Research article
● Open access
Recurrent Pregnancy Loss: A Comprehensive Review of Etiology, Pathophysiology, Diagnostic Approaches, and Therapeutic Strategies
Abstract
Background: Polyamide 6 (PA6) is a widely used engineering thermoplastic known for its excellent mechanical properties, thermal stability, and wear resistance. However, its semi-crystalline structure and low thermal conductivity present significant challenges during machining operations, particularly in achieving optimal surface finish. Surface roughness is a critical quality indicator that affects the functional performance, fatigue life, and aesthetic appearance of machined polymer components. Understanding the complex interactions between machining parameters and environmental conditions is essential for optimizing the turning process of PA6.
Objective: This comprehensive review investigates the influence of machining parameters—cutting velocity (Vc), feed rate (FR), and depth of cut (Dc)—and machining environments—dry (D), compressed air (A), and air-water mixture (A+W)—on the surface roughness (Ra) of Polyamide 6 during turning operations. The study aims to identify the most influential parameters, quantify their percentage contributions, and determine the optimal combination for achieving minimum surface roughness.
Methods: A systematic experimental approach was combined with statistical analysis using Taguchi Experiment Design (TED) and Analysis of Variance (ANOVA). Experiments were conducted on a CU-500 lathe using a carbide cutting tool (Mitsubishi CNMG 120408 UE6020) with a PCLNR 2525 M12 tool holder. PA6 samples of 40 mm diameter and 500 mm length were machined at three levels for each parameter: cutting velocity (125, 200, 250 m/min), feed rate (0.05, 0.1, 0.15 mm/rev), depth of cut (2, 4, 6 mm), and three machining environments. Surface roughness was measured using an SRT5000 roughness tester. The Taguchi L9 orthogonal array was employed to design experiments efficiently, and the signal-to-noise ratio (SNR) with "smaller-is-better" criterion was used for optimization. ANOVA quantified the percentage contribution of each parameter.
Results: The experimental results demonstrate that feed rate is the most dominant factor affecting surface roughness, contributing 61% of the total effect. Machining environment contributes 15%, depth of cut 13%, and cutting velocity 11%. Lower feed rates (0.05 mm/rev) consistently produced superior surface finishes (Ra = 1.2 μm), while higher feed rates (0.15 mm/rev) resulted in rougher surfaces (Ra = 2.5 μm). The air-water mixture environment significantly improved surface quality compared to dry and compressed air conditions due to enhanced cooling and lubrication effects. Lower cutting velocities (125-200 m/min) and shallower depths of cut (2 mm) also contributed to better surface finishes by reducing cutting forces, vibration, and thermal deformation. The optimal combination for minimum surface roughness was identified as: cutting velocity of 125 m/min, feed rate of 0.05 mm/rev, depth of cut of 2 mm, and air-water mixture environment, achieving a minimum Ra of 1.2 μm.
Conclusion: This comprehensive investigation establishes that feed rate is the primary control parameter for achieving high-quality surface finishes in PA6 turning operations. The air-water mixture environment provides significant improvements in surface quality through effective cooling and lubrication. The study provides manufacturers with evidence-based guidelines for selecting optimal machining parameters to enhance product quality, reduce costs, and extend tool life. The findings contribute to the broader understanding of polymer machining and offer a foundation for developing predictive models and process optimization strategies.
Keywords
Recurrent Pregnancy Loss, Recurrent Miscarriage, Thrombophilia, Genetic Polymorphisms, M2/ANXA5 Haplotype, Uterine Anomalies, Antiphospholipid Syndrome, Progesterone Therapy.
References
Andreeva, T., Komsa-Penkova, R., Langari, A., Krumova, S., Golemanov, G., Georgieva, G. B., Taneva, S. G., Giosheva, I., Mihaylova, N., Tchorbanov, A., & Todinova, S. (2021). Morphometric and nanomechanical features of platelets from women with early pregnancy loss provide new evidence of the impact of inherited thrombophilia. International Journal of Molecular Sciences, 22(15), 7778. https://doi.org/10.3390/ijms22157778
Ang, K. C., Bogdanova, N., Markoff, A., Ch'ng, E. S., & Tang, T. H. (2019). Association between M2/ANXA5 haplotype and repeated pregnancy loss: A meta-analysis. Fertility and Sterility, 111(5), 971-981. https://doi.org/10.1016/j.fertnstert.2019.01.015
Angelova, L., Tsvetkova, M., & Levkova, M. (2021). Chromosomal polymorphism in Bulgarian patients with reproductive problems - one genetic centre experience. Journal of IMAB - Annual Proceeding (Scientific Papers), 27(4), 4133-4138. https://doi.org/10.5272/jimab.2021274.4133
Ardizzone, A., Capra, A. P., Mondello, S., Briuglia, S., La Rosa, M. A., Campolo, M., & Esposito, E. (2022). H1299R variant in factor V and recurrent pregnancy loss: A systematic review and meta-analysis protocol. Genes, 13(6), 1019. https://doi.org/10.3390/genes13061019
Capra, A. P., Ardizzone, A., Briuglia, S., La Rosa, M. A., Mondello, S., Campolo, M., & Esposito, E. (2022). A systematic review and meta-analysis of the association between the FV H1299R variant and the risk of recurrent pregnancy loss. Biology, 11(11), 1608. https://doi.org/10.3390/biology11111608
Carbonnel, M., Pirtea, P., de Ziegler, D., & Ayoubi, J. M. (2021). Uterine factors in recurrent pregnancy losses. Fertility and Sterility, 115(3), 538-545. https://doi.org/10.1016/j.fertnstert.2020.12.003
Carp, H. J. A. (2020). Threatened miscarriage and recurrent pregnancy loss. In H. Carp (Ed.), Recurrent Pregnancy Loss (pp. 145-152). https://doi.org/10.1201/9780429450303-15
Cozaru, G. C., Aschie, M., Mitroi, A., Brinzan, C., & Chisoi, A. (2019). The genetic profile of thrombophilia in reproductive disorders. Revista de Chimie, 70(11), 3830-3834. https://doi.org/10.37358/RC.19.11.7654
Dugalic, S., Petronijevic, M., Stefanovic, A., Stefanovic, K., Perovic, M., Pantic, I., Vrzic Petronijevic, S., Stanislavijevic, D., & Zaric, M. (2019). Perinatal complications related to inherited thrombophilia: Review of evidence in different regions of the world. The Journal of Maternal-Fetal & Neonatal Medicine, 32(24), 4175-4182. https://doi.org/10.1080/14767058.2019.1669017
ESHRE Guideline Group on RPL, Atik, R. B., Christiansen, O. B., Elson, J., Kolte, A. M., Lewis, S., Middeldorp, S., Mcheik, S., Peramo, B., Quenby, S., Neilsen, H. S., van der Hoorn, M. L., Vermeulen, N., & Goddijn, M. J. (2023). ESHRE guideline: Recurrent pregnancy loss: An update in 2022. Human Reproduction Open, 2023(1), hoad002. https://doi.org/10.1093/hopen/hoad002
Hadjidekova, S., Staykova, S., Staneva, R., Pancheva, M., Serafimova, M., Nikolova, K., Toncheva, D., & Stamenov, G. (2022). The utility of Preimplantation Genetic Test in couples with history of infertility and pregnancy loss. Proceedings of the Bulgarian Academy of Sciences, 75(4), 590-595. https://doi.org/10.7546/CRABS.2022.04.14
Ivanov, P. D., Komsa-Penkova, R. S., Konova, E. I., Tsyvaktovska, T. M., Kovacheva, K. S., Simeonova, M. N., & Tanchev, S. Y. (2020). Polymorphism A1/A2 in the cell surface integrin subunit β3 and disturbance of implantation and placentation in women with recurrent pregnancy loss. Fertility and Sterility, 94(7), 2843-2845. https://doi.org/10.1016/j.fertnstert.2010.05.015
Jalilvand, A., Yari, K., & Heydarpour, F. (2022). Role of polymorphisms on the recurrent pregnancy loss: A systematic review, meta-analysis and bioinformatic analysis. Gene, 830, 146804. https://doi.org/10.1016/j.gene.2022.146804
Kolte, A. M., Olsen, L. R., Mikkelsen, E. M., Christiansen, O. B., & Nielsen, H. S. (2015). Depression and emotional stress is highly prevalent among women with recurrent pregnancy loss. Human Reproduction, 30(4), 777-782. https://doi.org/10.1093/humrep/dev014
Langari, A., Strijkova, V., Komsa-Penkova, R., Danailova, A., Krumova, S., Taneva, S. G., Giosheva, I., Gartchev, E., Kercheva, K., Savov, A., & Todinova, S. (2022). Morphometric and nanomechanical features of erythrocytes characteristic of early pregnancy loss. International Journal of Molecular Sciences, 23(9), 4512. https://doi.org/10.3390/ijms23094512
Lesesve, J. F., Franczak, C., & Perrin, J. (2019). Erythrocytes morphology in pregnancy. Annales de Biologie Clinique, 77(2), 113-115. https://doi.org/10.1684/abc.2018.1409
Levkova, M., Hachmeryian, M., Stoyanova, M., Miteva, V., & Angelova, L. (2020). Comparison between thrombophilic gene polymorphisms among high-risk patients. Romanian Journal of Internal Medicine, 58(1), 20-26. https://doi.org/10.2478/rjim-2019-0021
McQueen, D. B., Maniar, K. P., Hutchinson, A., Confino, R., Bernardi, L., & Pavone, M. E. (2021). Redefining chronic endometritis: The importance of endometrial stromal changes. Fertility and Sterility, 116(3), 855-861. https://doi.org/10.1016/j.fertnstert.2021.04.036
Mihailă, R. (2020). Coagulation challenges in pregnancy: From thrombophilia involvement and management to the utility of thrombin generation monitoring. Clinical and Experimental Obstetrics & Gynecology, 47(6), 814. https://doi.org/10.31083/j.ceog.2020.06.5499
Pencheva, D. T., Coffey, A., McKenna, S. P., & Monov, S. V. (2023). Adaptation and validation of the Bulgarian version of the systemic lupus erythematosus quality of life questionnaire (L-QoL). Clinical Rheumatology, 42(7), 1811-1817. https://doi.org/10.1007/s10067-023-06523-w
Practice Committee of the American Society for Reproductive Medicine. (2020). Definitions of infertility and recurrent pregnancy loss: A committee opinion. Fertility and Sterility, 113(3), 533-535. https://doi.org/10.1016/j.fertnstert.2019.11.025
Robeva, R., Marinova, E., Nikolaev, G., Andonova, S., Savov, A., Tanev, D., Nikolov, G., & Konakchieva, R. (2022). Melatonin receptor 1B polymorphisms and reproductive failure - a pilot study. Proceedings of the Bulgarian Academy of Sciences, 75(5), 745-751. https://doi.org/10.7546/CRABS.2022.05.15
Sosic, G. M., Sretenovic, S., Radivojevic, D., Jovic, N., & Varjacic, M. (2020). The impact of the gene variants FV Leiden, FII G20210A, MTHFR C677T and PAI-1 4G/5G on pregnancy loss in women from Central Serbia. Serbian Journal of Experimental and Clinical Research, 21(1), 19-25. https://doi.org/10.1515/sjecr-2017-0070
Sowmya, S., Ayyali, A., Vidya, K. R., & Nagesh, H. N. (2022). Genetic variation of folate metabolic pathway in recurrent pregnancy loss - A systematic review. International Journal of Medical Reviews and Case Reports, 6(1), 50-53. https://doi.org/10.5455/IJMRCR.172-1661674148
Turesheva, A., Aimagambetova, G., Ukybassova, T., Marat, A., Kanabekova, P., Kaldygulova, L., Amanzholkyzy, A., & Atageldiyeva, K. (2023). Recurrent pregnancy loss etiology, risk factors, diagnosis, and management: A comprehensive review. Journal of Clinical Medicine, 12(12), 3982. https://doi.org/10.3390/jcm12123982
Tüttelmann, F., Ivanov, P., Dietzel, C., Sofroniou, A., Tsvyatkovska, T. M., Komsa-Penkova, R. S., Markoff, A., Wieacker, P., & Bogdanova, N. (2023). M2/ANXA5 haplotype as a predisposition factor in German and Bulgarian women with early recurrent pregnancy loss. Journal of Assisted Reproduction and Genetics, 40(3), 617-624. https://doi.org/10.1007/s10815-022-02701-8
Verma, U. (2023). Current status of hysteroscopy in the diagnosis and management of recurrent pregnancy loss. Journal of Minimally Invasive Gynecology, 30(2), 98-106. https://doi.org/10.1016/j.jmig.2022.11.008
Ang, K. C., Bogdanova, N., Markoff, A., Ch'ng, E. S., & Tang, T. H. (2019). Association between M2/ANXA5 haplotype and repeated pregnancy loss: A meta-analysis. Fertility and Sterility, 111(5), 971-981. https://doi.org/10.1016/j.fertnstert.2019.01.015
Angelova, L., Tsvetkova, M., & Levkova, M. (2021). Chromosomal polymorphism in Bulgarian patients with reproductive problems - one genetic centre experience. Journal of IMAB - Annual Proceeding (Scientific Papers), 27(4), 4133-4138. https://doi.org/10.5272/jimab.2021274.4133
Ardizzone, A., Capra, A. P., Mondello, S., Briuglia, S., La Rosa, M. A., Campolo, M., & Esposito, E. (2022). H1299R variant in factor V and recurrent pregnancy loss: A systematic review and meta-analysis protocol. Genes, 13(6), 1019. https://doi.org/10.3390/genes13061019
Capra, A. P., Ardizzone, A., Briuglia, S., La Rosa, M. A., Mondello, S., Campolo, M., & Esposito, E. (2022). A systematic review and meta-analysis of the association between the FV H1299R variant and the risk of recurrent pregnancy loss. Biology, 11(11), 1608. https://doi.org/10.3390/biology11111608
Carbonnel, M., Pirtea, P., de Ziegler, D., & Ayoubi, J. M. (2021). Uterine factors in recurrent pregnancy losses. Fertility and Sterility, 115(3), 538-545. https://doi.org/10.1016/j.fertnstert.2020.12.003
Carp, H. J. A. (2020). Threatened miscarriage and recurrent pregnancy loss. In H. Carp (Ed.), Recurrent Pregnancy Loss (pp. 145-152). https://doi.org/10.1201/9780429450303-15
Cozaru, G. C., Aschie, M., Mitroi, A., Brinzan, C., & Chisoi, A. (2019). The genetic profile of thrombophilia in reproductive disorders. Revista de Chimie, 70(11), 3830-3834. https://doi.org/10.37358/RC.19.11.7654
Dugalic, S., Petronijevic, M., Stefanovic, A., Stefanovic, K., Perovic, M., Pantic, I., Vrzic Petronijevic, S., Stanislavijevic, D., & Zaric, M. (2019). Perinatal complications related to inherited thrombophilia: Review of evidence in different regions of the world. The Journal of Maternal-Fetal & Neonatal Medicine, 32(24), 4175-4182. https://doi.org/10.1080/14767058.2019.1669017
ESHRE Guideline Group on RPL, Atik, R. B., Christiansen, O. B., Elson, J., Kolte, A. M., Lewis, S., Middeldorp, S., Mcheik, S., Peramo, B., Quenby, S., Neilsen, H. S., van der Hoorn, M. L., Vermeulen, N., & Goddijn, M. J. (2023). ESHRE guideline: Recurrent pregnancy loss: An update in 2022. Human Reproduction Open, 2023(1), hoad002. https://doi.org/10.1093/hopen/hoad002
Hadjidekova, S., Staykova, S., Staneva, R., Pancheva, M., Serafimova, M., Nikolova, K., Toncheva, D., & Stamenov, G. (2022). The utility of Preimplantation Genetic Test in couples with history of infertility and pregnancy loss. Proceedings of the Bulgarian Academy of Sciences, 75(4), 590-595. https://doi.org/10.7546/CRABS.2022.04.14
Ivanov, P. D., Komsa-Penkova, R. S., Konova, E. I., Tsyvaktovska, T. M., Kovacheva, K. S., Simeonova, M. N., & Tanchev, S. Y. (2020). Polymorphism A1/A2 in the cell surface integrin subunit β3 and disturbance of implantation and placentation in women with recurrent pregnancy loss. Fertility and Sterility, 94(7), 2843-2845. https://doi.org/10.1016/j.fertnstert.2010.05.015
Jalilvand, A., Yari, K., & Heydarpour, F. (2022). Role of polymorphisms on the recurrent pregnancy loss: A systematic review, meta-analysis and bioinformatic analysis. Gene, 830, 146804. https://doi.org/10.1016/j.gene.2022.146804
Kolte, A. M., Olsen, L. R., Mikkelsen, E. M., Christiansen, O. B., & Nielsen, H. S. (2015). Depression and emotional stress is highly prevalent among women with recurrent pregnancy loss. Human Reproduction, 30(4), 777-782. https://doi.org/10.1093/humrep/dev014
Langari, A., Strijkova, V., Komsa-Penkova, R., Danailova, A., Krumova, S., Taneva, S. G., Giosheva, I., Gartchev, E., Kercheva, K., Savov, A., & Todinova, S. (2022). Morphometric and nanomechanical features of erythrocytes characteristic of early pregnancy loss. International Journal of Molecular Sciences, 23(9), 4512. https://doi.org/10.3390/ijms23094512
Lesesve, J. F., Franczak, C., & Perrin, J. (2019). Erythrocytes morphology in pregnancy. Annales de Biologie Clinique, 77(2), 113-115. https://doi.org/10.1684/abc.2018.1409
Levkova, M., Hachmeryian, M., Stoyanova, M., Miteva, V., & Angelova, L. (2020). Comparison between thrombophilic gene polymorphisms among high-risk patients. Romanian Journal of Internal Medicine, 58(1), 20-26. https://doi.org/10.2478/rjim-2019-0021
McQueen, D. B., Maniar, K. P., Hutchinson, A., Confino, R., Bernardi, L., & Pavone, M. E. (2021). Redefining chronic endometritis: The importance of endometrial stromal changes. Fertility and Sterility, 116(3), 855-861. https://doi.org/10.1016/j.fertnstert.2021.04.036
Mihailă, R. (2020). Coagulation challenges in pregnancy: From thrombophilia involvement and management to the utility of thrombin generation monitoring. Clinical and Experimental Obstetrics & Gynecology, 47(6), 814. https://doi.org/10.31083/j.ceog.2020.06.5499
Pencheva, D. T., Coffey, A., McKenna, S. P., & Monov, S. V. (2023). Adaptation and validation of the Bulgarian version of the systemic lupus erythematosus quality of life questionnaire (L-QoL). Clinical Rheumatology, 42(7), 1811-1817. https://doi.org/10.1007/s10067-023-06523-w
Practice Committee of the American Society for Reproductive Medicine. (2020). Definitions of infertility and recurrent pregnancy loss: A committee opinion. Fertility and Sterility, 113(3), 533-535. https://doi.org/10.1016/j.fertnstert.2019.11.025
Robeva, R., Marinova, E., Nikolaev, G., Andonova, S., Savov, A., Tanev, D., Nikolov, G., & Konakchieva, R. (2022). Melatonin receptor 1B polymorphisms and reproductive failure - a pilot study. Proceedings of the Bulgarian Academy of Sciences, 75(5), 745-751. https://doi.org/10.7546/CRABS.2022.05.15
Sosic, G. M., Sretenovic, S., Radivojevic, D., Jovic, N., & Varjacic, M. (2020). The impact of the gene variants FV Leiden, FII G20210A, MTHFR C677T and PAI-1 4G/5G on pregnancy loss in women from Central Serbia. Serbian Journal of Experimental and Clinical Research, 21(1), 19-25. https://doi.org/10.1515/sjecr-2017-0070
Sowmya, S., Ayyali, A., Vidya, K. R., & Nagesh, H. N. (2022). Genetic variation of folate metabolic pathway in recurrent pregnancy loss - A systematic review. International Journal of Medical Reviews and Case Reports, 6(1), 50-53. https://doi.org/10.5455/IJMRCR.172-1661674148
Turesheva, A., Aimagambetova, G., Ukybassova, T., Marat, A., Kanabekova, P., Kaldygulova, L., Amanzholkyzy, A., & Atageldiyeva, K. (2023). Recurrent pregnancy loss etiology, risk factors, diagnosis, and management: A comprehensive review. Journal of Clinical Medicine, 12(12), 3982. https://doi.org/10.3390/jcm12123982
Tüttelmann, F., Ivanov, P., Dietzel, C., Sofroniou, A., Tsvyatkovska, T. M., Komsa-Penkova, R. S., Markoff, A., Wieacker, P., & Bogdanova, N. (2023). M2/ANXA5 haplotype as a predisposition factor in German and Bulgarian women with early recurrent pregnancy loss. Journal of Assisted Reproduction and Genetics, 40(3), 617-624. https://doi.org/10.1007/s10815-022-02701-8
Verma, U. (2023). Current status of hysteroscopy in the diagnosis and management of recurrent pregnancy loss. Journal of Minimally Invasive Gynecology, 30(2), 98-106. https://doi.org/10.1016/j.jmig.2022.11.008