De zwangerschap wordt in de literatuur vergeleken met een getransplanteerd orgaan. Het moederlijke immuunsysteem moet een zwangerschap accepteren; het zwangerschapsweefsel is voor de helft lichaamsvreemd. Mogelijk speelt het moederlijke immuunsysteem een rol bij het krijgen van miskramen. Daarom wordt het humaan leukocyten antigeen (HLA) in de literatuur in verband gebracht met het krijgen van miskramen.

ESHRE Guideline group on RPL (2022)

Summary of literature

Due to the different ways HLA² can influence immune reactions, studies of HLA in RPL can be divided into three main categories: 1) studies of HLA allele compatibility (sharing) between partners with RPL, 2) studies of HLA allele prevalence in women with RPL and 3) studies of HLA-C and -G alleles in partners with RPL.

HLA compatibility
Increased HLA compatibility between partners was originally thought to decrease the probability of the mother to produce so-called blocking antibodies that were suggested to protect against fetal rejection. A meta-analysis reported that allele sharing in the HLA-A, -B and -C loci was not found with different frequencies in RPL and control couples whereas sharing in the HLA-DR locus was borderline significantly increased (Beydoun and Saftlas, 2005). In a subsequent large case-control study using up-to-date DNA-based HLA determination no increased HLA-DR sharing was found in RPL couples (Aruna et al., 2011).

HLA allele prevalence in women with RPL
In one case-control study of 588 Caucasian women with RPL and 562 Caucasian controls, the HLA-DRB1*03 allele was found significantly more often in women with RPL than controls also after correction for multiple comparisons (Kruse et al., 2004). The association to HLA-DRB1*03 was stronger in women with ≥4 previous pregnancy losses or women with secondary RPL (OR = 1.8, 95% CI 1.3-2.5). This dose response effect supports a causative role for HLA-DRB1*03 (or a gene variant in LD with this allele) in RPL (or at least secondary RPL) (Kruse et al., 2004). In a recent very large case-control study  including 1078 Caucasian women with RPL and 2066 controls it was found that the HLA-DRB1*07 allele was highly significantly associated to RPL (OR = 1.29, 95% CI 1.09-1.52 in heterozygous RPL patients and OR = 2.27,  95% CI 1.31-3.93 in homozygous patients) (Thomsen et al. 2021). In this study, the association did not become stronger with increased number of miscarriages or in patients with secondary RPL and the association to HLA-DRB1*03 was not confirmed. Other studies have been conducted on the HLA class II genes (HLA-DRB1 or –DQB1) but they included insufficient numbers of patients and controls to have sufficient power after correction for multiple testing, which is essential when studying multiple HLA alleles. There are no prospective studies investigating the prognostic impact of carrying HLA-DRB1*03, or other HLA genes in patients with primary RPL whereas several studies of the impact of carriage of maternal HLA class II have been performed in women with secondary RPL.

In a cohort study, it has been suggested that the prior birth of a boy in women with secondary RPL can affect subsequent pregnancy outcome negatively (for birth after a firstborn boy vs. a firstborn girl; adjusted OR 0.37; 95% CI 0.2-0.7) (Nielsen et al., 2008). A prospective study (n=358) provided evidence that women with secondary RPL after the birth of a boy have a significantly lower (22%) subsequent live birth rate when they carried one of three HLA class II alleles DRB1*15:01; -DQB1*05:01/05:02 and -DRB3*03:01 known to predispose to clinically relevant anti-HY immune reactions (Nielsen et al., 2009).

Carrying two of these HLA alleles was associated with a significantly higher risk than carrying zero or one allele suggesting a dose-response relationship. In a subsequent cohort study of long-term outcome (n=585) the negative prognostic effect of HLA-DRB1*15 and -*DQB1*05:01/02 was confirmed. Furthermore, HLA-DRB1*07:01 and HLA-DRB3*03:01 also seemed to have a negative prognostic effect, though probably weaker. As in the Nielsen study, the negative prognostic effect of maternal carriage of HY-restricting HLA class II alleles on subsequent live birth was only observed for women with a firstborn boy (Kolte et al., 2016).

HLA-C and -G alleles in couples
Reactions of NK cells (cytotoxicity and cytokine production) in pregnant women are suggested to be modified by interactions between specific receptors (Killer immunoglobulin-like receptors or KIRs) on the NK cells and HLA-C or HLA-G, which are the only HLA genes expressed on the trophoblast.³ Hiby and colleagues reported that the combination of the woman carrying KIR genes that are mainly inhibitory and the man carrying C2 allotypes is more frequent among RPL than control couples (Hiby et al., 2008). Another case-control study reported that maternal inhibitory KIRs in combination with C2 homozygosity in both partners was found significantly more often in controls (Faridi and Agrawal, 2011). In a third study no association between maternal activating or inhibitory KIR and RPL could be detected in 52 women with RPL (Witt et al., 2004), whereas smaller studies found a significant increase in activating or decrease of inhibitory KIRs in women with RPL (Vargas et al., 2009, Varla-Leftherioti et al., 2003). Due to the contradictive findings concerning KIR genotyping in couples with RPL, KIR and HLA-C typing is not suitable for diagnostic and therapeutic purposes at present.

Another set of studies have investigated HLA-G polymorphisms in RPL. Soluble HLA-G is suggested to modulate NK cytotoxicity and cytokine secretion at the feto-maternal interface. Low plasma soluble HLA-G levels may be associated with homozygosity for a HLA-G14 bp insertion in the HLA-G gene. Two meta-analyses reported that the HLA-G14 bp insertion frequency was significantly increased in women with RPL (OR 1.27 (1.04-1.55) and 1.47 (1.13-1.91), respectively) (Wang et al., 2013, Fan et al., 2014). Since the HLA-G14 bp insertion is in strong positive linkage disequilibrium with the HLA-DRB1*03 allele (Hviid and Christiansen, 2005), the question remains whether the association of RPL to the HLA-G14 bp insertion is secondary to a primary association to the HLA-DRB*03 allele.

2 The HLA region comprises several genetic loci located on chromosome 6 and it contains the most polymorphic genes known in humans. Dependent on the genetic distance between the various HLA loci, the alleles of the genes in each locus display various degrees of linkage disequilibrium (LD), which means that alleles in different loci are inherited together more or less often than expected by chance. LD to genetic variants in other loci in the HLA region must be considered when finding a specific allele associated with RPL.

3 HLA-C alleles can be divided into C1 and C2 groups according to a genetic dimorphism leading to changes in the segment of HLA-C molecule that can bind KIR. This binding between KIR and HLA-C will ultimately result in either inhibition or activation of NK cell function.

Recommendations

Justifications

The association between subsequent pregnancy outcome and HLA polymorphisms in women or couples with RPL is not sufficiently studied. For HLA compatibility and HLA-C alleles in couples, the evidence for an association with RPL is inconsistent, while a weak association is reported for specific HLA-G alleles in RPL women. Investigation of HLA-DR (or other classical HLA genes) in women with RPL is not recommended in clinical practice, but could be performed in a research setting. An exception could be investigation of class II HLA in women with secondary RPL after the birth of a boy, even though this has only been shown in a large Scandinavian study and needs further confirmation in non-Scandinavian women. With the availability of additional data, the information on the specific HLA alleles to be determines was adapted in the recommendation.

References
The references for this submodule can be found here.

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.