最近一篇国际权威性综述文章比较准确的描述了淋巴免疫活疗治疗反复自然流产的状况 – 理论不清，治疗效果不明确, 副作用大，需谨慎使用。
Recurrent Pregnancy Losses and the Role of Immunotherapy. Review Article, Arch Gynecol Obstet (2000) 264:3-12
Charles A. Omwandho, Hans R. Tinneberg, Aloys G. Tumbo-Oeri, Timothy K. Roberts, John Falconer,) C.A. Omwandho · A.G. Tumbo-Oeri Department of Biochemistry, University of Nairobi, Kenya H.R. Tinneberg (.) Department of Obstetrics and Gynecology, Institute of Reproductive Medicine, Rosenh?he Hospital, An der Rosenh?he 27, D-33647 Bielefeld, Germany T.K. Roberts Biological Sciences Department, The University of Newcastle, Australia J. Falconer Discipline of Reproductive Medicine, The University of Newcastle, Australia
Abstract Post implantation pregnancy losses are psychologically and economically stressful to the childbearing population. The etiology in the vast majority of cases is unknown but is partly thought to result from a breakdown of the maternal tolerance to the fetoplacental unit. Immunologically based therapy remains controversial but no alternative therapy is available at the moment. This article reviews the conceived immunological basis of recurrent pregnancy losses, discussing the controversies arising, and recommending the use of intravenous immunoglobulin, IVIg, in well controlled experiments for further clinical trials.
Recurrent pregnancy loss occurs in 1—2% of the childbearing population . In the vast majority of the cases, the etiology is unknown and several hypotheses have been made on the basis of available data.
However, given the psychological and economic stresses suffered by the affected couples, there is need to focus a lot more effort into finding out the mechanisms involved immunological or otherwise with the view to enhancing the development of therapy.
Immunotherapy for management of recurrent spontaneous abortions In about half of the couples suffering recurrent spontaneous abortions, no specific cause (chromosomal, anatomical, endocrine, or microbial) can be found. It was claimed that these couples could be treated with a high success rate by immunisation with paternal lymphocytes. The model for active immunotherapy was also based on the finding that pre-transplant blood transfusion significantly increased renal allograft survival  and that successful pregnancies resulted in the production of blocking antibodies, suppressor cells, and auto antiidiotypic
Active immmunotherapy vs. spontaneous cure rates
Table 1 shows the results of subsequent reproductive performance of recurrent aborters following active immunotherapy.
Table 1 Results of immunotherapy on subsequent reproduction in women with recurrent abortion
Number of Patients
Type of Therapy
Gafter et al. 
Increase in IL-10, TNFa secretion +
cells decreae in IL-1, IL-2, IL-6, IL-12,
TNF á, TGF ?, NK and LAK
cells post immunisation
Malinowski et al. 
non pregnant aborters have high
CD4/CD8 ratio & high incidence of anticardiolipin, ACA. Lower success rates in women with medium to high ACA levels
Maejima et al. 
Tamura et al. 
(1) MLR was +ve in 15/17 (82.4%) of successful patients tested and only in 1/10 (10%) unsuccessful patients tested
(2) blocking of MLR significantly
increased with prenatal course in
patients who succeeded
Tanaka et al. 
Pena et al. 
(1) 50% successful cases produced MLR blocking abs, 5 subsequent losers had but 2 did not have MLR blocking
(2) 4/5 (80%) of patients who tested +ve for cytotoxic antibodies aborted but 11/12 (91.7%) who tested –ve succeeded
Dupont et al. 
Katano et al. 
low NK activity in peripheral blood preparations seen in most successful cases
Pfeiffer et al. 
hemolysed and UV
Stray Pedersen and
Stray Pedersen 
psychological support, bed rest, tender lovingcare
Although the data provided in Table 1 look convincing, leukocyte immunotherapy has attracted substancial controversies. Of interest was the claim that immunotherapy with leukocytes and trophoblast membranes does not significantly improve the reproductive performance of
aborting women . The authors critically evaluated the then existing methods employed and concluded that this form of therapy was of no consequence. Similarly, it was suggested that the subsequent pregnancy success rates claimed from various therapies could be accounted for by
spontaneous cure rates typical of this order .
The authors reported that the probability of a subsequent abortion after three consecutive abortions was only 20% thus giving an 80% spontaneous cure rate. These figures are similar to those presented elsewhere by Stray-Pederson and Stray-Pederson  claiming that tender loving care alone was as effective a therapy in achieving a subsequent live birth for the couple as any reported in the literature. In these studies, successful healthy deliveries were reported in 32 of 37 couples (86.5%) of habitual aborters following psychological support, bed rest, and tender loving care alone and in another 8 of 24 (33%) couples without special care. More studies have shown that dedication to supportive care with and without pharmacological or surgical intervention facilitates successful pregnancies.
Paradoxically, these observations, suggested that leukocyte immunotherapy per se may be of no clinical consequence. Interestingly, however, those authors who discounted immunotherapy and supported spontaneous cure rates and or tender loving care alone did not invite the participation of immunology into play. Thus without taking sides, one would argue that the spontaneous cure rates achieved after three or more consecutive abortions may result from a slow but consistent build up of immunological factors such as blocking antibodies with every pregnancy lost. Thus, given that each of the lost fetuses would have had a unique set of paternal genes, it may be speculated that the mother may have attempted immunological responses at the gene products there to but was inadequate
each time. However, the cumulative effect of three or more aborted fetuses may have exposed the mother to a larger repertoire of paternal antigens leading to an adequate build up of blocking antibodies that sustained the subsequent pregnancies hence the apparent spontaneous cure rates. This speculation may not necessarily hold true in every case of spontaneous cure following recurrent abortion, in as much as it would make immunological sense but should not be downplayed.
A new dimension of study has further put to test the merits of immunotherapy with leukocytes. In this study recurrent aborters were immunised with killed streptococcal preparations before and during pregnancy, and the authors reported success in 17 of 23 (73.9%) women which compared very well with 154 of 205 (75.1%) success rates recorded in women that were immunized with paternal lymphocytes. Elsewhere, 36 recurrent aborters were treated with intramuscular injections of extracorporally hemolysed and ultra violet (UV) irradiated autologous blood . Again 19 of 22 (86%) women gave birth to live newborns compared with a 64% live births in the control group. These observations question the concept that immunisation with leukocytes evoked maternal immune responses to specific leukocyte antigens that are necessary for success of pregnancy. According to a review using a 95% confidence intervals in a large meta analysis , only as few as 4 to as many as 167 women would need to receive leukocyte immunization to achieve one additional live birth .
In addition, lymphocyte immunotherapy has been associated with some adverse side effects such as erythrocyte sensitization, thrombocytopenia and intrautering growth retardation among others [35, 45, 49]. Also, the fact that leukocyte immunotherapy uses whole cells with intact nuclear material works against its merits. This form of therapy must therefore be treated with caution especially after the global realisation that diseases such as the aquired immunodeficiency syndrome (AIDS) could be transferred from one individual to another by blood transfusions.
Immunotherapy with intravenous ? immunoglobulin (IVIg)
Given the controversies that have surrounded leukocyte immunotherapy, Intravenous gamma immunoglobulin, IVIg has been used by some workers as a safer alternative method of treatment to recurrent spontaneous abortion.
Table 3 Potential side effects of immunotherapy
Mode of Action
Potential Side Effects
Risk of Infection
Induction of blocking antibodies
– transfusion reactions
– erythrocyte and platelet sensitization
– intra-uterine growth retardation,.
– graft versus host disease,、thrombocytopenia
– neonatal death
Intravenous immunoglobulin immunization IVIg
passive transfer of blocking antivbiodies
– intrauterine growth retardation
Conclusion – 结论
The post implantation immunology of pregnancy has registered commendable achievements in the last thirty five years with such great findings as the expression of HLAG on the human placenta, an observation that directly supports the concept that a well regulated maternal immune response may be critical in the success of pregnancies.This set of information together with the others discussed in the literature have improved our understanding of the immunology of pregnancy and guided the course of immunotherapy to date. However, despite the recent advances in reproductive medicine and the brilliant experimental data obtained in the last thirty five or more years, the affected couples have continued languishing in the psychological and financial stresses associated with this condition.
Similarly, huge losses have been experienced in the livestock Industry due to undetected preclinical pregnancy losses. This has also remained a nagging source of stress to the physicians who cannot answer such questions as what caused the loss and what are the chances that a subsequent pregnancy is at risk.
Therapy for alloimmune reproductive failures remain anecdotal partly because the diagnosis for alloimmune recurrent spontaneous abortion has not been convincingly developed and a well designed clinical trial has not been satisfactorily accomplished to date.