The level of serum matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1 in newborns from mothers with undifferentiated connective tissue dysplasia




newborns, undifferentiated connective tissue dysplasia, matrix metalloproteinases


Laboratory markers of undifferentiated connective tissue dysplasia (UCTD) are indicators of the matrix metalloproteinases (MMP) system, which are involved in the remodeling of connective tissue components, morphogenesis, inflammation.

Purpose - to analyze the correlation between signs of UCTD in postpartum women and the level of serum MMP-1, tissue inhibitor of MMP-1 (TIMP-1) and the MMP-1/TIMP-1 ratio in newborns.

Materials and methods. We examined 122 women in labor and their 122 newborn children with a gestational age (GA) of 28-42 weeks, a body weight (BW) of 1270-4070 g. Clinical and anamnestic data and biochemical markers (level of serum MMP-1, TIMP-1, MMP-1/TIMP-1) were investigated in children. Clinical signs of UCTD in women in labor were registered. The main group (n=82) involved women with ≥3 UCTD markers, the control group (n=40) consisted of women with ≤2 UCTD features and their newborns. Accordingly, the main group of newborns - children from mothers with ≥3 markers of UCTD, the control group - babies from mothers with ≤2 signs of UCTD. For statistical analysis, Mann-Whitney (U) test and Cramer’s coefficient (φc) were used.

Results. Newborns of the main group had a longer GA (U=1069.5; p=0.002), a lower Apgar score (U=1522.5; p=0.04), a smaller weight-for-age ratio (U=1511.0; p=0.038), higher concentrations of MMP-1 (U=55.0; p=0.000013) and higher values of the MMP-1/TIMP-1 (U=76.0; p=0.000323). The optimal range of MMP-1 in newborns is 2.72-3.91 ng/ml, TIMP-1 - 16.08-17.49 ng/ml, MMP-1/TIMP-1 - 0.16-0.24. MMP-1 concentration ranges ≥4.51 ng/ml and MMP-1/TIMP-1 values ≥0.31 were more typical for full-term infants (p<0.01) than prematurely born, and for children with lower BW (p<0.01). UCTD-associated obstetric complications were related to ranges of MMP-1 ≥4.51 ng/ml (p<0.001-0.05), TIMP-1  ≤16.07 ng/ml (p<0.05), MMP-1/TIMP-1 ≥0.31 (p<0.001-0.05) in children.

Conclusions. UCTD in parturient mothers is an unfavorable factor in the formation of small weight-for-age ratio (p=0.038), a low postnatal adaptation (p=0.04), imbalance of serum MMP-1 (p=0.000013) and MMP-1/TIMP-1 (p=0.000323) in children. The optimal level of serum MMP-1 for newborns is 2.72-3.91 ng/ml, TIMP-1 - 16.08-17.49 ng/ml, MMP-1/TIMP-1 - 0.16-0.24. The values of MMP-1 ≥4.51 ng/ml and MMP-1/TIMP-1 ≥0.31 are markers of delayed physical development of the fetus (p<0.01). UCTD-associated obstetric complications are prognostically unfavorable for imbalance of MMP-1, TIMP-1, MMP-1/TIMP-1 in newborns.

The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of an institution. The informed consent to participate in the study was obtained from each mother.

No conflict of interests was declared by the authors.

Author Biography

O.Yu. Chumak, Shupyk National Healthcare University of Ukraine, Kyiv

Lugansk State Medical University, Rivne, Ukraine


Arese V, Murabito P, Ribero S et al. (2019). Autoimmune connective tissue diseases and pregnancy. Italian Journal of Dermatology and Venereology. 154 (3): 263-276.; PMid:30650958

Berard RA, Laxer RM. (2016). Pediatric Mixed Connective Tissue Disease. Current Rheumatology Reports. 18 (5).; PMid:27032791

Bobra VV, Shoenfeld Ye. (2019). Exacerbations of autoimmune diseases during pregnancy and postpartum. Best Practice & Research Clinical Endocrinology & Metabolism. 33 (6): 101321.; PMid:31564626

Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosaet C et al. (2020). The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int. J. Mol. Sci. 21 (24): 55.; PMid:33419373 PMCid:PMC7767220

Chang M. (2023). Matrix metalloproteinase profiling and their roles in disease. RSC Advances 13: 6304-6316.; PMid:36825288 PMCid:PMC9942564

Chumak OYu, Volokha AP. (2021). Pathological conditions in newborns against the background of undifferentiated connective tissue dysplasia in their mothers. Modern Pediatrics. Ukraine. 6 (118): 25-31.

Cui N, Hu M, Khalil RA. (2017). Biochemical and biological attributes of matrix metalloproteinases. Progress in Molecular Biology and Translational Science. 147: 1-73.; PMid:28413025 PMCid:PMC5430303

Dobrianska VYu. (2022). Predyktory rozvytku akusherskykh uskladnen ta alhorytm vedennia vahitnykh iz spoluchnotkanynnoiu dysplaziieiu sertsia. Zbirnyk naukovykh prats asotsiatsii akusheriv-hinekolohiv Ukrainy. 1 (49): 16-25.

Freitas-Rodríguez S, Folgueras AR, López- Otín C. (2017). The role of matrix metalloproteinases in aging: Tissue remodeling and beyond. Biochim Biophys Acta. 1864 (11): 2015-2025.; PMid:28499917

Gao R, Zeng X, Qin L. (2021). Systemic autoimmune diseases and recurrent pregnancy loss: research progress in diagnosis and treatment. Chinese Medical Journal. 134 (17): 2140-2142.; PMid:34432653 PMCid:PMC8439985

Grandone E, Grigoryev KN, Nakaidze IA, Gashimova NR et al. (2022). Metalloproteinases as biochemical markers of pregnancy pathology. Obstetrics, Gynecology and Reproduction. 16 (1): 38-47.

Iudici M, Cuomo G, Vettori S, Avellino M, Valentini G. (2013). Quality of life as measured by the short-form 36 (SF-36) questionnaire in patients with early systemic sclerosis and undifferentiated connective tissue disease. Health and Quality of Life Outcomes. 11 (23): 1-6.; PMid:23442975 PMCid:PMC3598545

Khokha R, Murthy A, Weiss A. (2013). Metalloproteinases and their natural inhibitors in inflammation and immunity. Nature Reviews Immunology. 13: 649-665.; PMid:23969736

Kostiuk AL. (2017). Features of obstetric and perinatal pathology at women with an undifferentiated dysplasia of connective tissue. Health of woman. 7 (123): 96-98.

Mosca M, Tani C, Vagnani S, Carli L, Bombardieri S. (2014). The diagnosis and classification of undifferentiated connective tissue diseases. Journal of Autoimmunity. 48 (49): 50-52.; PMid:24518855

Ostensen M, Cetin I. (2015). Autoimmune connective tissue diseases. Best Practice and Research Clinical Obstetrics and Gynaecology. 29 (5): 658-670.; PMid:25891380

Pollock L, Ridout A, Teh J, Nnadi C, Stavroulias D et al. (2021). The Musculoskeletal Manifestations of Marfan Syndrome: Diagnosis, Impact, and Management. Current Rheumatology Reports. 23: 1-18.; PMid:34825999 PMCid:PMC8626407

Radin M, Schreiber K, Cecchi I et al. (2020). A multicentre study of 244 pregnancies in undifferentiated connective tissue disease: maternal/fetal outcomes and disease evolution. Rheumatology (Oxford). 59 (9): 2412-2418.; PMid:31943123

Raeeszadeh-Sarmazdeh M, Do LD, Hritz BG. (2020). Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics. Cells. 9 (5): 1313.; PMid:32466129 PMCid:PMC7290391

Serena C, Clemenza S, Simeone S. (2022). Undifferentiated Connective Tissue Disease in Pregnancy: A Topic Yet to be Explored. Frontiers in Pharmacology. 13: 1-10.; PMid:35126164 PMCid:PMC8811283

Smirnova TL, Gerasimova LI, Sidorov AE, Chernyshov VV. (2018). Features of the course of pregnancy and childbirth in women with syndrome of undifferentiated connective tissue dysplasia. Practical medicine. 16 (6): 39-44.

Spinillo A, Beneventi F, Caporali R et al. (2017). Undifferentiated connective tissue diseases and adverse pregnancy outcomes. An undervalued association? American J Reproductive Immunology. 78 (6): e12762.; PMid:28921728

Spinillo A, Beneventi F, Locatell E et al. (2016). The impact of unrecognized autoimmune rheumatic diseases on the incidence of preeclampsia and fetal growth restriction: a longitudinal cohort study. BMC Pregnancy Childbirth. 16 (1): 313.; PMid:27756248 PMCid:PMC5069792

Voloshin OM, Chumak OYu. (2017). Undifferentiated connective tissue dysplasia and respiratory diseases in children and adolescents (review of literature). Child's health. 12 (6), 720-727.

Voloshin OM, Marushko YuV. (2022). Comprehensive analysis of serum concentration of matrix metalloproteinase 1 and tissue inhibitor of metalloproteinase 1 in preschool children suffering from recurrent respiratory infections. Modern Pediatrics. Ukraine. 7 (127): 29-37.

Vovk VM. (2019). Efektyvnist profilaktyky zakhvoriuvan, shcho vyklykaiutsia Streptococcus pneumoniae u ditei z nedyferentsiiovanoiu dysplaziieiu spoluchnoi tkanyny. Dys. na zdobuttia nauk. stupenia kand. med. nauk: spets. 14.01.10 - Pediatriia: 72-87.

Zhuraiev RK. (2012). Syndrom Marfana: evoliutsiia diahnostychnykh kryteriiv. Ukrainskyi medychnyi chasopys. 1 (87): 98-102.

Zucchi D, Tani C, Monacci F et al. (2020). Pregnancy and undifferentiated connective tissue disease: outcome and risk of flare in 100 pregnancies. Rheumatology 59 (6): 1335-1339.; PMid:31593595