2015, Volume 31, Number 2, Page(s) 111-118
Chromosome Abnormalities Identified in 457 Spontaneous Abortions and Their Histopathological Findings
Sezin YAKUT1, Havva Serap TORU2, Zafer ÇETİN3, Deniz ÖZEL4, Mehmet ŞİMŞEK5, İnanç MENDİLCİOĞLU5, Güven LÜLECİ1
1Department of Medical Biology and Genetics, Akdeniz University, School of Medicine, ANTALYA, TURKEY
2Department of Pathology, Akdeniz University, School of Medicine, ANTALYA, TURKEY
3Department of Medical Biology and Genetics, SANKO University, School of Medicine, GAZİANTEP, TURKEY
4Department of Biostatistics and Medical Informatics, Akdeniz University, School of Medicine, ANTALYA, TURKEY
5Department of Obstetrics and Gynecology, Akdeniz University, School of Medicine, ANTALYA, TURKEY
Keywords: Chromosomal abnormalities, Cytogenetic abnormalities, Pathology, Spontaneous abortion
About 15% of clinically recognized pregnancies result
in spontaneous abortion in the first trimester and the vast majority
of these are the result of chromosome abnormalities. Studies of
chromosomal constitutions of first trimester spontaneous abortions
have revealed that at least 50% of the abortions have an abnormal
karyotype. In this study we aimed to report the single centre
experience of anomalies detected in spontaneous abortions.
Material and Method: We present rare numerical and structural
cytogenetic abnormalities detected in spontaneous abortion materials
and the histopathological findings of rest material of abortion
specimens in our study population.
Results: Among 457 cases, 382 were successfully karyotyped while
cell culture of 75 cases failed. Cytogenetic abnormalities were
detected in 127 of 382 cases (33.24%). Autosomal trisomies were the
predominant chromosomal abnormalities with a frequency of 48.8%.
Structural chromosomal abnormalities were infrequent in conception
materials. The mean age of the mothers was highest in trisomy group,
the difference being significantly important (ANOVA p< 0.001). The
most frequent chromosomal abnormalities were Turner syndrome,
triploidy and trisomy of chromosome 16 followed by trisomy of
chromosomes 22 and 21 and tetraploidy. Double trisomies and
structural chromosomal abnormalities were rare. Trisomies were
more frequent in advanced maternal age.
Conclusion: Detection of chromosomal abnormalities in spontaneous
abortion materials is very important to clarify the causes of loss of
pregnancy. Detection of structural chromosomal abnormalities
in the cases and their carrier parents can provide proper genetic
counseling to these families. These families can be directed towards
pre-implantation genetic diagnosis to prevent further pregnancies
About 15% of clinically recognized pregnancies result
in spontaneous abortion (SAB) in the first trimester and
the vast majority of these are the result of chromosome
. Studies of chromosomal constitutions
of first trimester spontaneous abortions have revealed that
at least 50% of abortions have an abnormal karyotype4-6
There are several etiologies that might be associated with
pregnancy losses including endocrine, immunological,
environmental factors, infections, anatomic malformations
and genetic abnormalities7
. The most common
chromosomal abnormality observed within first trimester
spontaneous abortions is single trisomies8
clinically recognizable SABs occur between 7 and 11
weeks of gestation. Around 50% of spontaneous abortions
are caused by de novo aneuploidy or polyploidy due to
meiotic or post zygotic mitotic error, de novo unbalanced
rearrangements, and unbalanced segregation products of the
parental balanced translocations. Unbalanced chromosome
constitution could affect placental development resulting in
. Carriers of balanced reciprocal
translocations have a high reproductive risk of conceiving
chromosomally abnormal embryos as a result of imbalances
during meiosis, leading to recurrent abortions or birth of
. Chromosomal abnormalities can
be detected by using conventional cytogenetic analysis.
Evaluation of chromosomal abnormalities in pregnancy
losses is important to understand the associations between
chromosomal abnormalities and pregnancy losses and
to provide proper genetic counseling to the parents.
Histopathological evaluation of abortion material is also
important because it may not be possible or reasonable
to undertake complex cytogenetic studies of spontaneous
abortion on a routine basis because of the expense and as it
adds little to management.
We present here rare numerical and structural cytogenetic
abnormalities detected in spontaneous abortion materials
and the histopathological findings of rest material of
abortion specimens in our study population.
In our eleven-year experience, we had a total number of
457 miscarriage cases. Conception products were provided
to Department and Medical Biology and Genetics by the
department of the Obstetrics and Gynecology of the Akdeniz
University Hospital to perform conventional cytogenetic
analysis and the rest material of miscarriage samples
were sent to pathology department for histopathological
evaluation. Gestational ages varied from 7 to 36 weeks.
Detailed reproductive histories were obtained from the
families including gestational age, maternal age and
outcome of previous pregnancies. To avoid maternal blood
contamination, miscarriage samples containing chorionic
villi were washed three times in physiological serum
saline solution. Fetal or fetus-derived extra-embryonic
tissues were identified and dissected from surrounding
maternal deciduas. Selected tissue samples were minced
and cultivated in T-25 tissue culture flasks including 5
ml Amniopan and Amniogrow complete mediums (Biotech,
Cytogen), 0.05 ml penicillin-streptomycin solution
(Biological Industries) and 0.05 ml L-Glutamine (Biological
Industries). Metaphase chromosomes were harvested and G
banded by GTG banding following standard procedures. In
each case, at least twenty metaphase plates were evaluated
by light microscopy.
The rest miscarriage material of 76 of 457 cases was sent
to the pathology department. Formalin-fixed and paraffinembedded
blocks were sectioned in 3μ thickness and
stained with hematoxylin eosin. These hematoxylin eosinstained
sections were examined under the light microscope
by an experienced pathologist.
Descriptive analyses were given as frequency, percentage,
mean and Standard Deviation (SD). The Pearson Chisquare
test was used for analysis of categorical data. For
comparing the age difference between the chromosomal
abnormality groups, the ANOVA (Analysis of Variance)
test was used and after finding a significant difference the
Bonferroni test was used for pair-wise comparison. ROC
(Receiver Operating Characteristic) analysis was used for
differentiating the chromosomally abnormal group from
the normal group according to age. For statistical analyses,
the SPSS 18.0 package software was used. p < 0.05 was
accepted as statistically significant.
Among the 457 cases, 382 were successfully karyotyped
(culture success rate: 83.58%) while the cell culture of 75
cases failed (culture failure rate: 16.42%). Cytogenetic
abnormalities were detected in 127 of 382 cases (33.24%).
We included 257 cases of 382 karyotyped cases in our
study group. This study group consisted of 127 cases of the
karyotypically abnormal group and 130 cases of the control
group with normal karyotype (with ages and abortion rates
similar to the karyotypically abnormal group). The design
of our study is given in Table I
. The mMean maternal
age in the karyotypically abnormal cases was 31.11 years
(Standard Deviation (SD) ± 5.49) and the mean gestational
age was 9.44 weeks (SD ± 3.39).
Normal chromosomal constitution was detected in 255
cases (66.76%). The female/male sex ratio of the cases
with a normal karyotype was 1.74 (162 females/93 males).
The frequency of chromosomal abnormalities was higher
in the group composed of cases with an age over 35 years
than in younger cases (41.86% vs 30.67%). Chromosome
abnormalities were more frequent in first trimester
conceptions than second trimester conceptions (43.6% vs
7.77%). Turner syndrome and trisomy 16 were the most frequent abnormalities in the cases aged below 35 years
of age, whereas trisomy 16 and trisomy 21 were the most
frequent abnormalities in the cases aged over 35 years.
Autosomal trisomies were the predominant chromosomal
abnormalities with a frequency of 48.8% of all chromosome
abnormalities, followed by 45, X, (n: 21, 16.5%), triploidies
including mosaics (n: 17, 13.38%), tetraploidies (n: 7 cases;
5.5%), double or triple trisomies of various chromosomes
(n: 6 cases, 4.72%), and XY/XX/XXY mosaicism (n: 1 case, 0.78%). The most common trisomies were trisomy 16
(n: 16, 12.7%), 22 (n: 10, 7.8%), 21 (n: 7, 5.5%), 13 (n:4,
3.1%) and 10 (n:4, 3.1 %) (Table II). Among the triploid
cases, 12 cases had 69, XXY (one of them had an associated
anomaly) and 5 cases were 69, XXX karyotypes (3 of them
had an associated anomaly). 4 cases with tetraploidy had
the 92, XXYY karyotype whereas 3 cases had the 92, XXXX
Karyotype descriptions of the cases with double trisomies
were 48,XY,+7,+21, 48,XX,+16,+21, 48,XX,+13,+15,
48,XY,+2,+21. Trisomies of chromosomes 8, 16 and 21 were
observed in one case. Also, trisomies of chromosomes 8, 12,
18, 20 were observed in another case.
Structural chromosomal abnormalities were infrequent
in conception materials, and some rare structural
abnormalities including de novo structural chromosome
abnormalities such as derdic13(13;18)(p11.1;p11.1)
leading to partial trisomy 18p11.1-pter, del(18)(p11.2-pter)
and del(7)(q22q32) were found. Unbalanced products of
the parental balanced Robertsonian translocations were
observed in four cases. In case 10, a derivative chromosome
from adjacent-1 segregation of the paternal balanced
reciprocal translocation t (6; 13) (p23; q12) resulted in
partial monosomy 6p23-pter and partial trisomy 13q12-
qter regions. In case 11, de novo der5 t(5;13) (p15; q12)
resulted in partial monosomy 5p15-pter and partial trisomy
13q12-qter regions. Case 12 had interchange trisomy 7,
resulting from 3:1 segregation of the familial reciprocal
translocation t(5;7) (q13:p11.2). Co-existence of trisomy
16 and a familial transmitted balanced translocation t(1;5)
(p22;q13) was observed in case 13 (Table III).
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|Table III: Rare numerical and structural chromosomal abnormalities detected in spontaneous abortion materials
In cytogenetically abnormal groups; the mean age of the
mothers was 28.57 (SD: ±4.79) years in the Turner group,
32.95 (SD: ± 5.01) in the trisomy group, 29, 29 (SD: ± 5.19)
in the triploid and tetraploid group, and 28.42 (SD: ± 6.40)
in the structural abnormalities group. The mean age of the
mothers was highest in the trisomy group and the difference
was significant (ANOVA p< 0.001). In the chromosomally
abnormal group 8 of 21 Turner cases (38.1%), 37 of 70
trisomy cases (52.9%), 10 of triploidy-tetraploidy cases
(41.7%), and 8 of 12 structural anomaly cases (66.7%)
had a previous spontaneous abortion history. Statistically
there was no significant difference between chromosomally
abnormal cases (Chi-square, p=0.332) (Table IV). The
mean age of the chromosomally normal 130 cases was
30.57 (SD: ± 5.31) years. The cut-off age for trisomies was
30 years (criterion values and coordinates of ROC curve are
given in Figure 1).
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|Table IV: Mean age and abortus history of each karyotypically abnormal cases
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|Figure 1: ROC analysis of ages determining cut off age of trisomy
ROC: Receiver Operating Characteristic, PPV: Positive Predictive Value, NPV: Negative Predictive Value, OR: Odds Ratio, CI: Confidence Interval
Histopathological examination was performed for 72
cases and 53 cases (73.6%) had nonspecific changes (such
as perivillous fibrin, hydropic villi), 11 cases (15.3%)
were exaggerated placental site and 8 cases (11.1%) were
incomplete mole hydatidiform. Exaggerated placental
site cases cytogenetically consisted of 3 (27.3%) Turner
syndrome, 1 (9.1%) trisomy 10, 1 (9.1%) trisomy 9, 2
(18.2%) tetraploidy and 2 (18.2%) rare trisomy cases.
Partial mole hydatidiform cases cytogenetically consisted
of 2 each of triploidy and structural anomaly, and one
each of Turner syndrome, Trisomy 16, Trisomy 13 and
double trisomy cases. There was no clinically significant
relationship between histopathological diagnosis and
The most frequent chromosomal abnormalities were
Turner syndrome, triploidy and trisomy of chromosome
16 followed by trisomy of chromosomes 22 and 21 and
tetraploidy in our study population while double trisomies
and structural chromosomal abnormalities were rare. These
findings were in concordance with the literature7,12
We detected several rare double trisomies and structural
chromosomal abnormalities in spontaneous abortion
Double trisomy is a rare and could be detected in nearly
1.2% of the karyotyped spontaneous miscarriage materials
with inter-institutional variability ranging between 0.80-
2.64 percent13,14. In our study, frequency of the double
trisomy was 1.3% and in concordance with the literature.
After the first report of a patient with Down-Klinefelter
syndrome, more than 385 double trisomies have been
reported14. Double trisomies were more frequent in
cases with advanced maternal age greater than 35 years. The
mean age of our cases with double or multiple trisomies was
35.6 years. Autosomal chromosomes frequently observed
in single trisomies such as chromosomes 8, 13,15,16,18
and 21 and sex chromosomes were also the most frequently
involved chromosomes in double trisomies in spontaneous
abortions. According to the recent reviews, double trisomy
of chromosomes X&22 was the first while trisomy 2&21
and trisomy 7&21 were the second reported cases in the
literature. Triple or multiple trisomies are also rare with a
frequency of 0.05% in spontaneous abortion materials15.
This figure was 0.52% in our study population.
Trisomies are more frequent in advanced maternal age16. The maternal age in the trisomy group was higher
than the other chromosomally abnormal groups and
the chromosomally normal group in our study as in the
literature. The cut-off value for maternal age that increases
the risk of trisomy was 30 years. The prenatal evaluation
of a fetus where the maternal age is over 30 years should
be more detailed because the estimated trisomy ratio is
higher than the maternal age under 30 years. The most
common trisomy is trisomy 21 in all pregnancy materials
and live births17,18. It is known that the most common
trisomy in spontaneous abortion is trisomy 1619. In our
study, trisomy 16 was the most common abnormality in the
trisomy group. Our cases were in the missed abortion group
and this may show that trisomy 21 usually does not cause
missed abortion as much as trisomy 16 and 22, but we can
not say the same thing for the other trisomy groups because
they are actually rare in all pregnancy materials13,18.
Reciprocal translocations are the most common structural
chromosomal rearrangements in humans with an estimated
incidence of 1:712 in newborns20. In meiosis, the
translocated chromosomes might be segregated in different
segregation modes resulting in different chromosomal
constitutions in gametes. Only alternate segregation
results in normal or balanced gametes. Analysis of meiotic
segregation modes by FISH in pre-implantation embryos
from pre-implantation genetic diagnosis cycles showed
that 2:2 segregation was the predominant segregation
mode (59.1%) followed by, 3:1 segregation (22.0%), and
4:0 segregation (2.0%). In the 2:2 segregations, incidence
of adjacent-1 (26.8%) was higher than that of alternate
(22.4%) or adjacent-2 (6.1%) segregation11. Most of the
embryos with unbalanced genetic content were eliminated
by spontaneous abortions and still births21. In case 10,
der6 t (6;13) (p23;q12) had developed from adjacent-1
segregation of the paternal translocation and resulted
in partial trisomy 13q13-qter region and concomitant
monosomy of the 6p23-pter. However, in case 11, the der5 t(5;13) (p15;q12) derivative chromosome was de novo
and resulted in partial trisomy 13q12-qter and monosomy
5p15-pter, The rate of interchange trisomy resulting from
3:1 segregation was higher in balanced translocations with
acrocentric chromosomes with a frequency of 9.5% than
that without acrocentric chromosomes at 4.3%11. To our
knowledge, our case 12 is the first case with interchange
trisomy of the chromosome 7 detected in spontaneous
abortion material resulting from 3:1 segregation of the
familial translocation t(5;7)(q13;p11.2).
The coexistence of a reciprocal translocation and
chromosomal aneuploidy in an individual is also a rare
event and several reciprocal translocation carrier Down
syndrome patients have been reported22-24. In some
of the cases, an inter-chromosome effect between these
two events has been suggested25. To the best of our
knowledge, this is the first report of the coexistence of
trisomy 16 and familial transmitted balanced reciprocal
translocation t(1;5) (p22; q13) detected in spontaneous
Another rare case had interstitial deletion of the q22-q32
band interval of the chromosome 7 and was spontaneously
aborted at 9 weeks gestation. Intermediate interstitial
deletion of chromosome 7 spanning from q22 to q31 bands
is rare and causes multiple congenital malformations in
the affected children26,27. Only a few rare prenatally
detected cases presenting with fetal growth retardation and
ultrasonographic findings such as cranial malformations,
syndactyly in the lower extremities, renal pelvic dilatation, elevated nuchal fold thickness and cardiac malformations
have been reported27-29.
The evaluation of spontaneously aborted specimens has
changed greatly and histopathological evaluation is not
enough for a better understanding of the pathogenesis of
the defects in aborted specimens. It is well known that it
is necessary to know the chromosomal constitution19.
In our study there was no significant relationship between
histopathological diagnosis and chromosomal abnormality.
The number of histopathologically evaluated cases are
few and the literature and our findings suggest that
histopathological evaluations provide limited data about
the pathogenesis of the spontaneous abortions19.
In conclusion, detection of chromosomal abnormalities
in spontaneous abortion materials is very important
to clarify the causes of pregnancy losses. Detection of
structural chromosomal abnormalities in the cases and
their carrier parents can provide proper genetic counseling
to these families. These families can be directed towards
pre-implantation genetic diagnosis to prevent further
pregnancies with complications.
This study was supported by the Akdeniz University
Scientific Research Project Management Foundation,
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