**5. Immunological factors**

To be successful in pregnancy, the maternal organism needs to undergo immunological changes that allow and assist in the trophoblastic invasion of the embryo. During pregnancy, the maternal immune system faces a dilemma: it needs to protect the mother against infection while accepting the semi-allogeneic fetus [29]. Leukocytes are important components of the endometrium, and their concentration increases in the middle of the secretory phase in which embryonic implantation is expected and continues to increase during early pregnancy [30]. The progesterone plays a key role in this balance by creating an appropriate environment for embryonic implantation and development [28]. This change in maternal endometrial immunology becomes essential for early pregnancy implantation and success. Changes in this phase can lead to implantation failure, miscarriage, and other unfavorable obstetric outcomes such as preeclampsia.

### **5.1 Natural killer (NK) cell**

The uterine natural killer (uNK) cells are the most commonly found leukocytes in the maternal endometrium. Two phenotypes are observed—CD56bright and CD16dim—unlike peripheral blood where CD56dim and CD16+ are the largest population [31]. There is a variability of their own concentration during the menstrual cycle. There are a significant increase of NK cells in the endometrium 6 to 7 days after the peak of luteinizing hormone (LH), which persists throughout the early pregnancy. This increase suggests an important role of these cells in embryonic implantation, but the exact function is still unknown [30].

### *5.1.1 Killer immunoglobulin-like receptors (KIR)*

The placental formation is regulated by the interaction between the killer immunoglobulin-like receptors (KIR) and the surface human leukocyte antigens on the embryo trophoblastic cells (HLA-C). The embryo presents maternal and paternal HLA-C, and both haplotypes are presented to NK cells that, in turn, will recognize the human leukocyte antigen (HLA) 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: A, which is inhibitory, and B, which is stimulating. The receptors can then be AA, AB, or BB. The presence of haplotype B confers pregnancy protection, and its absence (in the cases of KIR AA) increases the risk of gestational complications.

Studies have shown that when maternal KIR is homozygous for haplotype A (KIR AA), there is an increased risk of gestational complications if the embryo carries paternal HLA-C2 [32, 33]. In the future, these studies may be applicable to couples who will undergo IVF. Further studies on the subject are still needed, and these tests are not quoted to be traced by societal guidelines.

### **5.2 Macrophages**

The macrophages represent 20–30% of leukocytes in the maternal endometrium and are the second largest group behind only NK cells. Macrophages differ in specific 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 have anti-inflammatory function [34]. For maternal and fetal tolerance to occur, more macrophages are polarized into the M2 subtype with immunosuppressive properties necessary for normal pregnancy

**165**

*Recurrent Pregnancy Loss: Investigations and Interventions*

cells, leading to an inadequate immune response [29].

to occur [35]. When polarization of these cells does not occur correctly favoring the M1 subgroup, improper remodeling of the arteries and trophoblastic invasion occurs, leading to a higher incidence of miscarriage, preeclampsia, and prema-

Regulatory T cells (Treg) are a subpopulation of T cells that play an essential 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, thus modulating the immune response. Depending on the released cytokines, T cells may differentiate into Treg cells expressing interleukin 10 and transforming growth factor β (TGFβ) responsible for immune tolerance to the conceptus or Th17 expressing interleukins 17, 21, and 22 responsible for autoimmunity and gestational loss. Treg cells will then regulate the response to foreign antigens when an aggressive response is not appropriate, having the ability to inhibit type 1 helper (Th1) cells. There is evidence in the cases of recurrent gestational loss of unknown cause to increase Th17 and to decrease Treg

Uterine anatomical abnormalities, both acquired and congenital, are associated with RPL. It is estimated that uterine factors may account for 10–50% of

Congenital uterine anomalies (CUA) arise from defects along any stage of the Müller duct development process during embryonic development, whether in formation, fusion, or reabsorption. The frequency of CUA has been reported between 1.8 and 37.6% in women with a history of RLP. This variation is due to the different diagnostic methods and criteria [37]. Septate uterus is the most common anomaly in patients with a history of abortion. Arched, septate, and bicornuate

In a meta-analysis it was observed that patients with septate or bicornuate uterus had a higher rate of miscarriage in the first and second trimester than a control group [39]. In another meta-analysis, the evaluation of uterine abnormality subtypes resulting from fusion defect showed that women with unicornuate and bicornuate uterus were more likely to have first-trimester abortion compared to

ASRM's original classification system for congenital uterine anomalies has been modified and adapted and is still the most widely used today [41]. In 2012, ESHRE/ ESGE published a classification system aiming to replace the subjective criteria of ASRM's classification by the absolute morphometric criteria [42]. Based on this classification, up to 58% of women previously diagnosed with ASRM arched uterus would be reclassified as having a partial septate uterus. There would be a potential increase in the number of surgical corrections for uterine anomaly, without any evidence showing that such a practice would be beneficial [43]. Therefore, caution is needed in using this new classification until further prospective, randomized,

*DOI: http://dx.doi.org/10.5772/intechopen.89590*

ture birth [35].

**5.3 Regulatory T cells**

**6. Anatomical factors**

**6.1 Congenital uterine anomalies**

those with normal uterus [40].

*6.1.1 Congenital Müllerian duct anomalies*

uterus account for up to 85% of anomalies [38].

RPL [36].

to occur [35]. When polarization of these cells does not occur correctly favoring the M1 subgroup, improper remodeling of the arteries and trophoblastic invasion occurs, leading to a higher incidence of miscarriage, preeclampsia, and premature birth [35].

### **5.3 Regulatory T cells**

*Innovations in Assisted Reproduction Technology*

unfavorable obstetric outcomes such as preeclampsia.

onic implantation, but the exact function is still unknown [30].

these tests are not quoted to be traced by societal guidelines.

*5.1.1 Killer immunoglobulin-like receptors (KIR)*

the risk of gestational complications.

To be successful in pregnancy, the maternal organism needs to undergo immunological changes that allow and assist in the trophoblastic invasion of the embryo. During pregnancy, the maternal immune system faces a dilemma: it needs to protect the mother against infection while accepting the semi-allogeneic fetus [29]. Leukocytes are important components of the endometrium, and their concentration increases in the middle of the secretory phase in which embryonic implantation is expected and continues to increase during early pregnancy [30]. The progesterone plays a key role in this balance by creating an appropriate environment for embryonic implantation and development [28]. This change in maternal endometrial immunology becomes essential for early pregnancy implantation and success. Changes in this phase can lead to implantation failure, miscarriage, and other

The uterine natural killer (uNK) cells are the most commonly found leukocytes in the maternal endometrium. Two phenotypes are observed—CD56bright and CD16dim—unlike peripheral blood where CD56dim and CD16+ are the largest population [31]. There is a variability of their own concentration during the menstrual cycle. There are a significant increase of NK cells in the endometrium 6 to 7 days after the peak of luteinizing hormone (LH), which persists throughout the early pregnancy. This increase suggests an important role of these cells in embry-

The placental formation is regulated by the interaction between the killer immunoglobulin-like receptors (KIR) and the surface human leukocyte antigens on the embryo trophoblastic cells (HLA-C). The embryo presents maternal and paternal HLA-C, and both haplotypes are presented to NK cells that, in turn, will recognize the human leukocyte antigen (HLA) 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: A, which is inhibitory, and B, which is stimulating. The receptors can then be AA, AB, or BB. The presence of haplotype B confers pregnancy protection, and its absence (in the cases of KIR AA) increases

Studies have shown that when maternal KIR is homozygous for haplotype A (KIR AA), there is an increased risk of gestational complications if the embryo carries paternal HLA-C2 [32, 33]. In the future, these studies may be applicable to couples who will undergo IVF. Further studies on the subject are still needed, and

The macrophages represent 20–30% of leukocytes in the maternal endometrium and are the second largest group behind only NK cells. Macrophages differ in specific 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 have anti-inflammatory function [34]. For maternal and fetal tolerance to occur, more macrophages are polarized into the M2 subtype with immunosuppressive properties necessary for normal pregnancy

**5. Immunological factors**

**5.1 Natural killer (NK) cell**

**164**

**5.2 Macrophages**

Regulatory T cells (Treg) are a subpopulation of T cells that play an essential 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, thus modulating the immune response. Depending on the released cytokines, T cells may differentiate into Treg cells expressing interleukin 10 and transforming growth factor β (TGFβ) responsible for immune tolerance to the conceptus or Th17 expressing interleukins 17, 21, and 22 responsible for autoimmunity and gestational loss. Treg cells will then regulate the response to foreign antigens when an aggressive response is not appropriate, having the ability to inhibit type 1 helper (Th1) cells. There is evidence in the cases of recurrent gestational loss of unknown cause to increase Th17 and to decrease Treg cells, leading to an inadequate immune response [29].
