Critical Appraisals of Immunological Treatment (PRO)
H.J.A. Carp
Depts. of Obstetrics and Gynecology, Embryology and Teratology
Sheba Medical Center, Tel Hashomer, and University of Tel Aviv, Israel
Introduction
Comparative trials of immunopotentiation to prevent recurrent miscarriage have claimed both active immunization with paternal leucocytes and intravenous immunoglobulin, to be beneficial1,2, and futile3-5. As there is a 60% live birth rate in untreated patients with three or more unexplained miscarriages, it is difficult to show that any treatment is beneficial. However, no trial has matched for the clinical predictive factors influencing the 60 % live birth rate: maternal age, primary or secondary aborter status, time to conceive, presence of anti-paternal HLA antibodies (APCA), and the number of previous miscarriages, (each subsequent miscarriage lowers the live birth rate by 23%. Therefore the design of previous double blind trials prevent them from showing meaningful results. The RMITG metaanalysis6 of double blind trials which showed a 10% benefit from immunization, reported a greater effect in the 1o aborter than the 2o aborter, and a 37% benefit in patients who seroconvert to APCA positive. Daya and Gunby7 recalculated the figures of the RMITG metaanalysis when only patients with primary abortions who were APCA negative were assessed. They reported a 24% increase in the live birth rate. In order to assess immunopotentiation, we selected patients with a poor prognosis, who had little chance of sustaining a pregnancy to term, i:e women with five or more first trimester miscarriages.
Methods
The figures in the RMITG register were reassessed according to:- 5 ormore abortions,1o, 2o or 3o aborter status, APCA negative at initial testing and seroconversion to APCA positive as a result of immunization8. In our series 414 patients were immunized with paternal leucocytes and 201 patients were controls. Immunoglobulinwas administered to patients with five or more miscarriages, who miscarried despite paternal leucocyte immunization, or despite APCA positive status, or if there was a contraindication to active immunization.
Results
The recalculated RMITG figures for 5 or more miscarriages are summarized in Fig. 1 and show that the relative risk of a live birth was higher after immunization in 1o and 3o aborters, but not 2o aborters.
FIG. 1. Proportion Of Live Births And 95% Confidence Intervals In Each Subgroup In RMITG Metaanalysis
TABLE 1: Multivariate Analysis by Logistic Regression for Predicting a live birth. (after excluding non significant variables).
Table 1 is from our series using a model correlating the live birth rate and APCA status to the subsequent pregnancy using logistic regression for the other predictive factors. Immunized patients had an odds ratio for a live birth 2.07 times higher than non immunized patients. The odds ratio increases to 3.99 if seroconversion occurs, illustrating the benefit of booster immunizations. There were 266 live births in 414 immunized patients (64%), as opposed to 81 births in 201 (40.3%) control patients (24% benefit). When the 1o or 3oaborters with five or more abortions were selected, and matched for initial APCA status and seroconversion, 39 live births occurred in 63 patients (62%) as opposed to 5 live births in 29 control patients (17%).
Immunoglobulin was followed by a 50% live birth rate (Fig 2.). Using this combined approach, there is an 81% live birth rate in women with five or more abortions.
FIG. 2. Live Births With Immunoglobulin
Conclusions
Immunopotentiation is not a panacea, but is the only therapy which improves the prognosis in poor prognosis patients. Future trials need to be selective in their inclusion criteria, and only assess patients with a poor prognosis. Under these conditions, immunopotentiation is highly effective. Correcting the figures for fetal chromosomal abberations, and a more accurate diagnosis of the cause of abortion, may reduce the number of patients requiring immunization. Meanwhile, it is unacceptable to say that the patient with 3 abortions has a 60% chance of a live delivery. This is of no use to the patient with 7 abortions, and ignores the needs of the 40% who do not have a live birth.
References
1. MOWBRAY JF, GIBBINGS CR, LIDELL H, et al. Controlled trial of treatment of recurrent spontaneous abortions by immunisation with paternal cells. Lancet I:941-943, 1985
2. COULAM CB, Immunotherapy for recurrent spontaneous abortion. Early Pregnancy. 1:13-26, 1995
3. HO HN, GILL TJ, HSIEH H, et al, Immunotherapy for recurrent spontaneous abortion in Chinese population. Am J Rep Imm. 25:10-15, 1991
4. CAUCHI MN, LIM D, YOUNG DE, et al. Treatment of recurrent aborters by immunization with paternal cells - Controlled trial. Am J Rep Imm. 25:16-17, 1991.
5. GERMAN RSA/IVIG GROUP. Intravenous immunoglobulin in the prevention of recurrent miscarriage. Br J Obs Gyn. 101:1072-1077, 1994
6. RECURRENT MISCARRIAGE IMMUNOTHERAPY TRIALISTS GROUP. Worldwide collaborative observational study and metaanalysis on allogenic leucocyte immunotherapy for recurrent spontaneous abortion. Am J Rep Imm. 32:55-72, 1994.
7. DAYA S, GUNBY J. The effectiveness of allogeneic leucocyte immunization in unexplained primary recurrent spontaneous abortion. Am J Rep Imm. 32:294-302, 1994
8. CARP HJA, TORCHINSKY A, PORTUGUESE S. et al., Paternal leukocyte immunization after five or more miscarriages. Hum. Rep. 12:250-255., 1997