Transcriptome analysis reveals hepatic disordered lipid metabolism, lipotoxic injury, and abnormal development in IUGR sheep fetuses due to maternal undernutrition during late pregnancy.

Although lipid metabolism in fetal livers under intrauterine growth restriction (IUGR) conditions has been widely studied, the implications of maternal undernutrition on fetal hepatic lipid metabolism, lipotoxic injury, and abnormal development remain largely unknown. Therefore, this study investigated the effects of maternal undernutrition on disordered hepatic lipid metabolism, lipotoxic injury, and abnormal development in IUGR sheep fetuses using transcriptome analysis. Seventeen singleton ewes were randomly divided into three groups on day 90 of pregnancy: a control group (CG; 0.63 MJ metabolic energy/body weight (ME/BW)0.75/day, n = 5), maternal undernutrition group 1 (MU1; 0.33 MJ ME/BW0.75/day, n = 6), and maternal undernutrition group 2 (MU2; 0.20 MJ ME/BW0.75/day, n = 6). The fetuses were euthanized and recovered on day 130 of pregnancy. The levels of free fatty acids (FFA) in maternal blood (P < 0.01), fetal blood (P < 0.01), and fetal livers (P < 0.05) were increased in the MU1 and MU2 groups, but fetal hepatic triglyceride (TG) levels in the MU2 group (P < 0.01) and ß-hydroxybutyrate levels in the MU1 and MU2 groups (P < 0.01) were decreased compared to the CG. Severe inflammatory cell infiltration and increased non-alcoholic fatty liver disease activity scores were observed in MU1 and MU2 fetuses (P < 0.01). Progressive deposition of fetal hepatic reticular fibers and collagen fibers in the fetal livers of the MU1 and MU2 groups and significant hepatic fibrosis were observed in the MU2 fetuses (P < 0.05). Gene set enrichment analysis showed that genes involved in lipid accumulation and FFA beta oxidation were downregulated in both MU groups compared to those in the controls. The fetal liver mRNA expression of the ß-oxidation regulator, acetyl-CoA acetyltransferase 1, and the TCA regulator, isocitrate dehydrogenase were reduced in MU1 (P < 0.05) and MU2 (P < 0.01) fetuses, and downregulated mRNA expression of long chain fatty acid CoA ligase 1 (P < 0.05) and glycerol-3-phosphate acyltransferase (P < 0.01) was observed in MU2 fetuses. Differentially expressed genes (DEGs) in MU1 versus CG (360 DEGs) and MU2 versus CG (746 DEGs) were identified using RNA sequencing. Bioinformatics analyses of the 231 intersecting DEGs between MU1 versus CG and MU2 versus CG indicated that neutrophil extracellular traps (NETs) were induced and played a central role in fetal hepatic injury in IUGR sheep. Increased maternal blood myeloperoxidase (MPO) levels (P < 0.01), NE (Elane)-positive areas in fetal liver sections (P < 0.05), and fetal liver MPO protein expression (P < 0.01) were found in the MU1 and MU2 groups; however, MPO levels were reduced in the fetal membrane (P < 0.01) and fetal blood (P < 0.05) in the MU1 group, and in the maternal-fetal placenta and fetal blood in the MU2 group (P < 0.01). Analysis of gene expression trends in the intersecting DEGs between MU1 versus CG (129 DEGs) and MU2 versus CG (515 DEGs) further revealed that 30 hub genes were essential regulators of the G2/M cell cycle, all of which were associated with hepatocellular carcinoma. G0/G1 phase cells of the fetal liver were reduced in the MU1 (P < 0.05) and MU2 (P < 0.01) groups, whereas G2/M phase cells were elevated in the MU1 and MU2 groups (P < 0.01). The representatives of upregulated hub genes and fetal liver protein expression of maternal embryonic leucine zipper kinase and protein regulator of cytokinesis 1 were progressively enhanced in the MU1 and MU2 groups (P < 0.01), and topoisomerase II alpha protein expression in the MU2 group (P < 0.05), as expected. These results indicate that FFA overload, severe lipotoxic injury, and NETs were induced, and disease-promoting regulators of the G2/M cell cycle were upregulated in the fetal liver of IUGR sheep. These findings provide new insights into the pathogenesis of impaired hepatic lipid metabolism and abnormal development and the molecular origin of post-natal liver disease in IUGR due to maternal undernutrition. This information can support the development of new therapeutic strategies.

Dietary supplementation with dihydroartemisinin improves intestinal barrier function in weaned piglets with intrauterine growth retardation by modulating the gut microbiota.

The aim of this study was to investigate whether dietary dihydroartemisinin (DHA) supplementation could improve intestinal barrier function and microbiota composition in intrauterine growth restriction (IUGR) weaned piglets. Twelve normal birth weight (NBW) piglets and 24 IUGR piglets at 21 d of age were divided into three groups, which were fed a basal diet (NBW-CON and IUCR-CON groups) and an 80 mg/kg DHA diet (IUGR-DHA group). At 49 d of age, eight piglets of each group with similar body weights within groups were slaughtered, and serum and small intestine samples were collected. The results showed that IUGR piglets reduced growth performance, impaired the markers of intestinal permeability, induced intestinal inflammation, decreased intestinal immunity, and disturbed the intestinal microflora. Dietary DHA supplementation increased average daily gain, average daily feed intake, and body weight at 49 d of age in IUGR-weaned piglets (P < 0.05). DHA treatment decreased serum diamine oxidase activity and increased the numbers of intestinal goblet cells and intraepithelial lymphocytes, concentrations of jejunal mucin-2 and ileal trefoil factor 3, and intestinal secretory immunoglobin A and immunoglobin G (IgG) concentrations of IUGR piglets (P < 0.05). Diet supplemented with DHA also upregulated mRNA abundances of jejunal IgG, the cluster of differentiation 8 (CD8), major histocompatibility complex-I (MHC-I), and interleukin 6 (IL-6) and ileal IgG, Fc receptor for IgG (FcRn), cluster of differentiation 8 (CD4), CD8, MHC-I, IL-6 and tumor necrosis factor α (TNF-α), and enhanced mRNA abundance and protein expression of intestinal occludin and ileal claudin-1 in IUGR piglets (P < 0.05). In addition, DHA supplementation in the diet improved the microbial diversity of the small intestine of IUGR piglets and significantly increased the relative abundance of Actinobacteriota, Streptococcus, Blautia and Streptococcus in the jejunum, and Clostridium sensu_ stricto_in the ileum (P < 0.05). The intestinal microbiota was correlated with the mRNA abundance of tight junction proteins and inflammatory response-related genes. These data suggested that DHA could improve the markers of intestinal barrier function in IUGR-weaned piglets by modulating gut microbiota. DHA may be a novel nutritional candidate for preventing intestinal dysfunction in IUGR pigs.

Intrauterine growth retardation (IUGR) is defined as the restricted development of the mammalian fetus or its organs during pregnancy, which has high morbidity and mortality during the perinatal period and improves the risk of metabolic diseases in the long term. Dihydroartemisinin (DHA) is a derivative of artemisinin that possesses anti-inflammatory and immunoregulatory effects. Therefore, this experiment was conducted to investigate whether dietary DHA supplementation could improve the intestinal barrier function and microbiota composition in IUGR-weaned piglets. The result showed that IUGR could lead to intestinal barrier dysfunction. Dietary supplementation with DHA improved growth performance and attenuated intestinal barrier dysfunction by decreasing the markers of intestinal permeability, increasing the mucus layer barrier, enhancing immunity, and reducing the inflammatory response in IUGR piglets, which may be attributed to the improvement of the intestinal microbiota. Moreover, the study indicated that the gut microflora was correlated with the gene expression of tight junction proteins and immune function. This study may provide a new nutritional strategy for the maintenance of intestinal health in IUGR pigs.

Dietary glycine supplementation activates mechanistic target of rapamycin signaling pathway in tissues of pigs with intrauterine growth restriction.

The mechanistic target of rapamycin (mTOR) cell signaling pathway serves as the central mechanism for the regulation of tissue protein synthesis and growth. We recently reported that supplementing 1% glycine to corn- and soybean meal-based diets enhanced growth performance between weaning and market weights in pigs with intrauterine growth restriction (IUGR). Results of recent studies have revealed an important role for glycine in activating mTOR and protein synthesis in C2C12 muscle cells. Therefore, the present study tested the hypothesis that dietary glycine supplementation enhanced the mTOR cell signaling pathway in skeletal muscle and other tissues of IUGR pigs. At weaning (21 d of age), IUGR pigs and litter mates with normal birth weights (NBW) were assigned randomly to one of the two groups: supplementation with either 1% glycine or 1.19% l-alanine (isonitrogenous control) to a corn- and soybean meal-based diet. Tissues were obtained from the pigs within 1 wk after the feeding trial ended at 188 d of age to determine the abundances of total and phosphorylated forms of mTOR and its two major downstream proteins: eukaryotic initiation factor 4E-binding protein-1 (4EBP1) and ribosomal protein S6 kinase-1 (p70S6K). Results showed that IUGR decreased (P < 0.05) the abundances of both total and phosphorylated mTOR, 4EBP1, and p70S6K in the gastrocnemius muscle and jejunum. In the longissimus lumborum muscle of IUGR pigs, the abundances of total mTOR did not differ (P > 0.05) but those for phosphorylated mTOR and both total and phosphorylated 4EBP1 and p70S6K were downregulated (P < 0.05), when compared to NBW pigs. These adverse effects of IUGR in the gastrocnemius muscle, longissimus lumborum muscle, and jejunum were prevented (P < 0.05) by dietary glycine supplementation. Interestingly, the abundances of total or phosphorylated mTOR, 4EBP1, and p70S6K in the liver were not affected (P > 0.05) by IUGR or glycine supplementation. Collectively, our findings indicate that IUGR impaired the mTOR cell signaling pathway in the tissues of pigs and that adequate glycine intake was crucial for maintaining active mTOR-dependent protein synthesis for the growth and development of skeletal muscle.

Soybean meal is the major source of dietary protein for growing pigs in many regions of the world, including North America, South America, and Asia. However, this conventional feedstuff is recognized to be severely deficient in glycine (the most abundant amino acid in the bodies of animals, including pigs). Compared to pigs with normal birth weights (NBW), pigs with intrauterine growth restriction (IUGR) have a lower ability to synthesize glycine and reduced growth performance between weaning and market weights. Results of recent studies with cultured muscle cells have revealed that glycine stimulates the mechanistic target of rapamycin (mTOR) cell signaling pathway (the master activator of initiation of protein synthesis in tissues) to promote protein synthesis and cell growth. There is also evidence that the mTOR pathway is impaired in the skeletal muscle of young IUGR pigs. Thus, dietary glycine supplementation may play an important role in maintaining an active mTOR cell signaling pathway for the growth of tissues, particularly skeletal muscle. Results of this study indicated that market-weight IUGR pigs had lower abundances of both total and phosphorylated mTOR, as well as its downstream target proteins in the gastrocnemius muscle, longissimus lumborum muscle, and jejunum, when compared with NBW pigs. In contrast, neither IUGR nor glycine supplementation affected the mTOR cell signaling pathway in the liver of pigs. Taken together, these novel findings indicate that IUGR pigs have insufficient cell signaling via the mTOR cell pathway in a tissue-specific manner during their growing-finishing phases of development and that this negative impact of IUGR can be mitigated by supplementing corn- and soybean meal-based diets with 1% glycine.

Dietary glycine supplementation enhances glutathione availability in tissues of pigs with intrauterine growth restriction.

This study tested the hypothesis that dietary supplementation with glycine enhances the synthesis and concentrations of glutathione (GSH, a major antioxidant) in tissues of pigs with intrauterine growth restriction (IUGR). At weaning (21 d of age), IUGR pigs and litter mates with normal birth weights (NBW) were assigned randomly to one of two groups, representing supplementation with 1% glycine or 1.19% l-alanine (isonitrogenous control) to a corn- and soybean meal-based diet. Blood and other tissues were obtained from the pigs within 1 wk after the feeding trial ended at 188 d of age to determine GSH, oxidized GSH (GSSG), and activities of GSH-metabolic enzymes. Results indicated that concentrations of GSH + GSSG or GSH in plasma, liver, and jejunum (P < 0.001) and concentrations of GSH in longissimus lumborum and gastrocnemius muscles (P < 0.05) were lower in IUGR pigs than in NBW pigs. In contrast, IUGR increased GSSG/GSH ratios (an indicator of oxidative stress) in plasma (P < 0.001), jejunum (P < 0.001), both muscles (P < 0.05), and pancreas (P = 0.001), while decreasing activities of γ-glutamylcysteine synthetase and GSH synthetase in liver (P < 0.001) and jejunum (P < 0.01); and GSH reductase in jejunum (P < 0.01), longissimus lumborum muscle (P < 0.01), gastrocnemius muscle (P < 0.05), and pancreas (P < 0.01). In addition, IUGR pigs had greater (P < 0.001) concentrations of thiobarbituric acid reactive substances (TBARS; an indicator of lipid peroxidation) in plasma, jejunum, muscles, and pancreas than NBW pigs. Compared with isonitrogenous controls, dietary glycine supplementation increased concentrations of GSH plus GSSG and GSH in plasma (P < 0.01), liver (P < 0.001), jejunum (P < 0.001), longissimus lumborum muscle (P = 0.001), and gastrocnemius muscle (P < 0.05); activities of GSH-synthetic enzymes in liver (P < 0.01) and jejunum (P < 0.05), while reducing GSSG/GSH ratios in plasma (P < 0.001), jejunum (P < 0.001), longissimus lumborum muscle (P < 0.001), gastrocnemius muscle (P = 0.01), pancreas (P < 0.05), and kidneys (P < 0.01). Concentrations of GSH plus GSSG, GSH, and GSSG/GSH ratios in kidneys were not affected (P > 0.05) by IUGR. Furthermore, glycine supplementation reduced (P < 0.001) TBARS concentrations in plasma, jejunum, muscles, and pancreas. Collectively, IUGR reduced GSH availability and induced oxidative stress in pig tissues, and these abnormalities were prevented by dietary glycine supplementation in a tissue-specific manner.

Pigs have the highest rate of intrauterine growth restriction (IUGR) among livestock species. These pigs, which have low birth weights (<1.1 kg) and account for ~15% to 20% of newborn pigs, are often culled after birth because they have lower growth performance and feed efficiency due to multiple factors (including oxidative stress in tissues), when compared with litter mates with normal birth weights (NBW). Much evidence shows that glutathione, which is a tripeptide synthesized from glutamate, glycine, and cysteine via enzymes (biological catalysts, γ-glutamylcysteine synthetase, and glutathione synthetase), is a major low-molecular-weight antioxidant in animal cells. Based on the findings of our recent study that dietary glycine supplementation enhanced the growth performance of IUGR pigs from weaning to market weight, the current study tested the hypothesis that this nutritional strategy increased the synthesis and availability of glutathione in their tissues. Our results indicated that the key organs of the digestive system (the small intestine, liver, and pancreas) as well as both longissimus lumborum and gastrocnemius muscles of IUGR pigs had lower concentrations of glutathione as compared with NBW pigs, due to reductions in both the activities of glutathione-synthetic enzymes and the availability of glycine. Dietary supplementation with 1% glycine prevented these metabolic deficiencies in tissues of IUGR pigs. Our findings support the notion that IUGR pigs fed conventional corn- and soybean meal-based diets do not synthesize adequate glutathione and that dietary glycine supplementation plays an important role in enhancing the availability of glutathione and mitigating oxidative stress to improve health and growth in these compromised animals.

Implications for miR-339-5p regulation of trophoblast proliferation and migration in placentas associated with porcine intrauterine growth retardation using integrated transcriptome sequencing analysis.

Placental dysfunction is considered as one of the main etiologies of fetal intrauterine growth retardation (IUGR). MicroRNAs (miRNAs) have been demonstrated to be a vital epigenetic modification involved in regulating the placental function and pregnancy outcomes in mammals. However, the mechanisms underlying placenta-specific miRNAs involved in the occurrence and development of pig IUGR remain unclear. In this work, we compared the placental morphologies of piglets with IUGR and normal birth weight (NBW) by using histomorphological analysis and performed a miRNA-mRNA integrative analysis of the gene expression profiles of IUGR and NBW placentas through RNA sequencing. We also investigated the role of differentially expressed ssc-miR-339-5p/GRIK3 through an in vitro experiment on porcine trophoblast cells (PTr2). IUGR piglets had significantly lower birth weight, placental weight, placental efficiency, and placental villus and capillary densities compared with the NBW piglets (P < 0.05). A total of 81 differentially expressed miRNAs and 726 differentially expressed genes in the placentas were screened out between the IUGR and NBW groups. The miRNA-mRNA interaction networks revealed the key core miRNA (ssc-miR-339-5p) and its corresponding target genes. Subsequently, we found that upregulation of ssc-miR-339-5p significantly inhibited the migration and proliferation of PTr2 cells (P < 0.05). The dual-luciferase reporter system showed that GRIK3 was the target gene of ssc-miR-339-5p, and the transcription level of GRIK3 may be negatively regulated by ssc-miR-339-5p. Additionally, overexpression of ssc-miR-339-5p significantly increased (P < 0.05) the mRNA expression levels of genes involved in the cytokine-cytokine receptor interaction pathway. These results indicate that ssc-miR-339-5p may affect the migration and proliferation of trophoblast cells by regulating the expression of GRIK3 and altering the placental inflammatory response, resulting in a suboptimal morphology and function of the placenta and the development of pig IUGR.

Intrauterine growth restriction defined by increased brain-to-liver weight ratio affects postnatal growth and protein efficiency in pigs.

Intrauterine growth restriction (IUGR) refers to impaired foetal growth during gestation, resulting in permanent stunting effects on the offspring. This study aimed to investigate the effects of IUGR on growth performance, body composition, blood metabolites, and meat quality of pigs from birth (n = 268) to slaughter (n = 93). IUGR piglets have prioritised brain development as a foetal adaptive reaction to placental insufficiency. This survival mechanism results in a higher brain-to-liver weight ratio (BrW/LW). One day (±1) after birth, computed tomography (CT) was performed on each piglet to assess their brain and liver weights. A threshold value of 0.78 (mean + SD) was chosen to divide the piglets into two categories - NORM (BrW/LW < 0.78) and IUGR (BrW/LW > 0.78). Moreover, each piglet was classified as either normal (score 1), mild IUGR (score 2), or severe IUGR (score 3) based on the head morphology. BW was recorded weekly, and average daily gain (ADG) was calculated for lactation, starter, grower, and finisher periods. Body composition was assessed after weaning (29.6 ± 0.7 d), at 20 kg (64 ± 7.2 d), 100 kg (165 ± 12.3 d), and on the carcasses using Dual-energy X-ray absorptiometry (DXA). Content and deposition rates of single nutrients, as well as energy and CP efficiency, were measured at 20 and 100 kg. Feed intake was recorded from 20 kg to slaughter. Meat quality was assessed on the carcasses. A total of 70% of the piglets assigned a score of 3 were NORM according to their BrW/LW. The IUGR category showed a lower ADG in the lactation (P < 0.01), starter (P = 0.07), and grower phases (P < 0.05) and a reduced CP efficiency in the grower-finisher period (P < 0.01) compared to the NORM group. IUGR pigs had a lower gain-to-feed ratio in the finisher period (P = 0.01) despite similar average daily feed intake, and they required more days (P < 0.01) to reach the slaughter weight. Additionally, their meat was darker (P = 0.01) than that of NORM pigs. The BrW/LW was inversely proportional to the ADG from birth to slaughter and negatively correlated with the CP deposition rate and efficiency in the grower-finisher period (P < 0.01). Furthermore, the higher the BrW/LW, the longer it took the pigs to reach the slaughter weight (P < 0.01). In conclusion, the identification of IUGR piglets based on the head morphology does not always agree with an increased BrW/LW. IUGR affects growth performance from birth to slaughter, CP efficiency in the grower-finisher period and meat quality.

Neonatal resveratrol administration promotes skeletal muscle growth and insulin sensitivity in intrauterine growth-retarded suckling piglets associated with activation of FGF21-AMPKα pathway.

BACKGROUND: Skeletal muscle is a major insulin-sensitive tissue with a pivotal role in modulating glucose homeostasis. This study aimed to investigate the effect of resveratrol (RES) intervention during the suckling period on skeletal muscle growth and insulin sensitivity of neonates with intrauterine growth retardation (IUGR) in a pig model. RESULTS: Twelve pairs of normal birth weight (NBW) and IUGR neonatal male piglets were selected. The NBW and IUGR piglets were fed basal formula milk diet or identical diet supplemented with 0.1% RES from 7 to 21 days of age. Myofiber growth and differentiation, inflammation and insulin sensitivity in skeletal muscle were assessed. Early RES intervention promoted myofiber growth and maturity in IUGR piglets by ameliorating the myogenesis process and increasing thyroid hormone level. Administering RES also reduced triglyceride concentration in skeletal muscle of IUGR piglets, along with decreased inflammatory response, increased plasma fibroblast growth factor 21 (FGF21) concentration and improved insulin signaling. Meanwhile, the improvement of insulin sensitivity by RES may be partly regulated by activation of the FGF21/AMP-activated protein kinase α/sirtuin 1/peroxisome proliferator activated receptor-γ coactivator-1α pathway. CONCLUSION: Our results suggest that RES has beneficial effects in promoting myofiber growth and maturity and increasing skeletal muscle insulin sensitivity in IUGR piglets, which open a novel field of application of RES in IUGR infants for improving postnatal metabolic adaptation. © 2023 Society of Chemical Industry.

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

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

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

Dietary glycine supplementation enhances postweaning growth and meat quality of pigs with intrauterine growth restriction.

Pigs with intrauterine growth restriction (IUGR) have suboptimum growth performance and impaired synthesis of glycine (the most abundant amino acid in the body). Conventional corn- and soybean meal-based diets for postweaning pigs contain relatively low amounts of glycine and may not provide sufficient glycine to meet requirements for IUGR pigs. This hypothesis was tested using 52 IUGR pigs and 52 litter mates with normal birth weights (NBW). At weaning (21 d of age), IUGR or NBW pigs were assigned randomly to one of two nutritional groups: supplementation of a corn-soybean meal-based diet with either 1% glycine plus 0.19% cornstarch or 1.19% L-alanine (isonitrogenous control). Feed consumption and body weight (BW) of pigs were recorded daily and every 2 or 4 wks, respectively. All pigs had free access to their respective diets and clean drinking water. Within 1 wk after the feeding trial ended at 188 d of age, blood and other tissue samples were obtained from pigs to determine concentrations of amino acids and meat quality. Neither IUGR nor glycine supplementation affected (P > 0.05) feed intakes of pigs per kg BW. The final BW, gain:feed ratio, carcass dressing percentages, and four-lean-cuts percentages of IUGR pigs were 13.4 kg, 4.4%, 2%, and 15% lower (P < 0.05) for IUGR pigs than NBW pigs, respectively. Compared with pigs in the alanine group, dietary glycine supplementation increased (P < 0.05) final BW, gain:feed ratio, and meat a* value (a redness score) by 3.8 kg, 11%, and 10%, respectively, while reducing (P < 0.05) backfat thickness by 18%. IUGR pigs had lower (P < 0.05) concentrations of glycine in plasma (-45%), liver (-25%), jejunum (-19%), longissimus dorsi muscle (-23%), gastrocnemius muscle (-26%), kidney (-15%), and pancreas (-6%), as compared to NBW pigs. In addition, dietary glycine supplementation increased (P < 0.05) concentrations of glycine in plasma and all analyzed tissues. Thus, supplementing 1% of glycine to corn-soybean meal-based diets improves the growth performance, feed efficiency, and meat quality of IUGR pigs.

About 15­20% of pigs are born naturally with low birth weights (<1.1 kg) due to intrauterine growth restriction (IUGR). These pigs are often culled after birth because they have lower growth performance and feed efficiency during the production period from weaning to market weight, compared with litter mates with normal birth weights (NBW). In many countries and regions (including North America, South America, and Asia), postweaning pigs are generally fed corn- and soybean meal-based diets that contain relatively a low amount of glycine. Glycine is the most abundant amino acid in the plasma and tissue proteins of pigs but may not be formed adequately from other amino acids in the body, particularly IUGR pigs that are now known to have an impaired ability for glycine synthesis. Results of the present study indicate that IUGR pigs fed conventional corn-SBM-based diets had lower concentrations of glycine in plasma and tissues (including skeletal muscle), compared with NBW litter mates. Dietary supplementation with 1% glycine improved the growth performance, feed efficiency, and meat quality of IUGR pigs. This simple nutritional means is expected to enhance the productivity of the global swine industry.

Placental assessment using spectral analysis of the envelope of umbilical venous waveforms in sheep.

INTRODUCTION: This study was designed to test the efficacy of an ultrasound flow measurement method to evaluate placental function in a hyperandrogenic sheep model that produces placental morphologic changes and an intrauterine growth restriction (IUGR) phenotype. MATERIALS AND METHODS: Pregnant ewes were assigned randomly between control (n = 12) and testosterone-treatment (T-treated, n = 22) groups. The T-treated group was injected twice weekly intramuscularly (IM) with 100 mg testosterone propionate. Control sheep were injected with corn oil vehicle. Lambs were delivered at 119.5 ± 0.48 days gestation. At the time of delivery of each lamb, flow spectra were generated from one fetal artery and two fetal veins, and the spectral envelopes examined using fast Fourier transform analysis. Base 10 logarithms of the ratio of the amplitudes of the maternal and fetal spectral peaks (LRSP) in the venous power spectrum were compared in the T-treated and control populations. In addition, we calculated the resistive index (RI) for the artery defined as ((peak systole - min diastole)/peak systole). Two-tailed T-tests were used for comparisons. RESULTS: LRSPs, after removal of significant outliers, were -0.158 ± 0.238 for T-treated and 0.057 ± 0.213 for control (p = 0.015) animals. RIs for the T-treated sheep fetuses were 0.506 ± 0.137 and 0.497 ± 0.086 for controls (p = 0.792) DISCUSSION: LRSP analysis distinguishes between T-treated and control sheep, whereas RIs do not. LRSP has the potential to identify compromised pregnancies.

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

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

Seasonal and temporal variation in the placenta during melatonin supplementation in a bovine compromised pregnancy model.

Compromised pregnancies result in a poorly functioning placenta restricting the amount of oxygen and nutrient supply to the fetus resulting in intrauterine growth restriction (IUGR). Supplementing dietary melatonin during a compromised pregnancy increased uteroplacental blood flow and prevented IUGR in a seasonal-dependent manner. The objectives were to evaluate seasonal melatonin-mediated changes in temporal alterations of the bovine placental vascularity and transcript abundance of clock genes, angiogenic factors, and nutrient sensing genes in 54 underfed pregnant Brangus heifers (Fall, n = 29; Summer, n = 25). At day 160 of gestation, heifers were assigned to treatments consisting of adequately fed (ADQ-CON; 100% NRC; n = 13), nutrient restricted (RES-CON; 60% NRC; n = 13), and ADQ or RES supplemented with 20 mg/d of melatonin (ADQ-MEL, n = 13; RES-MEL, n = 15). The animals were fed daily at 0900 hours until day 240 where Cesarean sections were performed in the morning (0500 hours) or afternoon (1300 hours) for placentome collections. In both seasons, we observed a temporal alteration of the core clock genes in the cotyledonary tissue in a season-dependent manner. In the fall, ARNTL, CLOCK, NR1D1, and RORA transcript abundance were decreased (P ≤ 0.05) in the afternoon compared to the morning; whereas in the summer, ARNTL, PER2, and RORA expression were increased (P ≤ 0.05) in the afternoon. Interestingly, in both seasons, there was a concomitant temporal increase (P ≤ 0.05) of cotyledonary blood vessel perfusion and caruncular melatonin receptor 1A transcript abundance. Melatonin supplementation did not alter the melatonin receptor 1A transcript abundance (P > 0.05), however, in the summer, melatonin supplementation increased cotyledonary VEGFA, CRY1, and RORA (P ≤ 0.05) transcript abundance. In addition, during the summer the placentomes from underfed dams had increased average capillary size and HIF1α transcript abundance compared to those adequately fed (P ≤ 0.05). In conclusion, these data indicate increased cotyledonary blood vessel size and blood distribution after feeding to better facilitate nutrient transport. Interestingly, the maternal nutritional plane appears to play a crucial role in regulating the bovine placental circadian clock. Based on these findings, the regulation of angiogenic factors and clock genes in the bovine placenta appears to be an underlying mechanism of the therapeutic effect of dietary melatonin supplementation in the summer.

Maternal nutrient restriction during the last trimester of pregnancy impairs the fetal development, increases morbidity and mortality, and reduces its performance in adult life. Animals with compromised pregnancies exhibit a reduction in uterine blood flow thereby limiting the nutrients available for the fetus to grow and develop. Melatonin, a hormone that many people use as a sleep aid, could be a solution as a potential therapeutic in cattle since it has antioxidant properties and has been shown to regulate blood flow and rescue fetal weight during compromised pregnancies. In the current study, we examined the changes in placental vascularity and gene expression when supplementing underfed dams with dietary melatonin during late gestation in a group of fall-calving and spring-calving heifers. Contrary to our hypothesis melatonin did not control the placental circadian clock gene network, while maternal nutrient restriction disrupted the gene expression in the placenta. Furthermore, this study found that gene expression in the placenta is seasonally dependent.

Postnatal persistence of nonhuman primate sex-dependent renal structural and molecular changes programmed by intrauterine growth restriction.

BACKGROUND: Poor nutrition during fetal development programs postnatal kidney function. Understanding postnatal consequences in nonhuman primates (NHP) is important for translation to our understanding the impact on human kidney function and disease risk. We hypothesized that intrauterine growth restriction (IUGR) in NHP persists postnatally, with potential molecular mechanisms revealed by Western-type diet challenge. METHODS: IUGR juvenile baboons were fed a 7-week Western diet, with kidney biopsies, blood, and urine collected before and after challenge. Transcriptomics and metabolomics were used to analyze biosamples. RESULTS: Pre-challenge IUGR kidney transcriptome and urine metabolome differed from controls. Post-challenge, sex and diet-specific responses in urine metabolite and renal signaling pathways were observed. Dysregulated mTOR signaling persisted postnatally in female pre-challenge. Post-challenge IUGR male response showed uncoordinated signaling suggesting proximal tubule injury. CONCLUSION: Fetal undernutrition impacts juvenile offspring kidneys at the molecular level suggesting early-onset blood pressure dysregulation.

Primary myoblasts from intrauterine growth-restricted fetal sheep exhibit intrinsic dysfunction of proliferation and differentiation that coincides with enrichment of inflammatory cytokine signaling pathways.

Intrauterine growth restriction (IUGR) is linked to lifelong reductions in muscle mass due to intrinsic functional deficits in myoblasts, but the mechanisms underlying these deficits are not known. Our objective was to determine if the deficits were associated with changes in inflammatory and adrenergic regulation of IUGR myoblasts, as was previously observed in IUGR muscle. Primary myoblasts were isolated from IUGR fetal sheep produced by hyperthermia-induced placental insufficiency (PI-IUGR; n = 9) and their controls (n = 9) and from IUGR fetal sheep produced by maternofetal inflammation (MI-IUGR; n = 6) and their controls (n = 7). Proliferation rates were less (P < 0.05) for PI-IUGR myoblasts than their controls and were not affected by incubation with IL-6, TNF-α, norepinephrine, or insulin. IκB kinase inhibition reduced (P < 0.05) proliferation of control myoblasts modestly in basal media but substantially in TNF-α-added media and reduced (P < 0.05) PI-IUGR myoblast proliferation substantially in basal and TNF-α-added media. Proliferation was greater (P < 0.05) for MI-IUGR myoblasts than their controls and was not affected by incubation with TNF-α. Insulin increased (P < 0.05) proliferation in both MI-IUGR and control myoblasts. After 72-h differentiation, fewer (P < 0.05) PI-IUGR myoblasts were myogenin+ than controls in basal and IL-6 added media but not TNF-α-added media. Fewer (P < 0.05) PI-IUGR myoblasts were desmin+ than controls in basal media only. Incubation with norepinephrine did not affect myogenin+ or desmin+ percentages, but insulin increased (P < 0.05) both markers in control and PI-IUGR myoblasts. After 96-h differentiation, fewer (P < 0.05) MI-IUGR myoblasts were myogenin+ and desmin+ than controls regardless of media, although TNF-α reduced (P < 0.05) desmin+ myoblasts for both groups. Differentiated PI-IUGR myoblasts had greater (P < 0.05) TNFR1, ULK2, and TNF-α-stimulated TLR4 gene expression, and PI-IUGR semitendinosus muscle had greater (P < 0.05) TNFR1 and IL6 gene expression, greater (P < 0.05) c-Fos protein, and less (P < 0.05) IκBα protein. Differentiated MI-IUGR myoblasts had greater (P < 0.05) TNFR1 and IL6R gene expression, tended to have greater (P = 0.07) ULK2 gene expression, and had greater (P < 0.05) ß-catenin protein and TNF-α-stimulated phosphorylation of NFκB. We conclude that these enriched components of TNF-α/TNFR1/NFκB and other inflammatory pathways in IUGR myoblasts contribute to their dysfunction and help explain impaired muscle growth in the IUGR fetus.

Myoblasts are stems cells whose functional capacity can limit muscle growth. However, stressful intrauterine conditions cause these cells to be intrinsically dysfunctional. This restricts muscle growth capacity, leading to intrauterine growth restriction (IUGR) of the fetus, low birth weight, and less muscle mass after birth. Consequently, meat yield is reduced in IUGR-born food animals and glucose homeostasis is impaired in IUGR-born humans, which contributes to metabolic dysfunction. Intrinsic dysfunction of IUGR myoblasts has been previously observed, but the fetal programming changes (i.e., permanent changes in the development of cellular mechanisms that explains different functional outcomes) have not been identified. This study shows that one mechanism is the enhancement of signaling pathways for TNF-α and other inflammatory cytokines. These cytokines have roles in stress responses and regulation of muscle growth. Programmed enhancement of these pathways means that IUGR myoblasts are more responsive to even normal amounts of circulating cytokines. Unfortunately, the primary response of myoblasts to cytokines is slower differentiation (i.e., cellular transformation necessary for muscle growth). Programmed enhancement of this response directly impedes myoblast-dependent muscle growth, and the deficit is lifelong. However, identifying this mechanism is a fundamental step for developing strategies to improve muscle growth in low birth weight offspring.

Novel intrauterine growth retardation model: effects of maternal subtotal nephrectomy on neonates.

Changes in body weight (BW), systolic blood pressure (SBP), and localization of renin in the kidneys of neonates born to normal mothers (C neonates) or to five-sixths (5/6) nephrectomized (2/3 left kidney and right kidney) mothers (Nx neonates) were studied. Maternal 5/6 nephrectomy caused weight loss in neonates but no differences in SBP or renin localization. Culling Nx neonates to a litter of 3 at 1 day after birth resulted in growth catching up with C neonates from 3 weeks old and increases in both SBP and renin-positive cells in neonatal kidney. These findings revealed that maternal 5/6 nephrectomy results in low-birth-weight neonates and that these neonates are at increased risk of metabolic syndrome by catch-up growth.

Curcumin reduces oxidative stress and fat deposition in longissimus dorsi muscle of intrauterine growth-retarded finishing pigs.

Dietary curcumin possessing multiple biological activities may be an effective way to alleviate oxidative damage and fat deposition in intrauterine growth retardation (IUGR) finishing pigs. Therefore, this study was conducted to evaluate effects of dietary curcumin on meat quality, antioxidant capacity, and fat deposition of longissimus dorsi muscle in IUGR finishing pigs. Twelve normal birth weight (NBW) and 24 IUGR female piglets at 26 days of age were divided into 3 dietary groups: NBW (basal diet), IUGR (basal diet), and IUGR + Cur (basal diet supplemented with 200 mg/kg curcumin). The trial lasted for 169 days. Results showed that IUGR increased concentrations of malondialdehyde (MDA) and protein carbonyls (PC) and fat deposition in longissimus dorsi muscle. However, curcumin decreased the intramuscular fat content and the levels of MDA and PC and improved meat quality in IUGR pigs. Furthermore, curcumin inhibited the decrease of nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression and decreased peroxisome pro liferator-activated receptors γ (PPARγ) expression in IUGR pigs. These findings suggested that dietary addition of 200 mg/kg curcumin could improve meat quality, alleviate oxidative stress through activating Nrf2 signaling pathway, and reduce fat deposition via inhibiting PPARγ expression in longissimus dorsi muscle of IUGR finishing pigs.

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

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

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

Leucine alters blood parameters and regulates hepatic protein synthesis via mammalian/mechanistic target of rapamycin activation in intrauterine growth-restricted piglets.

Neonatal piglets often suffer low birth weights and poor growth performance accompanied by the disruption of protein metabolism, when intrauterine growth restriction (IUGR) takes place during pregnancy, leading to a higher mortality and bigger economic loss than expected. Leucine has been proposed to function as a nutritional signal-regulating protein synthesis in numerous studies. The aim of this study was to determine the effect of dietary leucine supplementation on the blood parameters and hepatic protein metabolism in IUGR piglets. Weaned piglets were assigned to one of four treatments in a 2 × 2 factorial arrangement: 1) piglets fed a basal diet with normal birth weight, 2) piglets fed a basal diet plus 0.35% l-leucine with normal birth weight, 3) IUGR piglets fed a basal diet with low birth weight, and 4) IUGR piglets fed a basal diet plus 0.35% l-leucine with low birth weight. The results showed that IUGR decreased serum aspartate aminotransferase and alkaline phosphatase activities and increased serum cortisol and prostaglandin E2 levels at 35 d of age (P < 0.05), suggesting the occurrence of liver dysfunction and stress response. Leucine supplementation increased serum alkaline phosphatase activity and decreased serum cortisol levels at 35 d of age (P < 0.05). IUGR decreased the lysozyme activity and complement 3 level in serum (P < 0.05), which were prevented by dietary leucine supplementation. IUGR piglets showed increased hepatic DNA contents while showing a reduced RNA/DNA ratio (P < 0.05). Piglets supplied with leucine had decreased RNA/DNA ratio in the liver (P < 0.05). Leucine supplementation stimulated hepatic protein anabolism through upregulating protein synthesis-related genes expression and activating the phosphorylation of mammalian/mechanistic target of rapamycin (mTOR) (P < 0.05). Moreover, IUGR inhibited the mRNA expression of hepatic protein degradation-related genes, indicating a compensatory mechanism for the metabolic response. Dietary leucine supplementation attenuated the suppression of the protein catabolism induced by IUGR in the liver. These results demonstrate that dietary leucine supplementation could alter the blood parameters and alleviated the disrupted protein metabolism induced by IUGR via enhanced mTOR phosphorylation to promote protein synthesis in weaned piglets.

Intrauterine growth restriction (IUGR) produces a notable disturbance of protein metabolism in piglets, leading to lower birth weights and economic loss. Leucine supplementation positively regulates protein metabolism in animals and has the potential to recover the impaired balance between protein synthesis and degradation. Our study showed that leucine supplementation alleviated the abnormal changes in blood parameters and stimulated protein synthesis through the mammalian/mechanistic target of rapamycin signal pathway in the liver. Leucine supplementation attenuated the suppression of protein degradation induced by IUGR, which might be involved in a hepatic compensatory mechanism contributing to health status.

Intermittent maternofetal oxygenation during late gestation improved birthweight, neonatal growth, body symmetry, and muscle metabolism in intrauterine growth-restricted lambs.

In humans and animals, intrauterine growth restriction (IUGR) results from fetal programming responses to poor intrauterine conditions. Chronic fetal hypoxemia elevates circulating catecholamines, which reduces skeletal muscle ß2 adrenoceptor content and contributes to growth and metabolic pathologies in IUGR-born offspring. Our objective was to determine whether intermittent maternofetal oxygenation during late gestation would improve neonatal growth and glucose metabolism in IUGR-born lambs. Pregnant ewes were housed at 40 °C from the 40th to 95th day of gestational age (dGA) to produce IUGR-born lambs (n = 9). A second group of IUGR-born lambs received prenatal O2 supplementation via maternal O2 insufflation (100% humidified O2, 10 L/min) for 8 h/d from dGA 130 to parturition (IUGR+O2, n = 10). Control lambs (n = 15) were from pair-fed thermoneutral ewes. All lambs were weaned at birth, hand-reared, and fitted with hindlimb catheters at day 25. Glucose-stimulated insulin secretion (GSIS) and hindlimb hyperinsulinemic-euglycemic clamp (HEC) studies were performed at days 28 and 29, respectively. At day 30, lambs were euthanized and ex vivo HEC studies were performed on isolated muscle. Without maternofetal oxygenation, IUGR lambs were 40% lighter (P < 0.05) at birth and maintained slower (P < 0.05) growth rates throughout the neonatal period compared with controls. At 30 d of age, IUGR lambs had lighter (P < 0.05) hindlimbs and flexor digitorum superficialis (FDS) muscles. IUGR+O2 lambs exhibited improved (P < 0.05) birthweight, neonatal growth, hindlimb mass, and FDS mass compared with IUGR lambs. Hindlimb insulin-stimulated glucose utilization and oxidation rates were reduced (P < 0.05) in IUGR but not IUGR+O2 lambs. Ex vivo glucose oxidation rates were less (P < 0.05) in muscle from IUGR but not IUGR+O2 lambs. Surprisingly, ß2 adrenoceptor content and insulin responsiveness were reduced (P < 0.05) in muscle from IUGR and IUGR+O2 lambs compared with controls. In addition, GSIS was reduced (P < 0.05) in IUGR lambs and only modestly improved (P < 0.05) in IUGR+O2. Insufflation of O2 also increased (P < 0.05) acidosis and hypercapnia in dams, perhaps due to the use of 100% O2 rather than a gas mixture with a lesser O2 percentage. Nevertheless, these findings show that intermittent maternofetal oxygenation during late gestation improved postnatal growth and metabolic outcomes in IUGR lambs without improving muscle ß2 adrenoceptor content.

Review: Improving the performance of neonatal piglets.

Newborn piglets have a high incidence of preweaning mortality that is not only associated with low birth weights but also with the presence of intra-uterine growth-restricted (IUGR) piglets. Such IUGR piglets are commonly seen in litters from hyperprolific sows as a result of insufficient placental transfer of nutrients. Nutritional strategies can be used prior to and during gestation to enhance foetal development and can also be implemented in the transition period to reduce the duration of farrowing and increase colostrum yield. Recent findings showed that the energy status of sows at the onset of farrowing is crucial to diminish stillbirth rate. Newborn piglets often fail to consume enough colostrum to promote thermostability and subsequent growth, and this is particularly problematic in very large litters when there are fewer available teats than the number of suckling piglets. One injection of 75 IU of oxytocin approximately 14 h after farrowing can prolong the colostral phase, hence increasing the supply of immunoglobulins to piglets. Nevertheless, assistance must be provided to piglets after birth in order to increase their chance of survival. Various approaches can be used, such as: (1) optimising the farrowing environment, (2) supervising farrowing and assisting newborn piglets, (3) using cross-fostering techniques, (4) providing nurse sows, and 5) providing artificial milk. Although research advances have been made in developing feeding and management strategies for sows that increase performance of their newborn piglets, much work still remains to be done to ensure that maximal outcomes are achieved.