRADE ⊕⊕OO).It is uncertain whether high birth weight is associated with psychiatric disorders in general, very low certainty of evidence (GRADE ⊕OOO).Outcomes are listed in One case–control study with moderate risk of bias reported no association of LGA with autism or Asperger syndrome . Two cohFour cohort studies reported results on associations between high birth weight/LGA and behavior/attention problems among children and adolescents aged 6–16 years, of which three reported an association between LGA and behavioral problems –108.In a study with low risk of bias, a higher risk for externalizing behaviors  was found in high birthweight children . In anotIn five cohort studies with low or moderate risk of bias, high birth weight was associated with high cognitive ability –115 and Eight cohort studies investigated the association between high birth weight and intellectual performance, seven with moderate and one with serious risk of bias. Five of these studies consisted of a study population of Nordic conscripts –121, oneConclusion: High birth weight and/or LGA may be associated with a slight increase in autism and behavioral problems, low certainty of evidence (GRADE ⊕⊕OO). High birth weight may be positively associated with cognitive ability, low certainty of evidence (GRADE ⊕⊕OO). No association was found between high birth weight and/or LGA and intellectual performance, moderate certainty of evidence (GRADE ⊕⊕⊕O).Outcomes are listed in The SR and meta-analysis by Zhang et al. , includiFourteen original studies –138, notConclusion: There may be an association between high birth weight and hypertension in childhood, low certainty of evidence (GRADE ⊕⊕OO).There may be an inverse association between high birth weight and hypertension in adulthood, low certainty of evidence (GRADE ⊕⊕OO).One SR of high quality including 27 articles on birth weight and CHD in adults was identified . A meta-Only one original study  from theConclusion: There is probably no difference in the risk of CHD in men and women born with high birth weight compared with adults born with normal birth weight, moderate certainty of evidence (GRADE ⊕⊕⊕O).Two studies with serious  and modeTwo studies found higher thickness of the radial artery intima  and the Conclusion: It is uncertain if there is an association between high birth weight or LGA and altered cardiovascular function in adulthood, very low certainty of evidence (GRADE ⊕OOO).Outcomes are listed in Two SR and meta-analyses , 146 mo–152, andOf the 20 original studies, four were assessed being of low, six of moderate, and the rest of critical or serious risk of bias.Our meta-analysis, including 13 studies, found a pooled OR of 1.15 (95% CI 1.05–1.26) for type 1 diabetes when comparing birth weight >4,000 g with <4,000 g . For LGAConclusion: High birth weight and/or LGA is probably associated with a slight increase in type 1 diabetes, moderate certainty of evidence (GRADE ⊕⊕⊕O).Four SR investigated the association between birth weight/high birth weight and type 2 diabetes –170. ThrConclusion: High birth weight may be associated with a slight increase in type 2 diabetes, low certainty of evidence (GRADE ⊕⊕ OO).In this systematic review and meta-analysis, we have summarized the evidence for an association between high birth weight and/or LGA and some severe long-term outcomes for the children . The outThe systematic literature search identified a huge number of articles which were scrutinized and 173 of these publications were selected for this review.The choice of the selected types of malignancies was based on the number of publications. Thus, our SR does not include all types of malignancies, but the ones where most publications were identified. The metabolic part was limited to diabetes type 1 and 2. Cardiovascular and psychiatric diseases were selected due to being common in the population and having a high impact on human health.in utero and/or epigenetic mechanisms, both associated with fetal birth weight and cancer risk (We found a small to moderately increased risk for all types of malignancies studied, with estimates of OR between 1.19 and 1.69. The most pronounced association was found for Wilm's tumor. The biological mechanism linking fetal growth and cancer is largely unknown . The obscer risk .per se, may increase a risk to later psychiatric problems (Four out of six cohort studies on high birth weight and/or LGA and schizophrenia reported an increased risk of developing schizophrenia in the offspring while no association was found in two studies in adjusted models. All these studies were performed in the Nordic countries and the limit for being born with high birth weight varied being >4,000 and >4,500 g. The mechanisms underlying the association between high birth weight and schizophrenia are unclear. It has been suggested that potential fetal exposure to gestational diabetes may play a role, as an association between maternal diabetes and schizophrenia among offspring has been found , 178. Fuproblems , 94. Intproblems .Interestingly, a recent systematic review suggested that high birth weight was protective of psychotic disorders in general . It was,In many studies, several types of psychiatric disturbances were investigated and even combined. This may explain the contradictory results concerning high birth weight/LGA and psychiatric disorders. Environmental and socioeconomic status probably play an important role in a person's susceptibility for a psychiatric disease making those with higher socioeconomic status less vulnerable .per se, associated with later behavioral problems (There might be an association between high birth weight/LGA and negative behaviors in adolescence. The reasons for this connection are largely unknown. Family and genetic factors certainly are important in the tendency of developing behavior problems, but the neurobiological mechanisms underlying interactions to high birth weight are unclear . Due to problems .Most of the studies about intellectual performance and high birth weight have been carried out on male conscripts generally excluding women and part of the most vulnerable men. A reassuring notice was that no association was found between high birth weight/LGA and risk of intellectual disability, or low IQ score. However, according to Lundgren et al.  high BMICognitive performance was positively related to high birth weight at least up to the birth weight of 4,200 g . This asBased on the current evidence, there may be an age-related association between high birth weight/LGA and high blood pressure in childhood while the opposite is found in adulthood. For CHD or cardiovascular function in adults, there was no obvious association with high birth weight or LGA. In the study by Wang et al.  the focuIn general, individuals with high birth weight are taller and heavier later in life than subjects with normal birth weight . HoweverContradictory to the findings of a lower risk of CHD in children born with high birth weight, babies are more likely to be born large-for-gestational age in mothers with diabetes, increasing the risk of diabetes and CHD later in the children's life . High biIn our meta-analysis, high birth weight was associated with a slightly higher risk of type 1 diabetes in line with previous meta-analyses , 146.per se that are responsible for this association. Gestational diabetes and maternal overweight during pregnancy are risk factors for increased birth weight (The mechanism between high birth weight and type 1 diabetes seems unknown. It may be other factors besides the birth weight h weight , 185. Ith weight , 187. Fuh weight .For type 2 diabetes, recently performed meta-analyses of high quality found some divergent results. Knop et al.  identifiThe major strength of this systematic review is the comprehensive literature search, identifying a considerable number of relevant articles. The ability to present meta-analyses, either of high quality and recently published or new meta-analyses performed for the purpose of this SR, makes interpretation of the summarized literature easier to capture. The main limitation is that all data are based on observational studies, both cohort studies being of higher quality but also case–control studies with their inborn risk of selection bias. Our conclusions are, however, based mainly on meta-analyses and/or on studies with low risk of bias.In conclusion, this systematic review and meta-analysis, investigating high birth weight and LGA as risk factors for adverse outcome in offspring, found elevated risks for certain malignancies in childhood, breast cancer, several psychiatric disorders, hypertension in childhood, although not in adulthood, and type 1 and type 2 diabetes. Although these risks represent serious health effects, both in childhood and in adulthood, the size of these effects seems moderate. The results are important for the overall implications of increasing birth weight and will contribute to the ongoing discussion of the pros and cons of fresh or frozen embryo transfer cycles in ART.The original contributions presented in the study are included in the article/ÅM, HL, AL, NO, AP, LR, VS-A, and CB contributed to conception and design of the study. ÅM and CB search databases. Screening of abstracts and of full papers for inclusion was done by pairs of reviewers by ÅM, HL, AL, NO, AP, LR, VS-A, and CB. MP performed the statistical analysis. ÅM, HL, AL, NO, AP, LR, VS-A, MP, and CB wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This review will explore how some cytokines also influence early embryonic development. We term these types of molecules as embryokines. Understanding how cytokines serve as embryokines could offer new opportunities to improve embryo development and the overall health of the embryo so that pregnancies will be retained after embryo transfer and so that viable offspring are produced. At least two cytokines may offer these benefits to bovine embryos produced in vitro. Additional cytokines also are identified in this review that may contain beneficial activities on bovine embryos.The term “embryokine” has been used to denote molecules produced by the endometrium, oviduct, or by embryo itself that will influence embryo development. Several cytokines have been identified as embryokines in cattle and other mammals. This review will describe how these cytokines function as embryokines, with special emphasis being placed on their actions on in vitro produced (IVP) bovine embryos. Embryokines are being explored for their ability to overcome the poor development rates of IVP embryos and to limit post-transfer pregnancy retention efficiencies that exist in IVP embryos. This review will focus on describing two of the best-characterized cytokines, colony-stimulating factor 2 and interleukin 6, for their ability to modify bovine embryo quality and confirmation, promote normal fetal development, and generate healthy calves. Additional cytokines will also be discussed for their potential to serve as embryokines. The dairy and beef industries are rapidly adopting the use of in vitro embryo production to produce calves of a desired genetic makeup. This is being achieved by coupling in vitro production (IVP) with ovum pickup (OPU) and embryo transfer (ET). These combined technologies maximize the number of calves that can be produced from genetically desirable dams and sires. Over 1 million transferrable IVP bovine embryos were produced globally in 2019 . Ar. Ar50].  embryos . The preIn the cow, there is convincing evidence that CSF2 serves as an embryokine, and recent evidence from our group supports the notion that IL6 should also be categorized as an embryokine . Both ofTwo definitive conclusions that can be made at this point: (1) it is clear that some cytokines are serving as embryokines in cattle, and (2) the cytokines studied thus far appear to function primarily by improving IVP bovine embryo quality and competency rather than by increasing the number of transferrable IVP embryos. Further investigations are necessary to provide mechanistic knowledge of how these and other cytokines function as embryokines. Another gap in our knowledge is exploring other cytokines as embryokines. Cytokines that should be considered in future research include IL1A, IL1B, SCF, CCR10 ligands, and other IL6 family members.


The diffusion tensor imaging and neurite orientation dispersion and density imaging models were used to obtain maps of fractional anisotropy, radial diffusivity, orientation dispersion and neurite density indices. Tract-based spatial statistics was used to test associations between metrics of white matter microstructure with breastmilk, macronutrient  and energy intake. Associations between white matter microstructure and cognitive outcomes were also examined. Compared to children who did not meet enteral feeding recommendations, those who achieved enteral protein, lipid and energy recommendations during the first postnatal month showed improved white matter maturation at 5 years. Among the macronutrients, greater protein intake contributed most to the beneficial effect of nutrition, showing widespread increases in fractional anisotropy and reductions in radial diffusivity. No significant associations were found between white matter metrics with breastmilk or carbohydrate intake. Voxel-wise analyses with cognitive outcomes revealed significant associations between higher fractional anisotropy and neurite density index with higher processing speed scores. Lower radial diffusivity and orientation dispersion index were also associated with improved processing speed. Our findings support the long-term impacts of early nutrition on white matter microstructure, which in turn is related to cognitive outcomes. These results provide strong support for early postnatal nutritional intervention as a promising strategy to improve long-term cognitive outcomes of infants born at very low birth weight.Infants born at very low birth weight (<1500 g) are vulnerable to nutritional deficits during their first postnatal month, which are associated with poor neurodevelopmental outcomes. Despite this knowledge, the impact of early postnatal nutrition on white matter microstructure in children born with very low birth weight has not been investigated. In this prospective cohort study, we employed a whole-brain approach to investigate associations between precise estimates of nutrient intake within the first postnatal month with white matter microstructure at 5 years of age. Detailed information about breastmilk, macronutrient and energy intakes during this period were prospectively recorded for all participants. Multi-shell diffusion and T Sato et al. report the long-term associations between early neonatal nutrient intake and later white matter microstructure in children born very low birth weight. Their findings are important for understanding white matter development and for guiding early postnatal nutritional interventions in these high-risk children.  The third trimester, during which very low birth weight  or very preterm [<32 weeks gestational age (GA)] infants are born, is a period vulnerable to nutritional deficits in the ex utero environment as placental supply is abruptly discontinued.,,,Recent studies have shown that higher energy and lipid intake in the first two postnatal weeks were associated with improved white matter maturation and a lower incidence of brain injury at term-equivalent age in very preterm infants.,,,,Despite advances in neonatal care and increased survival of infants born VLBW, short and long-term cognitive morbidities remain high in this population.,,In this prospective cohort study, we examined the association between precise estimates of postnatal nutrition, specifically mother’s breastmilk and macronutrient intake, and white matter microstructural parameters in VLBW children at 5 years of age. Diffusion tensor imaging (DTI) and the more recent neurite orientation dispersion and density imaging (NODDI)Children born VLBW were recruited as part of a 5-year follow-up (NCT02759809) to the randomized clinical trial, Donor Milk for Improved Neurodevelopmental Outcomes (ISRCTN35317141). The study was designed to evaluate the effects of donor milk, in comparison to preterm formula, as a supplement to mother’s breastmilk in infants born VLBW. The feeding protocols and study outcomes have been published.n = 316) and their families who took part in the original randomized clinical trial were approached for the 5-year follow-up study. About 158 (50% follow-up rate) participated in the 5-year follow-up between August 2016 and July 2018 at the Hospital for Sick Children (SickKids), Toronto, Canada. This study aimed to recruit 20 VLBW children for each of the three enteral feeding groups during initial hospitalization: (i) donor milk , (ii) preterm formula  or (iii) exclusively fed their mother’s breastmilk (i.e. no donor milk or preterm formula supplementation). The study protocol was reviewed and accepted by the SickKids Research Ethics board. All children were screened and approved for MRI compatibility and provided verbal assent while parents gave written informed consent in accordance with the Declaration of Helsinki.All surviving children  and neonatal morbidities . Clinical radiological review of cranial ultrasounds completed during initial hospitalization at birth defined brain injury as the presence of at least one of the following findings at birth: Echodense intraparenchymal lesions, white matter lesions, periventricular leukomalacia, porencephalic cysts and ventriculomegaly with or without intraventricular haemorrhage. At least two neonatologists and one radiologist assessed the cranial ultrasound scans for the presence of brain injury.,,As part of the feeding intervention, detailed information about macronutrient and energy intakes for all infants were prospectively recorded. These details have been previously published.Cognitive performance was assessed using the Wechsler Preschool and Primary Scale of Intelligence-IV (WPPSI-IV),1-weighted anatomical image was acquired for each participant with a 3 D magnetization prepared rapid acquisition gradient echo sequence . Multi-shell diffusion images were acquired based on the echo planar imaging diffusion pulse sequence . A B0 map of the main magnetic field was estimated to correct for distortions in the diffusion data using a double-echo gradient-recalled echo sequence . All imaging sequences were collected while children were awake and watching a movie.MRI scans were acquired on a 3 T MAGNETOM Siemens PrismaFIT with a 20-channel head and neck coil. A TUsing MRtrix3 and the FMRIB Software Library (FSL), diffusion data were denoizedA whole-brain approach was taken to analyse diffusion images using FSL’s tract-based spatial statistics (TBSS).t-test for continuous variables and a chi-square test for categorical variables. Hypothesis tests were two-tailed and P < 0.05 was considered statistically significant.Descriptive statistics were conducted for demographic and clinical variables. Differences between sexes were assessed using an independent samples P < 0.05 following corrections for multiple comparisons. In all 41 children, we investigated associations between mother’s breastmilk intake and duration of breastfeeding with DTI and NODDI metrics using a general linear model (GLM), adjusting for both sex and birth weight. In separate models, we tested the association between macronutrient  and energy intake with DTI and NODDI metrics, adjusting for both sex and birth GA. Birth weight was not included in these models as there was a significant difference in the mean birth weight between infants who achieved enteral nutrient recommendations during Postnatal Days 9–29 versus those who did not, and thus did not meet the requirements of a covariate.FSL’s randomizen = 19), those fed mother’s breastmilk supplemented with donor milk (n = 13), and those fed mother’s breastmilk supplemented with preterm formula (n = 9). The primary exploratory analysis compared the donor milk and the preterm formula group. If no differences were noted between the feeding groups, these two groups were combined and compared with the reference group: Those fed exclusively mother’s breastmilk. To visualize results for significant associations, the John Hopkins University DTI-based tractography atlasExploratory analyses were conducted comparing the type of enteral feeding during initial hospitalization. Children born VLBW were divided into the following three groups based on in-hospital enteral feeding: Those fed exclusively mother’s breastmilk , MRI incompatibility (n = 4), their inability to lie still as reported by parents (n = 16), or if the anticipated number of participants (i.e. 20) were recruited from their respective enteral feeding group . Of the 158 VLBW children who attended the 5-year follow-up, 56 consented to a second visit where they underwent an MRI scan and were included in the present analyses. A total of 41 out of 56 children with complete multi-shell scans were included in subsequent analyses after passing inspection for gross motion artefacts. Details on the flow of VLBW participants from the original randomized clinical trial to the present study are summarized in Children were not included into the neuroimaging portion of the study if they were ineligible due to a medical condition  are shown in No significant associations were found between mother’s breastmilk intake with DTI and NODDI metrics in children. The association between duration of breastfeeding with DTI and NODDI metrics was also not significant. Significant associations, however, were present between enteral protein, lipid and energy intakes with DTI metrics (FA and RD), independent of sex and birth GA. The children who met enteral protein recommendations during Postnatal Days 9–29 showed increased FA compared to those who did not . RegionsFig. 1B andIn exploratory analyses, we compared children fed mother’s breastmilk supplemented with donor milk to those supplemented with preterm formula during initial hospitalization. There were no significant differences in DTI or NODDI metrics between the donor milk and preterm formula supplement groups. Thus, these two groups (preterm formula and donor milk) were combined and compared with the reference group: Children who were fed exclusively mother’s breastmilk. However, we also found no significant differences between these groups in any of the DTI or NODDI metrics.Significant associations were found between DTI and NODDI metrics with processing speed scores. Higher NDI  and FA  was assoTo our knowledge, this is the first study to investigate associations between early postnatal nutrition and white matter microstructure in preschool-age children born VLBW. We leveraged detailed nutritional data collected during neonatal intensive care unit stays following birth to determine the longer-term associations with brain maturation. We found significant associations between early macronutrient intake and white matter microstructure at 5 years of age. Specifically, children who achieved enteral protein, lipid and energy recommendations during Postnatal Days 9–29 showed improved white matter microstructure (increased FA and reduced RD) compared to children who did not meet nutrient recommendations. These effects were independent of sex and birth GA, which are known predictors of neurodevelopmental outcomes in children born VLBW. The DTI and NODDI metrics were, in turn, correlated with cognitive outcomes. Voxel-wise analyses revealed a significant positive association between increased FA and NDI with higher processing speed scores. Lower RD and ODI were also associated with improved processing speed. Importantly, we did not find significant associations between mother’s breastmilk intake or duration of breastfeeding with white matter microstructure.,Our findings demonstrated that among the macronutrients, achieving protein recommendations during Postnatal Days 9–29 contributed to the beneficial effect of nutrition on white matter microstructure at 5 years of age. This was evident by the widespread associations between protein intake with higher FA and lower RD in many overlapping white matter tracts. Proteins are essential for brain development and myelination during the early postnatal preterm period,We further found that meeting enteral lipid and energy recommendations during Postnatal Days 9–29 was associated with higher FA and lower RD in major posterior white matter tracts such as the posterior thalamic radiation and corpus callosum. These results extend previous findings showing associations between lipid and energy intake with improved white matter maturation and reduced brain injury in preterm infants at term-equivalent age.,,,,,,Long-chain polyunsaturated fatty acids have also been linked to the beneficial effects of lipids on white matter maturation and neurodevelopment.,,,,The associations between white matter microstructure and cognitive outcomes were also very interesting. Alterations in FA and other DTI metrics have been correlated with early cognitive and motor outcomes in very preterm children,n = 16) did not consent to neuroimaging. Thus, lower functioning VLBW children, who were unable to participate or complete the scan protocol, were not represented in the current sample. Faster scan times and improved scan protocols adapted for paediatric populations will improve the retention and quality of data in the future. Secondly, as is typical in the field, nutrient concentrations of mother’s breastmilk feeds were not directly measured. Weekly macronutrient and energy estimates were instead calculated based on known changes in milk composition over time.While the present study has many strengths, including the use of DTI and NODDI metrics to assess the microstructural properties of white matter in children born VLBW, there are some limitations to consider. Firstly, the relatively small sample of 41 VLBW children was due to a combination of factors, including parental decline to participate and ineligibility for neuroimaging. Our sample size was further reduced due to the exclusion of data that did not pass strict inspection for motion artefacts or were incomplete due to the young participants’ inability to finish scanning protocols. While this data loss is a common challenge faced by others working in paediatric neuroimaging, we acknowledge that our sample may not be representative of all VLBW children. For instance, parents who deemed their children unable to lie still during the scan (,Our findings address an important gap in the literature, examining the impact of specific nutritional factors on white matter microstructure measured at preschool-age. We also examined the association between DTI and NODDI metrics with cognitive outcomes. Given the critical role white matter development has on brain function and the many reports of altered white matter in children born VLBW, our study indicates a potential underlying contributor of this impaired white matter maturation. Importantly, our study also highlights the importance of macronutrients such as protein and lipids during this early postnatal period. With the high rates of cognitive difficulties experienced by infants born preterm,Brain Communications online.fcab066_Supplementary_DataClick here for additional data file.


The infants with and without LSV had similar perinatal characteristics, placental pathologies, cytomegalovirus infection rates, and clinical morbidities. The late-onset LSV group comprised 45 (88.2%) infants who had a significantly higher rate of being small for gestational age (SGA) and used oxygen for longer than the infants without LSV. After adjusting a multivariable regression model for GA and SGA, analysis showed that the duration of oxygen usage was an independent risk factor for late-onset LSV development in VLBW infants . Conclusion: LSV may be a nonspecific marker of perinatal insult to the developing brains of preterm infants. Prolonged postnatal oxygen usage may predispose VLBW preterm infants to late-onset LSV development. The long-term clinical impacts of LSV should be clarified.Background: The pathogenesis and clinical significance of lenticulostriate vasculopathy (LSV) are unclear. Our study aimed to determine the prevalence, presentation, and evolution of LSV, and the perinatal risk factors associated with LSV among very-low-birth-weight (VLBW) preterm infants. Methods: One-hundred-and-thirty VLBW preterm infants were retrospectively enrolled in this study. Serial cranial ultrasound examinations were performed regularly from birth until a corrected age of 1 year. Infants with LSV were assigned to early-onset  and late-onset  groups. Data describing the infants’ perinatal characteristics, placental histopathology, and neonatal morbidities were collected, and the groups were compared. Results: Of the VLBW infants, 39.2% had LSV before they were 1 year old. Linear-type LSV was the most common presentation, and >50% of the infants had bilateral involvement. LSV was first detected at 112 ± 83 postnatal days, and its detection timing correlated negatively with gestational age (GA) (R Lenticulostriate vasculopathy (LSV) refers to hyperechogenic vessels detected in neonates’ thalami and basal ganglia, using cranial ultrasound (cUS). Growing awareness of LSV over the past 10 years has led to demonstrations of its associations with a variety of fetal and neonatal diseases, which can antenatally or postnatally affect the developing brain .4 was associated with LSV in preterm neonates in a large cohort study [The incidence of LSV in preterm neonates varies from 2.2% to 32% . Mittendrt study . Variousrt study . Howeverrt study ,7,8; datThis 7-year retrospective, observational cohort study involved preterm neonates who were admitted to the neonatal intensive care unit (NICU) of Cathay General Hospital in Taipei between January 2011 and March 2018, and whose birth body weights (BBW) were <1500 g. Neonates with major congenital or chromosomal abnormalities, and those who died in the NICU, were excluded. All neonates underwent regular cUS scanning, from birth until a corrected age of 1 year. At our institute, VLBW preterm neonates are routinely scheduled to undergo cUS on postnatal days (PNDs) 1, 3, 7, and 21, and then every 2 weeks until discharge. After discharge, cUS examinations are scheduled every 2 months until a corrected age of 1 year. Well-trained technical staff who were blinded to the enrolled neonates’ perinatal characteristics performed the cUS, using an HD 11 Ultrasound System  and a 6 MHz curved-array transducer. The cUS examinations were conducted through the anterior fontanelle, and standard images of the coronal and sagittal planes were captured, as previously described , and werLSV is defined as the presence of punctate, linear, or branching hyperechogenic lesions in the basal ganglia–thalamic region in coronal and parasagittal views. An LSV diagnosis was confirmed by an independent neonatologist and neurologist. The presence of other major cranial lesions, including intraventricular hemorrhage and periventricular leukomalacia, were also recorded. We used Hemachandra’s classification to separate the neonates into early-onset and late-onset LSV groups . Early-o4 usage, C-reactive protein (CRP), and blood white blood cell (WBC) counts before delivery, and the presence of histological chorioamnionitis (HCAM). Two independent pathologists performed pathologic examinations of the placentas, and HCAM severity was graded according to Redline et al. [To determine LSV-associated risk factors, maternal and neonatal clinical characteristics were recorded. Maternal risk factors included preeclampsia, gestational diabetes mellitus (GDM), preterm premature rupture of the membranes (PPROM) >18 h, delivery mode, antenatal steroids and MgSOe et al. . The neoe et al. ,13, an Ae et al.   and 95% confidence intervals (CIs) were calculated to estimate the relative risks of LSV. The statistical analyses were performed using SPSS (version 15.0) for Windows . A value of p < 0.05 was considered significant.Relationships between PND, postmenstrual age (PMA), and GA, and the first LSV detection were examined using linear regression analyses. Infants with and without LSV and early- or late-onset LSV were compared regarding demographic and perinatal variables using chi-squared analyses or Fisher’s exact test for categorical variables and an independent sample During the study period, 168 preterm neonates who weighed <1500 g were admitted to the NICU. Three neonates had multiple congenital anomalies and were excluded. Thirty-one neonates died during hospitalization, and four were lost to follow-up. Finally, 130 neonates were enrolled in the study, and their mean GA was 28.2 ± 2.3 weeks and the was 1097 ± 247 g. Seventy-two (55.4%) neonates were boys.Of the 130 VLBW enrolled neonates, 51 (39.2%) were diagnosed with LSV based on ≥1 cUS examination from birth until a corrected age of 1 year. LSV presented as linear A, branchEarly-onset LSV was first detected in 11.8% (6 of 51) of neonates within 10 days of life, and late-onset LSV was present in 88.2% (45 of 51) of neonates. p = 0.045). Infants with LSV used oxygen for longer durations than neonates without LSV; however, the multivariate logistic regression analyses that were adjusted for GA and the LSV-associated covariates listed in BBW, birth body weight; BPD, bronchopulmonary dysplasia; CMV, cytomegalovirus; CRP, C-reactive protein; GA, gestational age; GDM, gestational diabetes mellitus; HCAM, histological chorioamnionitis; IVH, intraventricular hemorrhage; LGA, large for gestational age; LSV, lenticulostriate vasculopathy; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; PPHN, persistent pulmonary hypertension of the newborn; PPROM, preterm premature rupture of the membranes; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; SGA, small for gestational age; ROP, retinopathy of prematurity; WBC, white blood cell.p = 0.032). ( 0.032). .BBW, birth body weight; BPD, bronchopulmonary dysplasia; CMV, cytomegalovirus; GA, gestational age; GDM, gestational diabetes mellitus; HCAM, histological chorioamnionitis; LGA, large for gestational age; LSV, lenticulostriate vasculopathy; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; PPROM, preterm premature rupture of the membranes; RDS, respiratory distress syndrome; SGA, small for gestational age; ROP, retinopathy of prematurity.This 7-year retrospective, observational cohort study enrolled all VLBW preterm infants born at a single institution. The neonates underwent frequent cUS for longer than infants involved in previous studies of LSV ,7,8. TheThe precise incidence of LSV in preterm neonates is unclear, because of poor interrater agreement regarding LSV identification . In our The definition of and the diagnostic criteria for LSV lack consensus. The most widely accepted definition of LSV is branching or linear hyperechogenic lesions in the basal ganglia and/or thalamus on cUS images but technological advances in cUS may mean that some hyperechogenic lines could be echo reflections from normal lenticulostriate arteries ,23; therLSV tends to appear soon after birth in term infants, but it usually becomes more prominent weeks after birth in preterm neonates ,2,7,25. As with the findings in previous studies, most of our neonates (88.2%) had late-onset LSV ,10,26. SPreviously, LSV was considered an unchanging sonographic finding at birth that did not resolve or progress over time ,28. HoweNo consensus exists regarding the antenatal or postnatal risk factors for LSV development in term neonates. While LSV was thought to be initially associated with congenital infections, it is also associated with many noninfectious etiologies, including trisomies, fetal alcohol syndrome, maternal drug exposure, twin-to-twin transfusion syndrome, cardiac disease, neonatal lupus erythematosus, and perinatal asphyxia and hypoxia ,31,32,33After adjusting for GA and other confounding factors, we found that longer postnatal oxygen exposure may be associated with a higher risk of late-onset LSV development in preterm infants. This finding has not been previously reported, but hypoxia/ischemia is an important etiologic factor associated with LSV . We coulCongenital CMV infection is the most common infectious cause of neonatal LSV ,34,35. IOur study has several limitations. First, this was a single-center, retrospective observational cohort study. While our cUS examination protocols for each VLBW neonate were uniform, some bias remained. For example, CMV screening was often performed on neonates with clinical symptoms or signs of congenital infection, including SGA, cholestasis, or prominent LSV lesions. CMV infection may have been over-diagnosed in the LSV group; consequently, we could not differentiate between prenatal and postnatal insults-related LSV based on the timing of LSV appearance. Finally, we could not address the impacts of LSV on clinical and neurodevelopmental outcomes.In conclusion, LSV is not an uncommon finding in cUS scans of VLBW preterm infants. It may be a nonspecific marker of perinatal insults to the developing brains of these infants. The PND on which LSV was first detected was negatively associated with GA. Prolonged oxygen usage may predispose VLBW preterm infants to late-onset LSV development. The long-term clinical impacts of LSV should be investigated further.


Mechanical ventilation is an effective treatment for acute respiratory distress syndrome (ARDS), which can improve the prognosis of ARDS to a certain extent. However, it may further aggravate lung tissue injury, which is defined as ventilator-induced lung injury (VILI). Intermedin (IMD) belongs to the calcitonin gene-related peptide (CPRP) superfamily. Our previous studies have found that IMD reduces the expression proinflammatory cytokines, down-regulates nuclear translocation and improves the integrity of endothelial barrier in ARDS. However, the effect of IMD on VILI has not been clarified. Oxidative stress imbalance and apoptosis are the main pathophysiological characteristics of VILI. In the current study, we used C57B6/J mice and human pulmonary microvascular endothelial cells (HPMECs) to establish a VILI model to analyze the effects of IMD on VILI and explore its potential mechanism. We found that IMD alleviated lung injury and inflammatory response in VILI, mainly in reducing ROS levels, upregulating SOD content, downregulating MDA content, reducing the expression of Bax and caspase-3, and increasing the expression of Bcl-2. In addition, we also found that IMD played its anti-oxidative stress and anti-apoptotic effects via JAK2/STAT3 signaling. Our study may provide some help for the prevention and treatment of VILI. Acute respiratory distress syndrome (ARDS) is one of the most common critical diseases of the respiratory system, with high mortality and a heavy social burden . MechaniIntermedin (IMD) is a novel polypeptide belonging to the calcitonin superfamily. IMD is widely expressed throughout the body, and its sequence is highly conserved among different species . IMD is In the present study, we used 18% cyclic stretching (CS)-induced human pulmonary microvascular endothelial cells (HPMECs) and mechanical ventilation (MV)-induced C57BL/6J mice as VILI models to clarify the anti-apoptotic and anti-oxidative stress effects of IMD. Our study may provide some help for the prevention and treatment of VILI.1. VILI animal model2O, and the duration of MV was 4 h. IMD1-53  (50 ng/kg) or an IMD inhibitor  (100 ng−7 mol/L) or IMDinh (10−6 mol/L) 1 h before CS. In some experiments, which detected the potential effects of the JAK2/STAT3 pathway in IMD-mediated protection, Colivelin TFA  was administrated half an hour before IMD1-53 pretreatment.3. Hematoxylin and eosin (H&E) staining and lung histology injury evaluationHPMECs (from ScienCell) were cultured in EC medium containing 1% EC growth supplement, 10% fetal bovine serum and 1% penicillin–streptomycin in an incubator. Cyclic stretching (CS) was performed for 4 h to establish EC models (18% CS for VILI model and 5% CS for the spontaneous breathing model) using a Flexcell FX-4000 Tension System  . In addi4. Measurement of SOD and MDAThe mice lung tissues were soaked in 4% paraformaldehyde. Next, the specimens were embedded in paraffin, cut into sections and stained with hematoxylin and eosin (H&E). The stained slides were analyzed using a microscope . The lung injury score was measured as previously described .4. Measu5. ImmunohistochemistryThe levels of SOD and MDA were measured using SOD or MDA assay kit  followed by the manufacturer’s instructions.2O2 for 15 min. Then sections were washed and then blocked with goat serum for 1 h and incubated overnight at 4°C with the anti-primary antibody . Then, the sections were washed and incubated with secondary antibody  for 30 min, and then stained with DAB solution. Sections were counterstained with hematoxylin, dehydrated, vitrified and sealed.6. Flow cytometry for reactive oxygen species (ROS)Lung tissue sections from the left mice were deparaffinized with xylene, rehydrated in ethanol, and incubated in 3% H7. Quantitative real-time PCR (qRT-PCR)An ROS detection kit  was used to detect ROS levels. The ECs were cultured in DCFH-DA solution at 37°C for 20 min, washed with serum-free cell culture medium. Then, the cell suspensions were collected. Finally, ROS levels were analyzed using a flow cytometer .8. Western blottingTotal RNA was isolated from the cells and mice lung tissues using RNAiso Plus . Then, 1 μg of total RNA was used as a template for amplifying the cDNA using the PrimeScript™ RT reagent kit . cDNA was used for qPCR amplification using TB Green™ Premix Ex Taq™ II . All data were calculated using the 2-ΔΔCt method and normalized to β-actin. Primer sequences for the mice were as follows: Bax ; caspase-3 ; Bcl-2 ; IL-6 ; TNF-α ; β-Catenin .9. ROS stainingTotal proteins were extracted from tissues and ECs using RIPA, and the concentration was detected by BCA kit . Equal amounts of protein were loaded into each well for separation via SDS-PAGE and electrophoresed onto PVDF membranes. The membranes were blocked with 5% skim milk or 5% BSA for 1 h, incubated with primary antibodies   overnight at 4°C, and then incubated with secondary antibodies . Finally, the protein bands were measured using the ECL Substrate kit  and images were captured using Imaging System .10. Flow cytometryFresh lung tissues were embedded in the OTC and sliced. The sections were rewarmed to room temperature while controlling the moisture content, after which an autofluorescence quenching agent was added and cleaned. Thereafter, the sections were stained with ROS dye and kept away from light for 30 min. Finally, they were counterstained with DAPI, sealed, and observed under a fluorescence microscope.11. Statistical analysisAn apoptosis detection kit was used to access cell apoptosis. All processes were in accordance with the manufacturer’s requirements. A flow cytometer  was used to analyzed the data.p < 0.05.Continuous data are displayed as the mean ± standard deviation (SD). T-test or ANOVA is performed to detected significance between groups if the data are normally distributed, while the Mann-Whitney U test or Kruskal-Wallis test is used if the data are non-normally distributed. To assess subgroup analysis, Tukey test or Dunn’s multiple comparisons test is measured. The chi-squared test is used to compare categorical variables between groups. Statistical significance is set at 1. IMD attenuated lung injury and inflammation in VILIIn vivo, IMD or IMDinh (inhibitor of IMD) was administered 1 h before MV and then MV was administered for 4 h. H&E and lung injury score results showed that IMD pretreatment significantly attenuated lung tissue injury caused by MV, mainly manifesting as narrowing of the alveolar septum, reduction of neutrophil infiltration, perivascular edema, protein edema fluid exudation, and patchy bleeding. IMDinh was truncated structure of IMD, which was worked as a competitive inhibitor of IMD. It inhibited the biological functions of endogenous IMD and aggravated lung tissue injury caused by MV  or 5% CS  for 4 h. IMD or IMDinh was given 1 h before 18% CS. PCR results showed that compared with the VILI group, the mRNA levels of IL-6 and TNF-α in the VILI + IMD group were significantly alleviated. However, IMDinh further exacerbated the mRNA levels of proinflammatory cytokines (IL-6 and TNF-α)  . The aboin vivo and in vitro.3. IMD alleviated oxidative stressThe expression of apoptosis related protein  was detected by western blotting, PCR, and immunohistochemistry to evaluate the anti-apoptotic role of IMD in VILI. Western blotting and qPCR showed that in the VILI model group, the expression of Bax and caspase-3 increased significantly while the expression of Bcl-2 decreased significantly . However13. We found that IMD significantly reduced the generation of ROS in the VILI group (In vivo and in vitro, compared with the VILI group, IMD pretreatment significantly increased SOD levels and decreased MDA levels (in vivo and in vitro.4. JAK2/STAT3 pathway was involved in IMD-mediated protectionExcessive oxidative stress generated by injured ECs is widely involved in the progression of lung damage during VILI . The imbLI group . In HPMELI group . SOD andLI group . In vivoA levels . HoweverTo further clarify the participation of the JAK2/STAT3 signaling in VILI, the phosphorylation of JAK2 and STAT3 was measured by western blotting. In both mice and ECs, compared with the control group, the phosphorylation of JAK2 and STAT3 in the VILI group was significantly higher, and IMD reduced VILI-induced phosphorylation of JAK2 and STAT3 . Future,In the current study, we used C57B6/J mice and HPMECs to establish a VILI model to analyze the effect of IMD on VILI and its potential mechanism. We found, for the first time, that IMD improved lung injury and alleviated inflammatory factor expression in VILI. In addition, IMD also reduced oxidative stress by reducing ROS levels, upregulating SOD content, and downregulating MDA content. Western blot and immunohistochemical results showed that IMD also alleviated apoptosis, mainly by reducing the expression of Bax and caspase-3 and increasing the expression of Bcl-2. IMD exerted protective effects against VILI via JAK2/STAT3 signaling .in vivo, and IMD1-53 has strong biological activity (in vivo, we used IMD inhibitor to interfere the effect of endogenous IMD. Compared with the VILI group, the VILI + IMDinh group had more severe lung injury, more expression of inflammatory factors, and higher levels of apoptosis and oxidative stress. These results indicated that IMD inhibitor counteracted the protective effect of endogenous IMD. Overall, we confirmed the protective effect of IMD on VILI.The IMD gene is located on human chromosome 22q13.33, and the encoded polypeptide chain is composed of 148 amino acids . The N-tactivity . IMD is activity . IMD alsactivity . In septactivity . Our preactivity . In the ECs are widely distributed throughout the body and have a large surface area. They mainly regulate the body’s homeostasis through six functions: regulating vasodilation-contraction, vascular permeability, cell growth, immunity and inflammation, coagulation function, cell growth, and lipid metabolism . BecauseThe JAK2/STAT3 pathway is an intracellular signal transduction pathway that is involved in various biological processes and provides a direct mechanism for the regulation of gene expression by extracellular factors. Cytokines bind to receptors, resulting in receptor-coupled JAK aggregation and the activation of adjacent JAKs through mutual phosphorylation. The activated JAKs phosphorylate the tyrosine site on the receptor, causing the receptor to generate a STAT binding region and then phosphorylate STATs . In a seHowever, this study had some limitations. We found a protective effect of IMD on VILI, which indicated that IMD may be a potential target for the prevention and treatment of VILI. However, its mechanism remains unclear. In addition, although EC injury is vital in VILI, the pathogenesis of VILI is complex and diverse, and other injury mechanisms should not be ignored. Basic and clinical follow-up studies are essential to further clarify the potential role of IMD in VILI.In conclusion, we found for the first time that IMD reduced VILI through anti-apoptotic and antioxidant stress in mice and HPMECs. In addition, we found that the anti-apoptotic and antioxidant stress effects of IMD were mediated by the inhibition of the JAK2/STAT3 signaling pathway.


Leptin was positively related to TG levels of pregnant women and newborns’ birth weight (p < 0.05). Logistic regression analysis showed that having greater than or equal to four meals a day  and liking to eat lightly flavored food during pregnancy  were independent risk factors of maternal dyslipidemia. Conclusions: The prevalence of dyslipidemia was relatively high in pregnant women and was affected by dietary behaviors. Abnormal lipid levels during pregnancy could affect weight and length at birth, which might be associated with increasing leptin levels in cord blood, and then the weight of infants would be influenced by birth weight.Background: Gestational diabetes can alter the trajectory of fetal development, but there are few studies on the effects of abnormal lipid metabolism on physical development of infants. We aimed to explore the prevalence of maternal dyslipidemia, its influencing factors and effects on the physical development of fetuses and infants, as well as the role of leptin in this process. Methods: Questionnaire surveys and main outcome measures were administered among 338 pairs of pregnant women and newborns. Results: The detection rate of maternal dyslipidemia was 31.5%. The median levels of TG (triglyceride) and TG/HDL (high-density lipoprotein) ratio were higher in large-for-gestational-age (LGA) newborns. Birth weight was positively related to infants’ height and weight at six months and one year old ( The prevalence of obesity in children and adolescents has increased substantially around the world . The cauThe changes in diet and exercise behavior, and the occurrence of complex physiological phenomena during pregnancy, will affect the levels of maternal blood lipid, including total cholesterol (TC), triglyceride, low-density lipoprotein (LDL) and high-density lipoprotein cholesterol. Elevation of blood lipid levels due to pregnancy to a certain extent is physiological . NeverthThe objective of the present study was to explore the influencing factors of women’s dyslipidemia during late gestation and its effects on the physical development of fetuses and infants, as well as the role of leptin in this process, in order to prevent maternal dyslipidemia and ensure the healthy growth and development of infants and young children.A population-based bidirectional cohort study of 338 pairs of pregnant women and newborns was performed between January 2020 and July 2021. The participants in this study were recruited from a third-class A hospital by convenient sampling in Shenyang, China. This study was approved by the Medical Ethics Committee of the Fourth Affiliated Hospital of China Medical University and all participants had provided written informed consent (Reference number: EC-2019-KS-027).Subjects were included in the study if: (1) they were aged ≥18 years old; (2) they were natural singleton conception; (3) the newborns were live birth. Subjects were excluded from the study if: (1) they were multiple pregnancy; (2) the newborns were birth defects and stillbirth; (3) they suffered from acute and chronic infectious diseases, tumors, cardiovascular diseases or diabetes before pregnancy; (4) they had mental and intellectual disabilities.2 (m)2.The basic information of pregnant women including general demographic characteristics, dietary frequency, dietary habits, exercise and sleep conditions was gathered by the trained pediatricians through face-to-face surveys using questionnaires, while the standard height and weight measuring instrument was used to measure the height and weight of pregnant women by professionals. Calculated body mass index (BMI) was based on these parameters: BMI = weight (Kg)/heightDiet-related information included the following aspects: (1) Main food intake frequencies included grains, meats, milk products, soy products, seafoods, vegetables, fruits, etc. (2) Snack intake frequencies included canned food, fried food, nuts, sweets, puffed food, beverages, etc. (3) Eating habits included breakfast, often to eat food before going to bed, whether to eat on time, meals per day, taste, types of drinking water, etc. Definition of snack intake frequencies was as follows: 4–5 times per week was regularly, 2–3 times per week was occasionally, and ≤1 time per week was barely.Fasting serum lipids: We informed pregnant women to fast for 12 h before getting up in the morning for blood sampling. TC, TG, HDL and LDL levels were detected by a fully automated biochemical analyzer (Siemens ADVIA2400). The abnormal lipid levels were evaluated by the Williams Obstetrics when TC, TG and LDL were, respectively, higher than 7.73 mmol/L, 4.31 mmol/L and 4.76 mmol/L, and HDL was lower than 1.34 mmol/L . PregnanThe birth weight (kg) and birth length (cm) of newborns were gathered from delivery records, and then the height (cm) and weight (kg) of infants at six months and one year old were followed up by the trained pediatricians. We divided newborns into large-for-gestational-age and appropriate for gestational age according to the growth reference standards of newborns’ birth weight of different gestational ages in China. Large-for-gestational-age infants were identified when birth weight was >90th percentile standardized birth weight .Cord blood samples obtained from umbilical veins were processed within one hour after birth. Serum was separated by centrifugation and stored at −80 °C until assayed. Leptin in 57 random neonatal cord blood samples was detected by ELISA kit .p value was set at 0.05.Data management and analysis were performed using SPSS 22.0. Categorical variables were expressed as n (%), chi-squared test or fisher exact test was used to compare differences between groups. Normality tests for continuous variables were conducted. Non-normality variables were expressed as median (quartiles), and the Mann–Whitney U test was used to compare differences between groups. Correlation between two continuous variables was tested by Partial correlation. The logistic regression analysis was used to assess the risk factors of maternal dyslipidemia. The significance level of the A total of 338 pairs of pregnant women and infants participated in this study. The age (29.31 ± 3.99 years old), height (162.30 ± 5.33 cm), weight before pregnancy (58.31 ± 9.99 kg) and antenatal weight (74.75 ± 10.54 kg) of pregnant women, the birth weight (3.38 ± 0.41 kg) and birth length (50.58 ± 1.57 cm) of newborns, the weight (8.75 ± 1.07 kg) and height (69.34 ± 2.77 cm) of infants at six months, and the weight (10.36 ± 1.15 kg) and height (77.10 ± 2.70 cm) of infants at one year old are shown in p < 0.001), as shown in According to the Williams Obstetrics, the overall abnormal rates of TC, TG, HDL-c, LDL-c of pregnant women were 7.1%, 23.4%, 1.7%, 6.4%. The prevalence of dyslipidemia was 31.5% under the standards that one of the above was abnormal. Meanwhile, the prevalence rate of maternal dyslipidemia was 5.2% as per self-report, far lower than 31.5% , while other blood lipid levels had nothing to do with the weight and height of infants in the case of controlling birth weight and birth length (p > 0.05). Birth weight was positively related to infants’ height and weight at six months and one year old , shown in The HDL levels were negatively related to the weight and height of infants at six months in the case of controlling birth weight and birth length (rp = 0.025), shown in p > 0.05, not shown in figures below).There was a positive correlation between leptin in cord blood and TG levels of pregnant women in the third trimester of pregnancy (p < 0.001), shown in p > 0.05, not shown in figures below).Leptin in cord blood was positively related to newborns’ birth weight (p > 0.05). There was no significant difference in the proportion of pregnant women with family history of diabetes or hypertension between the control group and the case group (p > 0.05), shown in Compared with the control group, the proportion of pregnant women whose age was higher than 30 years old, family financial status was well, or weight gain was excessive during pregnancy was higher in the case group , and the proportion of passive smoking before or after pregnancy was lower in the case group . None of the differences above were statistically significant (p > 0.05), as shown in Compared with the control group, the intake frequencies of common food, such as coarse grain, vegetables, fruits, soy products, and milk products, greater than or equal to 1 time/day for pregnant women during pregnancy were a bit higher, while the intake frequencies of lean meat and eggs greater than or equal to 1 time/day and of seafoods and liver greater than or equal to 4 times/week were a bit lower in the case group. None of the differences above were statistically significant (p > 0.05). The ‘barely intake’ frequencies of sweets and the ‘occasionally or regularly intake’ frequencies of nuts were around 60% in both control and case groups (p > 0.05). The ‘regularly intake’ frequencies of health products and the proportion of vitamin D supplement were between 71% and 81% in both control and case groups (p > 0.05), as shown in The ‘barely intake’ frequencies of canned food, barbecue, fried food, puffed food, beverages and coffee of pregnant women during pregnancy between the control and case groups were quite unanimous; all of them were higher than 85% (p < 0.05). There were no statistically significant differences in eating habits including breakfast, often eating food before going to bed, eating on time, other tastes, and types of drinking water between the control and case groups, as shown in Compared with the control group, the proportion of pregnant women who had equal to or more than three meals a day or who liked to eat lightly flavored food during pregnancy was higher in the case group . Furthermore, ways to go to work, exercise time per day, liking exercise before or after pregnancy, and sleep conditions between the control and case groups were about the same (p < 0.05), as shown in Compared with the control group, the proportion of pregnant women who had an elevator at home, watched TV more than 2 h per day, and played mobile more than 3 h per day were higher in the case group. None of the differences above were statistically significant  and liking to eat lightly flavored food during pregnancy  were independent risk factors of maternal dyslipidemia, as shown in Variables with a We found the prevalence rate of maternal dyslipidemia was 31.5% according to the Williams Obstetrics. A previous study showed that the detection rates of maternal dyslipidemia varies greatly by different criteria . This waWe found birth weight was affected by abnormal TG levels of pregnant women, which agreed with the results of many studies ,14,15. ILeptin could lead to an increase in triglyceride hydrolysis and a suppression of lipogenesis and in vivo studies have obviously demonstrated that leptin can reduce body fat mass . Our stuThe influencing factors of gestational dyslipidemia in the third trimester of pregnancy were explored. Studies have reported that the maternal lipid levels were affected by maternal age, BMI before pregnancy and weight gain during pregnancy ,26,27. HLogistic regression analysis showed that having greater than or equal to four meals a day and liking to eat lightly flavored food during pregnancy were independent risk factors for maternal dyslipidemia in the third trimester of pregnancy. Although liking to eat lightly flavored food during pregnancy was good for health, it might lead to a lack of protein and excessive carbohydrate intake. If the energy exceeded the body’s needs, carbohydrate-decomposed sugar would be converted into fat in the liver, leading to increased blood lipid levels in pregnant women ,35. Our Our study indicated that there was a positive relationship of maternal dyslipidemia during late gestation and the birth index and infants’ development as it was a population-based bidirectional cohort study. However, the follow-up bias was inevitable. Our research showed that the number of meals per day and preferring lightly flavored food during pregnancy might be risk factors for maternal dyslipidemia. Another limitation of our investigation was that the intake of various foods during pregnancy was not quantified, and it was impossible to compare the energy supply proportions of the three major macronutrients.Transient mild dyslipidemia during pregnancy could steadily return to normal after delivery, while more serious dyslipidemia was difficult to correct . Dyslipi