Hysteroscopy may be justified after two miscarriages

A. Weiss1, E. Shalev1,2,3 and S. Romano1

1 Department of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula, 18101 and 2 Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula, 18101, Israel. Email: shaleve{at}tx.technion.ac.il


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Recurrent pregnancy loss is traditionally investigated after three or more consecutive pregnancy losses. Although there is a trend to start investigation after two miscarriages, data are not available to date to justify this approach. We sought to compare the frequency of uterine anomalies between women referred to hysteroscopy for repeated miscarriages after two, and three or more, miscarriages respectively. METHODS: A retrospective analysis of acquired and congenital uterine anomalies in all patients undergoing hysteroscopy for repeated pregnancy loss at an academic and referral medical centre. RESULTS: Hysteroscopy was performed on 165 women referred for recurrent pregnancy loss: 67 after two and 98 after three or more consecutive miscarriages. The rate of uterine anomalies did not differ significantly and was 32 versus 28% respectively. CONCLUSIONS: Hysteroscopy may be justified following two spontaneous pregnancy losses.

Key words: hysteroscopy/recurrent miscarriage/uterine anomalies


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Recurrent pregnancy loss has traditionally been defined as three consecutive, unexplained terminations of pregnancy before the completion of 20 weeks of gestation or the expulsion of a fetus weighing <500 g. There is a trend towards liberalizing this criterion to include women presenting with only two miscarriages (Li et al., 2002Go). Investigating recurrent pregnancy loss after only two miscarriages would clearly increase the number of women investigated, though it has not been shown that doing so would influence the chances of finding a cause for the miscarriages. Investigative procedures for recurrent pregnancy loss include parental karyotyping, hysteroscopy, testing for maternal endocrinology disease, acquired and genetic thrombophilia, the presence of antiphospholipid antibodies and karyotyping of products of conception. While all of these tests are costly, hysteroscopy is also invasive and so should be justified before being recommended as a first line investigative procedure for recurrent pregnancy loss after only two miscarriages.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ha'Emek Medical Center is a referral community hospital serving the 500 000 residents of the Galilee and Jezreel valley of Northern Israel. We reviewed the results of hysteroscopy performed for patients referred for recurrent pregnancy loss from May 1996 to February 2004. When available, charts from hospital admissions and visits to the department clinic were reviewed. Included were women with two or more miscarriages with pregnancy losses occurring during the first 20 weeks of gestation. Only patients with consecutive miscarriages were included. A miscarriage was defined as: the spontaneous expulsion of products of conception; the disappearance of fetal heart activity on ultrasound; a gestational sac which does not grow in consecutive weekly ultrasound examinations; or the {beta}-hCG failing to rise in serial measurements. Women were not included if they (or their spouses) were known to be carriers of balanced chromosomal anomalies, had uncontrolled or previously undiagnosed endocrinological disease such as diabetes or hypothyroidism or had antiphospholipid syndrome.

Data were collected on patient age, number of pregnancies and their results, other investigative procedures already performed, results of karyotyping of products of conception, ethnicity (Arab or Jewish), findings at hysteroscopy and findings at laparoscopy or laparotomy when performed. An attempt was made to elucidate the exact gestational age at the time of miscarriage and whether a gestational sac, fetal shadow or heart activity was diagnosed at any time prior to miscarriage. Abortuses that were found to be aneuploid and molar pregnancies were not counted as unexplained miscarriages, but the women were not excluded if they had two or more other miscarriages.

Hysteroscopic findings were categorized as being normal, having congenital anomalies or acquired anomalies. Congenital anomalies included arcuate variation or various Müllerian anomalies. Acquired anomalies included endometrial adhesions, fibroids which distort the intrauterine cavity and endometrial polyps or polypoid endometrium. When Müllerian anomalies were found, the diagnosis was confirmed with laparoscopy or laparotomy findings when available.

Fifty-nine subjects in each arm of the study were needed in order to achieve a power of 80% with an alpha=0.05 in order to detect an increase in anomalies from 5 to 25%. Student's t-test was used for statistical comparison of continuous data. Fisher's exact test was used for comparing non-continuous variables between groups. P < 0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 193 patients were referred to our centre for recurrent pregnancy loss investigation. Twenty-eight of them had a karyotype done successfully on one of the abortuses. Of the 28, four were aneuploid and the remaining 24 were euploid. The ratio of 46,XX to 46,XY karyotypes among the euploid products of conception was 19:5. There were also three molar pregnancies, as revealed by histological studies. These seven pregnancies were not counted as unexplained abortions. Patients whose miscarriages were not consecutive (n=28) were removed from the study.

A total of 165 hysteroscopic investigations remained for the study. Sixty-seven patients were referred after two consecutive miscarriages, while 98 were referred after three or more consecutive miscarriages. Clinical data are presented in Table I. No statistical difference in age, proportion of patients with second trimester miscarriages, proportion of patients with previous births, or the proportion of patients with previous terminations of pregnancy (TOP) could be found between the two groups.


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Table I. Clinical data for patients presenting for hysteroscopy with recurrent pregnancy failure

 
Hysteroscopic findings are shown in Table II. By reviewing patient files, a definitive diagnosis differentiating septate versus bicornus uterus through laparoscopy or laparotomy (e.g. a prior Caesarean section) was made in all but two cases. Of the 165 women, 32 (19%) had congenital anomalies while 18 (11%) had acquired anomalies. One patient had both a congenital and an acquired anomaly. In all, 116 (70%) of the women had no pathological findings on hysteroscopy. The frequency or type of anomalies found did not differ in patients with two miscarriages versus those with three or more miscarriages (Table III).


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Table II. Hysteroscopic findingsa

 

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Table III. Hysteroscopic findings in recurrent aborters with 2 versus ≥3 consecutive miscarriagesa

 
Sub-analysis of our data to compare Arab versus Jewish patients revealed that Arab patients generally presented at a younger age and after experiencing more pregnancy losses than Jewish patients. Congenital anomalies were found more frequently in the Arab patients, but overall, the rate of congenital and acquired anomalies did not differ significantly between the two groups (Table IV).


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Table IV. Clinical data and findings as a function of ethnic background

 
The rate of pathological findings at hysteroscopy did not differ after two miscarriages versus three or more miscarriages when separated between Arab and Jewish patients (Table V).


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Table V. Frequency of anomalous findings relative to the number of miscarriages according to ethnic background

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Recurrent pregnancy loss has traditionally been defined as three consecutive spontaneous miscarriages. It has been suggested that this definition should be modified to two consecutive miscarriages as recurrence risks and subsequent outcome are similar for these two groups (Chauhan and Moghissi, 2002Go), though studies to support this assertion are lacking. In a study comparing patients with two miscarriages to those with three miscarriages, a difference in the rate of anomalies, as tested with hysterosalpingography, was not found (Portuondo et al., 1986Go).

Anatomical uterine defects, including Müllerian anomalies, adhesions and fibroids, are frequently found in women with recurrent miscarriage whether of the first or second trimester (Propst and Hill, 2000Go). The diagnosis of these abnormalities can be made with a combination of ultrasound, hysteroscopy and/or laparoscopy (Patton, 1994Go). While Müllerian anomalies can be successfully diagnosed using ultrasound, particularly three-dimensional ultrasound (Raga et al., 1996Go; Wu et al., 1997Go), hysteroscopy has the advantage in its ability to diagnose and treat intrauterine adhesions, fibroids and polyps.

Anatomical abnormalities can be classified as congenital or acquired. Congenital anomalies include the arcuate uterus and Müllerian anomalies. The role of the arcuate uterus as a cause of pregnancy loss is controversial. While some have demonstrated that the arcuate uterus has no impact on reproduction (Raga et al., 1997Go), others have found it to be associated with a poor pregnancy outcome (Acien, 1993Go; Woelfer et al., 2001). In our study, the arcuate uterus was equally divided between the two groups, so that even if they are counted with the normal cases, the statistical outcome is not changed (data not shown).

Diagnosing uterine anomalies, whether acquired or congenital, is consequential since many such anomalies are amenable to therapy. Studies have shown that hysteroscopic resection of the septum in a septate uterus improves pregnancy outcome in subsequent pregnancies in women with recurrent miscarriages (Porcu et al., 2000Go; Saygili-Yilmaz et al., 2003Go; Valli et al., 2004Go). Hysteroscopic adhesiolysis also improves pregnancy outcome in women with recurrent miscarriages (Goldenberg et al., 1995Go; Katz et al., 1996Go).

The rate of uterine anomalies reported in the literature for women at low risk or with a good obstetric history is between 2 and 5% (Ashton et al., 1988Go; Raga et al., 1997Go; Salim et al., 2003Go). The reported rate of anomalies for patients with recurrent miscarriages varies from 6.3 to >67% (Tulppala et al., 1993Go; Romer et al., 1994Go; Valli et al., 2001Go; Salim et al., 2003Go), with most studies showing ≥25% anomalies. This wide discrepancy for the rate of anomalies among patients with recurrent pregnancy losses represents differences in study design and in the types of anomalies reported. Our power analysis demonstrated that 59 patients are required in each study arm to demonstrate an increase from 5% anomalies to 25% anomalies between the two groups.

Our medical centre is the only referral centre serving our region and therefore our patients are representative of all segments of the population we serve. We found that patients with two consecutive miscarriages had 22% Müllerian anomalies and 12% acquired anomalies, or 32% of any pathological finding on hysteroscopy. Patients with three or more miscarriages had 17% Müllerian anomalies and 11% acquired anomalies, or 28% of any pathological finding. A significant difference was not found between the two groups, suggesting that patients who have suffered two miscarriages have the same likelihood of carrying a uterine pathology as those with three or more miscarriages.

It should be noted that few women in our study had cytogenetic analysis successfully performed on their abotuses. The overabundance of the 46,XX karyotype suggests a high rate of maternal contamination and therefore makes statistical analysis meaningless in this regard.

Only seven miscarriages were found to be due to an aneuploid or molar pregnancy. These pregnancies were not counted as unexplained miscarriages but the patients were not excluded from the study either, and hysteroscopy was performed if the patient had suffered two or more unexplained miscarriages. This is certainly justified for molar pregnancies since all products of conception at our institution undergo histological evauation. If a woman had recurrent miscarriages because of recurrent molar pregnancies, this would be apparent from the histological evaluation of the other pregnancy losses.

Excluding patients from the study with an aneuploid pregnancy would not be justified either. Since karyotyping is only attempted after three or more miscarriages at our institution, excluding women from the study would invoke a bias between the two groups. Furthermore, while aneuploid pregnancies are commonly the cause of a sporadic pregnancy loss, their role in recurrent pregnancy loss is more controversial. To date, there have been no large studies convincingly demonstrating that recurrent aneuploid pregnancies are an aetiology of recurrent miscarriages. A recent study actually showed that when a karyotype was performed on an abortus from a woman with a history of recurrent miscarriages, the chance of it being aneuploid was less than from women experiencing their first miscarriage, with an odds ratio of 0.47 and a confidence interval of 0.27–0.80 (Sullivan et al., 2004Go). Other studies have also concluded that women with recurrent miscarriages are less likely to carry aneuploid conceptions (Ogasawara et al., 2000Go; Carp et al., 2001Go). This suggests that women with recurrent miscarriages are more likely to have aetiologies other than aneuploidy as the cause of their pregnancy losses, and lends credence to the decision of keeping these women in the study.

One could ascertain two distinct populations in our study group. Those coming from the Jewish community tended to be older and have fewer miscarriages before seeking investigation. Conversely, those patients coming from the Arab community, tended to be younger, were more likely to have three or more miscarriages and were more likely to have congenital anomalies. These differences between Arabs and Jews are most likely cultural in origin. In our region, Arab women tend to marry younger and begin childbearing earlier (A. Weiss, unpublished data). There is a tendency to refer older patients for investigation after fewer miscarriages, which may explain why the Jewish patients were referred after fewer miscarriages, on average. The higher rate of congenital anomalies among the Arab population may be a result of the higher rate of consanguineous marriages among them. Nevertheless, analysing the data individually within each ethnic subgroup did not change the fact that the rate of hysteroscopic findings did not differ between those women with two consecutive miscarriages to those with three or more consecutive miscarriages, although the numbers in each group were too small for sufficient power.

A major drawback of our study is its retrospective nature. There may be physician biases affecting their decision to refer patients after two, three or more miscarriages, influencing the outcome of our study. It is our experience, though, that the decision to begin an investigation after two miscarriages is usually the result of a patient's request.

The question of when to investigate recurrent pregnancy loss is also one of cost-benefit. By beginning an investigation after two losses, we should expect a sharp increase in the number of women investigated. Woman with recurrent pregnancy loss generally have a good prognosis in their subsequent pregnancy. After two miscarriages, 76% of patients can expect a successful subsequent pregnancy outcome (Brigham et al., 1999Go) and therefore will not benefit from investigation. The same can be said, though, after three miscarriages, since the same study found 79% successful pregnancy outcome subsequent to three miscarriages. This is contradicted by another study (Knudsen et al., 1991Go), which found that the miscarriage rate increased substantially from 25 to 45% when comparing women with two or three previous miscarriages respectively. Other researchers found that a poor prognosis was to be expected only when the number of subsequent pregnancy losses increased to four (Quenby and Farquharson, 1993Go) and six (Clifford et al., 1997Go) miscarriages.

In conclusion, women after two spontaneous miscarriages can be advised that hysteroscopy will reveal congenital or acquired uterine defects in ~30% of cases. Many of the anomalies detected are amenable to therapy and may improve subsequent pregnancy outcome. The decision to begin an investigation after two miscarriages should be individualized. Since the majority of women, after two miscarriages, will have a successful subsequent pregnancy outcome, many will choose to defer an investigation. Others will want to begin an investigation after two miscarriages because of the stress and frustration associated with aborting rather than ‘wait for a third miscarriage’. These patients should not be denied the option of hysteroscopy after discussion of the risks and benefits and informed consent is provided. Our study supports the option of performing a hysteroscopy after two miscarriages since the likelihood of finding a congenital or acquired anomaly is the same as after three or more miscarriages.


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on February 3, 2005; resubmitted on March 15, 2005; accepted on April 13, 2005.





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