Pregnancy Metabolic Adaptation and Changes in Placental Metabolism in Preeclampsia

Yaxi Li; Ling Ma; Ruifen He; Fei Teng; Xue Qin; Xiaolei Liang; Jing Wang

doi:10.1055/a-2403-4855

Geburtshilfe und Frauenheilkunde, Table of Contents

CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2024; 84(11): 1033-1042
DOI: 10.1055/a-2403-4855

GebFra Science

Review

Pregnancy Metabolic Adaptation and Changes in Placental Metabolism in Preeclampsia

Metabolische Anpassung in der Schwangerschaft und Stoffwechseländerungen der Plazenta bei Präeklampsie

Authors

Yaxi Li

¹The First Clinical Medical College of Lanzhou University, Lanzhou, China
Ling Ma

¹The First Clinical Medical College of Lanzhou University, Lanzhou, China
Ruifen He

¹The First Clinical Medical College of Lanzhou University, Lanzhou, China
Fei Teng

¹The First Clinical Medical College of Lanzhou University, Lanzhou, China
Xue Qin

¹The First Clinical Medical College of Lanzhou University, Lanzhou, China
Xiaolei Liang

²Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Key Laboratory for Gynecologic Oncology Gansu Province, Lanzhou, China
Jing Wang

³The First Clinical Medical College of Lanzhou University, the First Hospital of Lanzhou University, Lanzhou City, Gansu Province, China

Abstract

Pregnancy is a unique physiological state in which the maternal body undergoes a series of changes in the metabolism of glucose, lipids, amino acids, and other nutrients in order to adapt to the altered state of pregnancy and provide adequate nutrients for the fetus’ growth and development. The metabolism of various nutrients is regulated by one another in order to maintain homeostasis in the body. Failure to adapt to the altered physiological conditions of pregnancy can lead to a range of pregnancy issues, including fetal growth limitation and preeclampsia. A failure of metabolic adaptation during pregnancy is linked to the emergence of preeclampsia. The treatment of preeclampsia by focusing on metabolic changes may provide new therapeutic alternatives.

Zusammenfassung

Die Schwangerschaft ist ein einzigartiger physiologischer Zustand, in dem der Körper der Mutter verschiedene Veränderungen des Glukose-, Fett-, und Aminosäurestoffwechsels durchmacht, um sich an den veränderten Zustand der Schwangerschaft anzupassen und ausreichende Nährstoffe für das Wachstum und die Entwicklung des Fetus zur Verfügung zu stellen. Die Stoffwechselvorgänge der verschiedenen Nährstoffe regulieren sich gegenseitig, um die Homöostase im Körper aufrechtzuerhalten. Unterbleibt diese Anpassung an die veränderten physiologischen Bedingungen der Schwangerschaft, kann dies zu verschiedenen Problemen in der Schwangerschaft führen, beispielsweise eine fetale Wachstumsrestriktion oder Präeklampsie. Störungen der metabolischen Anpassung während der Schwangerschaft werden mit der Entstehung von Präeklampsie in Verbindung gebracht. Neue Ansätze zur Behandlung der Präeklampsie, bei denen das Augenmerk auf metabolische Veränderungen gerichtet wird, könnten neue therapeutische Alternativen bieten.

Keywords

pregnancy - metabolic adaptation - preeclampsia - placenta - glucose - lipids - amino acids

Schlüsselwörter

Schwangerschaft - metabolische Anpassung - Präeklampsie - Plazenta - Glukose - Lipide - Aminosäuren

Full Text

References

References
1 Wang Y, Li B, Zhao Y. Inflammation in Preeclampsia: Genetic Biomarkers, Mechanisms, and Therapeutic Strategies. Front Immunol 2022; 13: 883404
2 Gumusoglu S, Scroggins S, Vignato J. et al. The Serotonin-Immune Axis in Preeclampsia. Curr Hypertens Rep 2021; 23: 37
3 Amylidi-Mohr S, Kubias J, Neumann S. et al. Reducing the Risk of Preterm Preeclampsia: Comparison of Two First Trimester Screening and Treatment Strategies in a Single Centre in Switzerland. Geburtshilfe Frauenheilkd 2021; 81: 1354-1361
4 Hart NR. Paradoxes: Cholesterol and Hypoxia in Preeclampsia. Biomolecules 2024; 14
5 Middleton P, Gomersall JC, Gould JF. et al. Omega-3 fatty acid addition during pregnancy. Cochrane Database Syst Rev 2018; (11) CD003402
6 Tain YL, Hsu CN. The Impact of Nutrient Intake and Metabolic Wastes during Pregnancy on Offspring Hypertension: Challenges and Future Opportunities. Metabolites 2023; 13: 418
7 Hu M, Li J, Baker PN. et al. Revisiting preeclampsia: a metabolic disorder of the placenta. FEBS J 2022; 289: 336-354
8 Amylidi-Mohr S, Kubias J, Neumann S. et al. Reducing the Risk of Preterm Preeclampsia: Comparison of Two First Trimester Screening and Treatment Strategies in a Single Centre in Switzerland. Geburtshilfe Frauenheilkd 2021; 81: 1354-1361
9 Dimitriadis E, Rolnik DL, Zhou W. et al. Pre-eclampsia. Nat Rev Dis Primers 2023; 9: 8
10 Burton GJ, Jauniaux E. The cytotrophoblastic shell and complications of pregnancy. Placenta 2017; 60: 134-139
11 Redman CW, Sargent IL, Staff AC. IFPA Senior Award Lecture: making sense of pre-eclampsia – two placental causes of preeclampsia?. Placenta 2014; 35: S20-S25
12 Broekhuizen M, de Vries R, Smits MAW. et al. Pentoxifylline as a therapeutic option for pre-eclampsia: a study on its placental effects. Br J Pharmacol 2022; 179: 5074-5088
13 Marlatt KL, Redman LM, Beyl RA. et al. Racial differences in body composition and cardiometabolic risk during the menopause transition: a prospective, observational cohort study. Am J Obstet Gynecol 2020; 222: 365.e1-365.e18
14 Pankiewicz K, Fijałkowska A, Issat T. et al. Insight into the Key Points of Preeclampsia Pathophysiology: Uterine Artery Remodeling and the Role of MicroRNAs. Int J Mol Sci 2021; 22: 3132
15 Gu W, Jones CT, Harding JE. Metabolism of glucose by fetus and placenta of sheep. The effects of normal fluctuations in uterine blood flow. J Dev Physiol 1987; 9: 369-389
16 Inuyama M, Ushigome F, Emoto A. et al. Characteristics of L-lactic acid transport in basal membrane vesicles of human placental syncytiotrophoblast. Am J Physiol Cell Physiol 2002; 283: C822-C830
17 Yin H, Li J, Tian J. et al. Uterine pyruvate metabolic disorder induced by silica nanoparticles act through the pentose phosphate pathway. J Hazard Mater 2021; 412: 125234
18 Yi-jie G, Shu-zhe D. Anti-oxidation of Pyruvate. Chinese Journal of Tissue Engineering Research 2006; 10: 141-143
19 Liu Y, Peng W, Qi H-B. [Glucose Metabolism-Derived Nicotinamide Adenine Dinucleotide Phosphate in Late-Onset Preeclampsia Placenta Tissue and Its Correlation with Oxidative Stress]. Sichuan Da Xue Xue Bao Yi Xue Ban 2022; 53: 1028-1032
20 Aye ILMH, Aiken CE, Charnock-Jones DS. et al. Placental energy metabolism in health and disease-significance of development and implications for preeclampsia. Am J Obstet Gynecol 2022; 226: S928-S944
21 Hodgman C, Khan GH, Atiomo W. Coenzyme A Restriction as a Factor Underlying Pre-Eclampsia with Polycystic Ovary Syndrome as a Risk Factor. Int J Mol Sci 2022; 23: 2785
22 Bloxam DL, Bullen BE, Walters BN. et al. Placental glycolysis and energy metabolism in preeclampsia. Am J Obstet Gynecol 1987; 157: 97-101
23 Xu P, Zheng Y, Liao J. et al. AMPK regulates homeostasis of invasion and viability in trophoblasts by redirecting glucose metabolism: Implications for pre-eclampsia. Cell Prolif 2023; 56: e13358
24 Lüscher BP, Marini C, Joerger-Messerli MS. et al. Placental glucose transporter (GLUT)-1 is down-regulated in preeclampsia. Placenta 2017; 55: 94-99
25 Ganguly A, Collis L, Devaskar SU. Placental glucose and amino acid transport in calorie-restricted wild-type and Glut3 null heterozygous mice. Endocrinology 2012; 153: 3995-4007
26 Yang Y, Jin H, Qiu Y. et al. Reactive Oxygen Species are Essential for Placental Angiogenesis During Early Gestation. Oxid Med Cell Longev 2022; 2022: 4290922
27 Liao T, Xu X, Ye X. et al. DJ-1 upregulates the Nrf2/GPX4 signal pathway to inhibit trophoblast ferroptosis in the pathogenesis of preeclampsia. Sci Rep 2022; 12: 2934
28 Goutami L, Jena SR, Swain A. et al. Pathological Role of Reactive Oxygen Species on Female Reproduction. Adv Exp Med Biol 2022; 1391: 201-220
29 Long J, Huang Y, Tang Z. et al. Mitochondria Targeted Antioxidant Significantly Alleviates Preeclampsia Caused by 11β-HSD2 Dysfunction via OPA1 and MtDNA Maintenance. Antioxidants (Basel) 2022; 11: 1505
30 Holland OJ, Cuffe JSM, Dekker Nitert M. et al. Placental mitochondrial adaptations in preeclampsia associated with progression to term delivery. Cell Death Dis 2018; 9: 1150
31 Nakagawa T, Lanaspa MA, Millan IS. et al. Fructose contributes to the Warburg effect for cancer growth. Cancer Metab 2020; 8: 16
32 Lanaspa MA, Ishimoto T, Cicerchi C. et al. Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. J Am Soc Nephrol 2014; 25: 2526-2538
33 Bazer FW, Seo H, Wu G. et al. Interferon tau: Influences on growth and development of the conceptus. Theriogenology 2020; 150: 75-83
34 Seval MM, Karabulut HG, Tükün A. et al. Cell free fetal DNA in the plasma of pregnant women with preeclampsia. Clin Exp Obstet Gynecol 2015; 42: 787-791
35 de Jong CL, Paarlberg KM, van Geijn HP. et al. Decreased first trimester uric acid production in future preeclamptic patients. J Perinat Med 1997; 25: 347-352
36 Nakagawa T, Ana A-H, Kosugi T. et al. Fructose might be a clue to the origin of preeclampsia insights from nature and evolution. Hypertens Res 2023; 46: 646-653
37 Ting L, Tao D. Maternal lipid metabolism and fetal growth. Chinese Journal of Practical Gynecology and Obstetrics 2018; 34: 963-966
38 Szczuko M, Kikut J, Komorniak N. et al. The Role of Arachidonic and Linoleic Acid Derivatives in Pathological Pregnancies and the Human Reproduction Process. Int J Mol Sci 2020; 21: 9628
39 Wojcik-Baszko D, Charkiewicz K, Laudanski P. Role of dyslipidemia in preeclampsia-A review of lipidomic analysis of blood, placenta, syncytiotrophoblast microvesicles and umbilical cord artery from women with preeclampsia. Prostaglandins Other Lipid Mediat 2018; 139: 19-23
40 Fügedi G, Molnár M, Rigó J. et al. Increased placental expression of cannabinoid receptor 1 in preeclampsia: an observational study. BMC Pregnancy Childbirth 2014; 14: 395
41 Maccarrone M, Bisogno T, Valensise H. et al. Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer. Mol Hum Reprod 2002; 8: 188-195
42 Liu N, Guo Y-N, Wang X-J. et al. Copy Number Analyses Identified a Novel Gene: APOBEC3A Related to Lipid Metabolism in the Pathogenesis of Preeclampsia. Front Cardiovasc Med 2022; 9: 841249
43 Zeljković A, Ardalić D, Vekić J. et al. Effects of Gestational Diabetes Mellitus on Cholesterol Metabolism in Women with High-Risk Pregnancies: Possible Implications for Neonatal Outcome. Metabolites 2022; 12: 959
44 Wolski H, Ożarowski M, Kurzawińska G. et al. Expression of ABCA1 Transporter and LXRA/LXRB Receptors in Placenta of Women with Late Onset Preeclampsia. J Clin Med 2022; 11: 4809
45 Baumann M, Körner M, Huang X. et al. Placental ABCA1 and ABCG1 expression in gestational disease: Pre-eclampsia affects ABCA1 levels in syncytiotrophoblasts. Placenta 2013; 34: 1079-1086
46 Berger N, van der Wel T, Hirschmugl B. et al. Inhibition of diacylglycerol lipase β modulates lipid and endocannabinoid levels in the ex vivo human placenta. Front Endocrinol (Lausanne) 2023; 14: 1092024
47 Yoon M. PPARα in Obesity: Sex Difference and Estrogen Involvement. PPAR Res 2010; 2010: 584296
48 Ramaswamy G, Karim MA, Murti KG. et al. PPARalpha controls the intracellular coenzyme A concentration via regulation of PANK1alpha gene expression. J Lipid Res 2004; 45: 17-31
49 Cleal JK, Lewis RM. The mechanisms and regulation of placental amino acid transport to the human foetus. J Neuroendocrinol 2008; 20: 419-426
50 Sugden MC, Caton PW, Holness MJ. PPAR control: it’s SIRTainly as easy as PGC. J Endocrinol 2010; 204: 93-104
51 Blanchard P-G, Festuccia WT, Houde VP. et al. Major involvement of mTOR in the PPARγ-induced stimulation of adipose tissue lipid uptake and fat accretion. J Lipid Res 2012; 53: 1117-1125
52 Nie C, He T, Zhang W. et al. Branched Chain Amino Acids: Beyond Nutrition Metabolism. Int J Mol Sci 2018; 19: 954
53 Kawano Y, Ersoy BA, Li Y. et al. Thioesterase Superfamily Member 2 (Them2) and Phosphatidylcholine Transfer Protein (PC-TP) Interact To Promote Fatty Acid Oxidation and Control Glucose Utilization. Mol Cell Biol 2014; 34: 2396-2408
54 Basak S, Duttaroy AK. Effects of fatty acids on angiogenic activity in the placental extravillious trophoblast cells. Prostaglandins Leukot Essent Fatty Acids 2013; 88: 155-162
55 Nema J, Randhir K, Wadhwani N. et al. Maternal vitamin D deficiency reduces docosahexaenoic acid, placental growth factor and peroxisome proliferator activated receptor gamma levels in the pup brain in a rat model of preeclampsia. Prostaglandins Leukot Essent Fatty Acids 2021; 175: 102364
56 Godhamgaonkar AA, Wadhwani NS, Joshi SR. Exploring the role of LC-PUFA metabolism in pregnancy complications. Prostaglandins Leukot Essent Fatty Acids 2020; 163: 102203
57 Godhamgaonkar AA, Wadhwani NS, Joshi SR. Exploring the role of LC-PUFA metabolism in pregnancy complications. Prostaglandins Leukot Essent Fatty Acids 2020; 163: 102203
58 Recinella L, Orlando G, Ferrante C. et al. Adipokines: New Potential Therapeutic Target for Obesity and Metabolic, Rheumatic, and Cardiovascular Diseases. Front Physiol 2020; 11: 578966
59 Tan L, Ouyang Z, Chen Z. et al. Adipokine chemerin overexpression in trophoblasts leads to dyslipidemia in pregnant mice: implications for preeclampsia. Lipids Health Dis 2023; 22: 12
60 Tan SK, Mahmud I, Fontanesi F. et al. Obesity-Dependent Adipokine Chemerin Suppresses Fatty Acid Oxidation to Confer Ferroptosis Resistance. Cancer Discov 2021; 11: 2072-2093
61 Zhu L, Huang J, Wang Y. et al. Chemerin causes lipid metabolic imbalance and induces passive lipid accumulation in human hepatoma cell line via the receptor GPR1. Life Sci 2021; 278: 119530
62 Yu M, Yang Y, Huang C. et al. Chemerin: A Functional Adipokine in Reproductive Health and Diseases. Biomedicines 2022; 10: 1910
63 Carlino C, Trotta E, Stabile H. et al. Chemerin regulates NK cell accumulation and endothelial cell morphogenesis in the decidua during early pregnancy. J Clin Endocrinol Metab 2012; 97: 3603-3612
64 Tan L, Chen Z, Sun F. et al. Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms. Clin Sci (Lond) 2022; 136: 257-272
65 Klemetti MM, Alahari S, Post M. et al. Distinct Changes in Placental Ceramide Metabolism Characterize Type 1 and 2 Diabetic Pregnancies with Fetal Macrosomia or Preeclampsia. Biomedicines 2023; 11: 932
66 Melland-Smith M, Ermini L, Chauvin S. et al. Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia. Autophagy 2015; 11: 653-669
67 Ying L, Tippetts TS, Chaurasia B. Ceramide dependent lipotoxicity in metabolic diseases. NHA 2019; 5: 1-12
68 Wang J, Dong X, Wu H-Y. et al. Relationship of Placental and Serum Lipoprotein-Associated Phospholipase A2 Levels with Hypertensive Disorders of Pregnancy. Int J Womens Health 2022; 14: 797-804
69 Phillips RJ, Fortier MA, López Bernal A. Prostaglandin pathway gene expression in human placenta, amnion and choriodecidua is differentially affected by preterm and term labour and by uterine inflammation. BMC Pregnancy Childbirth 2014; 14: 241
70 Maia J, Fonseca BM, Teixeira N. et al. The fundamental role of the endocannabinoid system in endometrium and placenta: implications in pathophysiological aspects of uterine and pregnancy disorders. Hum Reprod Update 2020; 26: 586-602
71 Bisogno T, Howell F, Williams G. et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 2003; 163: 463-468
72 Basak S, Mallick R, Banerjee A. et al. Maternal Supply of Both Arachidonic and Docosahexaenoic Acids Is Required for Optimal Neurodevelopment. Nutrients 2021; 13: 2061
73 Herrera E. Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine 2002; 19: 43-55
74 Faichney GJ, White GA. Effects of maternal nutritional status on fetal and placental growth and on fetal urea synthesis in sheep. Aust J Biol Sci 1987; 40: 365-377
75 Jahan-Mihan A, Luhovyy BL, El Khoury D. et al. Dietary proteins as determinants of metabolic and physiologic functions of the gastrointestinal tract. Nutrients 2011; 3: 574-603
76 Wang X, Luo W, Tan D. et al. Positive regulation of placentation by L-amino acid transporter-1 (lat1) in pregnant mice. Int J Clin Exp Pathol 2017; 10: 9551-9558
77 Felig P, Kim YJ, Lynch V. et al. Amino acid metabolism during starvation in human pregnancy. J Clin Invest 1972; 51: 1195-1202
78 Dasgupta S, Subramani E, Mitra I. et al. Discovery of novel metabolic signatures for early identification of women at risk of developing gestational hypertension. Metabolomics 2023; 19: 50
79 Pappa KI, Vlachos G, Theodora M. et al. Intermediate metabolism in association with the amino acid profile during the third trimester of normal pregnancy and diet-controlled gestational diabetes. Am J Obstet Gynecol 2007; 196: 65.e1-65.e5
80 Kadife E, Harper A, De Alwis N. et al. SLC38A4 Amino Acid Transporter Expression Is Significantly Lower in Early Preterm Intrauterine Growth Restriction Complicated Placentas. Int J Mol Sci 2022; 24: 403
81 Hermann A, Sitdikova G. Homocysteine: Biochemistry, Molecular Biology and Role in Disease. Biomolecules 2021; 11: 737
82 Memon SI, Acharya NS. The Association Between Serum Homocysteine Levels and Placenta-Mediated Complications: A Narrative Review. Cureus 2022; 14: e31305
83 Nandi AA, Wadhwani NS, Joshi SR. Altered metabolic homeostasis between vitamin D and long chain polyunsaturated fatty acids in preeclampsia. Med Hypotheses 2017; 100: 31-36
84 Acilmis YG, Dikensoy E, Kutlar AI. et al. Homocysteine, folic acid and vitamin B12 levels in maternal and umbilical cord plasma and homocysteine levels in placenta in pregnant women with pre-eclampsia. J Obstet Gynaecol Res 2011; 37: 45-50
85 Di Simone N, Maggiano N, Caliandro D. et al. Homocysteine induces trophoblast cell death with apoptotic features. Biol Reprod 2003; 69: 1129-1134
86 Broekhuizen M, Klein T, Hitzerd E. et al. l-Tryptophan-Induced Vasodilation Is Enhanced in Preeclampsia: Studies on Its Uptake and Metabolism in the Human Placenta. Hypertension 2020; 76: 184-194
87 Keaton SA, Heilman P, Bryleva EY. et al. Altered Tryptophan Catabolism in Placentas From Women With Pre-eclampsia. Int J Tryptophan Res 2019; 12: 1178646919840321
88 van Zundert SK, Broekhuizen M, Smit AJ. et al. The Role of the Kynurenine Pathway in the (Patho) physiology of Maternal Pregnancy and Fetal Outcomes: A Systematic Review. Int J Tryptophan Res 2022; 15
89 Herr N, Bode C, Duerschmied D. The Effects of Serotonin in Immune Cells. Front Cardiovasc Med 2017; 4: 48
90 Hadden C, Fahmi T, Cooper A. et al. Serotonin transporter protects the placental cells against apoptosis in caspase 3-independent pathway. J Cell Physiol 2017; 232: 3520-3529
91 Menichini D, Feliciello L, Neri I. et al. L-Arginine supplementation in pregnancy: a systematic review of maternal and fetal outcomes. J Matern Fetal Neona 2023; 36: 2217465
92 Tong S, Kaitu’u-Lino TJ, Hastie R. et al. Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia. Am J Obstet Gynecol 2022; 226: S1157-S1170
93 Vadillo-Ortega F, Perichart-Perera O, Espino S. et al. Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population: randomised controlled trial. BMJ 2011; 342: d2901
94 Gong S, Sovio U, Aye IL. et al. Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia. JCI Insight 2018; 3: e120723
95 Tuytten R, Syngelaki A, Thomas G. et al. First-trimester preterm preeclampsia prediction with metabolite biomarkers: differential prediction according to maternal body mass index. Am J Obstet Gynecol 2023; 229: 55.e1-55.e10
96 Wang W, Wu Z, Dai Z. et al. Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids 2013; 45: 463-477
97 Geddie G, Moores R, Meschia G. et al. Comparison of leucine, serine and glycine transport across the ovine placenta. Placenta 1996; 17: 619-627
98 Lewis RM, Godfrey KM, Jackson AA. et al. Low serine hydroxymethyltransferase activity in the human placenta has important implications for fetal glycine supply. J Clin Endocrinol Metab 2005; 90: 1594-1598
99 Rasmussen BF, Ennis MA, Dyer RA. et al. Glycine, a Dispensable Amino Acid, Is Conditionally Indispensable in Late Stages of Human Pregnancy. J Nutr 2021; 151: 361-369
100 Friesen RW, Novak EM, Hasman D. et al. Relationship of dimethylglycine, choline, and betaine with oxoproline in plasma of pregnant women and their newborn infants. J Nutr 2007; 137: 2641-2646
101 Bradford HF, Young AM, Crowder JM. Continuous glutamate leakage from brain cells is balanced by compensatory high-affinity reuptake transport. Neurosci Lett 1987; 81: 296-302
102 Payne M, Stephens T, Lim K. et al. Lysine Requirements of Healthy Pregnant Women are Higher During Late Stages of Gestation Compared to Early Gestation. J Nutr 2018; 148: 94-99
103 Elango R, Ball RO. Protein and Amino Acid Requirements during Pregnancy. Adv Nutr 2016; 7: 839S-844S
104 Levesque CL, Moehn S, Pencharz PB. et al. The threonine requirement of sows increases in late gestation. J Anim Sci 2011; 89: 93-102
105 Shrestha N, Melvin SD, McKeating DR. et al. Sex-Specific Differences in Lysine, 3-Hydroxybutyric Acid and Acetic Acid in Offspring Exposed to Maternal and Postnatal High Linoleic Acid Diet, Independent of Diet. Int J Mol Sci 2021; 22: 10223
106 Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation. J Nutr 2006; 136: 207S-211S
107 Feng Y, Lian X, Guo K. et al. A comprehensive analysis of metabolomics and transcriptomics to reveal major metabolic pathways and potential biomarkers of human preeclampsia placenta. Front Genet 2022; 13: 1010657
108 Deepa R, Mandal S, Van Schayck OCP. et al. Vitamin B6 Levels and Impaired Folate Status but Not Vitamin B12 Associated with Low Birth Weight: Results from the MAASTHI Birth Cohort in South India. Nutrients 2023; 15
109 Bjørke-Monsen A-L, Varsi K, Ulvik A. et al. A Vegetarian Diet Significantly Changes Plasma Kynurenine Concentrations. Biomolecules 2023; 13: 391
110 Ueland PM, Ulvik A, Rios-Avila L. et al. Direct and Functional Biomarkers of Vitamin B6 Status. Annu Rev Nutr 2015; 35: 33-70
111 Tanaka M, Itoh H. Hypertension as a Metabolic Disorder and the Novel Role of the Gut. Curr Hypertens Rep 2019; 21: 63
112 Kniss DA, Shubert PJ, Zimmerman PD. et al. Insulinlike growth factors. Their regulation of glucose and amino acid transport in placental trophoblasts isolated from first-trimester chorionic villi. J Reprod Med 1994; 39: 249-256
113 Vaughan OR, Fowden AL. Placental metabolism: substrate requirements and the response to stress. Reprod Domest Anim 2016; 51 (Suppl. 2) 25-35
114 Kinshella MW, Omar S, Scherbinsky K. et al. Effects of Maternal Nutritional Supplements and Dietary Interventions on Placental Complications: An Umbrella Review, Meta-Analysis and Evidence Map. Nutrients 2021; 13: 472
115 Weckman AM, McDonald CR, Baxter JB. et al. Perspective: L-arginine and L-citrulline Supplementation in Pregnancy: A Potential Strategy to Improve Birth Outcomes in Low-Resource Settings. Adv Nutr 2019; 10: 765-777
116 da Silva Lopes K, Ota E, Shakya P. et al. Effects of nutrition interventions during pregnancy on low birth weight: an overview of systematic reviews. BMJ Glob Health 2017; 2: e000389
117 Rahimi R, Nikfar S, Rezaie A. et al. A meta-analysis on the efficacy and safety of combined vitamin C and E supplementation in preeclamptic women. Hypertens Pregnancy 2009; 28: 417-434
118 Villar J, Purwar M, Merialdi M. et al. World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations of low nutritional status from developing countries. BJOG 2009; 116: 780-788