Diagnostic significance of proteome analysis of maternal plasma in fetal growth restriction

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Abstract

Objective: The objective of the study was to determine diagnostic criteria for fetal growth restriction based on quantitative proteome analysis of maternal blood plasma.

Materials and methods: Case-control study included 50 pregnant women, who were into 5 groups. Group I consisted of pregnant women with early fetal growth restriction (<32 weeks) (n=10). Group II included pregnant women with late fetal growth restriction (≥32 weeks) (n=10). Group III and IV comprised the patients, who delivered before and after 32 weeks (n=10/n=10), respectively. Group V included pregnant women with small for gestational age fetuses (≥32 weeks) (n=10). Postnatal assessment of growth and weight parameters in newborns (n=50) was conducted according to INTERGROWTH-21st charts to confirm the antenatal diagnosis of fetal growth restriction and small for gestational age newborns, as well as to determine the normal body weight in the group of women with preterm birth (before and after 32 weeks). Quantitative analysis of 125 plasma proteins was performed using BAK 125 Human Plasma Proteomics Kit (MRM Proteomics Inc., Montreal, Canada) by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Diagnostic models for fetal growth restriction and small for gestational age fetuses using logistic regression were developed after preliminary data processing.

Results: Based on the results of quantitative proteome analysis of maternal plasma proteins, three diagnostic models were developed. Model «1» (AUC=0.86), including alpha-2-macroglobulin as a variable, with 90% sensitivity and 90% specificity, enables to make the diagnosis of early fetal growth restriction. Model «2» (AUC=0.88), including the variables of proteins alpha-2-macroglobulin and apolipoprotein A-IV with 90% sensitivity and 80% specificity, enables to make the diagnosis of late fetal growth restriction. Model «3» (AUC=0.80), based on the variables of antithrombin-III and apolipoprotein C-I with 80% sensitivity and 80% specificity, enables to make the differential diagnosis of late fetal growth restriction and small for gestational age fetus.

Conclusion: The results of this study can be used in new approaches to diagnostic methods for different types of fetal growth restriction and small for gestational age fetus, as well as can be a starting point of future researches including potential therapeutic targets.

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About the authors

Maria V. Volochaeva

Academician V.I. Kulakov National Medical Research Centre of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Author for correspondence.
Email: volochaeva.m@yandex.ru
ORCID iD: 0000-0001-8953-7952

PhD, Senior Researcher, Department of Regional Cooperation and Integration; Physician, 1 Maternity Department

Russian Federation, Moscow

Alisa O. Tokareva

Academician V.I. Kulakov National Medical Research Centre of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: alisa.tokareva@phystech.edu
ORCID iD: 0000-0001-5918-9045

PhD, specialist, Laboratory of Clinical Proteomics

Russian Federation, Moscow

Alexey S. Kononikhin

Academician V.I. Kulakov National Medical Research Centre of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia; Skolkovo Institute of Science and Technology

Email: a_kononihin@oparina4.ru
ORCID iD: 0000-0002-2238-3458

PhD, Senior Researcher, Laboratory of Clinical Proteomics; Senior Researcher, Laboratory of Mass Spectrometry

Russian Federation, Moscow; Moscow

Evgenii N. Kukaev

Academician V.I. Kulakov National Medical Research Centre of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia; V.L. Talrose Institute for Energy Problems of Chemical Physics, N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences

Email: e_kukaev@oparina4.ru
ORCID iD: 0000-0002-8397-3574

PhD, Senior Researcher, Laboratory of Clinical Proteomics; Researcher

Russian Federation, Moscow; Moscow

Victor L. Tyutyunnik

Academician V.I. Kulakov National Medical Research Centre of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: tioutiounnik@mail.ru
ORCID iD: 0000-0002-5830-5099
SPIN-code: 1963-1359
Scopus Author ID: 56190621500
ResearcherId: B-2364-2015

Professor, Dr. Med. Sci., Leading Researcher of the Center for Scientific and Clinical Research

Russian Federation, Moscow

Natalia E. Kan

Academician V.I. Kulakov National Medical Research Centre of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: kan-med@mail.ru
ORCID iD: 0000-0001-5087-5946
SPIN-code: 5378-8437
Scopus Author ID: 57008835600
ResearcherId: B-2370-2015

Professor, Dr. Med. Sci., Deputy Director of Science

Russian Federation, Moscow

Natalia L. Starodubtseva

Academician V.I. Kulakov National Medical Research Centre of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: n_starodubtseva@oparina4.ru
ORCID iD: 0000-0001-6650-5915

PhD, Head of the Laboratory of Clinical Proteomics

Russian Federation, Moscow

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2. Figure. ROC curves and formulas of logistic regression models for the diagnosis of early, late growth restriction and low birth weight fetus: blue - early form of fetal growth restriction vs early control; black - late form of fetal growth restriction vs late control; red - late form of fetal growth restriction vs low gestational weight fetus

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