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Polymorphisms of ACE and thrombophilic genes: risk for recurrent pregnancy loss
  1. Olivera Miljanović1,2,
  2. Vesna Ilić3,
  3. Slađana Teofilov1,
  4. Bojana Cikota-Aleksić4,
  5. Zvonko Magić5
  1. 1Center for Medical Genetic and Immunology, Clinical Centre of Montenegro, Podgorica, Montenegro
  2. 2Faculty of Medicine, University of Montenegro, Podgorica, Montenegro
  3. 3Institute of Medical Research, Military Medical Academy, Beograd, Serbia
  4. 4Center of Clinical Pharmacology, Military Medical Academy, Beograd, Serbia
  5. 5Academy of Medical Sciences, Serbian Medical Society, Beograd, Serbia
  1. Correspondence to Dr Olivera Miljanović, Center for Medical Genetic and Immunology, Clinical Centre of Montenegro, Podgorica, Montenegro; olivera.miljanovic{at}


Background Recurrent pregnancy loss (RPL) affects up to 5% of pregnancies, but with no consensus on the definition. Inherited thrombophilia has been postulated as a risk factor for RPL. The aim of this study was to investigate the association of RPL with polymorphisms of five genes that influent the coagulation and fibrinolysis.

Methods This study was conducted on total of 224 women, 129 women with ≥2 early RPL or ≥1 late pregnancy loss, 95 women with at least two normal life births and no history of pregnancy loss. Five gene polymorphisms F2 20 210G>A (rs1799963), F5 1691G>A (rs6025), MTHFR 677C>T (rs1801133), SERPINE1 −675 4G/5G (rs1799762) and ACE I/D (rs1799752) were genotyped by PCR-based methods.

Results A significant relationship was found between SERPINE1 4G/4G and ACE D/D polymorphisms and RPL (p<0.001 both, OR 2.91 and 3.02, respectively). In contrast, no association was found between F2 20 210G>A, F5 1691G>A and MTHFR 677C>T polymorphisms and risk for RPL. A combination of hypofibrinolytic homozygotes SERPINE1 4G/4G+ACE D/D was observed as a highly associated with RPL (Cochran-Armitage test, p<0.001), and their strong independent association with RPL risk was confirmed by logistic regression analysis (both p values <0.001, OR 3.35 and 3.43, respectively).

Conclusion Our data have demonstrated that SERPINE1 and ACE gene polymorphisms, individually or in combination, appear to be a significant risk for RPL. This data may be useful in adding to the knowledge on inherited thrombophilia as an important contributor to RPL pathogenesis.

  • blood coagulation
  • fibrinolysis
  • genetics
  • pregnancy
  • thrombophilia

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • Handling editor Tahir S Pillay.

  • Twitter @OliveraMiljano1

  • Contributors OM and ZM designed the research; OM performed clinical management of the patients and data collection; VI and ST performed the genotyping; OM, BC-A and ZM analysed the data; OM wrote the paper; OM, ZM and BC-A revised the paper; all authors approved the final version of the paper.

  • Funding This research was a part of scientific project „Congenital anomalies in Montenegro: molecular mechanisms of genomic disorders, clinical and epidemiological characteristics“(KAMGKE), supported by the grants from the Ministry of Science (grant number: 01-404) and Ministry of Health (grant number: 01-2014) of Montenegro.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.