Translocations are infrequent among couples having repeated spontaneous abortions but no other abnormal pregnancies*

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Vol. 51, No.5, May 1989

FERTILITY AND STERILITY

Printed in U.S.A.

Copyright e 1989 The American Fertility Society

Translocations are infrequent among couples having repeated spontaneous abortions but no other abnormal pregnancies* Joe Leigh Simpson, M.D.t:j:§ Carole M. Meyers, M.D.t:j: Alice 0. Martin, Ph.D.:j:

Sherman Elias, M.D.t:j: Carole Ober, Ph.D.:!: II

The University of Tennessee, Memphis, Memphis, Tennessee, Northwestern University Medical School, and the University of Chicago, Chicago, Illinois

During the years 1977 to 1986, cytogenetic studies were performed on 342 women and 297 men whose reproductive history included one or more first trimester spontaneous abortions. Thirty-nine women and 35 men experienced not only early fetal losses but also one or more stillborn infants, liveborn anomalous infants, or early neonatal deaths. Among the 303 women and 262 men evaluated solely because of repetitive abortions, only 1 woman and 1 man showed a translocation. Two translocations were detected among the 39 women and 35 men having not only repetitive abortions but also a stillborn infant, anomalous liveborn, or unexplained neonatal death. Only among the 25 women having abortions and other abnormal perinatal events was the frequency of translocations high (2/25 or 8%). Our data continue to indicate that balanced chromosomal translocations are relatively infrequent in individuals having repeated abortions but no other adverse perinatal outcome. Fertil Steril51:811, 1989

Parental chromosomal rearrangements are an accepted explanation for repetitive spontaneous abortion. Individuals with balanced translocations are phenotypically normal, but predisposed to abnormal offspring with chromosomal imbalance. The prevalence of parental translocations initially

Received September 23, 1988; revised and accepted January 10,1988. * Supported by the National Institutes of Health grants HD 19866, HD 21414, and HD 82904, by The March of Dimes, and by The United States Agency for International Development (Institute for International Studies in Natural Family Planning). t Department of Obstetrics and Gynecology, University of Tennessee, Memphis. :j: Department of Obstetrics and Gynecology, Northwestern University Medical School. §Reprint requests: Joe Leigh Simpson, M.D., Faculty Professor and Chairman, Department of Obstetrics and Gynecology, University of Tennessee College of Medicine, Memphis, 853 Jefferson Avenue, Memphis, Tennessee 38163. II Department of Obstetrics and Gynecology, University of Chicago.

Vol. 51, No.5, May 1989

was believed to be nearly 10% of couples experiencing repeated abortions. 1- 4 Although a few small studies had shown intermediate risks (2% to 5%), our 1981 report was surprising in revealing a considerably lower frequency oftranslocations (0.4%) among individuals having repeated abortions but neither stillborn nor anomalous infants. 5 Since our original report, we have continued to observe the same low prevalence of such chromosomal rearrangements. This suggests that translocations may indeed be less frequent among repetitive aborters than heretofore believed. The purpose of this communication is, therefore, to update our previous report. MATERIALS AND METHODS

The sample was ascertained in Prentice Women's Hospital and Maternity Center, Northwestern Memorial Hospital. Referral patterns and organizational structure were described previously. 6 Of note is that the individuals we studied were almost Simpson et al.

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811

Table 1 Translocations in Individuals Experiencing Abortions but No Other Abnormal Events•

Number first trimester abortions 1 2 3 4 5 6 7 8 9-11 Unspecified • Total

Abortions only (no normal liveborns)

Abortions and normalliveborns

Females

Males

Females

Males

0/1 0/71 1 b/92 0/31 0/9 0/2 0/3 0/0 0/3 0/6 1/218 (0.46%)

0/5 0/71 1 c/81 0/27 0/6 0/1 0/1 0/0 0/2 0/5 1/199 (0.50%)

0/0 0/15 0/40 Od/14 0/9 0/6 0/0 0/0 0/1 0/0 Od/85 (0%)

0/1 0/13 0/33 0/7 0/5 0/3 0/0 0/1 0/0 0/0 0/63 (0%)

• Frequency of translocations among individuals presenting with one or more first trimester abortions but no unexplained stillborns, no anomalous stillborn or liveborn offspring, and no unexplained neonatal deaths. The sample is subdivided according to presence or absence of normal liveborn infants. Individuals were considered to have had normal liveborn infants if they presented with a pregnancy in the second trimester that ended normally. Ectopic gestations (n = 15) and molar pregnancies (n = 3) were included as first trimester losses. b 46,XX,rcp(3;13)(3pter .... 3q21::13q22 .... 13qter;13qter .... 13q22::3q21.... 3qter). c 46,XY,rcp(7:8)(7pter .... 7q36::8p11 .... 8pter;7qter .... 7q36:: 8p11 ....8qter). d 46,XX,inv(10)(pter ....p11::q21 .... p11::q21 .... qter) in one case. • Unspecified, usually because couples related that one or more bleeding episodes were stated by their gynecologist possibly to represent a fetal loss. However, anovulatory cycles represented alternate explanations.

and 104 men reported earlier. 5 Ofthe total sample, 39 women and 35 men had experienced not only early fetal losses but also one or more stillborn infants, liveborn anomalous infants, or early neonatal deaths. The few individuals with only a single first trimester abortion usually had experienced a stillbirth or anomalous infant. The remaining 303 women and 262 men had experienced repeated spontaneous abortions but no other adverse perinatal outcomes. The number of women studied was greater than the number of men because some of the latter were unavailable, usually because the individual presenting to us had remarried. Rarely was the converse true. Of the total sample, about three-fourths had no liveborn offspring: 243 (71 %) women and 221 (75%) men. All chromosomal studies were initiated from peripheral blood. At least 20 G-banded metaphases were counted or analyzed per individual. Additional techniques (C-banding, Q-banding, silverstaining) were used in selected cases to exclude or confirm subtle chromosomal rearrangements.

RESULTS Tables 1 and 2 show the relationship between previous reproductive outcome and presence or absence of balanced translocations. Among the 303 women and 262 men evaluated solely because of reTable 2 Translocations in Individuals Experiencing Both Repeated Abortions and Other Abnormal Perinatal Events •

always referred from other obstetrician-gynecologists. By contrast, other reports concerning repetitive abortions usually originate from laboratories whose referral base is pediatric as well as obstetric in nature. In such laboratories, couples experiencing repeated abortions may have been referred for cytogenetic studies less because of early fetal losses than because of coexisting stillborn or anomalous liveborn offspring. Furthermore, there may have been a tendency to refer patients only if initial parts of the evaluation (e.g., hyperosalpingography) revealed no abnormalities. Our unit and others based in departments of obstetrics and gynecology are instead more likely to attract referrals at the initiation of evaluation. During the years 1977 to 1986, cytogenetic studies were performed at Northwestern on 342 women and 297 men whose reproductive histories each included one or more first trimester spontaneous abortions. This sample includes the 120 women 812

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Translocations and repeated abortions

Number first trimester abortions 1 2 3 4 5 6 7 8 9-11 Unspecified Total

Abortions and other abnormal events but no normalliveborns

Abortions and other abnormal events with normalliveborns

Females

Males

Females

Males

0/8 0/8 0/3 1b/3 0/2 0/0 0/0 1 c/1 0/0 0/0 2/25 (8.0%)

0/8 0/7 0/2 0/3 0/1 0/1 0/0 0/0 0/0 0/0 0/22 (0%)

0/3 0/5 0/5 0/1 0/0 0/0 0/0 0/0 0/0 0/0 0/14 (0%)

0/4 0/3 0/5 0/1 0/0 0/0 0/0 0/0 0/0 0/0 0/13 (0%)

• Frequency of translocations among individuals experiencing abortions as well as one of the following adverse perinatal events: anomalous liveborn, stillborn infant, unexplained neonatal death. b 45,XX,rob(13;14)(13qter.... cen .... 14qter). c 46,XX,rcp(4;11)(4qter .... 4p16::11q13 .... 11qter;11pter .... 11q13::4p16.... 4pter).

Fertility and Sterility

Table 3

Frequency of Translocations (Pooled Data) a

Repeated spontaneous abortions with or without normal liveborn

Repeated spontaneous abortions with stillborn or abnormal liveborn

detected in a woman having eight spontaneous abortions, one child with polydactyly, and one child with polydactyly and cardiac defects. One other translocation (45,XX,rob( 13; 14)( 13qtercen-14qter) was detected in a woman having four spontaneous abortions and one stillborn infant.

Repeated spontaneous abortions without subcategorization

d

Female

Male

Female

Male

Female

Male

s

89/3723 2.4%

57/3651 1.6%

20/432 4.6%

7/409 1.7%

100/3074 3.3%

65/3069 2.1%

f y t

• Data pooled from current study and from 58 published reports, references for which are available from the authors on request.

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petitive abortions, only one man and one woman showed a translocation. One other woman showed a pericentric inversion (Table 1). The abnormal chromosomal complements were 46,XY,rcp(7;8) (7pter-7q36:: 8p n-8pter; 7qter-7 q36:: 8p n 8qter); 46,XX,rcp(3; 13)(3pter-3q21:: 13q22-13 qter; 13pter-13q22:: 3q21-3qter); and 46,XX, inv(10)(pter-pll: :q21pll: :q21-qter). Although sample sizes among subcategories are small, one other observation seems noteworthy. No translocations were detected in the subset of 33 women and 19 men having five or more abortions but no abnormal outcomes. During the interval of this study, one other woman experiencing a single abortion showed a balanced translocation (46,XX, rcp(1;3) (1qter - 1p36::3q27 - 3qter:3pter 3q27::1p36- 1pter)). However, she was referred not because of repetitive abortions but because of mental retardation in a relative and multiple abortions in her mother. Two translocations were detected among the 39 women and 35 men having not only repetitive abortions but also a stillborn infant, anomalous liveborn, or unexplained neonatal death (Table 2). One translocation - 46,XX,rcp(4;11)(4qter-4p16::11 q13-llqter; llpter-llq13::4p16-4pter)- was Table 4

Our data continue to indicate that balanced chromosomal translocations are relatively infrequent among repeated aborters. Among the total 639 individuals we studied, only 0.9% of the women and 0.3% of the men showed a translocation. Among the 565 individuals experiencing repeated abortions but having no other abnormal reproductive events, 0.33% of the women and 0.38% of the men showed a translocation; not a single translocation was observed among the subset of 85 women and 63 men having both abortions and normalliveborns. Only among the 25 women having not only abortions but other abnormal perinatal events was the frequency of translocations high (2/25 or 8%). Thus, we continued to observe a low frequency of translocations in the Northwestern sample, as we had in our earlier report. 5 Although sample vicissitudes naturally remain a possible explanation for differences between our observations and those of certain other investigators, other explanations should be considered. One possible explanation for the low frequency of translocations we observed is that the Northwestern referral base was almost exclusively from obstetrician-gynecologists. Moreover, frequent interaction of geneticists with referring gynecologists probably assured that almost all couples in our center who experience repeated abortions would undergo cytogenetic analysis. In other centers, patients may have been referred only if evaluation for uterine anomalies or endocrine dysfunction was unreveal-

Relationship of Translocation Prevalence to Number of Prior Abortions a

2 Abortions

%)

ctal o-

DISCUSSION

Sex not stated Female

Female

Male

2/260 (0.8%)

3/259 24/1096 5/301 (1.2%) (2.2%) (1.7%)

3 Abortions Male 5/285 (1.89%)

5 Abortions

4Abortions

Greater than 5 abortions

Sex not stated Female

Male

Sex not Sex not Sex not stated Female Male stated Female Male stated

21/870 (2.4%)

3/127 (2.4%)

13/370 (3.5%)

3/132 (2.3%)

1/34 (2.9%)

0/34 (0)

6/239 (2.5%)

0/18 (0)

0/14 (0)

-+

a Data pooled from 1) our report and four others in which numbers of prior abortions and sex of parents both were provided ("female" and "male" columns, each section), and from 2) six reports in which numbers of prior abortions but not sex of parents was provided, "sex not stated" column, each section. References provided on request.

ity

Vol. 51, No.5, May 1989

Simpson et al.

Translocations and repeated abortions

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ing. Indeed, cytogenetic studies at the onset of evaluation appeared to be the practice in only 5 of the 58 reports we reviewed. In 19 reports, some or all of the other causes of repetitive abortions were exeluded before cytogenetic analysis. In the other 34 reports, no relevant information was stated. Couples experiencing no other abnormal reproductive event (e.g., stillborn or anomalous liveborn) were thus as likely to be referred for cytogenetic studies in our center as couples having not only abortions but other abnormal events. The significance of differing patterns of ascertainment is that the latter (additional abnormal outcome) group may be more likely to exhibit a chromosomal rearrangement, at least in women. In support of this contention are data in Table 3, tabulated by pooling our data and 58 other series of repeated aborters (References for Tables 3 and 4 can be obtained from the author.). In the pooled data, frequencies of translocations were 2.4% in women having abortions but no other adverse perinatal events, and 1.6% in men. If other adverse events existed, the prevalences were 4.6% in women and 1. 7% in men. We have already observed that prevalence rates based on prior reports might be predicted to be higher than that we observed because, in most other studies, some or all other causes of repeated abortions were excluded before cytogenetic studies. It follows that samples consisting of a relatively higher percentage of women having a coexisting stillborn or anomalous liveborn might show a relatively higher prevalence for chromosomal rearrangements. If so, this could account for higher frequencies observed by some investigators. Ascertainment biases might even unwittingly pass unrecognized, if histories for adverse perinatal events are not sought vigorously. Still awaiting clarification is the relationship between frequency of translocations and numbers of prior abortions. This relationship is explored in Table 4, again using pooled data. There is some suggestion that couples with four losses have higher frequencies of translocations than couples with few losses. However, selection or unknown ascertainment biases could be responsible for the ostensibly increased frequency among individuals experiencing four or five losses. Irrespective, Table 4 demonstrates that little clinical advantage accrues

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Translocations and repeated abortions

from deferring cytogenetic studies until couples experience a very large number of abortions. In fact, individuals carrying balanced translocations or inversions would be predicted to experience normal pregnancies interspersed with abortions or perhaps anomalous liveborns. By contrast, immunologic or endocrinologic causes of repetitive abortions might be predicted to result in consecutive losses without intervening normal pregnancies. Comparing translocation rates in couples experiencing consecutive or nonconsecutive losses will thus be of interest. Although we believe obstetrician-gynecologists will detect chromosomal rearrangements relatively infrequently (1% to 2%) among couples having repeated abortions but no other abnormal perinatal events, the significance of a translocation with respect to clinical management still dictates that cytogenetic studies remain an integral part of the evaluation of couples experiencing repeated fetal losses. Chorionic villus sampling or amniocentesis should be offered couples found to have a rearrangement. Moreover, an occasional couple unfortunately will show a homologous translocation [e.g., t(21q;21q) or t(13q; 13q)] that precludes normal liveborns. Artificial insemination by donor or embryo transfer techniques thus would be appropriate. Cytogenetic evaluation should be initiated whenever an evaluation is considered appropriate for a given couple. At the same time, evaluation of other nongenetic causes of fetal wastage can be initiated. REFERENCES 1. Simpson JL: Genes, chromosomes and reproductive failure. Fertil Steril33:107, 1980 2. Kim H, Hsu L, Paciuc S, Cristian S, Quintena A, Hirschhorn K: Cytogenetics of fetal wastage. N Engl J Med 293: 844, 1975 3. Stenchever M, Parks K, Daines T, Allen M, Stenchever M: Cytogenetics of habitual abortion and other reproductive wastage. Am J Obstet Gynecol127:143, 1977 4. Tho PT, Byrd JR, McDonough PG: Etiologies and subsequent reproductive performance of 100 couples with recurrent abortion. Fertil Steril 32:389, 1979 5. Simpson JL, Elias S, Martin AO: Parental chromosomal rearrangements associated with repetitive spontaneous abortions. Fertil Steril 36:584, 1981 6. Simpson JL, Elias S, Gatlin M, Martin AO: Genetic counselling and genetic services in obstetrics and gynecology. Am J Obstet Gynecol140:70, 1981

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