Abstract
Objectives
Intrauterine growth restriction (IUGR) represents one of the main causes of perinatal mortality and morbidity. Nowadays, IUGR early diagnosis is mandatory in order to limit the occurrence of multiorgan failure, especially the brain. Therefore, we investigated whether longitudinal S100B assessment in maternal blood could be a trustable predictor of IUGR.
Methods
We conducted a prospective study in 480 pregnancies (IUGR: n=40; small for gestational age, SGA: n=40; controls: n=400) in whom S100B was measured at three predetermined monitoring time-points (T1: 8–18 GA; T2: 19–23 GA; T3: 24–28 GA).
Results
Lower S100B in IUGR fetuses than SGA and controls (p<0.05, for all) at T1–T3. Receiver operating characteristic curve showed that S100B at T1 was the best predictor of IUGR (sensitivity: 100 %; specificity: 81.4 %) than T2, T3.
Conclusions
The early lower S100B concentration in pregnant women lately complicated by IUGR support the notion that non-invasive early IUGR diagnosis and monitoring is becoming feasible. Results open the way to further studies aimed at diagnosing and monitoring fetal/maternal diseases at earliest time.
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Research funding: This work is part of the I.O. PhD International Program under the auspices of the Italian Society of Neonatology and was partially supported by grants to DG from “I Colori della Vita Foundation” 3/2020, and “L’Insieme” 4/2019 Italy. We thank Diasorin, Saluggia, Italy, for supporting analysis kits.
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Author contributions: L.A., E.D., M.S., V.B., E.A., M.C., L.M., A.M., M.T., C.Z., R.P., M.L., J.O., M.C. and F.C. contributed to the conceptualization, investigation and writing of the original draft. D.G. contributed to the project administration, conceptualization, investigation, supervision and writing—review and editing. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. All authors have read and agreed to the published version of the manuscript.
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Competing interests: The funding organizations played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of ASO SS Antonio, Biagio and C. Arrigo, Alessandria, Italy (CoMBINeASO.Neonat17.01).
References
1. Longo, S, Bollani, L, Decembrino, L, Di Comité, A, Angelini, M, Stronati, M. Short-term and long-term sequelae in intrauterine growth retardation (IUGR). J Matern Fetal Neonatal Med 2013;26:222–5. https://doi.org/10.3109/14767058.2012.715006.Search in Google Scholar PubMed
2. von Beckerath, AK, Kollmann, M, Rotky-Fast, C, Karpf, E, Lang, U, Klaritsch, P. Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction. Am J Obstet Gynecol 2013;208:130.e1–1306. https://doi.org/10.1016/j.ajog.2012.11.014.Search in Google Scholar PubMed
3. Colella, M, Frérot, A, Novais, ARB, Baud, O. Neonatal and long-term consequences of fetal growth restriction. Curr Pediatr Rev 2018;14:212–8. https://doi.org/10.2174/1573396314666180712114531.Search in Google Scholar PubMed PubMed Central
4. Kesavan, K, Devaskar, SU. Intrauterine growth restriction: postnatal monitoring and outcomes. Pediatr Clin North Am 2019;66:403–23. https://doi.org/10.1016/j.pcl.2018.12.009.Search in Google Scholar PubMed
5. Bernstein, IM, Horbar, JD, Badger, GJ, Ohlsson, A, Golan, A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol 2000;182:198–206. https://doi.org/10.1016/s0002-9378(00)70513-8.Search in Google Scholar PubMed
6. Jarvis, S, Glinianaia, SV, Blair, E. Cerebral palsy and intrauterine growth. Clin Perinatol 2006;33:285–300. https://doi.org/10.1016/j.clp.2006.03.009.Search in Google Scholar PubMed
7. Tideman, E, Marsál, K, Ley, D. Cognitive function in young adults following intrauterine growth restriction with abnormal fetal aortic blood flow. Ultrasound Obstet Gynecol 2007;29:614–8. https://doi.org/10.1002/uog.4042.Search in Google Scholar PubMed
8. 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. Mediat Inflamm 2018;2018:8476217. https://doi.org/10.1155/2018/8476217.Search in Google Scholar PubMed PubMed Central
9. Misan, N, Michalak, S, Kapska, K, Osztynowicz, K, Ropacka-Lesiak, M. Blood-brain barrier disintegration in growth-restricted fetuses with brain sparing effect. Int J Mol Sci 2022;23:12349. https://doi.org/10.3390/ijms232012349.Search in Google Scholar PubMed PubMed Central
10. Misan, N, Michalak, S, Rzymski, P, Poniedziałek, B, Kapska, K, Osztynowicz, K, et al.. Molecular indicators of blood-brain barrier breakdown and neuronal injury in pregnancy complicated by fetal growth restriction. Int J Mol Sci 2022;23:13798. https://doi.org/10.3390/ijms232012349.Search in Google Scholar
11. Figueras, F, Gratacós, E. Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol. Fetal Diagn Ther 2014;36:86–98. https://doi.org/10.1159/000357592.Search in Google Scholar PubMed
12. Gordijn, SJ, Beune, IM, Thilaganathan, B, Papageorghiou, A, Baschat, AA, Baker, PN, et al.. Consensus definition of fetal growth restriction: a Delphi procedure. Ultrasound Obstet Gynecol 2016;48:333–9. https://doi.org/10.1002/uog.15884.Search in Google Scholar PubMed
13. Rolnik, DL, Wright, D, Poon, LC, O’Gorman, N, Syngelaki, A, de Paco Matallana, C, et al.. Aspirin versus Placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017;377:613–22. https://doi.org/10.1056/NEJMoa1704559.Search in Google Scholar PubMed
14. Larroque, B, Bertrais, S, Czernichow, P, Léger, J. School difficulties in 20-year-olds who were born small for gestational age at term in a regional cohort study. Pediatrics 2001;108:111–5. https://doi.org/10.1542/peds.108.1.111.Search in Google Scholar PubMed
15. Crispi, F, Bijnens, B, Figueras, F, Bartrons, J, Eixarch, E, Le Noble, F, et al.. Fetal growth restriction results in remodeled and less efficient hearts in children. Circulation 2010;121:2427–36. https://doi.org/10.1161/CIRCULATIONAHA.110.937995.Search in Google Scholar PubMed
16. Verkauskiene, R, Figueras, F, Deghmoun, S, Chevenne, D, Gardosi, J, Levy-Marchal, M. Birth weight and long-term metabolic outcomes: does the definition of smallness matter? Horm Res 2008;70:309–15. https://doi.org/10.1159/000157878.Search in Google Scholar PubMed
17. van Vliet, EO, de Kieviet, JF, van der Voorn, JP, Been, JV, Oosterlaan, J, van Elburg, RM. Placental pathology and long-term neurodevelopment of very preterm infants. Am J Obstet Gynecol 2012;206:489.e1–4897. https://doi.org/10.1016/j.ajog.2012.03.024.Search in Google Scholar PubMed
18. Chan, PY, Morris, JM, Leslie, GI, Kelly, PJ, Gallery, ED. The long-term effects of prematurity and intrauterine growth restriction on cardiovascular, renal, and metabolic function. Int J Pediatr 2010;2010:280402. https://doi.org/10.1155/2010/280402.Search in Google Scholar PubMed PubMed Central
19. Michetti, F, Corvino, V, Geloso, MC, Lattanzi, W, Bernardini, C, Serpero, L, et al.. The S100B protein in biological fluids: more than a lifelong biomarker of brain distress. J Neurochem 2012;120:644–59. https://doi.org/10.1111/j.1471-4159.2011.07612.x.Search in Google Scholar PubMed
20. Bersani, I, Pluchinotta, F, Dotta, A, Savarese, I, Campi, F, Auriti, C, et al.. Early predictors of perinatal brain damage: the role of neurobiomarkers. Clin Chem Lab Med 2020;58:471–86. https://doi.org/10.1515/cclm-2019-0725.Search in Google Scholar PubMed
21. Gasparroni, G, Graziosi, A, Bersani, I, Caulo, M, Moataza, B, Aboulgar, H, et al.. S100B protein, cerebral ultrasound and magnetic resonance imaging patterns in brain injured preterm infants. Clin Chem Lab Med 2021;59:1527–34. https://doi.org/10.1515/cclm-2021-0278.Search in Google Scholar PubMed
22. Bersani, I, Gasparroni, G, Bashir, M, Aboulgar, H, Mufeed, H, Iskander, I, et al.. Early predictors of abnormal MRI patterns in asphyxiated infants: S100B protein urine levels. Clin Chem Lab Med 2022;60:1745–52. https://doi.org/10.1515/cclm-2022-0559.Search in Google Scholar PubMed
23. Gazzolo, D, Grutzfeld, D, Michetti, F, Toesca, A, Lituania, M, Bruschettini, M, et al.. Increased S100B in cerebrospinal fluid of infants with bacterial meningitis: relationship to brain damage and routine cerebrospinal fluid findings. Clin Chem 2004;50:941–4. https://doi.org/10.1373/clinchem.2003.021048.Search in Google Scholar PubMed
24. Gazzolo, D, Di Iorio, R, Marinoni, E, Masetti, P, Serra, G, Giovannini, L, et al.. S100B protein is increased in asphyxiated term infants developing intraventricular hemorrhage. Crit Care Med 2002;30:1356–60. https://doi.org/10.1097/00003246-200206000-00037.Search in Google Scholar PubMed
25. Florio, P, Michetti, F, Bruschettini, M, Lituania, M, Bruschettini, P, Severi, F, et al.. Amniotic fluid S100B protein in mid-gestation and intrauterine fetal death. Lancet 2004;364:270–2. https://doi.org/10.1016/S0140-6736(04)16677-4.Search in Google Scholar PubMed
26. Gazzolo, D, Frigiola, A, Bashir, M, Iskander, I, Mufeed, H, Aboulgar, H, et al.. Diagnostic accuracy of S100B urinary testing at birth in full-term asphyxiated newborns to predict neonatal death. PLoS One 2009;4:e4298. https://doi.org/10.1371/journal.pone.0004298.Search in Google Scholar PubMed PubMed Central
27. Gazzolo, D, Pluchinotta, F, Bashir, M, Aboulgar, H, Said, HM, Iman, I, et al.. Neurological abnormalities in full-term asphyxiated newborns and salivary S100B testing: the “Cooperative Multitask against Brain Injury of Neonates” (CoMBINe) international study. PLoS One 2015;10:e0115194. https://doi.org/10.1371/journal.pone.0115194.Search in Google Scholar PubMed PubMed Central
28. Gazzolo, D, Marinoni, E, Di Iorio, R, Lituania, M, Marras, M, Bruschettini, M, et al.. High maternal blood S100B concentrations in pregnancies complicated by intrauterine growth restriction and intraventricular hemorrhage. Clin Chem 2006;52:819–26. https://doi.org/10.1373/clinchem.2005.060665.Search in Google Scholar PubMed
29. Serpero, LD, Bianchi, V, Pluchinotta, F, Conforti, E, Baryshnikova, E, Guaschino, R, et al.. S100B maternal blood levels are gestational age- and gender-dependent in healthy pregnancies. Clin Chem Lab Med 2017;55:1770–6. https://doi.org/10.1515/cclm-2016-1127.Search in Google Scholar PubMed
30. Sannia, A, Zimmermann, LJ, Gavilanes, AW, Vles, HJ, Serpero, LD, Frulio, R, et al.. S100B protein maternal and fetal bloodstreams gradient in healthy and small for gestational age pregnancies. Clin Chim Acta 2011;412:1337–40. https://doi.org/10.1016/j.cca.2011.03.034.Search in Google Scholar PubMed
31. Abella, L, D’Adamo, E, Strozzi, M, Sanchez-de-Toledo, J, Perez-Cruz, M, Gómez, O, et al.. S100B maternal blood levels in gestational diabetes mellitus are birthweight, gender and delivery mode dependent. Int J Environ Res Publ Health 2022;19:1028. https://doi.org/10.3390/ijerph19031028.Search in Google Scholar PubMed PubMed Central
32. Velipaşaoğlu, M, Yurdakök, M, Özyüncü, Ö, Portakal, O, Deren, Ö. Neural injury markers to predict neonatal complications in intrauterine growth restriction. J Obstet Gynaecol 2015;35:555–60. https://doi.org/10.3109/01443615.2014.978848.Search in Google Scholar PubMed
33. Kilpatrick, SJ, Papile, LA, Macones, GA. Guidelines for perinatal care, 8th ed. Elk Grove Village: American Academy of Pediatrics; 2017.Search in Google Scholar
34. Lees, CC, Stampalija, T, Baschat, A, da Silva Costa, F, Ferrazzi, E, Figueras, F, et al.. ISUOG Practice Guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction. Ultrasound Obstet Gynecol 2020;56:298–312. https://doi.org/10.1002/uog.22134.Search in Google Scholar PubMed
35. Villar, J, Cheikh Ismail, L, Victora, CG, Ohuma, EO, Bertino, E, Altman, DG, et al.. International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet 2014;384:857–68. https://doi.org/10.1016/S0140-6736(14)60932-6.Search in Google Scholar PubMed
36. Bhide, A, Acharya, G, Bilardo, CM, Brezinka, C, Cafici, D, Hernandez-Andrade, E, et al.. ISUOG practice guidelines: use of Doppler ultrasonography in obstetrics. Ultrasound Obstet Gynecol 2013;41:233–9. https://doi.org/10.1002/uog.12371.Search in Google Scholar PubMed
37. Prechtl, HFR. Assessment methods for the newborn infant: a critical evaluation. In: Stratton, D, editor. Psychobiology of the human newborn, 3rd ed. Chichester, UK: Wiley; 1982.Search in Google Scholar
38. Hagberg, H, Mallard, C. Antenatal brain injury: aetiology and possibilities of prevention. Semin Neonatol 2000;5:41–51. https://doi.org/10.1053/siny.1999.0114.Search in Google Scholar PubMed
39. Lawn, JE, Cousens, S, Zupan, J. 4 Million neonatal deaths: when? Where? Why? Lancet 2005;365:891–900. https://doi.org/10.1016/S0140-6736(05)71048-5.Search in Google Scholar PubMed
40. Gazzolo, D, Vinesi, P, Marinoni, E, Di Iorio, R, Marras, M, Lituania, M, et al.. S100B protein concentrations in cord blood: correlations with gestational age in term and preterm deliveries. Clin Chem 2000;46:998–1000. https://doi.org/10.1093/clinchem/46.7.998.Search in Google Scholar
41. Amer-Wåhlin, I, Herbst, A, Lindoff, C, Thorngren-Jerneck, K, Marsál, K, Alling, C. Brain-specific NSE and S-100 proteins in umbilical blood after normal delivery. Clin Chim Acta 2001;304:57–63. https://doi.org/10.1016/s0009-8981(00)00408-3.Search in Google Scholar PubMed
42. Swissa, SS, Baron, J, Tirosh, D, Yaniv-Salem, S, Shelef, I, Hershkovitz, R, et al.. S100B in maternal circulation of pregnancies complicated by FGR and brain sparing. Prenat Diagn 2022;42:141–50. https://doi.org/10.1002/pd.6045.Search in Google Scholar PubMed
43. Van Eldik, LJ, Wainwright, MS. The Janus face of glial-derived S100B: beneficial and detrimental functions in the brain. Restor Neurol Neurosci 2003;21:97–108.Search in Google Scholar
44. Eriksen, JL, Gillespie, RA, Druse, MJ. Effects of in utero ethanol exposure and maternal treatment with a 5-HT(1A) agonist on S100B-containing glial cells. Dev Brain Res 2000;121:133–43. https://doi.org/10.1016/s0165-3806(00)00029-8.Search in Google Scholar PubMed
45. Brolese, G, Lunardi, P, Broetto, N, Engelke, DS, Lírio, F, Batassini, C, et al.. Moderate prenatal alcohol exposure alters behavior and neuroglial parameters in adolescent rats. Behav Brain Res 2014;269:175–84. https://doi.org/10.1016/j.bbr.2014.04.023.Search in Google Scholar PubMed
46. Akbari, HM, Whitaker-Azmitia, PM, Azmitia, EC. Prenatal cocaine decreases the trophic factor S-100 beta and induced microcephaly: reversal by postnatal 5-HT1A receptor agonist. Neurosci Lett 1994;170:141–4. https://doi.org/10.1016/j.bbr.2014.04.023.Search in Google Scholar
47. Amri, J, Sadegh, M, Moulaei, N, Palizvan, MR. Transgenerational modification of hippocampus TNF-α and S100B levels in the offspring of rats chronically exposed to morphine during adolescence. Am J Drug Alcohol Abuse 2018;44:95–102. https://doi.org/10.1080/00952990.2017.1348509.Search in Google Scholar PubMed
48. Kahyaoglu, I, Kayıkcioglu, F, Gücel, F, Demirtas, C, Ozdemirci, S, Mollamahmutoglu, L. Umbilical cord S100B levels in active and passive smoker women. Eur Rev Med Pharmacol Sci 2014;18:723–7.Search in Google Scholar
49. Lv, J, Mao, C, Zhu, L, Zhang, H, Pengpeng, H, Xu, F, et al.. The effect of prenatal nicotine on expression of nicotine receptor subunits in the fetal brain. Neurotoxicology 2008;29:722–6. https://doi.org/10.1016/j.neuro.2008.04.015.Search in Google Scholar PubMed PubMed Central
50. Gazzolo, D, Kornacka, M, Bruschettini, M, Lituania, M, Giovannini, L, Serra, G, et al.. Maternal glucocorticoid supplementation and S100B protein concentrations in cord blood and urine of preterm infants. Clin Chem 2003;49:1215–8. https://doi.org/10.1373/49.7.1215.Search in Google Scholar PubMed
51. Sannia, A, Risso, FM, Serpero, LD, Frulio, R, Michetti, F, Abella, R, et al.. Antenatal glucocorticoid treatment affects preterm infants’ S100B urine concentration in a dose-dependent manner. Clin Chim Acta 2010;411:1539–41. https://doi.org/10.1016/j.cca.2010.05.045.Search in Google Scholar PubMed
52. Melchiorre, K, Leslie, K, Prefumo, F, Bhide, A, Thilaganathan, B. First-trimester uterine artery Doppler indices in the prediction of small-for-gestational age pregnancy and intrauterine growth restriction. Ultrasound Obstet Gynecol 2009;33:524–9. https://doi.org/10.1002/uog.6368.Search in Google Scholar PubMed
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