Discussion
The cause of spontaneous abortion is generally attributed to two
sources, namely seed problems and environmental problems. Seed problems
are often considered to be abnormal parental chromosomes or abnormal
fetal chromosomes. The results of this study showed that the incidence
of chromosomal abnormalities in couples with recurrent miscarriage was
3.74%(Figure1). The present results consistent with previous studies
have shown that the incidence of chromosomal abnormalities in the
general population is less than 1%[15, 16] and RM population is
2%-5%[17, 18], indicating that parental chromosomal abnormalities
rate increased assuredly in the miscarriage couples.
Balanced translocation was the most common type, accounting for 38.02%
and consistent with other findings[11]. A meta-analysis from Zouhair
reported that frequency of chromosomal abnormalities in couples with RM
was 5.16% and the most common reciprocal translocation accounts 48.4%
in the worldwide literature review[12]. The balanced translocations
and inversions will not affect the parents themselves in phenotype, but
their unbalanced gametes during meiosis may indeed be part of the cause
of miscarriage. Similarly, Robertsonian translocation of parental
chromosomes can also cause miscarriage, birth defects or mental
retardation of offspring[19]. However, all these studies could not
demonstrate the explicit causality between aberrant chromosome and
abortions.
Additionally, the LBR of RM carriers in our reproductive center have
reached more than 70%, indicating that the proportion of miscarriage
caused by chromosomal abnormalities in RM couples was very slight. A
retrospective study from Howard et al. concluded that no statistically
significant was found in the LBR between RM couples with chromosomal
abnormality (45.2%, 33/73) and the normal couples was (55.3%,
325/588), regardless of number of miscarriages and rearrangement types
of chromosomal abnormalities [20]. In Goddijn’s study the screening
results of 1324 RM couples showed that all the 41 couples with abnormal
structure chromosomes did not yield an unbalanced fetal chromosome
pattern [21]. It is also consistent with Franssen’s study, the LBR
of RM carriers was equivalent to the normal couples after six
accumulated gestations, and had no relevance with the type of abnormal
chromosome (83% vs. 84%)[22]. However, Sugiura’s study showed
pregnancy prognosis was worsened with either maternal or paternal
reciprocal translocations than normal couples (63% vs. 78.7% of
LBR)[23]. Pregnancy outcomes for RM couples with chromosomal
abnormalities were still very satisfactory generally, although the
decrease in the live birth rate may not have been detected due to
insufficient sample size in our study.
Preimplantation genetic testing (PGD) has been proposed as a
controversial method in the worldwide for selecting normal chromosome
embryos in the IVF to lower risk of miscarriage for patients with
unexplained RM and balanced translocations carriers. However,
well-designed trials comparing EM (expectant management) to PGD have not
been performed. Several previous cases indicated benefits of PGD
including fewer miscarriages and shorter time to successful pregnancy
without taking into account the emotional and financial cost of a failed
or canceled cycle. More recent reports suggested clinical outcomes
including pregnancy
rate,
live birth rate (53% vs. 67%) and clinical miscarriage rate were
similar between PGD and EM among recurrent miscarriage patients[24].
Even in the parental carriers of structural chromosomal rearrangement
and history of RM, no significant difference with regards to
reproductive outcomes such as miscarriage rate, time to live birth, or
live birth rate was observed between couples who pursued PGD compared
with EM [25, 26]. These data combined with our results allow us to
reflect on the actual benefits of PGD to these patients, so clinicians
can be more cautious when making an alternative of PGD in clinical work.
Natural conception is also recommended as a good alternative for these
aberrant chromosomal carriers.
50%-60% of spontaneously aborted product of conception have been
detected with chromosomal abnormality [27]. The abnormal chromosomes
of the fetus are derived from the parental abnormal chromosomes or
produced in the process of gamete meiosis and mitosis of the fertilized
egg by mistake randomly. The types of fetus abnormality were often
mainly manifested as trisomies of chromosome 13, 18, 21 and X monosomy
(45, X) [28], but not consisted with the translocation chromosomes
of the parents showed as in the Figure 3. According to
Howard
Carp’s study, parental karyotyping was not particularly predictive of a
subsequent miscarriage, 43.5% of abortus from parental carriers were
euploidic and the parental aberration was passed on to the abortus in
only 10% of cases[29]. The phenotypes are inconsistent that
parental karyotyping prefers balanced translocations (No. 8, 2, 6) and
inversions (No. 9, 1, 6) rather than the more common numerical
aberrations such as trisomies (No. 13, 18, 21) and polyploidy in fetus.
Most aberrant chromosomes in the fetus are generated randomly and only a
small percent derives from their parents.
One of the most important results in our data is the influence of
parental chromosomes on live birth rate (LBR). In our study, the LBR of
both carriers and non-carriers can reach about 70% without relationship
of gender, female age, chromosome abnormal type, abortion times and
other pathological factors. Amounts of non-genetic pathological causes
related to endocrine, infection, immune and nutrition were detected not
only in aberrant chromosomal carriers but also in non-carriers, while
these factors have a strong impact on the pregnancy outcomes. After
effective treatments such as anticoagulation and immunotherapy, the LBR
of re-pregnancy after two recurrent miscarriages has reached more than
70% internationally. A prospective study showed that closely following
management and treatment of other high-risk factors can increase the LBR
of RM couples with chromosomal abnormalities from 25% to 70%[30]
or from 20% to 71% without the addition of assisted reproductive
technology[11]. The differences of LBR in RM carriers in previous
reports may due to the different management of non-genetic pathological
factors that are usually more important in fetal survival.
From these data, we strongly recommend that RM carriers should still
undergo comprehensive and systemic etiological screening. Therefore, it
is necessary to actively deal with other causes of miscarriage in order
to improve the chances of successful pregnancy for RM patients with
chromosomal abnormalities. In order to improve the live birth rate, our
treatment included surgical correction of the anatomically abnormal
uterus, male lymphocyte treatment, anticoagulation aimed at
anti-phospholipid antibody and immunosuppressive therapy were strongly
recommended besides chromosome abnormality in our opinions. The
formation frequency of abnormal gametes theoretically is not equal to
the birth rate of abnormal babies in practice, we still recommend that
the chromosome test or next-generation sequencing analysis of the
amniotic fluid through puncture should be performed around 18 weeks of
gestation for the natural pregnancy of RM patients with chromosomal
abnormalities, although the deletion or duplication of smaller fragments
still cannot be detected.
The present study did not detect the karyotype of aborted fetuses and
not achieve complete amniocentesis results from the pregnancy carriers.
So we could not assess the impact of fetal chromosomal problems came
from parents. In the study of embryo chromosome analysis of abortion
tissue, trisomy and polyploidy are the majority which account for 65%
and 17% respectively, a considerable proportion of fetus with
aberrations include trisomy, structural abnormality and low-frequency
mosaic could survive after birth[28]. The phenotypes are
inconsistent that parental karyotyping prefers balanced translocations
and inversions rather than the more common numerical aberrations such as
trisomy and polyploidy in fetus. In addition, G-banding karyotype
analysis used in this study can only detect a part of patients with
abnormal numerical and structural chromosomes. Conventional karyotype
analysis identifies balanced and unbalanced chromosomal rearrangements
and copy number variants (CNVs) to a∼5 Mb resolution. Due to the
limitations of the detection method itself, it could not exclude some
other types of genes or chromosome abnormalities related to miscarriage
problems, such as deletion, insertion, duplication and point mutation of
some gene fragments. In 2019, Chen et al. used low pass genome
sequencing (GS) to detect the chromosomes of RM couples with
abnormalities rate increased to 11.7% compared to traditional
karyotyping with 5.7%. However, inversions and copy-number variants
detected by GS additionally had not been confirmed to directly related
with miscarriage. 10 carriers observed in follow-up observations and
five of them miscarried again (miscarriage rate of 50%). The small
sample size did not indicate that the risk of miscarriage of abnormal
chromosome couples was higher than that of couples with normal
chromosomes[31].
Finally, the lack of samples even in this 11-year study and other
combined known and unknown non-genetic factors are shortcomings in the
present data. The etiology of recurrent miscarriage is complicated and
there are many controversies in the treatment. The coexistence of these
other pathological factors and chromosomal abnormalities makes the
results confused and controversial.