Er zijn associaties aangetoond tussen uterusafwijkingen en herhaalde miskramen. Deze module beschrijft de adviezen met betrekking tot congenitale en verworven uterusafwijkingen.

ESHRE Guideline group on RPL (2022) 

Summary of literature

Congenital uterine malformations
An association between congenital uterine malformations and recurrent pregnancy loss (RPL) has been well documented, but the exact prevalence in this population has not been clearly defined (Saravelos et al., 2008). Potentially relevant congenital Müllerian tract malformations include septate uterus, bicorporeal uterus with normal cervix (AFS bicornuate uterus), bicorporeal uterus with double cervix (AFS didelphic uterus) and hemi-uterus (AFS unicornuate uterus). The prevalence of uterine malformations is higher in women having a history of RPL (13.3%; 95% CI 8.9-20) than in the general/fertile population (5.5%; 95% CI 3.5-8.5). The prevalence of uterine malformations diagnosed with optimal test was similar in women with three or more losses (15.4%; 95% CI 10.3- 23) compared to women with two or more losses (10.9%; 95% CI 3.6-33.3) (Chan et al., 2011b, Saravelos et al., 2008).

Two systematic reviews have also reported a higher prevalence of miscarriage in women with congenital uterine malformations compared to controls (Chan et al., 2011a, Venetis et al., 2014). In a meta-analysis of comparative studies, women with septate uterus (RR 2.65, 95% CI 1.39-5.09, based on 6 studies, I²=93%) and bicornuate uterus (RR 2.32, 95% CI 1.05-5.13, I²=87%) had an increased probability of first-trimester PL, compared to their controls. Women with arcuate uterus (RR 2.27, 95% CI 0.64-7.96, based in 4 studies, I²=0%), septate uterus (RR 2.95, 95% CI 1.51-5.77, based on 5 studies, I²=39%) and bicornuate uterus (RR 2.90, 95% CI 1.56-5.41, based on 4 studies, I²=0%) had an increased probability of second-trimested PL, compared to their controls (Venetis et al., 2014).

Diagnosis of congenital uterine malformations

Based on the higher prevalence of uterine malformations in women with RPL, diagnostic imaging of the uterus should be considered in women with RPL (primary or secondary) (Jaslow and Kutteh, 2013).

Imaging for detection of uterine malformations has been performed with a range of different techniques, all with different potential and limitations for diagnosing the various types of malformations. An ESHRE consensus for diagnosis of congenital uterine malformations was published in 2016 (Grimbizis et al., 2016).

In the review by Saravelos, combined hysteroscopy and laparoscopy have been considered the gold standard in diagnosing uterine malformations, because they allow for a direct visualization of the internal and external contour of the uterus (Saravelos et al., 2008). The main disadvantage of hysteroscopy is the invasiveness of the procedure, although nowadays it can be performed in an office setting under local anesthetics.

Sonohysterography (or hysterosonography) (SHG) appears a safe procedure which provides more information about uterine abnormalities than hysterosalpingography (HSG) or ultrasound (US) alone (Tur-Kaspa et al., 2006). SHG is accurate in diagnosing and classifying congenital uterine malformations (Ventolini et al., 2004, Valenzano et al., 2006). In addition, SHG has a higher sensitivity and specificity than HSG or diagnostic hysteroscopy to diagnose uterine malformations in general (Ludwin et al., 2011). SHG uses the introduction of fluid (saline or contrast) into the uterine cavity to enhance US imaging studies, which could be uncomfortable for women. The diagnosis of septate uterus by SHG eliminates the need to perform laparoscopy prior to hysteroscopic metroplasty (Ludwin et al., 2011).

Three-dimensional US allows visualization of the internal and external contour of the uterus, has high sensitivity and specificity, and it is non-invasive (Caliskan et al., 2010, Saravelos et al., 2008). It appears to be very accurate for the diagnosis and classification of congenital uterine malformations and may conveniently become the only mandatory step in the assessment of the uterine cavity in women with a history of RPL, although further studies are required for confirmation (Ghi et al., 2009).

Two-dimensional US and hysterosalpingography (HSG) are non-invasive and widely available. Two-dimensional US has a low sensitivity, but a high specificity for diagnosis of malformations. HSG has a good sensitivity for diagnosing more pronounced uterine malformations, but it is limited in differentiating between the types of malformations (Saravelos et al., 2008). Overall, 2D transvaginal ultrasound (TV-US) and HSG are suboptimal to diagnose uterine malformations, based on a poor accuracy and limited potential in classifying malformations, especially when used as the only diagnostic technique (Saravelos et al., 2008). We found no data on differences between contrasts (gel and saline) used during ultrasound.

Magnetic resonance imaging (MRI) has been proposed as an optimal test that allows a simultaneous assessment of the cavity and fundus of the uterus, although controversy exist in whether MRI can replace combined hysteroscopy and laparoscopy (Chan et al., 2011b). The accuracy and practicality of MRI has not yet been determined for the diagnosis of uterine malformations (Oppelt et al., 2007, Saravelos et al., 2008). MRI can be used to extend the examination to the abdomen, which could be helpful in the detecting renal malformations that are frequently associated with uterine malformations (Hall-Craggs et al., 2013, Oppelt et al., 2007).

Sono-Embryoscopy and Uterine Doppler US have been suggested for the investigation of uterine malformations in women with RPL, but there is not enough evidence to support these techniques in the routine investigation of RPL (Ferreira et al., 2007, Frates et al., 1996, Robberecht et al., 2012).

Cervical weakness is a recognized cause of second-trimester pregnancy loss, but the true incidence is unknown, since the diagnosis is essentially a clinical one (Harger, 2002, Kassanos et al., 2001, Liddell and Lo, 2008). The diagnosis is usually based on a history of second-trimester miscarriage preceded by spontaneous rupture of membranes or painless cervical dilatation. There is currently no objective test able to identify women with cervical weakness in the non-pregnant state.

Acquired uterine malformations
Acquired uterine malformations (submucous myomas, endometrial polyps and uterine adhesions) have been found prevalent in women that suffered pregnancy loss, but the clinical relevance is unclear (Hooker et al., 2014).

In a study of Jaslow, acquired defects were found in 113 women with RPL (12.9%), congenital defects in 61 women (7.0%), and 5 women (0.6%) had both congenital and acquired defects (Jaslow and Kutteh, 2013). Saravelos and colleagues reported fibroids in 8.2% (79/966) of women with RPL (Saravelos et al., 2011).

Other uterine pathologies should also be assessed in anatomical investigations such as chronic endometritis and adenomyosis. Several papers showed that chronic endometritis (CE) is more prevalent in infertile patients and may be another reason for RPL (see chapter 1.4). Adenomyosis was shown to be associated with higher rates of pregnancy loss (Younes,Tulandi 2017; Stanekova et al. 2018).

Diagnosis of acquired uterine malformations
Although the relevance of acquired uterine malformations in RPL is unclear, these malformations can be diagnosed with imaging techniques used in the detection of congenital malformations.

2D US is not a sensitive method to detect uterine adhesions. When suspected, a hysteroscopy has to be performed (Bohlmann et al., 2010)

Submucosal fibroids and endometrial polyps can be detected with 3D US, SHG, 2D US, or HSG. There is no strong evidence on which technique is preferred. Hysteroscopy is considered the gold standard (Makris et al., 2007).

Both magnetic resonance imaging and ultra-sound are non-invasive tests with equivalent accuracy in diagnosing adenomyosis (area under curve 0.91 and 0.88, respectively) (Maheshwari et al. 2012)

HSC can show some suspicious signs for the diagnosis of chronic endometritis, but gold standard for diagnostic of CE seems to be IHC (CD 138) (Rimmer et al. 2021).

Recommendations

Justifications

From the evidence, it can be concluded that congenital uterine malformations are more prevalent in women with RPL, as compared to controls. However, the exact contribution that congenital uterine malformations make to RPL remains unclear; the reported variability in the prevalence reflects the differences in the diagnostic criteria and techniques, and the lack of homogeneity in the definition of RPL. Growing evidence showed that chronic endometritis and adenomyosis are associated with pregnancy loss and need to be rule out in all women with RPL.

The recommendation of uterine assessment in all women with RPL is consistent with the Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital malformations , which classifies women with RPL as ‘high risk’ for the presence of a female genital anomaly (Grimbizis et al., 2016). Transvaginal 3D Ultrasound was reported to have the highest sensitivity and specificity for diagnosing congenital malformations. Based on the higher costs and the absence of a diagnostic benefit compared to 3D US, MRI is not recommended as a first line option, but it can be used in the absence of 3D US, and for surgical planning. Apart from availability, local expertise could be relevant in selecting the diagnostic approach, as most techniques are highly dependent on operator skills.

Data from well-controlled prospective trials are needed to clarify the role of congenital uterine malformations in RPL and predict live birth rates per type of congenital uterine abnormality. Executing such studies is further complicated by difficulties to recruit a high number of eligible patients in a short period of time.

In a study of 202 women with uterine malformations (not RPL), 36% of the women had associated abnormalities, mostly renal, but also cardiac, skeleton and neurological abnormalities were detected (Oppelt et al., 2007). Another study suggested ultrasound for screening and MRI or CT (computed tomography) scan for confirmation of congenital malformations of the kidneys and upper urinary tract (Ramanathan et al., 2016). Based on the high prevalence, further investigations should be considered in women with uterine malformations.

The results of the summary of literature were adapted from the international ESHRE guideline Recurrent Pregnancy Loss (2022). More details about the methodology of the ESHRE guideline on RPL (2022) can be found in “Annex 5: Methodology” of the ESHRE guideline and in the Manual for ESHRE guideline development, version 2013, which can be consulted at the ESHRE website. The evidence tables and literature studies can be found at the ESHRE website in Supplementary data files.