Current Concept Management of Recurrent spontaneous abortion with Immunopathological Intervention

Recurrent spontaneous abortion (RSA) is defined as three or more sequential abortions before the twentieth week of gestation. There are evidences to support an allo-immunologic mechanism for RSA. The root cause of miscarriages often can not be found. A significant proportion of this unexplained RSA cases may be caused by immunopathological failure and immunopathological intervention.

Recurrent Spontaneous Abortion of Immunological Origin (RSAI) is currently diagnosed by the occurrence of 2-3 consecutive miscarriages of unknown origin. The psychological trauma incurred by these events is a serious ailment which may be potentially avoided if a method of analysis is derived which may forecast these events and in turn prevent them from occurring. Studies of recurrent spontaneous abortion (RSA) which use laboratory diagnosis and also studies of RSA that do not use laboratory diagnosis. Laboratory results are incorporated into the diagnosis of RSA/RSAI that treatment is highly successful whereas the absence of laboratory results severely hinders the effectiveness of treatment. It is worth noting that correlating treatment versus outcome is imprudent because of the multiple variables involved in patient cases. It is not imprudent, however, to say that incorporation of laboratory data is essential when diagnosing RSA/RSAI.

Recurrent spontaneous abortion (RSA), defined as three or more consecutive pregnancy losses before 20 weeks of gestation, is difficult to treat in the clinical setting. It affects 1%-5% of women of reproductive age. In the investigations of immunopathogenesis, diagnosis, and treatment of RSA since the late 1980s, it was found that RSA was associated with abnormal maternal local or systemic immune response. The pathogenesis of autoimmune RSA was mainly associated with antiphospholipid antibody (APA), while that of alloimmune RSA was due to the disturbance of maternofetal immunological tolerance. Systemic etiological screening process and diagnosis systems of RSA with immune type were developed, and anticardiolipin (ACL or ACA) + anti-β2-GP1 antibody combining multiple assays for effective diagnosis of RSA with autoimmune type was first established. According to the dynamic monitoring of clinical parameters before and during gestation, low-dose, short-course, and individual immunosuppressive therapy and lymphocyte immunotherapy for RSA with immune type were carried out. The outcomes of the offsprings of patients with RSA were followed up, and the safety and validity of the therapies. The research achievement leads to great progress in the diagnosis and treatment of RSA.

The Immunology Characteristic

The immunological characteristics of nonpregnant women with recurrent spontaneous abortions (RSA) of unknown etiology. The immunological state of individual groups of women with RSA and various types of RSA (primary vs. secondary aborters) might influence on results of paternal lymphocytes immunization. In this prospective study the immunological characteristics of 117 nonpregnant women with unexplained RSA in comparison to 44 healthy, nonpregnant multigravid women, were analyzed. The following immunological parameters were studied: peripheral blood lymphocyte subpopulations (CD3+, CD4+, CD8+, CD3+/HLA-DR+), lymphocyte proliferative response to phytohaemaglutynin (PHA) and allogenic lymphocytes (in mixed lymphocyte reaction–MLR), the effect of women’s sera on MLR, neutrophil chemiluminescence and anticardiolipin (ACA) as well as antinuclear (ANA) antibodies titers.

The studies found that in nonpregnant RSA women the CD8+ lymphocytes percentage was lower and the CD4+/CD8+ ratio higher as compared to the controls. In comparison with normal multigravidas in recurrent aborters an absence of serum factors suppressing MLR (blocking antibodies) and a high incidence of autoantibodies was observed. The pregnancy success ratio was significantly lower for alloimmunized women with medium/high titers of ACA than for those without ACA. It was proved there were no significant differences in the estimated immunological parameters between groups of women suffering from either primary or secondary abortions. It was also shown that there is an equally high efficiency of paternal lymphocyte immunization in preventing future abortions both in primary (88%) and secondary (86%) aborters.

The immunological conditions of nonpregnant women with recurrent spontaneous abortion of unexplained etiology differ from healthy and fertile women. These differences are mainly connected to the humoral immunity and manifested in absence of blocking antibodies in sera of women with RSA and in frequent occurrence of antinuclear and anticardiolipin antibodies. Among autoantibodies, only ACA at medium and high levels are the ones that can negatively influence on the pregnancy outcome in women with RSA who underwent paternal lymphocytes immunization. The clinical classification of women with RSA into primary and the secondary aborters is reflected neither in immunological results nor in efficacy of paternal lymphocytes immunization.

Coulam was to evaluate the clinical usefulness of immunologic assays proposed to assist in the diagnosis of alloimmune causes of recurrent spontaneous abortion. Human leukocyte antigen typing, maternal antipaternal lymphocytotoxic antibody testing, and mixed lymphocyte culture assays were performed on 609 couples with recurrent spontaneous abortion, 92 infertile couples, and 43 fertile couples. The frequency of HLA antigen sharing and the presence of lymphocytotoxic antibodies and mixed lymphocyte culture inhibitors was compared among the populations.

Sharing of two or more HLA-A, HLA-B, HLA-C, or HLA-DR antigens was observed in 41% couples with recurrent spontaneous abortion and in 34% with infertility compared with 63% of fertile couples. The frequency of lymphocytotoxic antibodies to paternal cells was significantly greater in the fertile population than in couples with recurrent spontaneous abortion and in infertile couples. Mixed lymphocyte culture inhibitors were also more prevalent in sera from fertile women compared with those with recurrent spontaneous abortion and infertile women.

Human leukocyte antigen sharing does not predict pregnancy outcome, and the presence of lymphocytotoxic antibodies and mixed lymphocyte culture inhibitors is a function of the number and duration of pregnancies. More sensitive and specific assays are needed to identify alloimmunologic causes of reproductive disorders.

The occurrence of maternal antipaternal lymphocytotoxic antibody (LCTA), mixed lymphocyte reaction blocking factors (MLRBF) and human leukocyte antigen (HLA) antigen sharing was studied in 115 couples with unexplained repeated spontaneous abortions (RSA). Comparisons were made to the same studies done on 41 couples with explained repeated miscarriages. One studies found no significant difference between the patient and control group with respect to the percent of couples sharing none, one, or two or more HLA-A,-B, or -DR antigens. Examination of the occurrence of LCTA and MLRBF likewise did not reveal differences between the groups, nor did the occurrence of these antibodies on initial testing correlate with HLA disparity between couples. Women with three or more spontaneous abortions were immunized with paternal mononuclear cells (MNC) if they met at least two of the following three criteria: they shared two or more HLA antigens; their serum was negative for paternal MNC-directed LCTA; their serum did not contain maternal versus paternal MLR blocking factors.

Complete HLA, LCTA and MLRBF data pre- and post-treatment are available on 60 women. Sixty-three percent of women converted to LCTA positive 6 +/- 1 weeks after immunization, and 35% of women converted from negative to positive for MLR blocking after immunization. Fifty-eight women who had all three tests done prior to immunization became pregnant after immunization. Only 50% of this selected group have experienced successful pregnancy as judged by delivery of a live-born infant. In the patients presented, successful pregnancy outcome did not correlate with HLA antigen disparity, but successful patients were more likely than aborters to have either LCTA or MLRBF prior to pregnancy (28 vs. 7%). Post-immunization conversion to LCTA positive was more prevalent in the women who aborted after immunization (74%) compared to those who had successful pregnancy (48%) while MLR blocking antibody conversion from negative to positive was the same in both groups.

The data indicate that neither HLA antigen sharing nor conversion to LCTA or MLR blocking positive after paternal WBC immunization are predictors for successful pregnancy outcome. Results so far suggest that conversion to LCTA positive after immunization may have a negative influence on pregnancy outcome.

Characterization of antibodies

Lubinski J et al identify and characterize the allo- and autoantibodies induced following successful paternal lymphocyte immunization to prevent recurrent spontaneous abortion. Firstly the titers of maternal anti-paternal antibodies in women with successful pregnancies as determined by the flow cytometry crossmatch (FCXM) were highly variable; however, in all cases, the initial pre-immunization titers were negative and the post-immunization titers were positive by the FCXM in successfully treated women.

The specificities of maternal alloantibodies to paternal HLA antigens (immunogen) were evaluated. No all predicted antibodies to mismatched paternal HLA antigens were found by microlymphocytotoxicity (MCX) assays and the specificities varied. Antibodies in post- but not preimmunization sera reacted with two lymphoid cell lines, SupT1 and SB; in addition, the rise and fall of the titers of these sera with paternal cells seemed to be reflected with the cell lines by the FCXM.

Autoantibodies to activated lymphocytes were detected and seemed to correlate with successful immunization since women who had another abortion following immunotherapy lacked these autoantibodies. These findings suggest that the antibody response following successful immunotherapy is complex and needs to be studied further to understand the mechanism of this treatment.

HLA antigen profiles; HLA antigen sharing, female serum MLR blocking factors and paternal leukocyte immunization.

Critical features of the trophoblast for immune protection in the mother are: (1) its resistance to cytotoxic lymphocytes and antibodies; (2) it forms a physical barrier to immune effector cells, but not antibody, from reaching the fetus; (3) it signals the migration of suppressor and other functionally hyporesponsive lymphocytes into the uterine decidua and uterine lymphatics; (4) it promotes the production of maternal serum MLR (mixed lymphocyte reaction) blocking antibody with paternal antigen specificity.

Some of these immunological features are lacking in women with recurrent abortions of immune etiology. Eleven women who aborted an additional time after immunization with paternal leukocytes were compared with 14 women who delivered infants at term post-immunization. It was found that those who aborted: (1) had HLA antigen profiles that did not differ significantly from those of control fertile couples or from observed antigen frequencies in North American Caucasians; (2) shared more HLA A, B, D/DR, and MT antigens with their spouses than controls; (3) were not more hyporesponsive in MLR to paternal antigens pre- and post-immunization when compared to controls; (4) failed to develop female serum MLR blocking factors post-immunization; (5) failed to develop humoral alloantibodies to B-cell alloantigens; (5) had lymphocytes in the uterine decidua mantling the conceptus and in the uterine lymphatics that were reactive/cytotoxic to paternal stimulating alloantigens.

These results are in sharp contrast to the immunodynamics of peripheral blood leukocytes and decidual leukocytes to paternal alloantigens in women who delivered infants at term post-immunization.

Study the prevalence of HLA sharing between spouses and its correlation with presence of antipaternal cytotoxic antibody (APCA) and mixed lymphocyte reaction (MLR) blocking factors in recurrent spontaneous aborters (RSA). Kishore R was carried out at Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGI), Lucknow, from 1988-1992. Hundred couples with 3 or more consecutive recurrent spontaneous abortions and equal number of age, parity and ethinically matched normal controls were selected for studying HLA, APCA and MLR blocking factors. Meta-analysis was performed using standard formula and significance was tested by Chi-square analysis.

Significant HLA sharing was observed in couples with RSA at A and DR loci compared to normal controls . Twenty-seven point eight percent of couples with RSA were positive for APCA compared to 49% of controls. MLR blocking factors were detected in 26% couples with RSA compared to 78% in controls . An inverse correlation between HLA sharing and APCA and MLR positivity was demonstrated. The study supports that greater HLA sharing between spouses, associated with lack of an appropriate immune response to them could be responsible for RSA.

Effectiveness of leukocyte immunotherapy

One of the methods for treatment of RSA is leukocyte therapy; however there is still controversy about effectiveness of this method. One studies evaluate the effectiveness of leukocyte therapy for treatment of RSA.

The present investigation showed the effectiveness of leukocyte therapy in primary but not in secondary RSA patients. Despite the current controversy and limitation of leukocyte therapy in RSA, the results of our investigation provide evidence supporting the use of allo-immunization in improving the outcome of pregnancy in primary RSA patients.

Intravenous immunoglobulin with immunopathological background

A multicentric clinical study started in 2000 to introduce an immunological screening protocol for patients suffering in idiopathic habitual abortion, and to use immunotherapy for their treatment if immunological background was defined. 120 patients with RSA were examined, and 32 of them got IVIG therapy during their next pregnancy. In 72% of cases IVIG treatment for RSA with immunopathological alloimmune background was successful, with the outcome of healthy newborn. Of the 9 unsuccessful cases, in 6 patients subsequently additional non-immunopathological reasons were diagnosed for their RSA. IVIG treatment of patients with clear alloimmune background was successful in 88.5%.

These studies results show that immunopathological checkup and immunotherapy is a useful treatment in the modern medicine for the patients with unexplained RSA. However the success of this method depends on the adherence of the checkup protocol, because unsuccessful therapy of non-clear cases can reduce the efficiency.

Lymphocyte immunization by the partner in prevention

The prognostic value of some immunological parameters on the course of subsequent pregnancy in 117 women with recurrent spontaneous abortion of unknown etiology subjected to paternal lymphocytes immunization, were estimated. Malinowski A, et al reported that neither antinuclear (ANA) nor low titers of anticardiolipin antibodies (ACA), nor mixed lymphocyte reaction–blocking antibodies (MLR-BAbs) have any significant influence on alloimmunization efficiency. However medium or high ACA titers significantly diminish changes for successful alloimmunization and are connected with most complications of subsequent pregnancy.

Takakuwa K, et al. Obserced in thirty-nine unexplained recurrent aborters underwent vaccination using husband’s lymphocytes according to the previously reported protocol. No mixed lymphocyte culture reaction-blocking antibodies (MLR-BAbs) were observed in these patients prior to vaccination. Of 35 newly pregnant patients after vaccination(s), pregnancy successfully continued in 28 (80.0%) and have already been terminated with a liveborn offspring.

Pregnancy outcome was also analyzed in unexplained recurrent aborters who revealed positive MLR-BAbs without immunotherapy. In this group, out of eight pregnancies in seven patients, 62.5% continued beyond their critical period of 14 wks of gestation. Three infants born from these pregnancies, however, presented severe abnormalities. Furthermore, outcome of 14 pregnancies in 12 unexplained recurrent aborters with negative MLR-BAbs was analyzed since they had become pregnant without immunotherapy; pregnancy was successfully continued in only four cases.

Vaccination using husband’s lymphocytes on unexplained recurrent aborters with negative MLR-BAbs is suggested to be effective. In addition, it is suggested that immunotherapy for patients with positive MLR-BAbs should be carefully followed.

Takakuwa reported that elucidate an immunological mechanism in terms of the effectiveness of vaccination of the unexplained habitual aborters with their husband’s lymphocytes, 20 patients were selected as the experimental group, and 10 fertile couples were selected as the control group. Subjects were studied by mixed lymphocyte reaction-blocking assay so as to determine whether they had blocking antibodies (BAbs) in their sera. In the experimental group, BAb levels were found to be significantly lower as compared to the ten control multiparous wives; 17 cases (85%) of them were proved not to have sufficient BAbs.

Significant sharing of HLA-D/DR antigens was observed in experimental couples. Then, 10 out of 17 patients with evidence of no produced BAbs were vaccinated with their husband’s lymphocytes, and all of them were observed to produce BAbs within three vaccinations. After vaccination, seven out of ten patients have so far become pregnant, five of these pregnancies have been successful, with evidence of continuing production of BAbs. Vaccination of the patients with husband’s lymphocytes was found to stimulate a production of BAbs, and it was thus strongly suggested that this may lead to their production in a subsequent pregnancy, which would allow its success.

Nonaka was conducted to examine the efficacy of immunotherapy for unexplained primary recurrent aborters using paternal lymphocytes. Two hundred and twenty-eight recurrent aborters were prospectively followed up regarding immunotherapy. Of the 228 patients, 165 underwent immunotherapy using freshly prepared paternal lymphocytes and pregnancy outcome was analyzed. No mixed lymphocyte culture reaction-blocking antibodies (MLR-BAbs) were observed in these patients prior to vaccinations. Pregnancy outcome was also analyzed in such as those patients positive for MLR-BAbs and who did not undergo immunotherapy, and in patients negative for MLR-BAbs and who had become pregnant without immunotherapy.

Of the 140 newly pregnant patients after immunotherapy, the pregnancy continued successfully in 110 (78.6%), and the pregnancy continued successfully in 24 of 32 patients (75.0%) who were positive for MLR-BAbs. The success rate of pregnancy was 30.0% in 18 non-immunized patients. Thus, the success rate was significantly higher among patients with immunotherapy and patients positive for MLR-BAbs than in non-immunized patients, negative for MLR-BAbs. Immunotherapy using paternal lymphocytes is considered to be effective for unexplained primary recurrent aborters negative for MLR-BAbs.

MLR blocking antibodies.

Tamura observed the relationship between mixed lymphocyte culture reaction (MLR) blocking antibodies (BAbs), immunological humoral factors, which generated in pregnant women and the outcome of pregnancy, the natural outcome of the third pregnancy in fifty-five patients with primary twice consecutive abortion was evaluated, and MLR-BAbs in sera were examined during their third pregnancy. The third pregnancy in 39 of 55 patients (70.9%) continued successfully, and remaining 16 patients (29.1%) experienced repeated abortion at the first trimester. Out of these 55 patients, MLR-BAbs were examined in 27 (17 with successful outcome and 10 with repeated abortion). The positive rate of MLR-BAbs was 82.4% in patients with successful outcome, and that in patients with repeated abortion was 10%. The positive rate of MLR-BAbs was significantly higher in the successful pregnancy group compared with that in the repeated abortion group.

The blocking effect on MLR significantly increased along with the prenatal course in patients with successful outcome. Thus, MLR-BAbs are strongly associated with the outcome of pregnancy in patients with primary twice consecutive spontaneous abortions.

Induction of MLR-Bf and protection of fetal loss

The present study was conducted to evaluate the efficacy of paternal lymphocyte (PL) immunotherapy and its relation with the development of mixed lymphocyte reaction blocking antibodies (MLR-Bf) and the success of pregnancy outcome in women with recurrent spontaneous abortion (RSA). A total of 124 women with unknown causes of abortions was registered for immunotherapy under double blind randomized trial by using the list of computer-generated numbers. Each 5 x 10(6) autologous lymphocyte (AL), third party lymphocyte (TPL) and PL was dissolved separately in 1 ml of sterile normal saline (NS). Each 1 ml of cell suspension and neat NS was injected in women with RSA through intramuscular (250 microl), intradermal (250 microl), subcutaneous (250 microl) and intravenous (250 microl) routes. All women participants with RSA received six identical immunizations at the regular interval of 4 weeks, and were then screened for the development of MLR-Bf after the completion of immunization course, and also at the first, second and third trimesters (12th, 24th and 36th weeks) of pregnancy.

However, nonimmunized MLR-Bf positive women with RSA did not receive any kind of therapy (NT) and were used as one of the control group in the present study. We have observed that PL-immunized women with RSA showed a significantly increased level of MLR-Bf (>30) and pregnancy success (84%) as compared to those women with RSA who received either AL (33%), TPL (31%), NS (25%) or those who did not receive any kind of treatment (NT, 44%; P<0.001). These study results indicated the importance of immunotherapy with PL in women with RSA and also showed that MLR-Bf can be considered as one of the important factors for pregnancy improvement.

Immunologically specific blocking factors (BF) are believed to play a protective role in the maintenance of pregnancy. Agrawal reported that compared the levels of BF in normal pregnant women and in patients with recurrent spontaneous abortion (RSA) and observed that the two groups differ significantly from one another. MLC inhibitory activity was present throughout normal pregnancy and was found to be specific to the husband's HLA antigens. Immunotherapy was performed in 28 recurrent aborters using husband's lymphocytes, after which levels of blocking antibodies increased in 23 patients. The difference in the label of MLR BF in the preimmunotherapy and postimmunotherapy groups was statistically significant and was associated with successful pregnancy outcome in 82.15% of cases.

The appearance of the MLR BF and its continuation in a successful pregnancy might represent an appropriate immune state that may be playing an important role in maintenance of pregnancy.

References:

Beaman KD, et al. Immune etiology of recurrent pregnancy loss and its diagnosis. Am J Reprod Immunol. 2012 Apr;67(4):319-25.

Lin QD, et al. Pathogenesis, diagnosis, and treatment of recurrent spontaneous abortion with immune type. Front Med China. 2010 Sep;4(3):275-9.

Malinowski A, et al. Immunological characteristics of nonpregnant women with unexplained recurrent spontaneous abortion who underwent paternal lymphocytes immunization. Zentralbl Gynakol. 1998;120(10):493-502

Coulam CB. Immunologic tests in the evaluation of reproductive disorders: a critical review. Am J Obstet Gynecol. 1992 Dec;167(6):1844-51.

Lubinski J, et al. Characterization of antibodies induced by paternal lymphocyte immunization in couples with recurrent spontaneous abortion. J Reprod Immunol. 1993 Jul;24(2):81-96.

Gharesi-Fard B, et al. Effectiveness of leukocyte immunotherapy in primary recurrent spontaneous abortion (RSA). Iran J Immunol. 2007 Sep;4(3):173-8.

Beer AE, et al. Pregnancy outcome in human couples with recurrent spontaneous abortions: HLA antigen profiles; HLA antigen sharing; female serum MLR blocking factors; and paternal leukocyte immunization. Exp Clin Immunogenet. 1985;2(3):137-53.

Bátorfi J, Intravenous immunoglobulin treatment of recurrent spontaneous abortion with immunopathological background. Orv Hetil. 2005 Nov 6;146(45):2297-302.

Kishore R, et al. HLA sharing, anti-paternal cytotoxic antibodies and MLR blocking factors in women with recurrent spontaneous abortion. J Obstet Gynaecol Res. 1996 Apr;22(2):177-83

Smith JB, Immunological studies in recurrent spontaneous abortion: effects of immunization of women with paternal mononuclear cells on lymphocytotoxic and mixed lymphocyte reaction blocking antibodies and correlation with sharing of HLA and pregnancy outcome. J Reprod Immunol. 1988 Nov;14(2):99-113.

Malinowski A, et al. Lymphocyte immunization by the partner in prevention of unexplained recurrent spontaneous abortion. II. Immunologic prognostic factors. Ginekol Pol. 1997 Apr;68(4):173-80.

Nonaka T, et al. Results of immunotherapy for patients with unexplained primary recurrent abortions–prospective non-randomized cohort study. Am J Reprod Immunol. 2007 Dec;58(6):530-6.

Takakuwa K, et al. Result of immunotherapy on patients with unexplained recurrent abortion: a beneficial treatment for patients with negative blocking antibodies. Am J Reprod Immunol. 1990 Jun;23(2):37-41.

Takakuwa K, et al. Production of blocking antibodies by vaccination with husband’s lymphocytes in unexplained recurrent aborters: the role in successful pregnancy.
Am J Reprod Immunol Microbiol. 1986 Jan;10(1):1-9.

Agrawal S, et al. Prevalence of MLR blocking antibodies before and after immunotherapy. J Hematother Stem Cell Res. 2000 Apr;9(2):257-62.

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