Differential changes in maternal proinflammatory IL6 plasmalevels as a putatively surrogate marker of candidacy andclinical utility during mid- and late pregnancy hyperglycemia:interventional impact of clinical pharmacist on maternal andneonatal outcomes in a randomized clinical trial

Main Article Content

Abla Albsoul
Nailya Bulatova https://orcid.org/0000-0001-6754-0325
Violet KASABRI https://orcid.org/0000-0003-1927-0193
Reem AlQuoqa
Nahla Khawaja https://orcid.org/0000-0001-8718-8568
Dana HYASSAT https://orcid.org/0000-0002-5368-3293
Mousa Abujbara https://orcid.org/0000-0001-5836-5000
Asma Basha https://orcid.org/0000-0002-1384-8487
Mohammad EL- KHATEEB https://orcid.org/0000-0002-5201-2287


clinical pharmacist intervention, gestational diabetes cardio-metabolic risk-based and related pharmacotherapy, interleukin 6, insulin, leptin/ adiponectin ratio, monocyte chemoattractant protein 1, macrophage migration inhibitory factor, oxytocin, thrombospondin 1


Background/methods: The impact of clinical pharmacist on undiagnosed pregnancy hyperglycemia (PHG) in mid- and late- pregnancy as a major preventable cause of maternal and neonatal (M/N) complications is investigated. This longitudinal randomized controlled study of changes in plasma levels of predictive/prognostic/diagnostic biomarkers of oxytocin, thrombospondin, MCP1, IL6, MIF, insulin and LAR and undesirable M/N pregnancy outcomes in women with/out PHG (pregnancy normoglycemia; PNG) following the implementation of clinical pharmacist interventions were investigated. Results: A total of 68 PHG (36 intervention vs. 32 non-intervention) vs. 21 PNG participants were enrolled at 20–28 weeks and followed up till delivery. BMI of intervention PHG (unlike non-intervention) was greater (p=0.036) compared to PNG’s. LAR and insulin, oxytocin, thrombospondin1, adiponectin and MCP1 plasma levels and their differences between 2nd and 3rd pregnancy trimesters lacked discrepancies in participants. Both PHG groups in mid pregnancy had substantially greater HbA1c %, FPG and IL6 levels vs. PNG, while PHG non-intervention’ leptin was greater than PNG’s. In late pregnancy, greater SBP, IL6 and MIF levels between either PHG groups vs. PNG’s were observed. Unlike PHG non-intervention and PNG; IL6 level in PHG intervention group decreased (-2.54±6.61; vs. non-intervention PHG’s 4.26±5.28; p<0.001 and vs. PNG’s 2.30±4.27; p=0.023). None of the assessed M/N outcomes was found of differential significance between any of the three study groups. Conclusions: Proinflammatory IL6 as a robust and generalizable cardiometabolic risk-based and related pharmacotherapy biomarker in mid and late hyperglycemic pregnancy with likely implications of novel therapeutic targets was delineated by clinical pharmacist interventions.

Abstract 207 | PDF Downloads 224


1. Capula C, Chiefari E, Vero A, et al. Prevalence and predictors of postpartum glucose intolerance in Italian women with gestational diabetes mellitus. Diabetes Research & Clinical Practice. 2014; 105(2):223-230. https://doi.org/10.1016/j.diabres.2014.05.008
2. Freebairn L, Atkinson J, Qin Y, et al. Diabetes in Pregnancy Modelling Consortium. ‘Turning the tide’ on hyperglycemia in pregnancy: insights from multiscale dynamic simulation modeling. BMJ Open Diabetes Research Care. 2020; 8:e000975. https://doi.org/10.1136/bmjdrc-2019-000975
3. Masood, SN, Baqai S, et al. GDM Guidelines Committee, Society of Obstetricians & Gynaecologists of Pakistan. Guidelines for Management of Hyperglycemia in Pregnancy (HIP) by Society of Obstetricians & Gynaecologists of Pakistan (SOGP)#. Journal of Diabetology. 2021; 12(1): 83-98. https://doi.org/10.4103/ jod.jod_88_20
4. Law KP, Zhang H. The pathogenesis and pathophysiology of gestational diabetes mellitus: Deductions from a three-part longitudinal metabolomics study in China. Clinica Chimica Acta. 2017; 468:60-70. https://doi.org/10.1016/ j.cca.2017.02.008
5. Amudha P, Nithya D, Pradeeba S, et al. Correlation between first trimester uric acid level and subsequent development of gestational diabetes mellitus. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2017; 6(2):606-610. https://doi.org/10.18203/2320-1770.ijrcog20170391
6. Bao W, Baecker A, Song Y, et al. Adipokine levels during the first or early second trimester of pregnancy and subsequent risk of gestational diabetes mellitus: A systematic review. Metabolism. 2015; 64(6):756-64. https://doi.org/10.1016/j. metabol.2015.01.013
7. Mousa A, Abell SK, Shorakae S, et al. Relationship between vitamin D and gestational diabetes in overweight or obese pregnant women may be mediated by adiponectin. Molecular Nutrition & Food Research. 2017; 61(11): 1700488. https://doi. org/10.1002/ mnfr.201700488
8. Badillo-Suárez PA, Rodríguez-Cruz M, Nieves-Morales X. Impact of Metabolic Hormones Secreted in Human Breast Milk on Nutritional Programming in Childhood Obesity. Journal of Mammary Gland Biology and Neoplasia. 2017; 22(3):171-191. https://doi.org/10.1007/s10911-017-9382-y
9. Morisset AS, Dubé MC, Côté JA, et al. Circulating interleukin-6 concentrations during and after gestational diabetes mellitus. Acta Obstetricia et Gynecologica Scandinavica. 2011; 90(5):524-530. https://doi.org/10.1111/j.1600-0412.2011.01094.x
10. Nergiz S, Altınkaya ÖS, Küçük M, et al. Circulating galanin and IL-6 concentrations in gestational diabetes mellitus. Gynecological Endocrinology. 2014; 30(3):236-40. https://doi.org/10.3109/09513590.2013.871519
11. Mac-Marcjanek K, Zieleniak A, Woźniak L, et al. Comparison of leukocyte IL6 expression in patients with gestational diabetes mellitus (GDM) diagnosed by the Polish Diabetes Association (PDA) 2011 and 2014 criteria. Endokrynologia Polska. 2017; 68(3):317-325. https://doi.org/10.5603/EP.a2017.0014
12. Yilmaz Ö, Küçük M, Kebapçilar L, et al. Macrophage migration-inhibitory factor is elevated in pregnant women with gestational diabetes mellitus. Gynecological Endocrinology. 2012; 28(1):76-9. https://doi:10.3109/ 09513590. 2011.588757
13. Telejko B, Kuzmicki M, Zonenberg A, et al. Circulating monocyte chemoattractant protein-1 in women with gestational diabetes. Folia Histochemica et Cytobiologica. 2007; 45 Suppl 1:S153-6. PMID: 18292825
14. Lewandowski K, Nadel I, Lewinski A, et al. Positive correlation between serum omentin and thrombospondin-1 in gestational diabetes despite lack of correlation with insulin resistance indices. Ginekologia Polska. 2010; 81(12):907-12. PMID: 21391440
15. Farias DR, Poston L, Franco-Sena AB, et al. Maternal lipids and leptin concentrations are associated with large-for-gestationalage births: a prospective cohort study. Scientific Reports. 2017; 7(1):804. https://doi.org/10.1038/s41598-017-00941-y
16. Wang Q, Würtz 1, Auro K, et al. Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence. BMC Medicine. 2016; 14(1):205. https://doi.org/10.1186/s12916-016-0733-0
17. Tarnowski M, Wieczorek A, Dziedziejko V, et al. IL16 and IL18 gene polymorphisms in women with gestational diabetes. Ginekologia Polska. 2017; 88(5):249-254. https://doi.org/10.5603/GP.a2017.0047
18. Vejrazkova D, Lischkova O, Vankova M, et al. Distinct response of fat and gastrointestinal tissue to glucose in gestational diabetes mellitus and polycystic ovary syndrome. Physiology Research. 2017; 66(2):283-292. https://doi.org/10.33549/ physiolres.933366
19. Zhang Y, Zhang HH, Lu JH, et al. Changes in serum adipocyte fatty acid-binding protein in women with gestational diabetes mellitus and normal pregnant women during mid- and late pregnancy. Journal of Diabetes Investigation. 2016; 7(5):797-804. https://doi.org/10.1111/jdi.12484
20. Kerem L, Lawson EA. The Effects of Oxytocin on Appetite Regulation, Food Intake and Metabolism in Humans. International Journal of Molecular Sciences. 2021; 22(14):7737. https://doi.org/10.3390/ijms22147737
21. Gojnic M, Pervulov M, Petkovic S, et al. Acceleration of fetal maturation by oxytocin-produced uterine contraction in pregnancies complicated with gestational diabetes mellitus: a preliminary report. Journal of Maternal-Fetal & Neonatal Medicine. 2004; 16(2):111-4. https://doi.org/10.1080/14767050400005715
22. (a)Tsingotjidou AS. Oxytocin: A Multi-Functional Biomolecule with Potential Actions in Dysfunctional Conditions; from Animal Studies and beyond. Biomolecules. 2022; 12:1603. https://doi.org/10.3390 /biom12111603 (b). Barengolts E. Oxytocin - an emerging treatment for obesity and dysglycemia: review of randomized controlled trials and cohort studies. Endocrine Practice. 2016; 22(7):885-94. https://doi.org/10.4158/ EP151192.RA
23. Naserallah R, Kasabri V, Naffa R, et al. The Levels of Oxytocin and Oxyntomodulin, Adiposity and Blood Indices in
Pharmacotherapy Naive Diabetic and Non-Diabetic Patients with Metabolic Syndrome. Jordan Journal of Pharmaceutical
Sciences. 2018;11(3):105-117
24. Jankowski M, Broderick TL, Gutkowska J. Oxytocin and cardioprotection in diabetes and obesity. BMC Endocrine Disorders.
2016; 16:34. https://doi.org/10.1186/s12902-016-0110-1
25. Lorenzo-Almorós A, Hang T, Peiró C, et al. Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases. Cardiovascular Diabetology. 2019; 18:140. https://doi.org/10.1186/ s12933-019-0935- 9
26. Yuan J, Zhang R, Wu R, et al. The effects of oxytocin to rectify metabolic dysfunction in obese mice are associated with increased thermogenesis. Molecular & Cellular Endocrinology. 2020; 514:110903. https://doi.org/10.1016/ j.mce.2020.110903
27. (a) Huvinen E, Lahti J, Klemetti MM, et al. Genetic risk of type 2 diabetes modifies the effects of a lifestyle intervention aimed at the prevention of gestational and postpartum diabetes. Diabetologia. 2022; 65(8):1291-1301. https://doi.org/10.1007/ s00125-022-05712-7 (b) Moon JH, Kwak SH, Jang HC. Prevention of type 2 diabetes mellitus in women with previous gestational diabetes mellitus. Korean Journal of Internal Medicine. 2017; 32(1):26-41. https://doi.org/10.3904/kjim.2016.203 (c)Vladu IM, Clenciu D, Mitrea A, et al. Maternal and Fetal Metabolites in Gestational Diabetes Mellitus: A Narrative Review. Metabolites. 2022; 12(5):383. https://doi.org/10.3390/metabo12050383
28. Farrar D. Hyperglycemia in pregnancy: prevalence, impact, and management challenges. International Journal of Women Health. 2016; 8:519-527. https://doi.org/10.2147/IJWH.S102117
29. Bianco ME, Josefson JL. Hyperglycemia during Pregnancy and Long-Term Offspring Outcomes. Current Diabetes Reports. 2019; 19(12):143. https://doi.org/10.1007/s11892-019-1267-6
30. (a).Guo Y, Han Z, Guo L, et al. Identification of urinary biomarkers for the prediction of gestational diabetes mellitus in early second trimester of young gravidae based on iTRAQ quantitative proteomics. Endocrine Journal. 2018; 65(7):727-735. https:// doi.org/10.1507/ endocrj.EJ17-0471 (b). Liu X, Wang X, Sun H, et al. Urinary metabolic variation analysis during pregnancy and application in gestational diabetes mellitus and spontaneous abortion biomarker discovery. Scientific Reports. 2019; 9:2605. doi.org/10.1038/s41598-019- 39259-2 (c.) Gutaj P, Matysiak J, Matuszewska E, et al. Maternal serum proteomic profiles of pregnant women with type 1 diabetes. Scientific Reports. 2022; 12:8696. doi.org/10.1038/s41598-022-12221-5 (d). Wang X, Zhao M, Guo Z, et al. Urinary proteomic analysis during pregnancy and its potential application in early prediction of gestational diabetes mellitus and spontaneous abortion. Annals of Translational Medicine. 2022; 10(13):736. https://doi. org/10.21037/atm-21-3497 (e). Zhang M, Yang H. Perspectives from metabolomics in the early diagnosis and prognosis of gestational diabetes mellitus. Frontiers in Endocrinology (Lausanne). 2022; 13:967191. https://doi.org/10.3389/fendo.2022.967191 (f). Xie J, Li L, Xing H. Metabolomics in gestational diabetes mellitus: A review. Clinica Chimica Acta. 2023; 539:134-143. https:// doi.org/10.1016/j.cca.2022.12.005
31. (a).Liu X, Sun J, Wen X, et al. Proteome profiling of gestational diabetes mellitus at 16-18 weeks revealed by LC-MS/MS. Journal of Clinical Laboratory Analysis. 2020; 34(9):e23424. https://doi.org/10.1002/jcla.23424 (b). Lu L, Li C, Deng J, et al. Maternal serum NGAL in the first trimester of pregnancy is a potential biomarker for the prediction of gestational diabetes mellitus. Frontiers in Endocrinology. 2022; 13:977254. https://doi.org/10.3389/ fendo.2022.977254
32. (a). Alesi S, Ghelani D, Rassie K, et al. Metabolomic Biomarkers in Gestational Diabetes Mellitus: A Review of the Evidence. International Journal of Molecular Sciences. 2021; 22(11):5512. https://doi.org/10.3390/ijms22115512 (b). Zhu Y, Barupal DK, Ngo AL, et al. Predictive Metabolomic Markers in Early to Mid-pregnancy for Gestational Diabetes Mellitus: A Prospective Test and Validation Study. Diabetes. 2022; 71(8):1807-1817. https://doi.org/10.2337/db21-1093 (c). Khan RS, Malik H. Diagnostic Biomarkers for Gestational Diabetes Mellitus Using Spectroscopy Techniques: A Systematic Review. Diseases. 2023; 11(1):16. https://doi.org/10.3390/diseases11010016
33. Sakurai K, Eguchi A, Watanabe M, et al. Exploration of predictive metabolic factors for gestational diabetes mellitus in Japanese women using metabolomic analysis. Journal of Diabetes Investigation. 2019; 10(2):513-520. https://doi.org/10.1111 /jdi.12887 (b) Diboun I, Ramanjaneya M, Majeed Y, et al. Metabolic profiling of pre-gestational and gestational diabetes mellitus identifies novel predictors of pre-term delivery. Journal of Translational Medicine. 2020; 18:366. https://doi.org/10.1186/s12967-020- 02531-5 (c) Meng X, Zhu B, Liu Y, et al. Unique Biomarker Characteristics in Gestational Diabetes Mellitus Identified by LC-MS-Based Metabolic Profiling. Journal of Diabetes Research. 2021; Article ID 6689414, 15 pages. https://doi.org/ 10.1155/2021/6689414 (d) Heath H, Luevano J, Johnson CM, et al. Predictive Gestational Diabetes Biomarkers with Sustained Alterations throughout Pregnancy. Journal of Endocrine Society. 2022; 6(12):bvac134. https://doi.org/10.1210/jendso/bvac134
34. Palomo M, Youssef L, Ramos A, et al. Differences and similarities in endothelial and angiogenic profiles of preeclampsia and COVID-19 in pregnancy. American Journal of Obstetrics and Gynecology. 2022; 227(2):277.e1-277.e16. https://doi.org/10.1016/j.ajog.2022.03.048
35. Vakhtangadze T, Gakhokidze N, Khutsishvili M, et al. The link between hypertension and preeclampsia/eclampsia-life-long cardiovascular risk for women. Vessel Plus. 2019; 3:19. https://doi.org/10.1016/j.preghy.2015.04.001
36. (a). Kivelä J, Sormunen-Harju H, Girchenko PV, et al. Longitudinal Metabolic Profiling of Maternal Obesity, Gestational Diabetes, and Hypertensive Pregnancy Disorders. Journal of Clinical Endocrinology and Metabolism. 2021; 106 (11): e4372–e4388. https://doi.org/10.1210/clinem/dgab475 (b). Agarwal NR, Kachhawa G, Oyeyemi BF, et al. Metabolic profiling of serum and urine in preeclampsia and gestational diabetes in early pregnancy. Medicine in Drug Discovery. 2022; 16: 100143. https://doi.org/10.1016/j.medidd.2022.100143
37. Lee SM, Kang Y, Lee EM, et al. Metabolomic biomarkers in mid trimester maternal plasma can accurately predict the development of preeclampsia. Scientific Reports. 2020; 10:16142. https://doi.org/10.1038/s41598-020-72852-4
38. (a).Cho GJ, Jung US, Sim JY, et al. Is preeclampsia itself a risk factor for the development of metabolic syndrome after delivery? Obstetrics & Gynecology Science. 2019; 62(4):233-241. https://doi.org/10.5468/ogs.2019.62.4.233 (b).Alonso-Ventura V, Pérez-López FR. Preeclampsia negatively affects future maternal metabolic and endocrine outcomes. Gynecological Endocrinology. 2021; 37:9, 773-774. https://doi.org/10.1080/09513590.2021.1948996
39. Ishaku SM, Karima T, Oboirien KA, et al. Metabolic syndrome following hypertensive disorders in pregnancy in a low-resource setting: A cohort study. Pregnancy Hypertension. 2021; 25:129-135. https://doi.org/10.1016/ j.preghy. 2021.05.018
40. Sylvester KG, Hao S, Li Z, et al. Gestational Dating by Urine Metabolic Profile at High Resolution Weekly Sampling Time points: Discovery and Validation. Frontiers in Molecular Medicine. 2022; 2:844280. https://doi.org/10.3389/fmmed.2022.844280
41. Batta RA, Kasabri V, Akour A, et al. Impact of clinical pharmacists’ intervention on management of hyperglycemia in pregnancy in Jordan. International Journal of Clinical Pharmacy. 2018; 40:48–55. https://doi.org/10.1007/s11096-017-0550-3
42. Ji C, Sun LJ, Li LT, et al. Impact of clinical pharmacist intervention on blood glucose control and perinatal outcomes in gestational diabetes mellitus through a diabetes management system. Clinical and Experimental Obstetrics & Gynecology. 2020; 47(5):645–652. https://doi.org/ 10.31083/ j.ceog.2020. 05.2212
43. Wang R, Yang Q, Sun T, et al. Physical Exercise is associated with Glycemic Control among Women with Gestational Diabetes Mellitus: Findings from a Prospective Cohort in Shanghai, China. Diabetes, Metabolic Syndrome and Obesity. 2021; 14:1949- 1961. https://doi.org/10.2147/DMSO.S308287
44. Wen L, Ge H, Qiao J, et al. Maternal dietary patterns and risk of gestational diabetes mellitus in twin pregnancies: a longitudinal twin pregnancies birth cohort study. Nutrition Journal. 2020; 19(1):13. https://doi.org/10.1186/s12937-020-00529-9
45. Stenina-Adognravi O, Plow EF. Thrombospondin-4 in tissue remodeling. Matrix Biology. 2019; 75-76:300-313. https://doi. org/10.1016/j.matbio.2017.11.006
46. Farberov S, Basavaraja R, Meidan R. Thrombospondin-1 at the crossroads of corpus luteum fate decisions. Reproduction. 2019; 157(3):R73-R83. https://doi.org/10.1530/REP-18-0530
47. Mavreli D, Evangelinakis N, Papantoniou N, et al. Quantitative Comparative Proteomics Reveals Candidate Biomarkers for the Early Prediction of Gestational Diabetes Mellitus: A Preliminary Study. In Vivo. 2020; 34(2):517-525. https://doi.org/10.21873/ invivo.11803 (b) Liu X, Sun J, Wen X, et al. Proteome profiling of gestational diabetes mellitus at 16-18 weeks revealed by LC-MS/MS. Journal of Clinical Laboratory Analysis. 2020; 34(9):e23424. https://doi.org/10.1002/jcla.23424
48. Viklund F, Hallingström M, Kacerovsky M, et al. Protein Concentrations of Thrombospondin-1, MIP-1β, and S100A8 Suggest the Reflection of a Pregnancy Clock in Mid-Trimester Amniotic Fluid. Reproductive Sciences. 2020; 27: 2146–2157. https://doi. org/ 10.1007/ s43032-020-00229-z
49. Ulu İ, Çekmez Y, Yıldırım Köpük Ş, et al. Maternal serum thrombospondin-1 is significantly altered in cases with established preeclampsia. Journal of Maternal-Fetal & Neonatal Medicine. 2019; 32(15):2543-2546. https://doi.org/10.1080/14767 058.2018.1441279
50. Marc C, Achille A, Frégeau G, et al. Abstract 004: Pro-angiogenic Effects of the Thrombospondin-1 Inhibitor Lskl in Preeclampsia Models. Hypertension. 2022; 79:A004. https://doi.org/10.1161/ hyp.79.suppl_1.004
51. Nakamura DS, Edwards AK, Ahn SH, et al. Compatibility of a Novel Thrombospondin-1 Analog with Fertility and Pregnancy in a Xenograft Mouse Model of Endometriosis. PLoS ONE. 2015; 10(3): e0121545. https://doi.org/ 10.1371/ journal.pone.0121545
52. Klein K, Satler M, Elhenicky M, et al. Circulating levels of MCP-1 are increased in women with gestational diabetes. Prenatal Diagnosis. 2008; 28(9):845-51. https://doi.org/10.1002/pd.2064
53. Corrêa-Silva S, Alencar AP, Moreli JB, et al. Hyperglycemia induces inflammatory mediators in the human chorionic villous. Cytokine. 2018; 111: 41-48. https://doi.org/10.1016/j.cyto.2018.07.02057 (b) Olmos-Ortiz A, Flores-Espinosa P, Díaz L, et al. Immunoendocrine Dysregulation during Gestational Diabetes Mellitus: The Central Role of the Placenta. International Journal of Molecular Sciences. 2021; 22(15):8087. https://doi.org/10.3390/ ijms22158087
54. Basu J, Datta C, Chowdhury S, et al. Gestational Diabetes Mellitus in a Tertiary Care Hospital of Kolkata, India: Prevalence, Pathogenesis and Potential Disease Biomarkers. Experimental and Clinical Endocrinology & Diabetes. 2020; 128(4):216-223. https://doi.org/10.1055/a-0794-6057
55. Gu P, Lin Y, Wan Q, et al. Oxytocin signal contributes to the adaptative growth of islets during gestation. Endocrine Connections.2021; 10(7):694-706. https://doi.org/10.1530/EC-21-0043
56. Liu J, Liang Y, Jiang X, et al. Maternal Diabetes-Induced Suppression of Oxytocin Receptor Contributes to Social Deficits in Offspring. Frontiers in Neuroscience. 2021;15:634781-95. https://doi.org/10.3389/fnins.2021.634781
57. Ko HJ, Hong SY, Bae JY. Pregnancy and neonatal outcomes of hyperglycemia caused by atosiban administration during pregnancy. Clinical and Experimental Obstetrics & Gynecology. 2021; 48(2):257–262. https://doi.org/10.31083/ j.ceog.2021.02.2364
58. Scerbo MJ, Gerdes JM. Bonding With β-Cells—A Role for Oxytocin in Glucose Handling. Diabetes. 2017; 66 (2): 256–257. https://doi.org/10.2337/dbi16-0053
59. Stocks S, Bremme K, Uvas-Moberg K. Is Oxytocin Involved in the Deterioration of Glucose Tolerance in Gestational Diabetes? Gynecologic and Obstetric Investigation. 1993; 36:81–86. https://doi.org/10.1159/000292601
60. McElwain CJ, McCarthy FP, McCarthy CM. Gestational Diabetes Mellitus and Maternal Immune Dysregulation: What We Know So Far. International Journal of Molecular Sciences. 2021; 22(8):4261. https://doi.org/10.3390/ijms22084261
61. Li C, Qiao B, Qi W, et al. Association of Macrophage Migration Inhibitory Factor Polymorphisms with Gestational Diabetes Mellitus in Han Chinese Women. Gynecologic and Obstetric Investigation. 2016; 81(1):84-9. https://doi.org/10.1159/ 000398796
62. Aslani S, Hossein-nezhad A, Maghbooli Z, et al. Genetic variation in macrophage migration inhibitory factor associated with gestational diabetes mellitus and metabolic syndrome. Hormone and Metabolic Research. 2011; 43: 557-561. https://doi. org/10.1055/s-0031-1275706
63. Radaelli T, Lepercq J, Varastehpour A, et al. Differential regulation of genes for fetoplacental lipid pathways in pregnancy with gestational and type 1 diabetes mellitus. American Journal of Obstetrics and Gynecology. 2009; 201(2):209.e1-209.e10. https://doi.org/10.1016/j.ajog.2009.04.019 (b) Zheng L, Li C, Qi WH, et al. Expression of macrophage migration inhibitory factor gene in placenta tissue and its correlation with gestational diabetes mellitus. Zhonghua Yi Xue Za Zhi. 2017; 97(43):3388-3391.https://doi.org/10.3760/cma.j.is sn.0376-2491.2017.43.006
64. (a)Napso T, Zhao X, Lligoña MI, et al. Placental secretome characterization identifies candidates for pregnancy complications. Communications Biology. 2021; 4:701. https://doi.org/10.1038/s42003-021-02214-x (b). Wei W, He Y, Wang X, et al. Gestational Diabetes Mellitus: The Genetic Susceptibility behind the Disease. Hormone & Metabolism Research. 2021; 53(8):489-498. https://doi.org/10.1055/a-1546-1652
65. Raczkowska BA, Mojsak P, Rojo D, et al. Gas Chromatography-mass spectroscopy-based metabolomics analysis reveals potential biochemical markers for diagnosis of gestational diabetes mellitus. Frontiers in Pharmacology. 2021; 12:770240. https://doi. org/10.3389/ fphar.2021.770240 (b). Sovio U, Clayton GL, Cook E, et al. Metabolomic Identification of a novel, externally validated predictive test for gestational diabetes mellitus. Journal of Clinical & Endocrinology Metabolism. 2022; 107(8): e3479–e3486. https://doi.org/10.1210/ clinem/dgac240
66. Wirestam L, Pihl S, Wetterö J, et al. Plasma C-Reactive protein and pentraxin-3 reference intervals during normal pregnancy. Frontiers in Immunology. 2021; 12:722118. https://doi.org/10.3389/fimmu.2021.722118
67. Hofer OJ, Alsweiler J, Tran T, et al. Glycemic control in gestational diabetes and impact on biomarkers in women and infants. Pediatric Research. 2023; 1-11. https://doi.org/10.1038/s41390-022-02459-0
68. Jack-Roberts C, Maples P, Kalkan B, et al. Gestational diabetes status and dietary intake modify maternal and cord blood allostatic load markers. BMJ Open Diabetes Research & Care. 2020; 8(1):e001468. https://doi.org/10.1136/ bmjdrc-2020-001468
69. Quotah OF, Poston L, Flynn AC, et al. Metabolic Profiling of Pregnant Women with Obesity: An Exploratory Study in Women at Greater Risk of Gestational Diabetes. Metabolites. 2022; 12(10):922. https://doi.org/10.3390/metabo12100922
70. Peltokorpi A, Irina L, Liisa V, et al. Preconceptual leptin levels in gestational diabetes and hypertensive pregnancy. Hypertension in Pregnancy. 2022; 41(1):70-77. https://doi.org/10.1080/10641955.2022.2033763
71. Florian AR, Cruciat G, Pop RM, et al. Predictive role of altered leptin, adiponectin and 3‑carboxy‑4‑methyl‑5‑propyl‑2‑furanpropanoic acid secretion in gestational diabetes mellitus. Experimental and Therapeutic Medicine. 2021; 21: 520. https://doi.org/10.3892/ etm.2021.9951
72. Saucedo R, Valencia J, Moreno-González LE, et al. Maternal serum adipokines and inflammatory markers at late gestation and newborn weight in mothers with and without gestational diabetes mellitus. Ginekologia Polska. 2021; 93(2):126–133. https:// doi.org/10.5603/GP.a2021.0083
73. Gázquez A, Rodríguez F, Sánchez-Campillo M, et al. Adiponectin agonist treatment in diabetic pregnant rats. Journal of Endocrinology. 2021; 251(1):1-13. https://doi.org/10.1530/JOE-20-0617 (b). Moyce Gruber BL, Dolinsky VW. The Role of Adiponectin during Pregnancy and Gestational Diabetes. Life. 2023; 13(2):301. https://doi.org/10.3390/ life13020301
74. (a)Dimosiari A, Patoulias D, Kitas GD, et al. Do Interleukin-1 and Interleukin-6 Antagonists Hold Any Place in the Treatment of Atherosclerotic Cardiovascular Disease and Related Co-Morbidities? An Overview of Available Clinical Evidence. Journal of Clinical Medicine. 2023; 12(4):1302. https://doi.org/10.3390/jcm12041302 (b).Kang S, Tanaka T, Inoue H, et al. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelialcells in cytokine release syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2020; 117(36):22351-22356. https://doi.org/10.1073/ pnas.2010229117 (c). Koshino A, Schechter M, Sen T, et al. Interleukin-6 and cardiovascular and kidney outcomes in patients with type 2 diabetes: new insights from CANVAS. Diabetes Care. 2022; 45 (11): 2644–2652. https://doi.org/10.2337/dc22-0866 (d). Kostina, D A, Pokrovskaya TG, et al. Interleukin-6 is a potential target for a correction of endothelial dysfunction associated with low-grade systemic inflammation. Research Results in Pharmacology & Clinical Pharmacy. 2017; 3(3):89-96. https://doi. org /10.18413/2313-8971-2017-3-3-89-96 (e).Ridker PM, Rane M. Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease. Circulation Research. 2021; 128(11):1728-1746. https://doi.org/10.1161/CIRCRESAHA 121.319077 (f). Su JH, Luo MY, Liang N, et al. Interleukin-6: A Novel Target for Cardio-Cerebrovascular Diseases. Frontiers in Pharmacology. 2021; 12: 745061. https://doi.org/10.3389/fphar.2021.745061 (g). Denga TM, Gunter S, Fourie S, et al. Interleukin-6 blockers improve inflammation-induced lipid metabolism impairments but induce liver fibrosis in collagen-induced arthritis. Endocrine Metabolic Immune Disorders-Drug Targets. 2023; 23(4):548- 557. https://doi.org/10.2174/ 1871530323666221017153157
75. (a).Amirian A, Mahani MB, Abdi F. Role of interleukin-6 (IL-6) in predicting gestational diabetes mellitus. Obstetrics & Gynecology Science. 2020; 63(4):407-416. https://doi.org/10.5468/ogs.20020 (b). Spence T, Allsopp PJ, Yeates AJ, et al. Maternal Serum Cytokine Concentrations in Healthy Pregnancy and Preeclampsia. Journal of Pregnancy. 2021; 2021:6649608. https://doi.org/10.1155/ 2021/ 6649608 (c) Vilotić A, Nacka-Aleksić M, Pirković A, et al. IL-6 and IL-8: An Overview of Their Roles in Healthy and Pathological Pregnancies. International Journal of Molecular Sciences. 2022; 23(23):14574. https://doi.org/10.3390/ijms232314574 (d). Bogdanet D, Reddin C, Murphy D, et al. Emerging protein biomarkers for the diagnosis or prediction of gestational diabetes-a scoping review. Journal of Clinical Medicine. 2021; 10(7):1533. https://doi.org/10.3390/jcm10071533 (e). Xiang LL, Chen C, Wang QY, et al. Impact of inflammatory factors, hemoglobin A1c, and platelet parameters in gestational diabetes mellitus. Archives of Gynecology & Obstetrics. 2023; 307(2):439-446. https://doi.org/10.1007/s00404-022-06528-x (f). Omazić J, Viljetić B, Ivić V, et al. Early markers of gestational diabetes mellitus: what we know and which way forward? Biochemical Medicine (Zagreb). 2021; 31(3):030502. https://doi.org/10.11613/ BM.2021.030502
76. Braga FO, Negrato CA, Matta MFBD, et al. Relationship between inflammatory markers, glycated hemoglobin and placental weight on fetal outcomes in women with gestational diabetes. Archives in Endocrinology & Metabolism. 2019; 63(1):22-29. https://doi.org/10.20945/2359-3997000000099
77. Ciampa E, Li Y, Dillon S, et al. Cerebrospinal Fluid Protein Changes in Preeclampsia. Hypertension. 2018; 72(1):219-226. https:// doi.org/10.1161/ HYPERTENSION AHA.118.11153
78. Madhu SV. Prediction of gestational diabetes mellitus: are we ready for a biomarker lead screening strategy for GDM? International Journal of Diabetes in Developing Countries. 2022; 42:573–575. https://doi.org/10.1007/ s13410-022-01146-4 (b). Karami M, Mousavi SH, Rafiee M, et al. Biochemical and molecular biomarkers: unraveling their role in gestational diabetes mellitus. Diabetology & Metabolic Syndrome. 2023; 15(5):5. https://doi.org/10.1186/s13098-023-00980-8 (c). Zou. J, Liu. Y, Shen. J, et al. The role of 25(OH)D3 and circRNAs in early diagnosis of gestational diabetes mellitus. Journal of Clinical Laboratory Analysis. 2023; 37:e24826. https://doi.org/10.1002/jcla.24826 (d). Khan RS, Malik H. Diagnostic Biomarkers for Gestational Diabetes Mellitus Using Spectroscopy Techniques: A Systematic Review. Diseases. 2023; 11(1):16. https://doi.org/10.3390/diseases1101001

Most read articles by the same author(s)