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Low Vitamin D is Associated With Infections and Proinflammatory Cytokines During Pregnancy

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Abstract

Vitamin D is known to regulate innate and adaptive immune processes at the cellular level, but the role of vitamin D status on associated inflammatory processes across pregnancy is unclear. Our primary objective was to evaluate the relationships between serum biomarkers of inflammation (interleukin [IL]-6, IL-10, tumor necrosis factor [TNF]-α), acute-phase proteins (C-reactive protein and hepcidin) and vitamin D status, 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D), measured across pregnancy and in the neonate at birth. A second objective was to identify associations between vitamin D status and clinically diagnosed infections. In this study, 158 racially and ethnically diverse pregnant adolescents were recruited from the Rochester Adolescent Maternity Program (RAMP) in Rochester, NY. Serum 1,25(OH)2D was significantly lower in adolescents and neonates with IL-6 concentrations above the 75th percentile at delivery (P =.04) and at birth (P =.004), respectively. After adjusting for other potential covariates of inflammation, maternal serum 1,25(OH)2D was significantly positively associated with TNF-α during pregnancy (P =.02), but at delivery 1,25(OH)2D and TNF-α were inversely associated with one another (P =.02). Teens with 25(OH)D concentrations <30 ng/mL were more likely to test positive for candida (P =.002) and bacterial vaginosis (P =.02) during pregnancy. African Americans exhibited significantly lower TNF-α concentrations at both mid-gestation (P =.009) and delivery (P =.001) compared to the Caucasian adolescents. These results suggest that lower maternal vitamin D status may increase risk of infection across gestation.

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References

  1. Saito S. Cytokine cross-talk between mother and the embryo/placenta. JReprod Immunol. 2001;52(1-2): 15–33.

    CAS  Google Scholar 

  2. Romero R, Erez O, Espinoza J. Intrauterine infection, preterm labor, and cytokines. J Soc Gynecol Investig. 2005;12(7): 463–465.

    PubMed  Google Scholar 

  3. Romero R, Brody DT, Oyarzun E, et al. Infection and labor. III. Interleukin-1: A signal for the onset of parturition. Am J Obstet Gynecol. 1989;160(5 pt 1): 1117–1123.

    CAS  PubMed  Google Scholar 

  4. Santhanam U, Avila C, Romero R, et al. Cytokines in normal and abnormal parturition: Elevated amniotic fluid interleukin-6 levels in women with premature rupture of membranes associated with intrauterine infection. Cytokine. 1991;3(2): 155–163.

    CAS  PubMed  Google Scholar 

  5. Romero R, Gomez R, Ghezzi F, et al. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol. 1998;179(1): 186–193.

    CAS  PubMed  Google Scholar 

  6. Majello B, Arcone R, Toniatti C, Ciliberto G. Constitutive and IL-6-induced nuclear factors that interact with the human C-reactive protein promoter. EMBO J. 1990;9(2): 457–465.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9): 1271–1276.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Saraiva M, O’Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol. 2010;10(3): 170–181.

    CAS  PubMed  Google Scholar 

  9. Curry AE, Vogel I, Skogstrand K, et al. Maternal plasma cytokines in early- and mid-gestation of normal human pregnancy and their association with maternal factors. J Reprod Immunol. 2008;77(2): 152–160.

    CAS  PubMed  Google Scholar 

  10. Logan CA, Thiel L, Bornemann R, et al. Delivery mode, duration of labor, and cord blood adiponectin, leptin, and C-reactive protein: Results of the population-based Ulm birth cohort studies. PLoSOne. 2016;11(2): e0149918.

    Google Scholar 

  11. Rehu M, Punnonen K, Ostland V, et al. Maternal serum hepcidin is low at term and independent of cord blood iron status. Eur J Haematol. 2010;85(4): 345–352.

    CAS  PubMed  Google Scholar 

  12. Lee S, Guillet R, Cooper EM, et al. Prevalence of anemia and associations between neonatal iron status, hepcidin, and maternal iron status among neonates born to pregnant adolescents. Pediatr Res. 2016;79(1-1): 42–48.

    CAS  PubMed  Google Scholar 

  13. Hewison M. Vitamin D and immune function: an overview. Proc NutrSoc. 2012;71(1): 50–61.

    CAS  Google Scholar 

  14. Rigby WF, Denome S, Fanger MW. Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA. J Clin Invest. 1987;79(6): 1659–1664.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O’Garra A. 1alpha, 25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol. 2001;167(9): 4974–4980.

    CAS  PubMed  Google Scholar 

  16. Noyola-Martinez N, Diaz L, Avila E, Halhali A, Larrea F, Barrera D. Calcitriol downregulates TNF-alpha and IL-6 expression in cultured placental cells from preeclamptic women. Cytokine. 2013;61(1): 245–250.

    CAS  PubMed  Google Scholar 

  17. Barrera D, Noyola-Martinez N, Avila E, Halhali A, Larrea F, Diaz L. Calcitriol inhibits interleukin-10 expression in cultured human trophoblasts under normal and inflammatory conditions. Cytokine. 2012;57(3): 316–321.

    CAS  PubMed  Google Scholar 

  18. Young BE, McNanley TJ, Cooper EM, et al. Vitamin D insufficiency is prevalent and vitamin D is inversely associated with parathyroid hormone and calcitriol in pregnant adolescents. J Bone Miner Res. 2012;27(1): 177–186.

    CAS  PubMed  Google Scholar 

  19. Institute of Medicine. Weight Gain During Pregnancy: Reexamining the Guidelines. Washington, DC: The National Academies Press; 2009.

    Google Scholar 

  20. Akoh CC, Pressman EK, Cooper E, Queenan RA, Pillittere J, O’Brien KO. Prevalence and risk factors for infections in a pregnant adolescent population. J Pediatr Adolesc Gynecol. 2017;30(1): 71–75.

    PubMed  Google Scholar 

  21. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7): 1911–1930.

    CAS  PubMed  Google Scholar 

  22. Lee S, Guillet R, Cooper EM, et al. Maternal inflammation at delivery affects assessment of maternal iron status. J Nutr. 2014;144(10): 1524–1532.

    CAS  PubMed  Google Scholar 

  23. Martin JA, Hamilton BE, Osterman MJ, Curtin SC, Matthews TJ. Births: Final data for 2012. Natl Vital StatRep. 2013;62(9): 1–68.

    Google Scholar 

  24. Davis LM, Chang SC, Mancini J, Nathanson MS, Witter FR, O’Brien KO. Vitamin D insufficiency is prevalent among pregnant African American adolescents. J Pediatr Adolesc Gynecol. 2010;23(1): 45–52.

    PubMed  Google Scholar 

  25. Ruiz RJ, Jallo N, Murphey C, Marti CN, Godbold E, Pickler RH. Second trimester maternal plasma levels of cytokines IL-1Ra, Il—6 and IL-10 and preterm birth. J Perinatol. 2012;32(7): 483–490.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Van Dyke AL, Cote ML, Wenzlaff AS, Land S, Schwartz AG. Cytokine SNPs: Comparison of allele frequencies by race and implications for future studies. Cytokine. 2009;46(2): 236–244.

    PubMed  PubMed Central  Google Scholar 

  27. Menon R, Velez DR, Morgan N, Lombardi SJ, Fortunato SJ, Williams SM. Genetic regulation of amniotic fluid TNF-alpha and soluble TNF receptor concentrations affected by race and preterm birth. Hum Genet. 2008;124(3): 243–253.

    CAS  PubMed  Google Scholar 

  28. Menon R, Thorsen P, Vogel I, Jacobsson B, Williams SM, Fortunato SJ. Increased bioavailability of TNF-alpha in African Americans during in vitro infection: Predisposing evidence for immune imbalance. Placenta. 2007;28(8-9): 946–950.

    CAS  PubMed  Google Scholar 

  29. Cao C, Pressman EK, Cooper EM, Guillet R, Westerman M, O’Brien KO. Placental heme receptor LRP1 correlates with the heme exporter FLVCR1 and neonatal iron status. Reproduction. 2014;148(3): 295–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Roytblat L, Rachinsky M, Fisher A, et al. Raised interleukin-6 levels in obese patients. Obes Res. 2000;8(9): 673–675.

    CAS  PubMed  Google Scholar 

  31. Sanders TR, Kim DW, Glendining KA, Jasoni CL. Maternal obesity and IL-6 lead to aberrant developmental gene expression and deregulated neurite growth in the fetal arcuate nucleus. Endocrinology. 2014;155(7): 2566–2577.

    PubMed  Google Scholar 

  32. Nieto-Vazquez I, Femtindez-Veledo S, Kramer DK, Vila-Bedmar R, Garcia-Guerra L, Lorenzo M. Insulin resistance associated to obesity: The link TNF-alpha. Arch Physiol Biochem. 2008;114(3): 183–194.

    CAS  PubMed  Google Scholar 

  33. Miyazaki Y, Pipek R, Mandarino LJ, DeFronzo RA. Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients. Int J Obes Relat Metab Disord. 2003;27(1): 88–94.

    CAS  PubMed  Google Scholar 

  34. Bodnar LM, Krohn MA, Simhan HN. Maternal vitamin D deficiency is associated with bacterial vaginosis in the first trimester of pregnancy. J Nutr. 2009;139(6): 1157–1161.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lim JH, Ravikumar S, Wang YM, et al. Bimodal influence of vitamin d in host response to systemic candida infection-vitamin d dose matters. J Infect Dis. 2015;212(4): 635–644.

    CAS  PubMed  Google Scholar 

  36. Noyola-Martinez N, Diaz L, Zaga-Clavellina V, et al. Regulation of CYP27B1 and CYP24A1 gene expression by recombinant proinflammatory cytokines in cultured human trophoblasts. J Steroid Biochem Mol Biol. 2014;144 Pt A: 106–109.

    CAS  PubMed  Google Scholar 

  37. Diaz L, Noyola-Martinez N, Barrera D, et al. Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts. J Reprod Immunol. 2009;81(1): 17–24.

    CAS  PubMed  Google Scholar 

  38. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: Double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011;26(10): 2341–2357.

    CAS  PubMed  Google Scholar 

  39. Zerofsky MS, Jacoby BN, Pedersen TL, Stephensen CB. Daily cholecalciferol supplementation during pregnancy alters markers of regulatory immunity, inflammation, and clinical outcomes in a randomized controlled trial. J Nutr. 2016;146(11): 2388–2397.

    CAS  PubMed  Google Scholar 

  40. Aaltonen R, Heikkinen T, Hakala K, Laine K, Alanen A. Transfer of proinflammatory cytokines across term placenta. Obstet Gynecol. 2005;106(4): 802–807.

    CAS  PubMed  Google Scholar 

  41. Zaretsky MV, Alexander JM, Byrd W, Bawdon RE. Transfer of inflammatory cytokines across the placenta. Obstet Gynecol. 2004;103(3): 546–550.

    CAS  PubMed  Google Scholar 

  42. Dahlgren J, Samuelsson AM, Jansson T, Holmang A. Interleukin-6 in the maternal circulation reaches the rat fetus in mid-gestation. PediatrRes. 2006;60(2): 147–151.

    CAS  Google Scholar 

  43. Much DH, Yeh SY. Prevalence of Chlamydia trachomatis infection in pregnant patients. Public Health Rep. 1991;106(5): 490–493.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Pal S, de la Maza LM. Mechanism of T-cell mediated protection in newborn mice against a Chlamydia infection. Microbes Infect. 2013;15(8-9): 607–614.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Yu S, Cheng X, Fang H, et al. 25 OHD analogues and vacuum blood collection tubes dramatically affect the accuracy of automated immunoassays. Sci Rep. 2015;5: 14636.

    CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Kimberly O. O’Brien PhD.

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Akoh, C.C., Pressman, E.K., Cooper, E. et al. Low Vitamin D is Associated With Infections and Proinflammatory Cytokines During Pregnancy. Reprod. Sci. 25, 414–423 (2018). https://doi.org/10.1177/1933719117715124

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