Correlation of fetal heart rate dynamics to inflammatory markers and brain-derived neurotrophic factor during pregnancy
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Luis Mercado
Abstract
Objectives
This study aims to show the relation between biomarkers in maternal and cord-blood samples and fetal heart rate variability (fHRV) metrics through a non-invasive fetal magnetocardiography (fMCG) technique.
Methods
Twenty-three women were enrolled for collection of maternal serum and fMCG tracings immediately prior to their scheduled cesarean delivery. The umbilical cord blood was collected for measurement of biomarker levels. The fMCG metrics were then correlated to the biomarker levels from the maternal serum and cord blood.
Results
Brain-derived neurotrophic factor (BDNF) had a moderate correlation with fetal parasympathetic activity (0.416) and fetal sympathovagal ratios (−0.309; −0.356). Interleukin (IL)-6 also had moderate-sized correlations but with an inverse relationship as compared to BDNF. These correlations were primarily in cord-blood samples and not in the maternal blood.
Conclusions
In this small sample-sized exploratory study, we observed a moderate correlation between fHRV and cord-blood BDNF and IL-6 immediately preceding scheduled cesarean delivery at term. These findings need to be validated in a larger population.
Funding source: National Institute of Biomedical Imaging and Bioengineering
Award Identifier / Grant number: R01-EB007826
Funding source: Sturgis Foundation for Diabetes Research, College of Medicine, Office of Research Intramural Grant Program
Award Identifier / Grant number: N/A
Award Identifier / Grant number: R01-HD105412
Acknowledgments
The authors would like to thank Heather Moody and Meredith McKinney for their help during the data acquisition and review, and all participants for their cooperation.
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Research ethics: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the UAMS Institutional Review Board (Protocol Numbers: #04234 on June 14th, 2017 and # 206700 on June 5th, 2017.
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Informed consent: All the participants provided informed written consent.
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Author contributions: HE and SR designed the study. LM, DE, and HE analyzed data and JW, SR, HP, and ES contributed to discussions. LM and ES performed the statistical analyses. LM, JW, and HE drafted the manuscript with contributions from DE, SR, ES, and HP.
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Competing interests: None of the authors reported any financial interests or potential conflicts of interest other than disclosed grant funding. Dr. Whittington is an active duty member of the Armed Forces. The views expressed are those of the author(s) and do not reflect the official policy of the Department of the Navy, Department of Defense, or the US Government. She is a military service member. This work was prepared as part of her official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States government.” Title 17 U.S.C. 101 defines a United States government work as a work prepared by a military service member or employee of the United States government as part of that person’s official duties.
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Research funding: This work was supported by the Sturgis Foundation for Diabetes Research, College of Medicine, Office of Research Intramural Grant Program and by National Institutes of Health–NIBIB grant R01-EB007826 and NICHD grant R01-HD105412.
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Data availability: All de-identified data will be made available on request and will be subject to institutional policies.
References
1. Akbaba, N, Annagür, BB, Annagür, A, Akbulut, H, Akyürek, F, Çelık, Ç. Neurotrophins and neuroinflammation in fetuses exposed to maternal depression and anxiety disorders during pregnancy: a comparative study on cord blood. Arch Womens Mental Health 2018;21:105–11. https://doi.org/10.1007/s00737-017-0774-1.Search in Google Scholar PubMed
2. Christian, LM, Franco, A, Iams, JD, Sheridan, J, Glaser, R. Depressive symptoms predict exaggerated inflammatory responses to an in vivo immune challenge among pregnant women. Brain Behav Immun 2010;24:49–53. https://doi.org/10.1016/j.bbi.2009.05.055.Search in Google Scholar PubMed PubMed Central
3. Uguz, F, Sonmez, EO, Sahingoz, M, Gokmen, Z, Basaran, M, Gezginc, K, et al.. Neuroinflammation in the fetus exposed to maternal obsessive–compulsive disorder during pregnancy: a comparative study on cord blood tumor necrosis factor-alpha levels. Compr Psychiatry 2014;55:861–5. https://doi.org/10.1016/j.comppsych.2013.12.018.Search in Google Scholar PubMed
4. Malamitsi-Puchner, A, Nikolaou, K, Puchner, K. Intrauterine growth restriction, brain-sparing effect, and neurotrophins. Ann N Y Acad Sci 2006;1092:293. https://doi.org/10.1196/annals.1365.026.Search in Google Scholar PubMed
5. Cai, Q-Y, Zhang, H-X, Wang, C-C, Sun, H, Sun, S-Q, Wang, Y-H, et al.. Placental and cord blood brain derived neurotrophic factor levels are decreased in nondiabetic macrosomia. Arch Gynecol Obstet 2017;296:205–13. https://doi.org/10.1007/s00404-017-4414-9.Search in Google Scholar PubMed
6. Antonakopoulos, N, Iliodromiti, Z, Mastorakos, G, Iavazzo, C, Valsamakis, G, Salakos, N, et al.. Association between brain-derived neurotrophic factor (BDNF) levels in 2nd trimester amniotic fluid and fetal development. Mediators Inflamm 2018;2018:1–7. https://doi.org/10.1155/2018/8476217.Search in Google Scholar PubMed PubMed Central
7. Briana, DD, Malamitsi-Puchner, A. Developmental origins of adult health and disease: the metabolic role of BDNF from early life to adulthood. Metabolism 2018;81:45–51. https://doi.org/10.1016/j.metabol.2017.11.019.Search in Google Scholar PubMed
8. Sahay, A, Kale, A, Joshi, S. Role of neurotrophins in pregnancy and offspring brain development. Neuropeptides 2020;83:102075. https://doi.org/10.1016/j.npep.2020.102075.Search in Google Scholar PubMed
9. Flöck, A, Weber, S, Ferrari, N, Fietz, C, Graf, C, Fimmers, R, et al.. Determinants of brain-derived neurotrophic factor (BDNF) in umbilical cord and maternal serum. Psychoneuroendocrinology 2016;63:191–7. https://doi.org/10.1016/j.psyneuen.2015.09.028.Search in Google Scholar PubMed
10. Christian, LM, Porter, K. Longitudinal changes in serum proinflammatory markers across pregnancy and postpartum: effects of maternal body mass index. Cytokine 2014;70:134–40. https://doi.org/10.1016/j.cyto.2014.06.018.Search in Google Scholar PubMed PubMed Central
11. Spann, MN, Monk, C, Scheinost, D, Peterson, BS. Maternal immune activation during the third trimester is associated with neonatal functional connectivity of the salience network and fetal to toddler behavior. J Neurosci 2018;38:2877–86. https://doi.org/10.1523/jneurosci.2272-17.2018.Search in Google Scholar
12. Thayer, JF. Vagal tone and the inflammatory reflex. Cleve Clin J Med 2009;76:S23–6. https://doi.org/10.3949/ccjm.76.s2.05.Search in Google Scholar PubMed
13. Yu, H-C, Huang, H-B, Huang Tseng, H-Y, Lu, M-C. Brain-derived neurotrophic factor suppressed proinflammatory cytokines secretion and enhanced microRNA (miR)-3168 expression in macrophages. Int J Mol Sci 2022;23:570. https://doi.org/10.3390/ijms23010570.Search in Google Scholar PubMed PubMed Central
14. Del Giudice, M, Gangestad, SW. Rethinking IL-6 and CRP: why they are more than inflammatory biomarkers, and why it matters. Brain Behav Immun 2018;70:61–75. https://doi.org/10.1016/j.bbi.2018.02.013.Search in Google Scholar PubMed
15. Canetta, S, Sourander, A, Surcel, H-M, Hinkka-Yli-Salomäki, S, Leiviskä, J, Kellendonk, C, et al.. Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort. Am J Psychiatry 2014;171:960–8. https://doi.org/10.1176/appi.ajp.2014.13121579.Search in Google Scholar PubMed PubMed Central
16. Rudolph, MD, Graham, AM, Feczko, E, Miranda-Dominguez, O, Rasmussen, JM, Nardos, R, et al.. Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring. Nat Neurosci 2018;21:765–72. https://doi.org/10.1038/s41593-018-0128-y.Search in Google Scholar PubMed PubMed Central
17. Chiera, M, Cerritelli, F, Casini, A, Barsotti, N, Boschiero, D, Cavigioli, F, et al.. Heart rate variability in the perinatal period: a critical and conceptual review. Front Neurosci 2020;14:999. https://doi.org/10.3389/fnins.2020.561186.Search in Google Scholar PubMed PubMed Central
18. Wan, R, Weigand, LA, Bateman, R, Griffioen, K, Mendelowitz, D, Mattson, MP. Evidence that BDNF regulates heart rate by a mechanism involving increased brainstem parasympathetic neuron excitability. J Neurochem 2014;129:573–80. https://doi.org/10.1111/jnc.12656.Search in Google Scholar PubMed PubMed Central
19. Sloan, RP, McCreath, H, Tracey, KJ, Sidney, S, Liu, K, Seeman, T. RR interval variability is inversely related to inflammatory markers: the CARDIA study. Mol Med 2007;13:178–84. https://doi.org/10.2119/2006-00112.sloan.Search in Google Scholar
20. Frasure-Smith, N, Lespérance, F, Irwin, MR, Talajic, M, Pollock, BG. The relationships among heart rate variability, inflammatory markers and depression in coronary heart disease patients. Brain Behav Immun 2009;23:1140–7. https://doi.org/10.1016/j.bbi.2009.07.005.Search in Google Scholar PubMed
21. Van Leeuwen, P, Werner, L, Hilal, Z, Schiermeier, S, Hatzmann, W, Groenemeyer, D. Fetal electrocardiographic measurements in the assessment of fetal heart rate variability in the antepartum period. Physiol Meas 2014;35:441. https://doi.org/10.1088/0967-3334/35/3/441.Search in Google Scholar PubMed
22. Lowery, CL, Govindan, R, Murphy, P, Eswaran, H. Assessing cardiac and neurological maturation during the intrauterine period. Semin Perinatol. 2008;32:263–8.10.1053/j.semperi.2008.04.006Search in Google Scholar PubMed PubMed Central
23. Vrba, J, McCubbin, J, Govindan, RB, Vairavan, S, Murphy, P, Preissl, H, et al.. Removal of interference from fetal MEG by frequency dependent subtraction. Neuroimage 2012;59:2475–84. https://doi.org/10.1016/j.neuroimage.2011.08.103.Search in Google Scholar PubMed PubMed Central
24. Camm, AJ, Malik, M, Bigger, JT, Breithardt, G, Cerutti, S, Cohen, RJ, et al.. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 1996;93:1043–65. https://doi.org/10.1161/01.cir.93.5.1043.Search in Google Scholar
25. Gustafson, KM, May, LE, Yeh, HW, Million, SK, Allen, JJ. Fetal cardiac autonomic control during breathing and non-breathing epochs: the effect of maternal exercise. Early Hum Dev 2012;88:539–46. https://doi.org/10.1016/j.earlhumdev.2011.12.017.Search in Google Scholar PubMed PubMed Central
26. David, M, Hirsch, M, Karin, J, Toledo, E, Akselrod, S. An estimate of fetal autonomic state by time-frequency analysis of fetal heart rate variability. J Appl Physiol 2007;102:1057–64. https://doi.org/10.1152/japplphysiol.00114.2006.Search in Google Scholar PubMed
27. Mercado, L, Escalona-Vargas, D, Blossom, S, Siegel, ER, Whittington, JR, Preissl, H, et al.. The effect of maternal pregestational diabetes on fetal autonomic nervous system. Physiol Rep 2023;11:e15680. https://doi.org/10.14814/phy2.15680.Search in Google Scholar PubMed PubMed Central
28. Nijhuis, J, Prechtl, HF, Martin, CBJr., Bots, R. Are there behavioural states in the human fetus? Early Hum Dev 1982;6:177–95. https://doi.org/10.1016/0378-3782(82)90106-2.Search in Google Scholar PubMed
29. Maeda, K. Fetal monitoring and actocardiogram in the evaluation of fetal behavior. Ultrasound Rev. Obstetr. Gynecol. 2004;4:12–25. https://doi.org/10.1080/14722240410001713920.Search in Google Scholar
30. Cohen, J. A power primer. Psychol Bull 1992;112:155. https://doi.org/10.1037/0033-2909.112.1.155.Search in Google Scholar
31. Bayman, MG, Inal, ZO, Hayiroglu, F, Ozturk, ENY, Gezginc, K. Foetal umbilical cord brain-derived neurotrophic factor (BDNF) levels in pregnancy with gestational diabetes mellitus. J Obstet Gynaecol 2022;42:1097–102. https://doi.org/10.1080/01443615.2021.2006159.Search in Google Scholar PubMed
32. Briana, DD, Papastavrou, M, Boutsikou, M, Marmarinos, A, Gourgiotis, D, Malamitsi-Puchner, A. Differential expression of cord blood neurotrophins in gestational diabetes: the impact of fetal growth abnormalities. J. Maternal Fetal Neonatal Med. 2018;31:278–83. https://doi.org/10.1080/14767058.2017.1281907.Search in Google Scholar PubMed
33. Nelson, SM, Sattar, N, Freeman, DJ, Walker, JD, Lindsay, RS. Inflammation and endothelial activation is evident at birth in offspring of mothers with type 1 diabetes. Diabetes 2007;56:2697–704. https://doi.org/10.2337/db07-0662.Search in Google Scholar PubMed
34. Al-Shargabi, T, Govindan, RB, Dave, R, Metzler, M, Wang, Y, du Plessis, A, et al.. Inflammatory cytokine response and reduced heart rate variability in newborns with hypoxic-ischemic encephalopathy. J Perinatol 2017;37:668–72. https://doi.org/10.1038/jp.2017.15.Search in Google Scholar PubMed PubMed Central
35. Borovikova, LV, Ivanova, S, Zhang, M, Yang, H, Botchkina, GI, Watkins, LR, et al.. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458–62. https://doi.org/10.1038/35013070.Search in Google Scholar PubMed
36. Martinowich, K, Manji, H, Lu, B. New insights into BDNF function in depression and anxiety. Nat Neurosci 2007;10:1089–93. https://doi.org/10.1038/nn1971.Search in Google Scholar PubMed
37. Prince, CS, Maloyan, A, Myatt, L. Maternal obesity alters brain derived neurotrophic factor (BDNF) signaling in the placenta in a sexually dimorphic manner. Placenta 2017;49:55–63. https://doi.org/10.1016/j.placenta.2016.11.010.Search in Google Scholar PubMed PubMed Central
38. Tonini, C, Segatto, M, Gagliardi, S, Bertoli, S, Leone, A, Barberio, L, et al.. Maternal dietary exposure to low-dose bisphenol A affects metabolic and signaling pathways in the brain of rat fetuses. Nutrients 2020;12:1–13. https://doi.org/10.3390/nu12051448.Search in Google Scholar PubMed PubMed Central
© 2024 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Corner of Academy
- The outcome of reduced and non-reduced triplet pregnancies managed in a tertiary hospital during a 15-year-period – a retrospective cohort study
- Original Articles – Obstetrics
- Parental refusal of prenatal screening for aneuploidies
- Analysis of maternal mortality in Berlin, Germany – discrepancy between reported maternal mortality and comprehensive death certificate exploration
- Second twin outcome at birth: retrospective analysis in a single tertiary centre in Malaysia
- Incidence and first trimester risk factors of stillbirth in Indonesia
- Correlation of fetal heart rate dynamics to inflammatory markers and brain-derived neurotrophic factor during pregnancy
- Preliminary assessment of the Healthy Early Life Moments (HELMS) webinars in empowering Developmental Origins of Health and Disease (DOHaD) concept among healthcare professionals – a pragmatic serial cross-sectional study
- Original Articles – Fetus
- The changing Doppler patterns and perinatal outcomes of monochorionic diamniotic twins with selective fetal growth restriction
- Effects of umbilical vein flow on midbrain growth and cortical development in late onset fetal growth restricted fetuses: a prospective cross-sectional study
- Original Articles – Neonates
- Prediction of bronchopulmonary dysplasia by the chest radiographic thoracic area on day one in infants with exomphalos
- Impact of birth weight to placental weight ratio and other perinatal risk factors on left ventricular dimensions in newborns: a prospective cohort analysis
- Changes in regional tissue oxygen saturation values during the first week of life in stable preterm infants
- Letters to the Editor
- Optimal closure of the uterus during cesarean section: beyond the two layers
- Reply to: “Optimal closure of the uterus during cesarean section: beyond the two layers” commenting on “The effect of uterine closure technique on cesarean scar niche development after multiple cesarean deliveries”
Articles in the same Issue
- Frontmatter
- Corner of Academy
- The outcome of reduced and non-reduced triplet pregnancies managed in a tertiary hospital during a 15-year-period – a retrospective cohort study
- Original Articles – Obstetrics
- Parental refusal of prenatal screening for aneuploidies
- Analysis of maternal mortality in Berlin, Germany – discrepancy between reported maternal mortality and comprehensive death certificate exploration
- Second twin outcome at birth: retrospective analysis in a single tertiary centre in Malaysia
- Incidence and first trimester risk factors of stillbirth in Indonesia
- Correlation of fetal heart rate dynamics to inflammatory markers and brain-derived neurotrophic factor during pregnancy
- Preliminary assessment of the Healthy Early Life Moments (HELMS) webinars in empowering Developmental Origins of Health and Disease (DOHaD) concept among healthcare professionals – a pragmatic serial cross-sectional study
- Original Articles – Fetus
- The changing Doppler patterns and perinatal outcomes of monochorionic diamniotic twins with selective fetal growth restriction
- Effects of umbilical vein flow on midbrain growth and cortical development in late onset fetal growth restricted fetuses: a prospective cross-sectional study
- Original Articles – Neonates
- Prediction of bronchopulmonary dysplasia by the chest radiographic thoracic area on day one in infants with exomphalos
- Impact of birth weight to placental weight ratio and other perinatal risk factors on left ventricular dimensions in newborns: a prospective cohort analysis
- Changes in regional tissue oxygen saturation values during the first week of life in stable preterm infants
- Letters to the Editor
- Optimal closure of the uterus during cesarean section: beyond the two layers
- Reply to: “Optimal closure of the uterus during cesarean section: beyond the two layers” commenting on “The effect of uterine closure technique on cesarean scar niche development after multiple cesarean deliveries”
