In the realization of a pregnancy, there are immunological and anatomical factors that allow the maternal organism to allow the embryo to settle and thus assist. Only in this way can the body adapt to the changes required for pregnancy. This article contains information on the role of these two factors in recurrent miscarriages.
During pregnancy, the maternal immune system faces a dilemma. It should protect the mother against infection while accepting a semi-allogeneic fetus. Leukocytes are important components of the endometrium and their concentration increases in the middle of the secretory phase where embryonic implantation is expected and continues to increase in early pregnancy. Progesterone plays a key role in this balance by creating a favorable environment for embryonic implantation and development. This change in maternal endometrial immunology becomes necessary for early pregnancy implantation and its success.
Changes at this stage can lead to implantation failure, miscarriage and other adverse obstetric outcomes such as preeclampsia. Immunological factors that play a role in recurrent miscarriages are as follows;
Natural killer (NK) cell
Uterine natural killer (uNK) cells are the most common leukocytes in the maternal endometrium. Unlike peripheral blood, where CD56dim and CD16 + are the largest population, two phenotypes – CD56bright and CD16dim are observed. There is a variation in their concentration during the menstrual cycle. There is a significant increase in NK cells in the endometrium 6 to 7 days after the peak of luteinizing hormone (LH), which persists in early pregnancy. This increase suggests that these cells play an important role in embryonic implantation, but their exact function is still unknown.
Killer immunoglobulin-like receptors (KIR)
Placental formation is regulated by the interaction between killer immunoglobulin-like receptors (KIR) and surface human leukocyte antigens on embryo trophoblastic cells (HLA-C). The embryo presents maternal and paternal HLA-C, and both haplotypes are presented to NK cells, which will recognize human leukocyte antigen (HLA) that is foreign to their organism. There are two types of HLA-C: C1 and C2, which are a strong ligand to the receptor. On the other hand, there are two KIR haplotypes: the inhibitor A and the stimulus B. The receptors can then be AA, AB or BB. The presence of haplotype B provides pregnancy protection and its absence (in cases of KIR AA) increases the risk of pregnancy complications.
Studies have shown that when maternal KIR is homozygous for haplotype A (KIR AA), there is an increased risk of pregnancy complications if the embryo carries HLA-C2 from the father. In the future, these studies may apply to couples undergoing IVF. More studies are still needed on the subject, and these tests are not quoted for follow-up according to community guidelines.
Macrophages represent 20-30% of leukocytes in the maternal endometrium and are the second largest group behind only NK cells. Macrophages differ in certain phenotypes to perform different biological functions and can be divided into two subgroups: M1 and M2. M1 macrophages are pro-inflammatory and antimicrobial whereas M2 has anti-inflammatory function. More macrophages for maternal and fetal tolerance are polarized to M2 subtype with the immunosuppressive properties necessary for normal pregnancy to occur. When the polarization of these cells does not occur correctly to support the M1 subgroup, improper remodeling of the arteries and trophoblastic invasion occurs, leading to a higher incidence of miscarriage, preeclampsia, and preterm labor.
Regulatory T cells
Regulatory T cells (Treg) are a subpopulation of T cells that plays an important role in maintaining maternal immune tolerance. These cells are activated by the presented antigens and from that moment secrete cytokines that will determine the differentiation of T cell subtypes and thus modulate the immune response. Depending on the cytokines released, T cells can differentiate into Treg cells that express interleukin 10 and express the growth factor (TGF) responsible for the concept immune tolerance, or interleukins 17, 21, and 22, which express Th17 responsible for autoimmunity and pregnancy loss. Treg cells will then regulate the response to foreign antigens by having the ability to inhibit type 1 helper (Th1) cells when an aggressive response is unsuitable.
Both acquired and congenital uterine anatomical abnormalities are associated with RPL. It is estimated that uterine factors may account for 10-50% of RPL. Anatomical factors are as follows;
A- Congenital Uterine Anomalies
Congenital Mullerian duct anomalies
Congenital uterine anomalies (CUA) are caused by defects at any stage of the Müller duct development process during embryonic development, whether it is formation, fusion or reabsorption. The frequency of CUA in women with a history of RLS has been reported between 1.8% and 37.6%. This variation is due to different diagnostic methods and criteria. Septate uterus is the most common anomaly in patients with a history of abortion. Arched, septate, and bicornuate uterus account for 85% of anomalies.
In a meta-analysis, it was observed that patients with septate or bicornuate uterus had higher miscarriage rates in the first and second trimesters compared to the control group. In another meta-analysis, evaluation of uterine abnormality subtypes caused by fusion defect showed that women with unicornuate and bicornuate uterus were more likely to have a miscarriage in the first trimester than those with a normal uterus.
The original classification system of ASRM for congenital uterine anomalies has been modified and adapted and is still most widely used today. In 2012, ESHRE / ESGE published a classification system aimed at replacing the subjective criteria of the ASRM classification with absolute morphometric criteria. According to this classification, up to 58% of women previously diagnosed with an ASRM arched uterus will be reclassified as having a partial septate uterus. Without any evidence that such a practice would be beneficial, there would be a potential increase in the number of surgical corrections for uterine anomalies.
Therefore, caution is required in using this new classification until prospective, randomized, controlled, long-term studies are available to associate the severity of uterine cavity distortion with reproductive outcomes.
Given the suspicion, it is necessary to use diagnostic methods that can clearly visualize the outer contour of the uterus and the endometrial cavity. Both inversion mode (3D US) 3D ultrasound and magnetic resonance imaging (MRI) can be used for this purpose with good correlation between them. The disadvantages of MRI are that it is a more expensive and less usable method compared to ultrasound. In a comparative study of different diagnostic modalities, higher accuracy of 3D hysterosonography was observed compared to 3D US and 2D hysterosonography, but the differences between these imaging techniques did not reach statistical significance in the diagnosis of curved, bicornuate, and septate uterus.
The uterine septum is the most common abnormality associated with RPL and is the only correctable one. Although there are no randomized and controlled prospective studies comparing surgery with expected treatment, limited studies suggest that hysteroscopy septal resection is associated with a reduction in subsequent miscarriage rates and an improvement in live birth rates in patients with RPL. After hysteroscopic resection of the septum, an interval of at least 2 months should be waited for the endometrial cavity to heal completely before a new pregnancy. Overall, CUA may be associated with kidney abnormalities in about 11-30% of individuals. Therefore, in these cases, there is a need for urinary tract examination.
Cervical insufficiency (CI) is the inability of the cervix to hold the intrauterine fetus in the absence of uterine contractions or labor (painless cervical dilatation) due to a functional or structural defect. It is a known cause of RPL in the second trimester, but the true incidence is unknown because the diagnosis is mainly clinical. CI can be congenital or acquired. The most common congenital cause is a defect in the embryological development of the Müllerian ducts. The most common acquired cause is cervical trauma such as cervical lacerations during labor, cervical conization, or forced cervical dilatation during uterine procedures.
Diagnosis is usually based on a history of miscarriage in the second trimester and is preceded by spontaneous membrane rupture or painless cervical enlargement. At present, there are no objective tests that can identify women with cervical weakness in the non-pregnant state. Transvaginal ultrasound can be used in patients at risk during pregnancy. CI can be suspected when a short cervical length is less than or equal to 25 mm, or when the membrane has a funnel-shaped projection with an enlarged internal opening but a closed external opening.
Many surgical and non-surgical modalities have been proposed to treat cervical insufficiency. Restriction of activities and bed rest among non-surgical activities were not effective in the treatment of cervical insufficiency. Isolated use is not recommended. The use of a vaginal pessary is another option, but evidence is still limited. Surgical approaches include transvaginal and transabdominal cervical cerclage.
B- Acquired Anatomical Factors
Commonly acquired anatomical factors associated with RPL include uterine fibroids, endometrial polyps, and uterine synechia. They usually develop after puberty due to physical or hormonal stimuli and are found in about 12% of patients with RPL.
Fibroids have been reported in 8.2% of women with RPL. Submucosal fibroids deform the endometrial space, affecting implantation and embryonic development. Hysteroscopy is considered the gold standard for diagnosing submucosal fibroids, but this pathology can be determined through other imaging examinations such as ultrasound mapping. As removal of submucosal fibroids in infertile patients reduces the chance of miscarriage, evaluation of the uterine cavity is highly recommended for all women with RPL. Regarding fibroids that do not disturb the uterine cavity, there is no evidence that myomectomy can reduce the chances of abortion.
There appears to be a higher prevalence of endometrial polyp in women with pregnancy loss (2.4%), but has no well-defined clinical significance. Hysteroscopy is considered the gold standard examination for the diagnosis and treatment of endometrial polyps, but it can also be identified by other imaging examinations such as color Doppler and ultrasound. Although there is no evidence of the benefit of polypectomy in women with RPL, hysteroscopic removal should be considered when the polyp is larger than 1 cm in the absence of any other known etiology. ASRM reports that research for uterine polyps in women with pregnancy loss is controversial, as there is no definitive evidence that surgical treatment reduces the risk of pregnancy loss.
Uterine synechia / Asherman syndrome
The prevalence of uterine synechiae varies between 0.5 and 28% in patients with RPL. Women with RPL are more likely to have uterine synechiae as they often undergo curettage or manual vacuum aspiration. Possible abortion pathophysiology occurs due to a decrease in the amount of functional endometrium that may prevent the invasion and normal development of the placenta. The gold standard examination for diagnosing synechiae is hysteroscopy and should be the preferred examination in case of doubt.
ESHRE concluded that there is insufficient evidence to recommend adhesiolysis in women with RPL as there are only small observational studies. ESHRE reinforces that treatment should focus on preventing the recurrence of adhesions. However, ASRM points out that significant uterine cavity defects need to be corrected surgically. Non-surgical experimental techniques for the treatment of uterine synechiae and endometrial fibrosis, such as stem cell therapy, should be further explored before they can be specified in clinical practice.
Author: Ozlem Guvenc Agaoglu