Am J Hum Genet 34:948-960, 1982

Minor Chromosomal Variants and Major Chromosomal Anomalies

in Couples with Recurrent Abortion
BRUCE D. BLUMBERG,' JEFFREY D. SHULKIN, JEROME I. ROTTER, THULUVANCHERI
MOHANDAS, AND MICHAEL M. KABACK

SUMMARY
One hundred three women with prior histories of recurrent spontaneous
abortion and 81 of their mates were karyotyped with Q-banding during
1976-1980. Recurrent abortion was defined as two or more spontaneous
pregnancy losses; no couple with a previous malformed fetus or child
was included. These cases were reviewed in order to examine the possible
contributions of minor polymorphic chromosomal variants and major
chromosomal abnormalities to recurrent spontaneous pregnancy loss.
Balanced translocations were detected in four women and two men in the
study; mosaic X aneuploidy was noted in one woman. Quantitative (lqh,
9qh, 16qh, Yqh) and qualitative (3c, 4c, 13p, 13s, 14p, 14s, l5p, 15s, 21p,
21s, 22p, 22s) heterochromatic polymorphisms were blindly assessed and
compared with a control group. Cases and controls did not differ in the
frequency of any qualitative polymorphisms or in the length of any
quantitative polymorphism. Thus, while major parental cytogenetic ab-
errations are significantly associated with fetal wastage, these data sug-
gest that minor polymorphic chromosomal variants do not play an im-
portant role in the etiology of recurrent spontaneous abortion.

INTRODUCTION
Human spontaneous pregnancy loss is a common phenomenon, and major cy-
togenetic abnormalities are well established as an important cause of both sporad-

Received August 14, 1981; revised March 18, 1982.

Supported in part by training grant DE-07076 and a contract from the Genetic Disease Section,
Maternal and Child Health Branch, Department of Health, State of California.
All authors: Division of Medical Genetics, Departments of Pediatrics and Medicine, Harbor-UCLA
Medical Center, 1000 W. Carson, Torrance, CA 90509. Request reprints from M. M. K.
© 1982 by the American Society of Human Genetics. All rights reserved. 0002-9297/82/3406-0012$02.00

948
 CHROMOSOMES IN RECURRENT ABORTION 949
ic and recurrent spontaneous abortion. It has been estimated that 50% of concep-
tuses are spontaneously lost prior to term, although only approximately 15% of
clinically recognizable pregnancies lead to fetal wastage [1]. Recently, Miller et al.,
documenting early pregnancies by serum 3-HCG assays, reported a 43% rate of
fetal loss following implantation [1].
As first reported by Carr in the mid-1960s, approximately 50% of karyotyped
first-trimester abortuses demonstrate gross structural or numerical chromosomal
anomalies [2, 3]. Although unbalanced translocations account for only about 1%
of these abnormalities, balanced parental translocations may be an important
cause of recurrent abortion. Several cytogenetic studies of couples experiencing
multiple losses have documented an average 5% incidence of such rearrangements
in this group of individuals [4-18].
More controversial is the role of minor or "normal" cytogenetic polymorphic
variants in the etiology of recurrent fetal loss. It has been speculated that the
heterochromatic polymorphisms demonstrated by standard banding techniques in
some karyotypes could predispose to aberrant gametogenesis and subsequent fetal
wastage [19]. In particular, several studies of repeatedly aborting couples have
implicated a "long Y" chromosome as a possible cause of recurrent pregnancy loss
[20-23]. An association between the "long Y" and unfavorable pregnancy out-
come is also supported by at least two population-based studies that provide
indirect evidence of a "long Y" effect [24, 25]. In contrast to the situation for the Y
chromosome, there are little or no convincing data linking other heterochromatic
variants to recurrent fetal wastage.
Our study was undertaken to delineate further the role of gross chromosomal
anomalies in repeated spontaneous abortion and to investigate the possible rela-
tionship of heterochromatic chromosomal polymorphisms to fetal loss.
MATERIALS AND METHODS

Study subjects included all individuals referred to the Harbor-UCLA Medical Center,
Division of Medical Genetics, Prenatal Diagnosis and Genetic Counseling Center, between
January 1, 1976, and December 31, 1980, for evaluation of recurrent pregnancy loss. All
women had experienced two or more spontaneous abortions, and no woman had produced
a malformed fetus or child. Whenever possible, the woman's mate was also studied. Obstet-
ric evaluation prior to referral varied considerably. One hundred three recurrently aborting
women (mean age 29.3 years) and 81 of their mates (mean age 32.6 years) were studied. Of
these women, 30 (29.4%) had a history of exactly two spontaneous abortions, and 72
(70.6%) had experienced three or more losses. (Details were unavailable for one woman.)
Forty-seven (46.5%) women had given birth to at least one normal child, while 54 (53.5%)
women were childless. (Details were unavailable for two women.) In a few instances, male
and female members of a couple had differing reproductive histories; in such cases, only the
females' histories were considered. Fifteen or more q-banded peripheral lymphocyte meta-
phases were examined, and two karyotypes were prepared for each study subject.
A normal control group was established by selecting amniotic fluid specimens from a
random group of women who underwent amniocentesis during the 1976-1980 study period.
This included 69 females and 96 male preparations. Only specimens from women with no
history of prior spontaneous abortion were included. Previous studies demonstrated a
similar frequency of Q-polymorphisms in karyotypes from peripheral blood lymphocytes
and cultured amniocyte preparations [26]. As for the study subjects, at least 15 Q-banded
950 BLUMBERG ET AL.
metaphases were analyzed and two karyotypes were constructed for each control. All
metaphases were routinely examined for gross structural or numerical cytogenetic anoma-
lies. For each case and control, two karyotypes were analyzed for heterochromatic poly-
morphisms by an observer who was unaware of the individual's case or control status. As
depicted in figure 1, studied qualitative polymorphisms included those located in the cen-
tromeric regions of chromosomes 3 and 4 (3c, 4c) and on the short arms and satellites of
chromosomes 13, 14, 15, 21, and 22 (13p, 13s, 14p, 14s, 15p, 15s, 21p, 21s, 22p, 22s). These
polymorphisms were designated as present or absent on each of the homologs in question.
The heterochromatic polymorphisms located on the long arms of chromosomes 1, 9, 16,
and (in males) Y were investigated quantitatively. The variable lengths of these regions were
measured with calipers and metric scale. Heterochromatin length was then expressed as a
fraction of total axial chromosomal length (het/tot). In addition, total Y-chromosome
length was compared to the axial length of chromosome 20 (tot/20). All measurements
were rounded off to the nearest 0.5 mm in order not to exceed the limits of resolution of the
human eye. Measurements were performed and ratios obtained for each of the two evaluat-
ed karyotypes. For chronmosomes 1, 9, and 16 in any given karyotype, the length of the
polymorphism (and therefore of the het/tot ratio) may have differed between homologs.
For this reason, the polymorphisms of one homolog was designated as the "longer" and
one as the "shorter" based upon these differences in het/tot ratio. For each case and
control, the "longer" ratio homologs of the two karyotypes were compared and a mean
"longer" het/tot ratio calculated. Similarly, a mean "shorter" het/tot ratio was obtained.
Chromosomal polymorphisms were analyzed in the first 88 of the 103 women and 71 of
the 81 men in the study group. Cases ascertained after August 1, 1980, were studied for
gross chromosomal aberrations, but heterochromatic polymorphisms were not inspected.
In addition, earlier study subjects who were found to possess a gross structural or numerical
chromosomal anomaly (and their mates) were excluded from the polymorphism phase of
the investigation. In such cases, the observed karyotypic abnormality was inferred to be
causally related to the history of reproductive loss, and the inclusion of such individuals in
the analysis of polymorphisms conceivably could have masked any potential association of
such polymorphisms with recurrent abortion.
Statistical analysis was performed by utilizing BMDP-77 Biomedical Computer Pro-
grams PIF, P7D, and P3S [27]. Data were examined for significance by Pearson chi square,
Mann-Whitney rank sum, and Student's t test.

FIG. I.-Heterochromatic polymorphisms. Note variability in the length of quantitative polymor-

phisms (Ilqh, 9qh, 16qh, Yqh) and variability in appearance of qualitative polymorphisms (3c, 4c, l13p,
13s, 14p, 14s, 15p, 15s, 21p, 21s, 22p, 22s).
 CHROMOSOMES IN RECURRENT ABORTION 951
RESULTS
Qualitative Polymorphisms
The study group and controls did not differ significantly in the distributions of
any of the qualitative polymorphisms. The frequency of occurrence of these qual-
itative polymorphisms is given in table 1. Some heterochromatic variants occur
quite infrequently; 14p was so uncommon in both controls and the abortion group
that a chi square could not be performed for this polymorphism. Of the 23 calcu-
lated chi squares (11 for males, 12 for females), none attained statistical signifi-
cance. (The P value of .03 for 13s in females is not significant when corrected for
the number of comparisons performed.)
Quantitative Polymorphisms
Chromosomes I and 9. The lengths of the heterochromatic regions of chromo-
somes 1 and 9 are presented in table 2. In both males and females, and for both
homologs of the 1 and 9 pairs, the lengths of lqh and 9qh were similar in study
subjects and controls.
Y chromosome. Mates of aborting women and control males did not differ in
their distributions of Y chromosomal length. Figure 2A and B graphically depict
these distributions; Yqh length is expressed as a fraction of total Y chromosomal
length, and the length of the Y chromosome is independently expressed as a
fraction of chromosome 20 length. The means and distributions of het/tot and
Y/20 ratios were similar in male study subjects and controls.
Chromosome 16. Initial measurements indicated that the mean length of this
heterochromatic polymorphism was longer in the abortion group than it was in
controls. However, it was recognized that quantitation of this chromosomal seg-
ment might not be accurate because of its small size and the limitations of hand
measurement. For this reason and in view of the potential importance of such a
finding, the control group (amniotic fluid cells) was enlarged and all measure-
ments were repeated using different metaphase cells. As with all previous mea-
surements, chromosomes were examined by an observer without knowledge of the
case/control origin of the cell analyzed. As depicted in table 3, this expanded
control group (no. = 165) did not differ from the study group in the length of the
chromosome 16 polymorphism. Data are tabulated for females, but males did not
differ from females in the length of the chromosome 16 polymorphism.
Gross Chromosomal Anomalies
Five of the 103 women (4.9%) and two of the 81 men (2.5%) studied exhibited
major chromosomal abnormalities. Thus seven of the 184 individuals studied
(3.8%) were karyotypically abnormal. Considering only the 81 couples in which
both members were studied, six abnormal karyotypes were found (7.4% of cou-
ples). Three of these abnormalities were detected among the 30 couples that had a
history of exactly two pregnancy losses (10.0%), while four anomalies were discov-
ered in the 72 couples with three or more abortions (5.6%). Only one of the
abnormalities occurred among the 47 couples that had at least one normal child
952 BLUMBERG ET AL.

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 CHROMOSOMES IN RECURRENT ABORTION 955
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(2.1%), whereas six anomalies were found in the 54 childless couples (11.1%). As
shown in table 4, none of these differences attain statistical significance. Four
women and two men were discovered to carry balanced translocations. Of the six
balanced translocations, two were Robertsonian (13/14), and the others involved
breaks and rearrangements of various autosomes. In addition, one woman (whose
mate was not studied) was found to exhibit mosiacism with a normal cell line as
well as two cell lines with varying degrees of X aneuploidy. Although 98 of her 100
examined cells were 46,XX, a single 47,XXX and 48,XXXX cells were discovered.
DISCUSS ION
Qualitative and Quantitative Polymorphisms
The human cell contains a large reservoir of DNA that is in excess of the
amount required for the coding of protein synthesis. Much of this extra DNA
956 BLUMBERG ET AL.
TABLE 3
QUANTITATIVE POLYMORPHISM OF CHROMOSOME 16: MEAN LENGTH AND STUDENT'S t TEST P VALUES

Female
"aborters" Female controls
(no. = 88) (no. = 165) P value

"Longer" polymorphism mean het/tot ratio ............ 0.116 0.117 P > .50
"Shorter" polymorphism mean het/tot ratio ........... 0.095 0.098 P > .25

consists of repetitive base-pair sequences that demonstrate staining properties that

distinguish them from genomic DNA. Some of these regions ("constitutive hetero-
chromatin") exhibit great variability in the general population. Although most
such polymorphisms are considered to be benign or "normal" variants, a possible
association with fetal wastage has been suggested [8, 19-25, 28, 29].
For the 12 qualitative polymorphisms (simply scored as to presence or absence)
examined in this study, individuals in the abortion group are demonstrated not to
differ statistically from controls. Although a P value of .03 was obtained by chi
square for the frequency differences between cases and controls of the satellite
heterochromatin of chromosome 13 in females, this result is not statistically signif-
icant when corrected for the multiple comparisons that were made [30].
Specific concern has been directed toward a possible role of the "long Y" chromo-
some in reproductive loss [20-25]. Several studies of the mates of recurrently
aborting women demonstrated an apparent excess of men with long heterochro-
matic regions on the long arm of the Y chrosomome (Yqh+)[20-23]. These inves-
tigations, for the most part, have been small and poorly controlled or conducted in
an "unblinded" fashion. Since the interpretation of heterochromatic polymor-
phisms is highly subjective and influenced by minor details of karyotype prepara-
tion (e.g., photographic technique), any meaningful study of polymorphism must

TABLE 4
CHROMOSOMAL ANOMALIES IN RELATION TO PRIOR REPRODUCTIVE HISTORY

A. Chromosomal Anomalies as a Function of No. Spontaneous Abortions

Two spontaneous > Two spontaneous

abortions abortions

No. couples studied ..................... 30 72

No. couples with abnormality .............. 3 (10%)* 4 (5.6%)*
B. Chromosomal Anomalies as a Function of Prior Reproductive Success

At least one No normal

normal Child children

No. couples studied ..................... 47 54

No. couples with abnormality .............. 1 (2.1%)* 6(11.1%)*
* Differences not statistically significant.
 CHROMOSOMES IN RECURRENT ABORTION 957
include a control group and must be performed blindly. Our study and another
performed in a similar controlled, blind manner [31] demonstrated no difference
in the incidence of Yqh+ between "aborters" and controls.
In comparing the raw data of our study to previously reported measurements of
Y chromosomal length, a minor methodologic difference should be noted. Pre-
vious studies have expressed Y chromosomal length in relationship to the diagonal
length of chromosome 20 (apparently to allow the convenient definition of a "long
Y" as one with a Y/20 ratio > 1). In our study, the axial length of chromosome
20 was used as a reference for Y chromosomal length, thereby avoiding variability
introduced by the splaying of chromatids on some metaphase preparations. Since
axial length generally is less than diagonal length, the Y/20 ratios of our study are
somewhat greater than those appearing in the literature. Cases and controls have
been compared by examining the means and distributions of Y chromosomal
length without arbitrarily selecting a cut-point to define a "long Y" chromosome.
At least two newborn surveys also examined the possible relationship of the
"long Y" chromosome to reproductive loss [24, 25]. Newborn boys were divided
into a "long Y" and "normal Y" group. The parents of the former group exhibited
prior reproductive histories that included more spontaneous losses than did the
histories of the "normal Y" parents. A potential association of Y heterochromatin
with fetal wastage is suggested by these surveys, but our study and the data of
Robertson et al. [31] imply that variations in Y heterochromatin are not signifi-
cantly associated with recurrent abortion.
An association of fetal wastage and polymorphisms of chromosomes 1 or 9 has
been suggested by uncontrolled or nonblind studies [8, 19, 29]. Such a potential
relationship has also be examined by Hemming and Burns in a controlled, blind
investigation, utilizing C-banding [32]. Cases and controls were discovered not to
differ in the distributions of chromosomes 1's or 9's heterochromatin length. Our
study, employing different staining techniques and statistical methodology, con-
firms these earlier results. Since the cytogenetic methods were different in the two
studies, it is not possible to compare directly the raw data (het/tot ratios) of
these investigations.
Probably relating to its small size, the heterochromatic region of chromosome
16 previously has not been examined for a possible relationship to recurrent
abortion. It has, however, been speculated that the observed high frequency of
trisomy 16 in abortuses may be influenced by variation in the heterochromatic
region of this chromosome [33]. In our study, with Q-banded preparations, the
diminutiveness (frequently < 0.5 mm) and indistinctness of this segment prevent-
ed the accurate quantitation of its length. The postulated relationship of the chro-
mosome 16 polymorphism to pregnancy loss thus remains hypothetical. It is hoped
that future studies will utilize higher resolution cytogenetic techniques (perhaps
Q- or C-banding of prophase chromosomes) in order to approach this question.
Gross Chromosomal Anomalies
The finding of major cytogenetic abnormalities in 3.8% of the individuals and in
7.4% of the couples studied for recurrent abortion is consistent with data appear-
958 BLUMBERG ET AL.
ing in the literature. Individuals studied demonstrated gross chromosomal aberra-
tions in from 0% to over 30% of repeatedly aborting couples [4-18]. The width of
this range, in part, may reflect random statistical variation, but methodologic
differences among studies probably account for these discrepant results [34]. In-
vestigators who have included couples with a previous malformed fetus or child in
addition to a history of fetal wastage generally reported higher incidences of
chromosomal anomalies than are found in studies restricted to couples with a
"pure history" of reproductive loss. Our study excludes any individual or couple
with a history of malformation in a fetus or child. This study design avoids the
ascertainment bias that might result from the inclusion of couples coming to
medical attention because of a malformed offspring rather than because of their
history of pregnancy loss.
Previous data suggest that chromosomal anomalies are slightly more likely to be
found in couples with three or more abortions than in those studied after only two
prior losses [34]. This concept is not supported by the present data. In this study,
10% of couples with exactly two spontaneous abortions were cytogenetically ab-
normal, while only 5.6% of couples with three or more pregnancy losses demon-
strated a karyotypic anomaly. These differences are not statistically significant.
Unfortunately, most studies ascertaining couples with two or more abortions fail
to make a distinction between those with exactly two and those with greater than
two miscarriages. Considering both the literature and present data, there is no
clear indication that an increasing number of abortions (over two) is associated
with an increased rate of parental chromosomal anomalies.
The literature also suggests that chromosomal anomalies are more common in
childless couples than in those who, in addition to their losses, previously gave
birth to at least one normal child [18]. In our study, 11.1% of childless couples
were chromosomally abnormal while only 2. 1% of those with normal children had
karyotypic anomalies. These data support the notion that cytogenetic anomalies
are more frequent in couples that have exclusively experienced pregnancy loss
than in those with a mixed history of reproductive successes and failures; however,
these differences fail to achieve statistical significance (table 4), possibly owing to
inadequate sample size.
CONCLUSION
Parental chromosomal abnormalities are one significant cause of recurrent spon-
taneous abortion. Summarizing published and present data, approximately 5%-10%
of couples with a history of repeated pregnancy loss will include an individual with
a balanced translocation. Maternal X chromosomal aneuploidy or mosaicism also
may be observed in aborting women, but the frequency of such anomalies is
unknown. Neither our study nor the literature provides clear evidence of a rela-
tionship between the number of prior abortions and the incidence of parental
chromosomal abnormality. Thus the yield of "positive" results in couples studied
after only two miscarriages is not statistically different than the yield when karyo-
type follows three or more losses. Couples with pure abortion histories are proba-
 CHROMOSOMES IN RECURRENT ABORTION 959
bly at greater risk for cytogenetic abnormality than are couples with normal chil-
dren in addition to abortions.
Heterochromatic polymorphic variants appear not to be an important factor in
recurrent abortion. Although the suggestive findings of newborn surveys should
not be ignored, new data indicate that Y chromosomal length is similar in the
mates of aborting women and in controls. The evaluation of chromosome 16
heterochromatin and its possible relationship to fetal wastage remains inconclu-
sive because of methodologic difficulties in quantitating this small region. The
concept of such an association remains attractive in view of the high frequency of
trisomy 16 in abortuses; it is suggested that future investigations of this question
employ high resolution cytogenetic techniques and prospectively select an appro-
priate control population for comparison.

ACKNOWLEDGMENTS
We would like to acknowledge the technical assistance of Florence Wong, Linda Wagner,
and Ann-Marie Bell.
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