Sotirios H. Saravelos

Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: a critical appraisal

BACKGROUND The prevalence of congenital uterine anomalies in women with reproductive failure remains unclear, largely due to methodological bias. The aim of this review is to assess the diagnostic accuracy of different methodologies and estimate the prevalence of congenital uterine anomalies in women with infertility and recurrent miscarriage (RM). METHODS Studies from 1950 to 2007 were identified through a MEDLINE search; all relevant references were further reviewed. RESULTS The most accurate diagnostic procedures are combined hysteroscopy and laparoscopy, sonohysterography (SHG) and possibly three-dimensional ultrasound (3D US). Two-dimensional ultrasound (2D US) and hysterosalpingography (HSG) are less accurate and are thus inadequate for diagnostic purposes. Preliminary studies (n = 24) suggest magnetic resonance imaging (MRI) is a relatively sensitive tool. A critical analysis of studies suggests that the prevalence of congenital uterine anomalies is approximately 6.7% [95% confidence interval (CI), 6.0-7.4] in the general population, approximately 7.3% (95% CI, 6.7-7.9) in the infertile population and approximately 16.7% (95% CI, 14.8-18.6) in the RM population. The arcuate uterus is the commonest anomaly in the general and RM population. In contrast, the septate uterus is the commonest anomaly in the infertile population, suggesting a possible association. CONCLUSIONS Women with RM have a high prevalence of congenital uterine anomalies and should be thoroughly investigated. HSG and/or 2D US can be used as an initial screening tool. Combined hysteroscopy and laparoscopy, SHG and 3D US can be used for a definitive diagnosis. The accuracy and practicality of MRI remains unclear.

Body mass index and risk of miscarriage in women with recurrent miscarriage

OBJECTIVE To investigate the effect of underweight, overweight, and obesity on the risk of miscarriage in the subsequent pregnancy in women with recurrent miscarriage. DESIGN Retrospective analysis of prospectively collected data from the database of a tertiary recurrent miscarriage center. SETTING The recurrent miscarriage clinic at Sheffield Teaching Hospitals. PATIENT(S) A total of 844 pregnancies from 491 patients with recurrent miscarriage were included in the analysis. MAIN OUTCOME MEASURE(S) The odds of miscarriage in the subsequent pregnancy for all pregnancies after referral to the recurrent miscarriage clinic as well as the first pregnancy post referral. RESULT(S) When analyzing all pregnancies, and compared to women with a normal body mass index, obese and underweight patients had a significantly higher odds of miscarriage in the subsequent pregnancy (OR, 1.71; 95% CI, 1.05-2.8; and OR, 3.98; 95% CI, 1.06-14.92; respectively), whereas there was no significantly increased odds of miscarriage in overweight women (OR, 1.02; 95% CI, 0.72-1.45). Logistic regression analysis showed that the most important factor predicting the occurrence of miscarriage was advanced maternal age (P=0.01) followed by an increased body mass index (P=0.04). CONCLUSION(S) In women with recurrent miscarriage, a mild increase in the body mass index does not increase the risk of miscarriage, whereas obese and underweight patients have a small but significant increased risk of miscarriage in the subsequent pregnancy.

The prevalence and impact of fibroids and their treatment on the outcome of pregnancy in women with recurrent miscarriage

BACKGROUND Although uterine fibroids have been associated with spontaneous miscarriage, to our knowledge there have been no studies in the literature assessing their role in the recurrent miscarriage (RM) population. The aims of this study are to examine the impact of different types of fibroids on the pregnancy outcome of women with RM and to investigate to what extent resection of fibroids distorting the uterine cavity affects the outcome of a future pregnancy. METHODS The study analysed retrospective and prospective data from a large tertiary referral RM clinic. Couples were investigated as per an established protocol. Fibroids were diagnosed using combined transvaginal ultrasound and hysterosalpingography. Fibroids distorting the uterine cavity were resected via hysteroscopy. Two study groups were subsequently examined: women with cavity-distorting fibroids who underwent surgery (n =25) and women with fibroids not distorting the cavity who did not undergo any intervention (n =54). The latter was compared with a control group of women with unexplained RM (n =285). RESULTS The prevalence of fibroids was found to be 8.2% (79/966). In total, 264 pregnancies of women with fibroids and 936 pregnancies of women with unexplained RM were analysed. Women with intracavitary distortion and undergoing myomectomy significantly reduced their mid-trimester miscarriage rates in subsequent pregnancies from 21.7 to 0% (P< 0.01). This translated to an increase in the live birth rate from 23.3 to 52.0% (P< 0.05). Women with fibroids not distorting the cavity behaved similarly to women with unexplained RM achieving a 70.4% live birth rate in their subsequent pregnancies without any intervention. CONCLUSIONS Fibroids are associated with increased mid-trimester losses amongst women with RM. Resection of fibroids distorting the uterine cavity can eliminate the mid-trimester losses and double the live birth rate in subsequent pregnancies. Women with fibroids not distorting the uterine cavity can achieve high live birth rates without intervention.

Unexplained recurrent miscarriage: how can we explain it?

Unexplained recurrent miscarriage (RM) can be a challenging and frustrating condition for both patients and clinicians. For the former, there is no diagnosis available for consolation, while for the latter there is little evidence-based treatment to offer. However, the majority of these patients have an excellent prognosis without the need for any treatment. Epidemiological associations suggest that the reason for this is that the majority of women with unexplained RM are in fact healthy individuals, with no underlying pathology, who have suffered three miscarriages purely by chance. Nevertheless, a certain proportion of women with unexplained RM will continue to miscarry, and preliminary studies suggest the presence of pathology in some women of this group. As a result, two types of unexplained RM can be described: Type I unexplained RM, which occurs by chance in women who have no underlying pathology and has a good prognosis; and Type II unexplained RM, which occurs due to an underlying pathology that is currently not yet identified by routine clinical investigations and has a poorer prognosis. Distinguishing between Types I and II unexplained RM can be achieved by considering several factors: the age of the woman, the definition used for RM (i.e. whether biochemical pregnancy losses are considered as miscarriages), the number of previous miscarriages suffered and the karyotype of the products of conception, where available. A better understanding of the two types of unexplained RM could lead to more targeted referrals, investigations and treatments, which would improve cost-effectiveness and overall clinical care.

The pattern of pregnancy loss in women with congenital uterine anomalies and recurrent miscarriage.

Congenital uterine anomalies (CUA) are a known cause of recurrent miscarriage (RM), but the pattern of pregnancy loss that different CUA produce remains unknown. This study included 665 women with RM who were screened for CUA using a combined two-dimensional ultrasound (2D-US) and hysterosalpingography (HSG) approach. All suspected CUA were definitively diagnosed and classified via a combined hysteroscopy/laparoscopy procedure. Pregnancy outcomes were evaluated and compared for each type of CUA versus a control group of women with no identifiable cause of RM (unexplained RM). Fifty-six women with CUA and 107 women with unexplained RM were identified. In total, 881 pregnancies were analysed. Analysis showed that women with a septate or bicornuate uterus suffered from significantly increased second-trimester miscarriages compared with controls (13.2% and 13.8% versus 1.0%; P<0.001 and P<0.05, respectively). Women with an arcuate, septate or bicornuate uterus showed significantly reduced rates of biochemical pregnancy losses compared with controls (9.5%, 11.1% and 11.1% versus 30.4%; P<0.01, P<0.01 and P<0.05, respectively). Pregnancies of women with RM and CUA are not associated with early implantation failure and are compromised at a more advanced gestational age.

Unexplained Recurrent Pregnancy Loss

Women with unexplained recurrent pregnancy loss (RPL) represent a highly heterogeneous group of patients. Past studies have investigated systemic endocrine and immunologic mechanisms as potential causes for pregnancy loss in unexplained RPL, while exciting new work has focused on spermatozoal, embryonic, and endometrial characteristics to explain the regulation of implantation and subsequent pregnancy loss. In the clinical and research context, stratification of women with unexplained RPL according to whether they have a high probability of pathologic status will help select women who are most appropriate for further investigation and potential future treatment.

Does free androgen index predict subsequent pregnancy outcome in women with recurrent miscarriage

BACKGROUND Several studies have investigated plasma androgen levels in women with recurrent miscarriage (RM) with conflicting results on whether an association between hyperandrogenaemia and RM exists. However, none of these studies included sensitive androgen measurements using a large data set. We therefore investigated the free androgen index (FAI) in a large number of women with RM in order to ascertain whether hyperandrogenaemia is a predictor of subsequent pregnancy outcome. METHODS We studied 571 women who attended the Recurrent Miscarriage Clinic in Sheffield and presented with > or =3 consecutive miscarriages. Serum levels of total testosterone and sex hormone-binding globulin were measured in the early follicular phase and FAI was then deduced. RESULTS The prevalence of hyperandrogenaemia in RM was 11% and in a subsequent pregnancy, the miscarriage rate was significantly higher in the raised FAI group (miscarriage rates of 68% and 40% for FAI > 5 and FAI < or = 5 respectively, P = 0.002). CONCLUSIONS An elevated FAI appears to be a prognostic factor for a subsequent miscarriage in women with RM and is a more significant predictor of subsequent miscarriage than an advanced maternal age (> or =40 years) or a high number (> or =6) of previous miscarriages in this study.

Endometrial thickness as a predictor of pregnancy outcomes in 10787 fresh IVF-ICSI cycles.

This retrospective study assessed the predictive value of endometrial thickness (EMT) on HCG administration day for the clinical outcome of fresh IVF and intracytoplasmic sperm injection (ICSI) cycles. A total of 8690 consecutive women undergoing 10,787 cycles over a 5-year period were included. The 5th, 50th and 95th centiles for EMT were determined as 8, 11 and 15 mm, respectively. Group analysis according to these centiles (Group 1: < 8 mm; Group 2: ≥ 8 and ≤11 mm; Group 3: > 11 and ≤15 mm; Group 4: > 15 mm) demonstrated significant differences (P < 0.001) in clinical pregnancy rates (23.0%, 37.2%, 46.2% and 53.3%, respectively), live birth rates per clinical pregnancy (63.3%, 72.0%, 78.1% and 80.3%, respectively), spontaneous abortion rates (26.7%, 23.8%, 19.9% and 17.5%, respectively), and ectopic pregnancy rates (10.0%, 4.3%, 2.1% and 2.2%, respectively). Logistic regression analyses showed EMT as one of the independent variables predictive of clinical pregnancy (OR = 1.097; P < 0.001), live birth (OR = 1.078; P < 0.001), spontaneous abortion (OR = 0.948; P < 0.001), and ectopic pregnancy (OR = 0.851; P < 0.001). Future research should aim to understand the underlying mechanisms relating EMT to conception, ectopic implantation and spontaneous abortion.

Comparison of reproductive outcome, including the pattern of loss, between couples with chromosomal abnormalities and those with unexplained repeated miscarriages

Chromosomal abnormalities are an important cause of repeated miscarriage. Several studies have discussed the association between chromosomal abnormalities and repeated miscarriage. This study attempts to describe the pattern of miscarriage in this group of women and the eventual pregnancy outcome of couples with chromosomal abnormalities compared with couples with unexplained repeated pregnancy loss.

The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies

What is the recommended diagnostic work-up of female genital anomalies according to the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) system? The ESHRE/ESGE consensus for the diagnosis of female genital anomalies is presented. Accurate diagnosis of congenital anomalies still remains a clinical challenge due to the drawbacks of the previous classification systems and the non-systematic use of diagnostic methods with varying accuracy, with some of them quite inaccurate. Currently, a wide range of non-invasive diagnostic procedures are available, enriching the opportunity to accurately detect the anatomical status of the female genital tract, as well as a new objective and comprehensive classification system with well-described classes and sub-classes. The ESHRE/ESGE Congenital Uterine Anomalies (CONUTA) Working Group established an initiative with the goal of developing a consensus for the diagnosis of female genital anomalies. The CONUTA working group and imaging experts in the field have been appointed to run the project. The consensus is developed based on (1) evaluation of the currently available diagnostic methods and, more specifically, of their characteristics with the use of the experts panel consensus method and of their diagnostic accuracy performing a systematic review of evidence and (2) consensus for (a) the definition of where and how to measure uterine wall thickness and (b) the recommendations for the diagnostic work-up of female genital anomalies, based on the results of the previous evaluation procedure, with the use of the experts panel consensus method. Uterine wall thickness is defined as the distance between interostial line and external uterine profile at the midcoronal plane of the uterus; alternatively, if a coronal plane is not available, the mean anterior and posterior uterine wall thickness at the longitudinal plane could be used. Gynaecological examination and two-dimensional ultrasound (2D US) are recommended for the evaluation of asymptomatic women. Three-dimensional ultrasound (3D US) is recommended for the diagnosis of female genital anomalies in “symptomatic” patients belonging to high-risk groups for the presence of a female genital anomaly and in any asymptomatic woman suspected to have an anomaly from routine avaluation. Magnetic resonance imaging (MRI) and endoscopic evaluation are recommended for the sub-group of patients with suspected complex anomalies or in diagnostic dilemmas. Adolescents with symptoms suggestive for the presence of a female genital anomaly should be thoroughly evaluated with 2D US, 3D US, MRI and endoscopy. The various diagnostic methods should be used in a proper way and evaluated by experts to avoid mis-, over- and underdiagnosis. The role of a combined ultrasound examination and outpatient hysteroscopy should be prospectively evaluated. It is a challenge for further research, based on diagnosis, to objectively evaluate the clinical consequences related to various degrees of uterine deformity.