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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, Utah.
Address reprint requests to: Amy Sullivan, md, Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Room 2B200, 50 North Medical Drive, Salt Lake City, Utah 84132; e-mail: amy.sullivan{at}hsc.utah.edu.
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ABSTRACT |
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METHODS: Recurrent miscarriage cases (n = 135) included women who had a subsequent miscarriage in which an abortus karyotype was obtained. Controls (n = 150) were patients experiencing a sporadic miscarriage who had fetal karyotypes performed as part of a study to assess the utility of abortus tissue for transplantation. Karyotype analysis was performed using standard G-banding techniques.
RESULTS: Abortuses from 122 cases and 133 controls were successfully karyotyped. Thirty-one (25.4%) abortuses from cases and 56 (42.1%) from controls were aneuploid (odds ratio 0.47, 95% confidence interval 0.27–0.80). Aneuploid abortuses occurred in 20% of cases and 25% of controls, aged 20–29 years, 19% of cases and 24% of controls, aged 30–34 years, 35% of cases and 47% of controls, aged 35–39 years, and 50% of both cases and controls, aged 40 years or older (not significant). Of 30 cases in whom 2 or more miscarriages were karyotyped, 3 (10%) had aneuploidy in each abortus.
CONCLUSION: In our population of recurrent miscarriage patients, abortus aneuploidy occurred significantly less often than in sporadic miscarriages. The rate of aneuploidy in this study was considerably lower than reported in other studies. If recurrent aneuploidy contributes to recurrent miscarriage, it does so in only a small number of patients.
LEVEL OF EVIDENCE: II-2
It is well known that approximately 50% of sporadic (nonrecurrent) miscarriages are a result of fetal aneuploidy.2–5 Some investigators have demonstrated an association between abortus aneuploidy and recurrent miscarriage,6–9 thereby raising the suspicion that recurrent fetal aneuploidy might be a cause of recurrent miscarriage. This relationship is further supported by preimplantation genetic studies of women with recurrent miscarriage, which demonstrate an aneuploidy rate of 50% in all embryos.10,11
A recent study reported the results of studies of 285 women presenting with recurrent miscarriage, in whom at least one miscarriage was sent for cytogenetic analysis.12 This study determined retrospectively the frequency of abortus aneuploidy in recurrent miscarriage cases and stratified the results with respect to maternal age. The results were then compared with historical data from an unselected population from 7 miscarriage studies. The authors concluded that, when stratified for maternal age, there was no difference in the distribution of abortus aneuploidy between women with recurrent miscarriage and a historic control group.
We performed a MEDLINE search that included the years 1975–2004. We used the search terms "aneuploidy," "recurrent aneuploidy," "recurrent miscarriage," and "recurrent abortion." Currently there exist no large studies wherein more than one abortus karyotype was performed in subjects presenting with idiopathic recurrent miscarriage. Instead, most authors report on the aneuploidy rate of subsequent pregnancies in recurrent miscarriage patients. Therefore, whether recurrent abortus aneuploidy in a patient does in fact contribute to recurrent miscarriage has not been appropriately addressed.
The purpose of this study was to investigate the relationship between fetal aneuploidy and recurrent miscarriage by estimating whether fetal aneuploidy is more common in patients with recurrent miscarriage than in patients with sporadic miscarriage. In addition, we estimated the rate of recurrent abortus aneuploidy in a subset of cases in whom abortus karyotypes were performed on 2 or more consecutive miscarriages to estimate whether recurrent abortus aneuploidy may be a cause of recurrent miscarriage.
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METHODS |
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2 consecutive spontaneous miscarriages), in whom a karyotype of a subsequent miscarriage had been performed. All cases had prior negative evaluations for parental chromosomal abnormalities, structural uterine anomalies, and antiphospholipid antibodies. Control subjects were 150 women who were experiencing their first spontaneous miscarriage, in which fetal karyotypes were performed as part of a study to assess the availability and utility of abortus tissue for human transplantation therapy.13 Abortus tissue was collected after institutional review board approval was obtained and the study participants had given appropriate consent. For cases with recurrent miscarriage, the abortus karyotype was performed as a matter of clinical care. For control subjects, abortus tissue was collected under institutional review board approval as part of a National Institutes of Health-sponsored study.13 The abortus tissue was obtained when cases presented with spontaneous miscarriage or at the time of uterine curettage. The control specimens were uniformly collected by trained medical personnel under sterile conditions. Karyotype analysis of the abortus tissue from both cases and controls was performed by an experienced cytogenetics laboratory using standard G-banding techniques. The medical records of the cases were reviewed to assure that only patients diagnosed with true idiopathic recurrent miscarriage were included in the analysis.
The frequency of fetal aneuploidy in each group was determined and compared. The distribution of the various types of cytogenetic abnormalities was also compared. The results are reported with odds ratios (OR) and 95% confidence intervals (CI). The data were also stratified with respect to maternal age, and the frequency of abortus aneuploidy in different age groups of cases and controls was compared using the 
2 test. In addition, the rate of fetal aneuploidy was determined in cases where more than one abortus karyotype was performed.
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RESULTS |
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For the case-control analysis, results of only one abortus karyotype was used from each case and compared with controls. As seen in Table 2, abortus tissue samples from 91 (74.6%) cases and 77 (57.9%) controls were euploid. Abortus tissue samples from 31 (25.4%) cases and 56 (42.1%) controls were aneuploid (OR 0.47, 95% CI 0.27–0.80). There was no difference in the distribution of the specific types of cytogenetic abnormalities between the cases and controls. In addition, when the data were stratified for maternal age, there was no difference in the rate of aneuploidy between cases and controls (Table 3). There were 30 cases with fetal karyotypes performed on 2 or more miscarriages. Of these 30 cases, only 3 (10%) displayed aneuploidy in each abortus.
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We also analyzed the data taking into consideration the fact that there is a background rate of fetal aneuploidy in both sporadic and recurrent miscarriage patients. We calculated the expected background rate of fetal aneuploidy in both cases and controls by using data from the published literature (Fig. 1). Given a theoretical control group of 100 women, one can assume a 10–15% rate of sporadic miscarriage.14 Of the patients in our study with sporadic miscarriage, we found a 42% abnormal fetal karyotype rate, which translates to 4–6 abnormal karyotypes per 100 pregnant women. This is the background rate of fetal aneuploidy in our population. Given a population of 100 women with recurrent miscarriage, 30–40% will have a subsequent loss.15 Of these recurrent miscarriage cases, we demonstrated a 24% fetal aneuploidy rate, which translates to 7–10 abnormal karyotypes per 100 recurrent miscarriage patients. This rate is approximately 3–6 per 100 above our background rate of fetal aneuploidy in patients with sporadic miscarriage.
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DISCUSSION |
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The rate of abortus aneuploidy of 57% in the control group of well-documented sporadic miscarriages from patients evaluated and treated at our institution is similar to other reported studies.2,4,5 However, the incidence of abortus aneuploidy among patients with recurrent miscarriage in our study (25%) is less than the 30–57% incidence that others have previously reported.9,12,16,17 The reason for this discrepancy is not clear. Some have suggested that different definitions of recurrent miscarriage could account for the variable results.16 We defined recurrent miscarriage as 2 or more consecutive miscarriages, as did Ogasawara17 and Stern,9 both of whom reported higher abortus aneuploidy rates in recurrent miscarriage patients (51% and 57%). Our data are nonetheless reliable because in our study almost 90% of the recurrent miscarriage abortus material was successfully karyotyped. Others report successful abortus karyotypes in only 50–75% of patients.16,17 In addition, of the abortus karyotypes from both cases and controls that were euploid, the female/male ratios were 43:57 and 46:54, which is comparable to the 50:50 ratio that would be expected in the general population. Thus, contamination of the specimens with maternal tissue, thereby leading to inaccurate results, is not an issue in our study. Therefore, we believe that our results accurately reflect the true aneuploidy rate among our cases with a history of recurrent miscarriage.
When analyzed with respect to maternal age, no significant difference was noted for the rate of fetal aneuploidy between cases and controls. As expected, the rate of aneuploidy significantly increased with increasing maternal age (Table 3). Maternal age, not a history of recurrent miscarriage, was associated with an increased incidence of fetal aneuploidy, most commonly trisomies.
When our data were analyzed taking into consideration a background rate of fetal aneuploidy in both the sporadic and recurrent miscarriage patients, we found that the fetal aneuploidy rate in the recurrent miscarriage cases was 3–6% above the expected background rate for our control population. Because this calculation is based on data published in the literature, we cannot comment on the statistical significance of this finding. Whether this small increase in the rate of fetal aneuploidy in our recurrent miscarriage cases bears much clinical relevance has yet to be determined. However, evidence in the literature from Drosophilae, mice, and in vitro studies demonstrates that meiosis is under genetic control.18–22 Aberrations in certain genes result in meiotic errors. Therefore, it is possible that similar genetic mutations exist in humans, which may predispose some women to abnormalities in meiosis and subsequent recurrent fetal aneuploidy.
To date there are few large published series that directly address the role that recurrent aneuploidy plays in recurrent miscarriage. The results of 273 patients who had karyotypes performed on tissue from 2 or more spontaneous abortions (not necessarily consecutive) indicate that having one aneuploid miscarriage does not place a patient at increased risk for a trisomic miscarriage in a subsequent pregnancy.23 Although this data set was large, the cases were not evaluated for known causes of recurrent miscarriage and, therefore, do not represent a population of unexplained recurrent miscarriage patients.
Data on idiopathic recurrent miscarriage patients who have had cytogenetic analysis of more than one abortus are sparse. This is most likely because karyotypes of the abortus material are not typically obtained unless patients have already been diagnosed with recurrent miscarriage. However, at that point the cytogenetic data on the first 2 miscarriages is lost. Because these data are unobtainable, data are usually collected from a subsequent abortus karyotype in recurrent miscarriage patients. This information is then extrapolated to estimate whether recurrent aneuploidy may be a cause of recurrent miscarriage. Furthermore, significant bias exists in both specimen collection and cytogenetic analysis because, at most centers, these are performed randomly at the discretion of each clinician. Although the number of cases in our study with more than one abortus karyotype is small (n = 30), it represents one of the larger data sets of multiple abortus karyotypes in well-defined idiopathic recurrent miscarriage patients (MEDLINE search terms "aneuploidy," "recurrent aneuploidy," "recurrent miscarriage," "recurrent abortion"; period of search 1975–2004). To provide patients with more complete information, larger analyses of recurrent miscarriage patients with more than one abortus karyotype would need to be performed.
The cause of recurrent miscarriage remains a clinical dilemma in the majority of patients. Our data and analysis of the literature demonstrate that recurrent aneuploidy may contribute to recurrent miscarriage, although only in a small proportion of patients. It is clear from both animal and in vitro studies that meiosis is genetically controlled, and therefore it is very likely that a similar scenario exists in humans. Further large studies are needed that include patients with idiopathic recurrent miscarriage in whom multiple abortus karyotypes have been performed.
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Footnotes |
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10.1097/01.AOG.0000137832.86727.e2
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