Vol 92, No 3 (2021)
Research paper
Published online: 2021-02-02

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Amniotic fluid metabolic fingerprinting indicated metabolites which may play a role in the pathogenesis of foetal Down syndrome — a preliminary report

Ewa Parfieniuk1, Karolina Pietrowska1, Paulina Samczuk1, Adam Kretowski12, Michal Ciborowski1, Monika Zbucka-Kretowska3
Pubmed: 33576476
Ginekol Pol 2021;92(3):188-194.


Objectives: Down syndrome is the most common human chromosomal aberration. It is commonly known that it is a genetic-
based disease, but still, pathomechanisms which lead to observed disorders have not been explained. The objective of this
study was to determine the metabolic fingerprinting of the amniotic fluid women carrying foetuses with Down syndrome (DS).
Material and methods: The study and control groups consisted of women who underwent routine amniocentesis between
the 15th and 18th week of gestation. After analysis of the karyotyping results, 13 women with foetal DS were chosen. For
the control group, 13 healthy patients with uncomplicated pregnancies who delivered healthy newborns at term was
selected. Amniotic fluid was analyzed using liquid chromatography combined with high resolution mass spectrometry.
Results: In the amniotic fluid of women with foetal DS compared to patients with healthy foetuses, we reported significant
differences in the level of four metabolites: methylhistidine, hexanoylcarnitine, diacetylspermine and p-cresol sulfate which
may be connected with improper development of nervous system and muscles. We detected bacterial metabolite, which
support the latest thesis about non-sterile intrauterine environment.
Conclusions: Based on our findings, we hypothesise that differences in the level of four metabolites in the amniotic fluid
may play role in the pathogenesis of DS. Defining their potential as biochemical pathogenic factors of DS requires further
investigation of the biological pathways involving in the foetal development.

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  1. Mai CT, Isenburg JL, Canfield MA, et al. National Birth Defects Prevention Network. National population-based estimates for major birth defects, 2010-2014. Birth Defects Res. 2019; 111(18): 1420–1435.
  2. What conditions or disorders are commonly associated with Down syndrome? (Eunice Kennedy Shriver National Institute of Child Health and Human Development). https://www.nichd.nih.gov/health/topics/down/conditioninfo (2017).
  3. Parfieniuk E, Samczuk P, Kowalczyk T, et al. Maternal plasma metabolic fingerprint indicative for fetal Down syndrome. Prenat Diagn. 2018; 38(11): 876–882.
  4. Kordalewska M, Macioszek S, Wawrzyniak R, et al. Multiplatform metabolomics provides insight into the molecular basis of chronic kidney disease. J Chromatogr B Analyt Technol Biomed Life Sci. 2019; 1117: 49–57.
  5. Ortmayr K, Causon T, Hann S, et al. Increasing selectivity and coverage in LC-MS based metabolome analysis. TrAC Trends in Analytical Chemistry. 2016; 82: 358–366.
  6. Bahado-Singh RO, Akolekar R, Mandal R, et al. Metabolomic analysis for first-trimester Down syndrome prediction. Am J Obstet Gynecol. 2013; 208(5): 371.e1–371.e8.
  7. Liu X, Quan S, Fu Y, et al. Study on amniotic fluid metabolism in the second trimester of Trisomy 21. J Clin Lab Anal. 2020; 34(3): e23089.
  8. Huang J, Mo J, Zhao G, et al. Application of the amniotic fluid metabolome to the study of fetal malformations, using Down syndrome as a specific model. Mol Med Rep. 2017; 16(5): 7405–7415.
  9. Trivedi DK, Iles RK. Shotgun metabolomic profiles in maternal urine identify potential mass spectral markers of abnormal fetal biochemistry - dihydrouracil and progesterone in the metabolism of Down syndrome. Biomed Chromatogr. 2015; 29(8): 1173–1183.
  10. Diaz SO, Barros AS, Goodfellow BJ, et al. Second trimester maternal urine for the diagnosis of trisomy 21 and prediction of poor pregnancy outcomes. J Proteome Res. 2013; 12(6): 2946–2957.
  11. Kolialexi A, Tounta G, Mavrou A, et al. Proteomic analysis of amniotic fluid for the diagnosis of fetal aneuploidies. Expert Rev Proteomics. 2011; 8(2): 175–185.
  12. Graça G, Duarte IF, Barros AS, et al. (1)H NMR based metabonomics of human amniotic fluid for the metabolic characterization of fetus malformations. J Proteome Res. 2009; 8(8): 4144–4150.
  13. Baraldi E, Giordano G, Stocchero M, et al. Untargeted Metabolomic Analysis of Amniotic Fluid in the Prediction of Preterm Delivery and Bronchopulmonary Dysplasia. PLoS One. 2016; 11(10): e0164211.
  14. Virgiliou C, Gika HG, Witting M, et al. Amniotic Fluid and Maternal Serum Metabolic Signatures in the Second Trimester Associated with Preterm Delivery. J Proteome Res. 2017; 16(2): 898–910.
  15. Bardanzellu F, Fanos V. The choice of amniotic fluid in metabolomics for the monitoring of fetus health - update. Expert Rev Proteomics. 2019; 16(6): 487–499.
  16. Gil-de-la-Fuente A, Godzien J, Saugar S, et al. CEU Mass Mediator 3.0: A Metabolite Annotation Tool. J Proteome Res. 2019; 18(2): 797–802.
  17. Pinto J, Almeida LM, Martins AS, et al. Impact of fetal chromosomal disorders on maternal blood metabolome: toward new biomarkers? Am J Obstet Gynecol. 2015; 213(6): 841.e1–841.e15.
  18. Fischer ST, Lili LN, Li S, et al. Low-level maternal exposure to nicotine associates with significant metabolic perturbations in second-trimester amniotic fluid. Environ Int. 2017; 107: 227–234.
  19. Umemori Y, Ohe Y, Kuribayashi K, et al. Evaluating the utility of N1,N12-diacetylspermine and N1,N8-diacetylspermidine in urine as tumor markers for breast and colorectal cancers. Clin Chim Acta. 2010; 411(23-24): 1894–1899.
  20. Taylor K, Ferreira DL, West J, et al. Differences in Pregnancy Metabolic Profiles and Their Determinants between White European and South Asian Women: Findings from the Born in Bradford Cohort. Metabolites. 2019; 9(9).
  21. Cheung CY, Roberts VHJ, Frias AE, et al. Effects of maternal western-style diet on amniotic fluid volume and amnion VEGF profiles in a nonhuman primate model. Physiol Rep. 2018; 6(20): e13894.
  22. Edwards SM, Cunningham SA, Dunlop AL, et al. The Maternal Gut Microbiome During Pregnancy. MCN Am J Matern Child Nurs. 2017; 42(6): 310–317.
  23. Gryp T, Vanholder R, Vaneechoutte M, et al. p-Cresyl Sulfate. Toxins (Basel). 2017; 9(2).
  24. D'Argenio V. The Prenatal Microbiome: A New Player for Human Health. High Throughput. 2018; 7(4).
  25. Neu J. The microbiome during pregnancy and early postnatal life. Semin Fetal Neonatal Med. 2016; 21(6): 373–379.
  26. Borre YE, O'Keeffe GW, Clarke G, et al. Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med. 2014; 20(9): 509–518.
  27. Nuriel-Ohayon M, Neuman H, Koren O. Microbial Changes during Pregnancy, Birth, and Infancy. Front Microbiol. 2016; 7: 1031.
  28. Rodríguez JM, Murphy K, Stanton C, et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015; 26: 26050.
  29. Stinson LF, Payne MS, Keelan JA. Planting the seed: Origins, composition, and postnatal health significance of the fetal gastrointestinal microbiota. Crit Rev Microbiol. 2017; 43(3): 352–369.
  30. Collado MC, Rautava S, Aakko J, et al. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep. 2016; 6: 23129.
  31. Ardissone AN, de la Cruz DM, Davis-Richardson AG, et al. Meconium microbiome analysis identifies bacteria correlated with premature birth. PLoS One. 2014; 9(3): e90784.
  32. Dey A, Bhowmik K, Chatterjee A, et al. Down Syndrome Related Muscle Hypotonia: Association with COL6A3 Functional SNP rs2270669. Front Genet. 2013; 4: 57.
  33. Naismith DJ. PREGNANCY | Metabolic Adaptations and Nutritional Requirements. Encyclopedia of Food Sciences and Nutrition. 2003: 4723–4728.
  34. Bahado-Singh RO, Akolekar R, Chelliah A, et al. Metabolomic analysis for first-trimester trisomy 18 detection. Am J Obstet Gynecol. 2013; 209(1): 65.e1–65.e9.
  35. Jones LL, McDonald DA, Borum PR. Acylcarnitines: role in brain. Prog Lipid Res. 2010; 49(1): 61–75.