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accounted for 3.75% in our unpublished data, consistent with 2%-5%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.