Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter June 1, 2005

Fetal and maternal Doppler velocimetry and cytokines in high-risk pregnancy

  • Mariusz Dubiel , Agnieszka Seremak-Mrozikiewicz , Grzegorz H. Breborowicz , Krzysztof Drews , Marek Pietryga and Saemundur Gudmundsson


Objective: Fetal hypoxia and preterm delivery are reported to be strongly associated with brain damage and neurodevelopmental delay. Doppler signs of fetal brain sparing have been described during chronic hypoxia, but whether they are related to brain damage is unknown. The aim of this study was to evaluate if markers of tissue injury, i.e., tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are related to signs of increased perinatal vascular impedance and/or fetal brain sparing in high-risk pregnancies.

Study design: TNF-α and IL-6 levels were evaluated in maternal blood serum of 67 high-risk pregnancies. Serum samples were taken at the time of umbilical, middle cerebral artery and uterine artery Doppler velocimetry examination. The values for TNF-α and IL-6 were correlated with reference median values obtained with gestational age in the form of a Z-score.

Results: TNF-α levels showed values within the normal range in only four cases. IL-6 values were found normal in 14 cases. The Z-score for mean middle cerebral artery pulsatility index (PI) showed a significant correlation to TNF-α and IL-6 levels, P<0.0001 and P<0.003, respectively. This might suggest a strong correlation between signs of fetal brain sparing and increased maternal serum TNF-α and IL-6 levels. Abnormal uterine artery PI and the presence of a “notch” were also highly significantly related to TNF-α and IL-6 levels, which were nearly two-fold higher compared to normal uterine artery blood flow and the absence of a “notch”. Abnormal cerebro/placental ratios showed significant correlations to TNF-α and IL-6 levels.

Conclusion: The present results suggest a strong correlation between levels of TNF-α and IL-6 not only for signs of fetal brain sparing, but also for uteroplacental blood flow. This finding supports the role of tissue injury in cases of fetal brain sparing, but whether this is a reflection of brain damage or secondary to placental pathology needs further evaluation.


Corresponding author: Saemundur Gudmundsson MD, PhD, Department of Obstetrics and Gynecology, University Hospital MAS, S-205 02 Malmö/Sweden. Tel.: +46-40-332095; Fax: +46-40-962600;


1 Akalin-Sel T, KH Nicolaides, J Peacock, S Campbell: Doppler dynamics and their complex interrelation with fetal oxygen pressure, carbon dioxide pressure, and pH in growth-retarded fetuses. Obstet Gynecol84 (1994) 439Search in Google Scholar

2 Bartha JL, R Romero-Carmona, M Escobar-Llompart, R Comino-Delgado: The relationships between leptin and inflammatory cytokines in women with pre-eclampsia. Br J Obstet Gynaecol108(12) (2000) 1272Search in Google Scholar

3 Bartha JL, R Romero-Carmona, R Comino-Delgado: Inflammatory cytokines in intrauterine growth retardation. Acta Obstet Gynecol Scand82(12) (2003) 1099Search in Google Scholar

4 Berner R, CM Niemeyer, JU Leititis, A Funke, C Schwab, U Rau, K Richter, MS Tawfeek, A Clad, M Brandis: Plasma levels and gene expression of granulocyte colony stimulating factor, tumor necrosis alpha, interleukin IL-1, IL-6, IL-8 and soluble intracellular adhesion molecule in neonatal early onset sepsis. Pediatr Res44 (1998) 469Search in Google Scholar

5 Cohn HE, EJ Sacks, MA Heymann, AM Rudolph: Cardiovascular responses to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol120 (1974) 817Search in Google Scholar

6 Conrad KP, TM Miles, DF Benyo: Circulating levels of immunoreactive cytokines in women with preeclampsia. Am J Reprod Immunol40(2) (1998) 102Search in Google Scholar

7 Duggan PJ, EF Maalouf, TL Watts, MH Sullivan, SJ Counsell, J Allsop, L Al-Nakib, MA Rutherford, M Battin, I Roberts, AD Edwards: Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet358 (2001) 1699Search in Google Scholar

8 Edvinsson L, ET MacKenzie, J McCulloch: Cerebral blood flow and metabolism. Raven Press, New York 1993, p. 4010.1097/00002093-199307020-00012Search in Google Scholar

9 Esmon CT, FB Taylor Jr, TR Snow: Inflammation and coagulation: linked processes potentially regulated through a common pathway mediated by protein C. Thromb Haemost66 (1991) 160Search in Google Scholar

10 Feng L, Y Xia, GE Garcia, D Hwang, CB Wilson: Involvement of reactive oxygen intermediates in cyclooxygenase 2 expression induced by IL-1, TNF alpha and lipopolysaccharides. J Clin Invest95 (1995) 1669Search in Google Scholar

11 Gosling RG, G Dunbar, DH King, DL Newman, CD Side, JP Woodcock, DE Fitzgerald, JS Keates, D MacMillan: The quantitative analysis of occlusive peripheral arterial disease by a nonintrusive ultrasound technique. Angiology22 (1971) 52Search in Google Scholar

12 Gramellini D, MC Folli, S Raboni, E Vadora, AF Merialdi: Cerebral-umbilical Doppler ratio as a predictor of adverse perinatal outcome. Obstet Gynecol79 (1992) 416Search in Google Scholar

13 Greig PC, AP Murtha, CJ Jimmerson, WNP Herbert, B Roitman-Johnson, J Allen: Maternal serum interleukin-6 during pregnancy and during term and preterm labor. Obstet Gynecol90 (1997) 465Search in Google Scholar

14 Gudmundsson S, K Marsal: Umbilical and uteroplacental blood flow velocity waveform in normal pregnancy – a cross-sectional study. Acta Obstet Gynecol Scand67 (1988) 347Search in Google Scholar

15 Hagberg H, E Gilliaud, E Bona: Enhanced expression of IL-1 and IL-6 m-RNA and bioactive protein after hypoxia ischemia in neonatal rats. Pediatr Res40 (1996) 603Search in Google Scholar

16 Hofstaetter C, M Dubiel, S Gudmundsson, K Marsal: Uterine artery color Doppler assisted velocimetry and perinatal outcome. Acta Obstet Gynecol Scand75 (1996) 612Search in Google Scholar

17 Maalouf EF, PJ Duggan, MA Rutherford, SJ Counsell, AM Fletcher, M Battin, F Cowan, AD Edwards: Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J Pediatr135 (1999) 351Search in Google Scholar

18 Malewski Z, Z Slomko, A Klejewski: Relationship between gestational age and birthweight in the Wielkopolska region. Klin Perinat GinII(Suppl 1) (1995) 734Search in Google Scholar

19 Mari G, RL Deter: Middle cerebral artery flow velocity waveforms in normal and small-for-gestational-age fetuses. Am J Obstet Gynecol166 (1992) 1262Search in Google Scholar

20 Nelson KB, JM Dambrosia, JK Grether, TM Phillips: Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol44 (1998) 665Search in Google Scholar

21 Oygur N, O Sonmez, O Saka, O Yegin: Predictive values of plasma and cerebrospinal fluid TNF-alpha and interleukin 1 beta concentrations on outcome of full term infants with hypoxic ischemic encephalopathy. Arch Dis Child Fetal Neonat Ed79 (1998) 190Search in Google Scholar

22 Peeters LL, RE Sheldon, MD Jones Jr, EL Makowski, G Meschia: Blood flow to fetal organs as a function of arterial oxygen content. Am J Obstet Gynecol135 (1979) 637Search in Google Scholar

23 Romero R, W Sepulveda: Tumor necrosis factor in preterm and term labor. Am J Obstet Gynecol166 (1992) 1575Search in Google Scholar

24 Savman K, M Blennow, K Gustafson, E Tarkowski, H Hagberg: Cytokine response in cerebrospinal fluid after birth asphyxia. Pediatr Res43 (1998) 746Search in Google Scholar

25 Scherjon S, J Briet, H Oosting, J Kok: The discrepancy between maturation of visual-evoked potentials and cognitive outcome at five years in very preterm infants with and without hemodynamic signs of fetal brain-sparing. Pediatrics105 (2000) 385Search in Google Scholar

26 Sheldon RE, LL Peeters, MD Jones Jr, EL Makowski, G Meschia: Redistribution of cardiac output and oxygen delivery in the hypoxemic fetal lamb. Am J Obstet Gynecol135 (1979) 1071Search in Google Scholar

27 Teran E, C Escudero, W Moya, M Flores, P Vallance, P Lopez-Jaramillo: Elevated C-reactive protein and pro-inflammatory cytokines in Andean women with pre-eclampsia. Int J Gynaecol Obstet75(3) (2001) 243Search in Google Scholar

28 Trudinger B, J Wang, N Athayde, L Beutler, X Wang: Association of umbilical placental vascular disease with fetal acute inflammatory cytokine responses. J Soc Gynecol Invest9(3) (2002) 152Search in Google Scholar

29 van den Wijngaard JA, IA Groenenberg, JW Wladimiroff, WC Hop: Cerebral Doppler ultrasound of the human fetus. Br J Obstet Gynaecol96 (1989) 845Search in Google Scholar

30 Vince GS, PM Starkey, R Austgulen, D Kwiatkowski, CW Redman: Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor receptors in women with pre-eclampsia. Br J Obstet Gynaecol102(1) (1995) 20Search in Google Scholar

31 Weiner Z, G Farmakides, H Schulman, B Penny: Central and peripheral hemodynamic changes in fetuses with absent end-diastolic velocity in umbilical artery: correlation with computerized fetal heart pattern. Am J Obstet Gynecol170 (1994) 509Search in Google Scholar

Published Online: 2005-06-01
Published in Print: 2005-01-01

©2005 by Walter de Gruyter Berlin New York

Downloaded on 30.9.2023 from
Scroll to top button