Detection of balanced chromosome rearrangements in 445 couples with repeated abortion and cytogenetic prenatal testing in carriers

Cytogenetic studies were performed in 445 couples presenting because of repetitive abortion. The authors detected a balanced translocation in 19 (4.2%) of the couples, pericentric inversions in 8 (1.8%), and polymorphisms in 52 (11.4%). The results were compared with those obtained in a series of 600 consecutive normal liveborns. Significantly higher frequencies for translocations and polymorphisms were present in couples with repetitive abortion. No sex predominance in translocation carriers was observed, and reciprocal translocations were more common (16 of 19) than the robertsonian type (3 of 19). Contrary to other reports, all of the translocations and inversions were detected among couples without previous abnormal offspring. Cytogenetic prenatal testing in 17 pregnancies from a carrier parent showed that none of the fetuses had the unbalanced karyotype, 13 carried the balanced rearrangement, and 4 had a normal karyotype. Although a risk profile can be obtained for these couples, prenatal testing must be offered to avoid anxiety and unjustified pregnancy interruptions.     

Cytogenetics of aborters and abortuses

783 aborters and 430 abortuses were studied in a prospective cytogenetic survey which attempted to link chromosome abnormalities and history of recurrent abortion. 425 female and 358 male spontaneous aborters and their 430 abortuses (310 were karotyped) showed 4 women and 2 men as balanced translocation carriers (3 Robertsonian and 3 reciprocal translocations) and a woman with an XXX karotype. 5 of the abortuses were successfully karotyped; 4 had inherited unbalanced translocation products, and the other had a balanced 13q14q translocation plus trisomy 18. Apparently, translocation chromosomes carried by aborters were transmitted to their abortuses. Structural chromosome abnormalities were found with higher frequency (.8%) among aborters than among the general adult population (.3%). Translocation carriers were more frequent among the aborters with histories of recurrent abortions (2.7%) as well as among aborters with a history of perinatal deaths (3.6%) than among those persons with no such histories (.6%). Data on 18 couples whose 2 or 3 successive spontaneous abortuses were karotyped are presented.     

Recurrent pregnancy losses and parental chromosome abnormalities: a review

Summary. A compilation of the cytogenetic results taken from 79 published surveys of couples with two or more pregnancy losses (comprising 8208 women and 7834 men) showed an overall prevalence of major chromosome abnormalities of 2.9%. This is five to six times higher than that of the general adult population. In every group of chromosome abnormalities in the parents a predominance of female to male affected was noted (2:1). Approximately 50% of all chromosome abnormalities detected were balanced reciprocal translocations, 24% were Robertsonian translocations, 12% were sex chromosomal mosaicisms in females, and the rest consisted of inversions and other sporadic abnormalities. Parents with two or more idiopathic pregnancy losses should be karyotyped to aid in management and counselling. When a translocation or other abnormality (e.g. X chromosomal mosaicism) predisposing to an abnormal zygote is found, prenatal diagnosis is indicated in future pregnancies. Even when parental karyotypes are normal, prenatal diagnosis should be considered in subsequent pregnancies of parents with two or more pregnancy losses because of the high incidence of chromosome abnormalities in spontaneous abortions. For the same reason, if a single previous pregnancy loss is known to have been chromosomally aneuploid, parental karyotypes may have to be examined (depending upon the finding in the pregnancy loss), and prenatal diagnosis should also be considered in subsequent pregnancies.     

Poor prognosis of recurrent aborters with either maternal or paternal reciprocal translocations

OBJECTIVE: To determine whether the miscarriage rate in recurrent miscarriage patients with an abnormal karyotype, especially reciprocal translocations, in either partner is worse than without an abnormal karyotype. DESIGN: Retrospectively analyzed prospectively obtained database. SETTING: Nagoya City University Hospital. PATIENT(S): One thousand and two hundred eighty-four couples with a history of 2 or more (2 to 12) consecutive first-trimester miscarriages. INTERVENTION(S): Patients with antiphospholipid antibodies were treated with low-dose aspirin and combined therapy. MAIN OUTCOME MEASURE(S): Subsequent miscarriages were compared for cases with and without an abnormal karyotype in either partner. A karyotype analysis was also conducted for each aborted conceptus and offspring of 95 pregnancies of 47 patients with reciprocal translocations. RESULT(S): Of the total of 1,284 couples, 58 (4.5%) had translocations, 11 being Robertsonian translocations. Eleven of the 18 cases (61.1%) where the husband had a reciprocal translocation suffered further miscarriage; this also was the case for 21 of the 29 cases (72.4%) where the wives had a reciprocal translocation. Those with reciprocal translocations in either partner miscarried significantly more frequently than those without an abnormal karyotype. Only one infant with an unbalanced translocation was found in 34 cases of successful pregnancy following habitual abortion. CONCLUSION(S): The pregnancy prognosis with either maternal or paternal reciprocal translocations is poorer than without them. The presence of a reciprocal translocation is thus a risk factor in couples who have recurrent miscarriages.     

Recurrent pregnancy losses and parental chromosome abnormalities: a review

A compilation of the cytogenetic results taken from 79 published surveys of couples with two or more pregnancy losses (comprising 8208 women and 7834 men) showed an overall prevalence of major chromosome abnormalities of 2.9%. This is five to six times higher than that of the general adult population. In every group of chromosome abnormalities in the parents a predominance of female to male affected was noted (2:1). Approximately 50% of all chromosome abnormalities detected were balanced reciprocal translocations, 24% were Robertsonian translocations, 12% were sex chromosomal mosaicisms in females, and the rest consisted of inversions and other sporadic abnormalities. Parents with two or more idiopathic pregnancy losses should be karyotyped to aid in management and counselling. When a translocation or other abnormality (e.g. X chromosomal mosaicism) predisposing to an abnormal zygote is found, prenatal diagnosis is indicated in future pregnancies. Even when parental karyotypes are normal, prenatal diagnosis should be considered in subsequent pregnancies of parents with two or more pregnancy losses because of the high incidence of chromosome abnormalities in spontaneous abortions. For the same reason, if a single previous pregnancy loss is known to have been chromosomally aneuploid, parental karyotypes may have to be examined (depending upon the finding in the pregnancy loss), and prenatal diagnosis should also be considered in subsequent pregnancies.     

Outcome of preimplantation genetic diagnosis of translocations

Objective: To review 35 cases of preimplantation genetic diagnosis (PGD) of translocations with several methods, including telomeric probes.

Design: Retrospective study.

Setting: Clinical IVF laboratory.

Patient(s): Thirty-five couples with one partner carrying a chromosomal translocation.

Intervention(s): PGD of translocation after polar-body or embryo biopsy.

Main Outcome Measure(s): Pregnancy outcome.

Result(s): Several trends were observed. First, PGD can achieve a statistically significant reduction in spontaneous abortion, from 95% to 13%. Second, the chances of achieving pregnancy are correlated with 50% or more of the embryos being chromosomally normal. Third, patients with robertsonian translocations produced fewer abnormal gametes and more pregnancies than did patients with reciprocal translocations. Fourth, a new fluorescence in situ hybridization protocol for PGD of translocations, which involves applying telomeric probes, has proved adequately reliable with a 6% average error rate.

Conclusion(s): PGD of translocations achieves a statistically significant reduction in spontaneous abortion, both for polar-body and blastomere biopsy cases. Pregnancy outcome depended on the number of normal embryos available for transfer, with patients having <50% abnormal embryos achieving the most pregnancies. Because robertsonian translocations caused fewer abnormal embryos than reciprocal translocations, they also resulted in higher rates of implantation.     

Chromosomal analysis in Japanese couples with repeated spontaneous abortions

Balanced chromosome rearrangements have been found at an increased frequency in couples with pregnancy wastage, especially recurrent spontaneous abortions, compared with the general population. In the present study, chromosomal analysis of peripheral blood cells, as one of the routine examinations of patients with repeated reproductive wastage, was performed on both partners of 639 Japanese couples. Among the 639 couples, 32 major chromosomal anomalies (5.0%) and 23 minor chromosomal variants (3.6%) were found. Both partners of one couple had an abnormal karyotype. The 32 major anomalies consisted of 19 reciprocal translocations, 9 Robertsonian translocations, one large inversion, two triple-X females, and one Turner mosaicism. The 23 minor variants included 15 cases of pericentric inversion of chromosome 9. The total number of pregnancies in the 54 couples with chromosomal anomalies was 181, but they resulted in only 18 normal liveborn neonates, indicating a 90.1% abortion rate. The present statistical study indicates that major chromosomal anomalies seem to be involved in repeated reproductive wastage.     

An evaluation of cytogenetic analysis as a primary tool in the assessment of recurrent pregnancy wastage.

Cytogenetic evaluation of couples with recurrent pregnancy wastage is frequently performed only after other possible etiologic factors have been excluded. Previous reports of studies using conventional and G-banding chromosome techniques in these couples have shown a higher frequency of translocations than that found in the general population. In the study reported here, both conventional and G-banded chromosome analyses were performed as a primary method of evaluation in 34 couples with recurrent fetal loss not ascertained by the birth of a child with a diagnosed chromosome disorder. Balanced translocations were found in 5 partners of the 34 couples studied. In only 2 of these cases was the translocation detected by conventional chromosome analysis. These results suggest that G-banded chromosome analysis should be a useful tool in the initial evaluation of couples with recurrent fetal wastage, rather than being recommended only after extensive investigation of other factors is unrewarding. The reproductive counseling of couples with a translocation detected on this basis is discussed.     

Chromosome abnormalities in 118 couples with recurrent spontaneous abortions

Cytogenetic studies were carried out on 118 couples with recurrent spontaneous abortions. Four major chromosomal abnormalities were found including two 13/14 Robertsonian translocations, one t(7;12) and one t(1;10) reciprocal translocation. The incidence of chromosomal abnormalities in this study was 3.39%, which is lower than the mean value of the published data. The clinical significance of balanced translocations in recurrent reproductive loss is discussed.     

染色体平衡易位携带者妊娠风险及妊娠结局的研究

目的 探讨染色体平衡易位携带者的妊娠风险及其妊娠结局.方法 194例染色体平衡易位携带者,根据平衡易位种类分成相互易位（135例）、非同源罗伯逊易位（52例）、同源罗伯逊易位（7例）3组.调查携带者生育史并随访诊断平衡易位后的妊娠情况,比较各组自然流产、先天缺陷及正常（或）平衡易位后代概率.结果 （1）194对夫妇共妊娠503例次,其中自然流产411例次（81.7%,411/503）;产前诊断胎儿异常而终止妊娠16例次（3.2%,16/503）;活产缺陷儿36例次（7.2%,36/503）;正常（或）平衡易位后代40例次（8.0%,40/503）.（2）相互易位、非同源罗伯逊易位、同源罗伯逊易位3组,活产缺陷儿比率分别为5.7%（20/350）、10.9%（14/128）、8.0%（2/25）,3组间相互比较,差异有统计学意义（P＜0.05）;3组正常（或）平衡易位后代比率分别为6.6%（23/350）、13.3%（17/128）、0,3组间相互比较,差异有统计学意义（P＜0.05）;而3组自然流产及产前诊断胎儿异常终止妊娠比率比较,差异无统计学意义（P＞0.05）.（3）52例次先天缺陷中活产36例次（69%）,经产前诊断确诊后引产16例次（31%）.27例次先天缺陷获得细胞遗传学诊断,唐氏综合征发生率为59%（16/27）.（4）相互易位组和非同源罗伯逊易位组共有39对夫妇得到40个正常（或）平衡易位后代,同源罗伯逊易位组无正常（或）平衡易位后代.40个正常（或）平衡易位后代中26个获得产前细胞遗传学诊断,正常核型6个（23%）,平衡易位核型20个（77%）.结论 染色体平衡易位携带者自然妊娠风险大,尤其同源罗伯逊易位携带者难以获得染色体正常（或）平衡易位的后代.     

Karyotypes of 1142 couples with recurrent abortion

Cytogenetic analysis was performed on 1142 couples with recurrent pregnancy loss. The frequency of major chromosomal abnormalities per couple was 4.8%. Among 771 couples who had only abortions, the rate of rearrangement did not correlate with the number of abortions. The highest incidence of cytogenetic abnormalities (6.6%) was found in 256 couples with abortion and a normal child. With regard to pregnancy outcome, no unbalanced fetal karyotype was found in prenatal diagnoses, and 40 normal children were born. The risk of unbalanced fetal karyotype is therefore low, but probably high enough for these couples to be offered the possibility of a prenatal diagnosis.     

Clinical outcome of treatment cycles using preimplantation genetic diagnosis for structural chromosomal abnormalities

OBJECTIVES: To explore oocyte recovery, embryo quality, the number of transferable embryos and pregnancy rate after preimplantation genetic diagnosis (PGD) in patients with structural chromosomal aberrations. METHODS: PGD was performed in seven couples with Robertsonian translocations (Rob), eight couples with reciprocal translocations (Rec), two couples with inversions and one couple with a deletion. A total of 43 treatment cycles were carried out. RESULTS: A total of 14.2 oocytes per cycle were retrieved. Fertilisation and cleavage rates were 63% and 58%, respectively. Of the biopsied embryos 20% were transferable. Comparison of the Rob and Rec group revealed no significant differences in number of oocytes, fertilisation or cleavage rates. The number of transferable embryos after biopsy was significantly higher in the Rob group than in the Rec group. When embryo transfer (ET) was performed the pregnancy rate did not differ between the Rob and the Rec groups. Twenty-eight embryo transfers (one or two embryos) were carried out leading to eight clinical pregnancies (29% per ET): two twins, four singletons, one miscarriage and one ectopic pregnancy. All the children are carriers of balanced chromosomal aberrations. CONCLUSION: An acceptable pregnancy rate can be achieved among couples with structural chromosomal abnormalities.     

Cytogenetic study in 50 couples with recurrent abortions

The presence of chromosome abnormalities in couples with repeated spontaneous abortion is known even if the phenomenon is far from a complete assessment. A cytogenetic investigation in 50 couples with a history of two or more spontaneous abortions is referred to in this study. A peripheral blood lymphocyte culture was harvested for each subject and the slides were stained by G- and C-banding. Of the 100 individuals examined, 4 were carriers of balanced translocations, 3 of which were of the Robertsonian type. A chromosomal fragility (chromatidic and/or chromosomic gaps) was seen in 2 cases. The incidence of balanced translocations found here is 8% which is near to the mode (about 9%) observed in previous studies. Those frequencies are greater than in the general population (0.1-0.4%). This indicates that balanced translocations have some importance in causing abortion while this is not the case for other chromosomal abnormalities (e.g. pericentric inversions). Thus, cytogenetic analyses should be recommended in couples with repeated spontaneous abortions, when clinical data fail to clarify the cause.     

502对反复自然流产夫妇的染色体研究

对反复自然流产２次或２次以上的５０２对夫妇进行外周血培养Ｇ显带染色体核型分析。发现异常核型５２例，占５．１８％；其中平衡易位３８例，占７３．０８％；染色体数目异常５例，占９．６２％；嵌合体８例，占１５．３８％；９号染色体臂间倒位１例，占１．９２％。结果表明，平衡易位携带者是反复自然流产夫妇中最常见的染色体异常，故流产史是检出人群中平衡易位携带者的重要临床指征。     

Cytogenetic studies in couples with repeated spontaneous abortions

Chromosome studies were carried out on both partners of 509 couples with a history of two or more spontaneous abortions. 1) Twenty-six individuals (2.6%) were carriers of a major chromosome abnormality. This incidence is at least six to seven times higher than that in the general adult population. 2) Of these, 10 were reciprocal translocations, 10 robertsonian translocations and 6 numerical aberrations of gonosomes. None of the carriers showed abnormal phenotypes. 3) Chromosome aberrations were more frequent in the women than in their husbands. There were 19 abnormalities in females and 7 in males. 4) The use of banding techniques in chromosome analysis improves the detection of balanced reciprocal translocations. 5) Prenatal diagnosis was performed in 5 subsequent pregnancies of 4 balanced translocation carriers. The fetal karyotypes were 2 normal and 3 balanced translocations. It would seem reasonable to recommend chromosome analysis for couples with repeated spontaneous abortions.     

染色体易位的植入前遗传学诊断

目的 观察染色体平衡易位和罗伯逊(罗氏)易位基因携带者夫妇进行植入前遗传学诊断(PGD)后的胚胎染色体遗传特征和胚胎着床、妊娠情况,探讨PGD在染色体易位基因携带者夫妇实现正常生育中的意义.方法 用荧光原位杂交(FISH)技术对36对夫妇的胚胎进行PGD,其中14例为染色体平衡易位(平衡易位组),22例为染色体罗氏易位(罗氏易位组),并对诊断结果和胚胎着床、妊娠情况进行分析.结果 36例患者共活检胚胎253个,成功诊断胚胎225个,成功率为88.9%(225/253),获得可供移植的正常或平衡的胚胎共58个.平衡易位组和罗氏易位组PGD后胚胎着床率分别为36%(5/14)和14%(6/44),临床妊娠率分别为4/9和26%(5/19).结论 PGD可有效诊断胚胎染色体平衡易位和罗氏易位,避免反复流产和不必要的非意愿性终止妊娠,并获得理想的胚胎着床率和临床妊娠率.     

Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion

A diagnostic screening program was applied to 195 couples with a prior history of habitual abortion (i.e., three or more consecutive abortions). Abnormalities were identified in 110 (56%) of the couples. Such identification was significantly more frequent in couples with primary habitual abortion than in couples with secondary habitual abortion (p less than 0.001) and also more frequent in couples with second-trimester abortions than in those with first-trimester abortions (p approximately equal to 0.01). The abnormalities most commonly observed were anomalies of the uterine body (15%), endometrial infections (15%), and cervical incompetence (13%). Hormonal dysfunctions were detected in 5%, and there were chromosomal aberrations in 3% of the couples. The women in the group showing abnormalities were offered surgical or medical treatment, and 80% of those who subsequently conceived carried their pregnancies to term. Among the couples with no abnormal findings, women receiving specific antenatal counseling and psychological support had a pregnancy success rate of 86%, as compared to a success rate of 33% observed in women who were given no specific antenatal care (p less than 0.001).     

Pregnancy outcome, health of children, and family adjustment after donor insemination

We evaluated the pregnancies of 427 women who conceived through artificial insemination by donor (AID) at our clinic over a 12-year period. Initial phone contact was followed by a questionnaire. Outcome was known for 594 of the 606 pregnancies, with a total of 502 live-born children including 15 sets of twins. The spontaneous abortion rate was 16.5%, with no difference between fresh- and frozen-semen pregnancies. Significant correlations were found between spontaneous abortion rate and maternal age (P less than .001) and spontaneous abortion rate and cycle of conception (P less than .025). Follow-up was completed on 481 children, among whom the following were found: one chromosomal anomaly, 22 major congenital anomalies, four children with possibly syndromic conditions, and 38 with minor congenital anomalies. Of the school-aged children, 5.8% had recognized learning disabilities and 10.5% were considered gifted by their schools. We also investigated the psychological impact of AID on each family. The majority of couples (71.7%) informed their obstetricians of the AID. Half of the couples did not tell any family or friends. Many couples did not (47%) or probably did not (14%) plan to tell their children of their origins. The divorce rate among those with AID children was 7.2%, which was significantly less (P less than .01) than that in a matched population. Psychological counseling specifically related to AID was sought by 2.8% of the couples. We conclude that AID children are at similar risk for congenital anomalies as normally conceived children, but they experience lower rates of family dissolution.     

Cytogenetic study of peripheral lymphocyte culture in couples with habitual abortion

We report on a cytogenetic investigation of lymphocytes in 241 couples and six women with at least three abortions. We found a balanced reciprocal translocation three times (1.2% of couples) and a balanced Robertsonian translocation twice (0.8% of couples). Four numerical aberrations of the gonosomes were detected (three of them as a mosaic), and one deletion Xq- as a mosaic. The heterochromatic region of the chromosomes 1, 9 or 16 was enlarged in 12 couples (4.9%). There was no couple with a pericentric inversion of the chromosomes 1 or 9. The enlarged Y-chromosome (five males) according to our results does not play any important role for the reproduction. Five translocations and one supernumerary chromosome each in one cell only indicate an enlarged frequency of breakage events in couples with habitual abortion.     

Spontaneous Abortions Are Reduced After Preconception Diagnosis of Translocations

Purpose: Preimplantation genetic diagnosis of translocations has seldom been attempted. Recently, a genetic test based on analyzing polar bodies at the methaphase stage, following fluorescent in situ hybridization with commercially available whole-chromosome painting DNA probes has been presented. Here we report the use of this method in seven couples in whom the female was a carrier of one of these balanced translocations: 45,XX,der (13q;14q)(q10;q10) (two cases), 46,XX,t(4;14)(p15.3;q24), 45,XX,der(14q;21q) (q10;q10), 46,XX,t(7;20)(q22;q11.2), 46,XX,t(9,11)(p24;q12), 46,XX,t(14;18)(q22;q11), and 46,XX,t(3;8)(q11;;q11). Methods: The original method was improved in two ways. First, centromeric probes for one or both chromosomes involved in the translocation were added to avoid misdiagnosis caused by possible confusion of first polar body monovalent chromosomes (with two chromatids each) with single chromatids. Second, for cases with terminal translocations where commercially available probes do not cover telomere sequences, a telomere probe labeling the translocated fragment was added. Results: A total of 26 abnormal, 18 balanced, and 22 normal eggs was detected. Nine normal and seven balanced embryos were transferred, resulting in eight (50%) implanting, of which one spontaneously aborted. To date, the remainder have produced karyotypically normal or balanced babies and ongoing pregnancies. The rate of spontaneous abortions after preimplantation genetic diagnosis (12.5%) was significantly reduced (P < 0.001) compared to natural cycles in the same patients (95%). Conclusions: With the above improvements, the test can characterize any translocation of maternal origin and produce a high pregnancy rate and an apparently low frequency of spontaneous abortion.