Discussion
Chromosomal abnormalities in couples with recurrent pregnancy loss accounted for 3.75% in our unpublished data, consistent with 2%-5% found in other studies, representing a 5-10 fold increase compared with that in the general population [4, 20]. Structural chromosomal abnormalities can lead to unbalanced gametes depending on specific recombination and segregation patterns during meiosis. The attendant reproductive risk depends on the type of rearrangement and its parental origin[21]. Some experts considered no significant impact of parental aberrant chromosomes on the pregnancy outcomes[9, 12, 15]while others did not[10, 11, 13, 14]. Additionally, Maureen Franssen analysed the live birth rate per couple of one time and more times pregnancies separately, and found a difference in the FPLBR and ALBR accordingly[17]. No coinciding views of the influence of parental chromosomal aberration on the pregnancy outcomes were found, such as live birth or miscarriage risk. The divergence in the above studies has prompted us to perform a meta-analysis to determine the real effect on the pregnancy outcomes of carriers and no similar earlier meta-analysis was found in the present literature. Generally, parental chromosomal aberration significantly increased the risk of miscarriage and decreased FPLBR in various populations of patients in this meta-analysis.
The innovation of the present meta-analysis compensates for the deficiency in the literature as follows: first, as the chance of finding an abnormality is very low, some previous studies did not obtain reliable results because of an insufficient sample size. More than 700 carriers and 5000 noncarriers were included from European, Asian, and North American countries. Second, chromosomal aberrant subtypes, such as translocation, inversion or numerical aberration were not calculated separately, while the different types had different degrees of influence on the pregnancy outcomes [9, 12, 15]. Subtype analysis could obtain a significant result more likely according to the different effects on the development of foetus. Finally, the live birth rate of one time or multiple pregnancies was not distinguished and unified in some studies. A higher live birth rate of one pregnancy indicates a lower miscarriage rate and vice versa, while this relationship does not exist between the live birth rate of multiple pregnancies and the miscarriage rate per couple. The data on the LBR and miscarriage rate per couple were processed uniformly in our study.
To determine real effect of parental chromosomal aberrations on the live birth and miscarriage rate, this systematic review investigated the available literature on pregnancy outcomes in recurrent miscarriage couples with parental chromosomal abnormalities and normalities. Different populations and areas were also included. Heterogeneity (I2) was no more than 50% in all the results. Overall, we found that parental chromosomal abnormalities increased the risk of miscarriage in couples with RPL, the initial live birth rate was significantly lower, particularly for the translocation carriers but not inversion carriers. However, these RPL carriers eventually achieved a satisfactory accumulated live birth rate per couple,a finding that agreed with a early study[22]. Natural conception should be considered a good alternative because its accumulated live birth rate is satisfactory for carriers with RPL. Carriers have a risk of miscarriage because of abnormal gametes, but can obtain a live child through trials of multiple pregnancies. Because carriers with translocations are more likely to produce unbalanced gametes than inversions, translocations may have a larger effect on miscarriage.
ESHRE recommends against performing routine karyotyping of RPL couples, but rather after an individual risk assessment such as female age [1]. Once chromosome aberrations are detected in RPL couples who are confronted with chaenging decisions, such as trying to naturally conceive again, undergoing amniocentesis in future pregnancies and terminating a pregnancy once an unbalanced foetal karyotype is found or performing IVF/PGD and choosing normal karyotype embryos to transfer. The treatment of chromosome abnormalities in RPL couples comprises PGD in many reproductive centres worldwide. Although PGD seems an attractive and promising option for couples who are desperate for help, the benefits of PGD have been inconclusive thus far before introducing this technique into our routine medical work. Some studies seemed to illustrate strong evidence for a significant association between the pregnancy outcomes of PGD in carriers and showed that PGD improved the outcomes[23, 24]. These studies were doubtful and equivocal because they compared the results before and after the PGD for carriers and could not exclude clinical management in addition to the PGD. Non-genetic treatment is valuable and the main intervention in the natural conception for carriers with recurrent miscarriage, such as immunotherapy[25].
PGD has been proposed to improve and optimize live birth since 1988 and has been used to identify genetic abnormalities before embryo transfer[26]. Thousands of cycles have been performed worldwide and partial studies have indicated that PGD could increase successful pregnancy outcomes in translocation carriers by selecting balanced embryos[27, 28]. However, limited evidence in couples with RPL shows definite benefits of PGD or natural conception. Three earlier systematic reviews of PGD did not show an advantage with this strategy compared with expectant management and no sufficient evidence showed that PGD improves the pregnancy outcomes in RPL carriers, compared with NC[29-31]. The above three meta-reviews only list some studies about the pregnancy outcomes of using PGD alone or using NC alone, without comparative studies included. In our data we found no significant difference in the accumulated LBR but a higher miscarriage rate comparing NC with PGD in RPL carriers in two comparative outcomes. PGD could help decrease miscarriage risk, but failed or canceled cycles with no normal embryos to transfer, IVF related complications and high cost are main concerns for patients considering PGD[32].
The quantity and quality of the evidence on the comparing pregnancy outcomes between the PGD and natural conception were low. The alternatives for patients are affected by various subjective and objective factors; thus we could hardly compare the benefits of PGD and natural conception randomly. According to the above situation, we should be very cautious before making any conclusions or recommendations to clinical patients. Doctors must recongnize that the pregnancy outcome of recurrent abortion is caused by many factors, includingunknown factors, and cannot regard any an abnormal result as the factual relationship of abortion.
The origin of the heterogeneity in the present review was not found among the included studies because the female age and miscarriage times were similar before diagnosis. Other factors, such as diversity in ethnicity, the type of translocation, PGD methods and study design, might be sources of heterogeneity without adjusting the data for these factors, representing a potential limitation of this study. Another limitation of our meta-analysis was the insufficient number of studies, particularly for subgroup analysis and PGD analysis.
Conclusion
The results of this systematic review may support that RPL carriers have a higher risk of miscarriage than noncarriers. Thus the live birth rate of one pregnancy is lower,but carriers can eventually obtain a satisfactory cumulative live birth rate through multiple pregnancies. Furthermore, additional studies of the benefits of PGD in the RPL carriers are urgently required.
Study funding: This work was supported by the National Key Research and Development Program of China (No. 2018YFC1002804), the National Natural Science Foundation of China (No. 81901497).
Conflict: All authors declare that they have no conflict of interest in the article.
1. Bender Atik, R., et al., ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open, 2018. 2018 (2): p. hoy004.
2. Alijotas-Reig, J. and C. Garrido-Gimenez, Current concepts and new trends in the diagnosis and management of recurrent miscarriage.Obstet Gynecol Surv, 2013. 68 (6): p. 445-66.
3. Jauniaux, E., et al., Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod, 2006. 21 (9): p. 2216-22.
4. Popescu, F., C.R. Jaslow, and W.H. Kutteh, Recurrent pregnancy loss evaluation combined with 24-chromosome microarray of miscarriage tissue provides a probable or definite cause of pregnancy loss in over 90% of patients. Hum Reprod, 2018. 33 (4): p. 579-587.
5. Fryns, J.P. and G. Van Buggenhout, Structural chromosome rearrangements in couples with recurrent fetal wastage. Eur J Obstet Gynecol Reprod Biol, 1998. 81 (2): p. 171-6.
6. Ogasawara, M., et al., Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril, 2000.73 (2): p. 300-4.
7. Carp, H., et al., Karyotype of the abortus in recurrent miscarriage. Fertil Steril, 2001. 75 (4): p. 678-82.
8. FitzSimmons, J., et al., Subsequent reproductive outcome in couples with repeated pregnancy loss. Am J Med Genet, 1983.16 (4): p. 583-7.
9. Carp, H., et al., Parental karyotype and subsequent live births in recurrent miscarriage. Fertil Steril, 2004. 81 (5): p. 1296-301.
10. Sugiura-Ogasawara, M., et al., Subsequent pregnancy outcomes in recurrent miscarriage patients with a paternal or maternal carrier of a structural chromosome rearrangement. J Hum Genet, 2008.53 (7): p. 622-628.
11. Ozawa, N., et al., Pregnancy outcomes of reciprocal translocation carriers who have a history of repeated pregnancy loss.Fertil Steril, 2008. 90 (4): p. 1301-4.
12. Kabessa, M., et al., Pregnancy outcomes among patients with recurrent pregnancy loss and chromosomal aberration (CA) without PGD. J Perinat Med, 2018. 46 (7): p. 764-770.
13. Dong, Y., et al., Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of chromosome abnormalities or polymorphisms. Genet Mol Res, 2014. 13 (2): p. 2849-56.
14. Sugiura-Ogasawara, M., et al., Poor prognosis of recurrent aborters with either maternal or paternal reciprocal translocations.Fertil Steril, 2004. 81 (2): p. 367-73.
15. Pal, S., et al., Chromosomal abnormalities and reproductive outcome in Malaysian couples with miscarriages. Singapore Med J, 2009.50 (10): p. 1008-12.
16. Flynn, H., et al., Comparison of reproductive outcome, including the pattern of loss, between couples with chromosomal abnormalities and those with unexplained repeated miscarriages. J Obstet Gynaecol Res, 2014. 40 (1): p. 109-16.
17. Franssen, M.T., et al., Reproductive outcome after chromosome analysis in couples with two or more miscarriages: index [corrected]-control study. Bmj, 2006. 332 (7544): p. 759-63.
18. Ikuma, S., et al., Preimplantation Genetic Diagnosis and Natural Conception: A Comparison of Live Birth Rates in Patients with Recurrent Pregnancy Loss Associated with Translocation. PLoS One, 2015.10 (6): p. e0129958.
19. Maithripala, S., et al., Prevalence and Treatment Choices for Couples with Recurrent Pregnancy Loss Due to Structural Chromosomal Anomalies. J Obstet Gynaecol Can, 2018. 40 (6): p. 655-662.
20. Elkarhat, Z., et al., Chromosomal abnormalities in couples with recurrent spontaneous miscarriage: a 21-year retrospective study, a report of a novel insertion, and a literature review. J Assist Reprod Genet, 2019. 36 (3): p. 499-507.
21. Kaser, D., The Status of Genetic Screening in Recurrent Pregnancy Loss. Obstet Gynecol Clin North Am, 2018. 45 (1): p. 143-154.
22. Stephenson, M.D. and S. Sierra, Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of a structural chromosome rearrangement. Hum Reprod, 2006. 21 (4): p. 1076-82.
23. Fischer, J., et al., Preimplantation genetic diagnosis (PGD) improves pregnancy outcome for translocation carriers with a history of recurrent losses. Fertil Steril, 2010. 94 (1): p. 283-9.
24. Huang, C., et al., Pregnancy outcomes of reciprocal translocation carriers with two or more unfavorable pregnancy histories: before and after preimplantation genetic testing. J Assist Reprod Genet, 2019. 36 (11): p. 2325-2331.
25. Carp, H., Immunotherapy for recurrent pregnancy loss. Best Pract Res Clin Obstet Gynaecol, 2019. 60 : p. 77-86.
26. Munné, S., et al., First pregnancies after preconception diagnosis of translocations of maternal origin. Fertil Steril, 1998.69 (4): p. 675-81.
27. Otani, T., et al., Preimplantation genetic diagnosis significantly improves the pregnancy outcome of translocation carriers with a history of recurrent miscarriage and unsuccessful pregnancies.Reprod Biomed Online, 2006. 13 (6): p. 869-74.
28. Lee, E., et al., The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review. Hum Reprod, 2015. 30 (2): p. 473-83.
29. Franssen, M.T., et al., Reproductive outcome after PGD in couples with recurrent miscarriage carrying a structural chromosome abnormality: a systematic review. Hum Reprod Update, 2011.17 (4): p. 467-75.
30. Musters, A.M., et al., Pregnancy outcome after preimplantation genetic screening or natural conception in couples with unexplained recurrent miscarriage: a systematic review of the best available evidence. Fertil Steril, 2011. 95 (6): p. 2153-7, 2157.e1-3.
31. Iews, M., et al., Does preimplantation genetic diagnosis improve reproductive outcome in couples with recurrent pregnancy loss owing to structural chromosomal rearrangement? A systematic review.Reprod Biomed Online, 2018. 36 (6): p. 677-685.
32. Schmutzler, A.G., Theory and practice of preimplantation genetic screening (PGS). Eur J Med Genet, 2019. 62 (8): p. 103670.