A substantive amendment to this systematic review was last made on 28 July 1996. Cochrane reviews are regularly checked and updated if necessary.Miscarriage is the most frequent complication of human pregnancy with approximately 1-2% of couples suffering recurrent early losses (Coulam 1991). The commonly accepted definition for recurrent miscarriage is the occurrence of three or more consecutive first-trimester spontaneous miscarriages. Primary aborters are sometimes defined as those women who have never had a successful pregnancy, and secondary aborters, as those whose repetitive losses follow a live birth. There is presently no specific classification for those women who have multiple spontaneous miscarriages interspersed with normal pregnancies. Whether previously unrecognized or occult early miscarriages now diagnosed by sensitive human chorionic gonadotropin tests should be included in these definitions is unclear. Although the term recurrent miscarriage has usually referred to those losses occurring in the first trimester, this time limit is arbitrary and does not take into account a variety of potential underlying causes which may result in fetal death anytime during the first half of pregnancy. With the development of ultrasound, it is more relevant to classify previous miscarriages based on whether a live fetus had been present or not (van Leeuwan 1993).Background and objectives: Immunologic aberrations may be the cause of recurrent early pregnancy loss in some women. The objective of this review was to assess the effects of leukocyte immunisation or other immunologic treatments on the live birth rate in women with previous recurrent miscarriages.
Search strategy: The Cochrane Pregnancy and Childbirth Group trials register and Medline were searched. Individual patient data were obtained from the American Society for Reproductive Immunology and by Medline search. Date of last search: May 1998.
Selection criteria: Randomised trials of immunotherapy in women with three or more prior miscarriages, no more than one live birth, all non-immunologic causes ruled out and no simultaneous treatment intervention.
Data collection and analysis: Eligibility and trial quality were assessed by one reviewer.
Main results: Seventeen trials of high quality were included. The various forms of immunotherapy did not show significant differences between treatment and control groups. For paternal cell immunisation, the odds ratios was 1.36, 95% confidence interval 0.92 to 2.00. For third party donor cell immunization, the odds ratio was 1.39, 95% confidence interval 0.68 to 2.82. For trophoblast membrane infusion the odds ratio was 0.40, 95% confidence interval 0.11 to 1.45. For intravenous immune globulin, the odds ratio was 1.23, 95% confidence interval 0.60 to 2.51.
Reviewers conclusions: Paternal cell immunization, third party donor leukocytes, trophoblast membranes, and intravenous immune globulin appear to provide no significant beneficial effect over placebo in preventing further miscarriages.
It has been postulated that immunologic aberrations may be the cause of recurrent early pregnancy loss in some women. Because the mechanisms that allow a mother to tolerate her semi-allogeneic conceptus are unclear, it is difficult to assess the role of immunologic factors in reproductive failure. Since the majority of women with recurrent miscarriages have no discernible cause, potential allogeneic factors have been suggested, and extensively investigated. Early reports proposed that HLA compatibility of couples, the absence of maternal leukocytotoxic antibodies, or the absence of maternal blocking antibodies were related to recurrent pregnancy loss. More recently, defects in molecular immunosuppressive factors (cytokines and growth factors) at the local decidual/trophoblast level have been implicated (Hill 1990; Johnson 1992). Although no alloimmune mechanism has yet been unequivocally shown to cause recurrent pregnancy loss in humans, several immunologic treatments have been advocated. Early attempts to improve maternal immunotolerance were based on evidence that pre-transplant blood transfusions decreased rejection of organ allografts; the rate of resorptions or abortions in animal models was also reduced by prior immunization with spleen cells from a paternally related strain (Scott 1987). The most popular immunologic regimen used clinically in humans has been injection of husband s leukocytes.
By no means does all evidence favor an alloimmune cause of recurrent miscarriage. Recent studies have shown little correlation between pregnancy outcome and histocompatibility or the presence of antipaternal leukocytotoxic or blocking antibodies. Extrapolation from animal models to the human situation may not be relevant because of interspecies endocrine, immunologic, and reproductive differences, and the beneficial effect of pre-transplant blood transfusions to ameliorate rejection has been questioned (Scott 1987,Scott 1995; Smith 1988; Coulam 1992). Since no clear picture has emerged regarding the value of immunotherapy, these therapies have remained controversial.
1. Three or more prior miscarriages
2. No more than one prior live birth
3. All non-immunologic causes ruled out
4. No simultaneous treatment co-intervention.
See: Collaborative Review Group search strategy
This Review has drawn on the search strategy developed for the Pregnancy and Childbirth Group as a whole.Relevant trials were identified in the Group s Specialised Register of Controlled Trials. See Review Group s details for more information.
Trials under consideration were evaluted for methodological quality and appropriateness for inclusion, without consideration of their results. Included trial data were processed as described in: Mulrow CD, Oxman AD (eds). Cochrane Collaboration Handbook (updated 1 March 1997). In: The Cochrane Library (database on disk and CDROM). The Cochrane Collaboration. Oxford: Update Software; 1996-. Updated quarterly.Individual patient data were collected from the principal investigator of each published and unpublished trial using a standardized form.
A. PATERNAL CELL IMMUNIZATION
Published trials:
1. Cauchi 1991*
2. Gatenby 1993*
3. Ho 1991*
4. Mowbray 1985*
5. Parrazzini 1994
Unpublished trials:
1. Christiansen 1994
2. Kilpatrick 1994
3. Reznikoff 1994
4. Stray-Pedersen 1994+
5. Scott 1994
B. THIRD PARTY DONOR CELL IMMUNIZATION
Published trials:
1. Chistiansen 1994
2. Ho 1991
Unpublished trials:
1. Scott 1993
C. TROPHOBLAST MEMBRANE IMMUNIZATION
Published trials:
1. Johnson 1991
D. INTRAVENOUS IMMUNE GLOBULIN
Published trials:
1. Christiansen 1995
2. Coulam 1995
3. German RSA/IVIG Group 1994
* Also updated from individual patient data sheets
+ Individual patient data not available
Only women that met the inclusion criteria were included, and the data were revised and updated from individual patient data forms. Heterogeneity among the studies was judged to be low. Variations included cell dose, number, and route of immunization, but none of these variables were associated with the outcome of pregnancy. There was relatively good consistency between the results of the trials. Availability of individual patient data sheets and selection criteria for women included in the review strengthened this constancy.
The results of this review indicate that there may be a small increase (6.6%, ie 61.6% vs 68.2%) in the live birth rate in these women after paternal cell immunization compared to controls, but the increase is not statistically significant. The published trials tended to give higher estimates of treatment effect suggesting the possibility of publication bias. Donor cell immunization, trophoblast membrane immunization, and intravenous immune globulin do not significantly improve the chance of a live birth in women with recurrent miscarriages.
The chance of a successful pregnancy resulting in a live birth with no treatment is approximately 60% (range 40-70%) in women with three or more early pregnancy losses (Scott 1995). The results of this review using odds ratios indicate that no improvement in outcome was achieved with paternal cell immunization or any of the immunotherapy regimens.However, when a slightly different data set was previously adjusted for two important prognostic variables (maternal age and number of miscarriages before immunization), the live birth rate with paternal cell immunization was significantly improved over placebo (Scott 1994). Another meta-analysis performed simultaneously using slightly different trial and patient selection criteria and different statistical methods also demonstrated a small but significant benefit from paternal cell immunization (Collins 1994; Coulam 1994).
The conclusions of the present review are compatible with but not identical to those from a meta-analysis based on published trials which showed no benefit from paternal leukocyte immunization (Fraser 1993). One meta-analysis found a slight benefit (Daya et al 1994); in another the relative live-birth ratio (RR) with paternal leukocyte immunization was RR 1.17; CI 0.97 to 1.28 using a fixed treatment effect model and RR 1.18; CI 0.97 to 1.42 using the random treatment effect model (Jeng 1995).
Thus, it appears that conclusions about the value of paternal cell immunization in recurrent miscarriage are conflicting and are highly dependent on the methods used for the meta-analysis (Jeng 1995).
Immunization using viable mononuclear cells carries the risk of any blood transfusion such as hepatitis B virus or human immunodeficiency virus (HIV). Reactions have been uncommon but include soreness and redness at the injection site, fever, maternal platelet alloimmunization, blood group sensitization, and one cutaneous graft-versus-host-like reaction (Clark 1991; Coulam 1994). Adverse pregnancy outcomes have been rare, but those encountered include placental abruption, placenta accreta, oligohydramnios, pre-eclampsia, fetal growth retardation, preterm delivery, renal anomalies, trisomy 21 and 13, and an unusual case of undefined immunodeficiency disease.
There seems to be no advantage of third party donor white cells or trophoblast membranes over paternal white cells. In fact, paternal cells are generally more acceptable to patients and may reduce the risk of transmitting HIV or other viruses. Moreover, at present there is no evidence that other immunologic treatment regimens such as intravenous immune globulin are more effective.
To establish definitively or to rule out the efficacy of paternal leukocyte immunization, further randomized controlled trials with larger numbers of patients are needed. These should be studies approved by institutional review boards in centers with research expertise and interest in this problem. It is possible that the treatment is more effective in an as yet undefined subset of patients. New therapeutic modalities should be tried under protocol with acceptable study designs. Finally, further studies on complications of treatment and long-term follow-up of offspring are necessary. The National Institutes of Health (NIH) in the United States and other funding agencies should be encouraged to support proposals that offer new and innovative approaches to this problem. The Agency of Health Care Policy and Research in the United States and similar funding agencies in other coutries need to support proposals to evaluate outcome of treatments especially for large trials.
References to studies included in this review
Cauchi 1991 (published and unpublished data) Cauchi MN, Lim D, Young DE, Kloss M, Pepperell RJ. Treatment of recurrent aborters by immunization with paternal cells - controlled trial. Am J Reprod Immunol 1991; 25: 16-17. Christiansen 1994 (published and unpublished data) Christiansen OB, Mathiesen O, Husth M, Lauritsen JG, Grunnet J. Placebo-controlled trial of active immunization with third party leukocytes in recurrent miscarriage. Acta Obstet Gynecol Scand 1994; 3: 261-268. Christiansen 1995 (published data only) Christiansen OB, Mathieson O, Husth M, Rasmussen K, Ingerslev JH, Lauritsen JG, Brunnet N: Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with iv immunoglobulin. Hum Reprod. 1995; 10: 2690-2695. Coulam 1995 (published data only) Coulam CB, Krysa L, Stern JJ, Bustillo M: Intravenous immunoglobulin for treatment of recurrent pregnancy loss. Am J Reprod Immun. 1995; 34: 333-337. Gatenby 1993 (published and unpublished data) Gatenby PA, Cameron K, Simes RJ, Adelstein S, Bennett MJ, Jansen RPS, Shearman RP, Stewart GJ, Whittle M, Doran T. Treatment of recurrent spontaneous abortion by immunization with paternal lymphocytes: Results of a controlled trial. Am J Reprod Immunol 1993; 29: 88-94. German RSA/IVIG (published data only) German RSA/IVIG Group: Invtravenous immunoglobulin for treatment of recurrent miscarriage. Br J Obstet Gynaecol. 1994; 101: 1072-1077. Ho 1991 (published and unpublished data) Ho HN, Gill TJ, Hsieh HJ, Jiang JJ, Lee TY, Hsieh CY. Immunotherapy for recurrent spontaneous abortions in a Chinese population. Am J Reprod Immunol 1991; 25: 10-15. Johnson 1991 (published data only) Johnson PM, Ramsden GH, Chia KV, Hart CA, Farquharson RG, Francis WJA. A combined randomized double-blind and open study of trophoblast membrane infusion (TMI) in unexplained recurrent miscarriage. In: Cellular Molecular Biology of the Materno-Fetal Relationship. Eds. Chaouate G, Mowbray J. Collegue INSERM/John Libbey Eurotext Ltd 1991; 212: 277-284. Kilpatrick 1994 (unpublished data only) Kilpatrick. Department of Transfusion Medicine, The Royal Infirmary, Edinburgh EH3 9HB, Scotland. (901; : -. Mowbray 1985 (published and unpublished data) Mowbray JF, Gibbings C, Liddell H, Reginald PW, Underwood JL, Beard RW. Controlled trial of treatment of recurrent spontaneous abortion by immunisation with paternal cells. Lancet 1985; 1: 941-943. Parazinni 1994 (published and unpublished data) Illeni MT, Marelli G, Parazinni F, Acaia B, Bocciolone L, Bontempelli M et al. Immunotherapy and recurrent abortion: a randomized clinical trial. Hum Reprod 1994; 9: 1247-1249. Reznikoff 1994 (unpublished data only) Reznikoff MF. INTS (Laboratoire), 6 rue Cabanel, 75015 Paris, France. (901; : -. Scott 1994 (published and unpublished data) Scott JR, Branch WD, Dudley D. Department of Obstetrics and Gynecology, University of Utah Medical Center, Salt Lake City, Utah 84132, USA. (901; : -. Stray-Pederson 1994 (unpublished data only) Stray-Pederson S. Department of Obstetric and Gynecology, University of Oslo, Oslo, 1 Norway. (901; : -. * indicates the major publication for the study References to studies excluded from this review Redman 1996 Redman CWG: UK multicenter paternal cell immunization trial. Nuffeld Department of Obstetrics and Gynecology Maternity Department, John Radcliffe Hospital, Headington, Oxford OX3 9DU. (901; : -. Ongoing studies Ober 1996 Additional references Clark 1991 Clark DA, Daya S. Trials and tribulations in the treatment of recurrent spontaneous abortion. Am J Reprod Immunol 1991; 25: 18-24. Collins 1994 Collins J, Roberts R. Immunotherapy for recurrent spontaneous abortion: Analysis 1. Am J Reprod Immunol 1994; 32: 275-80. Coulam 1991 Coulam CB. Epidemiology of recurrent spontaneous abortion. Am J Reprod Immunol 1991; 26: 23-27. Coulam 1992 Coulam CB. Immunologic tests in the evaluation of reproductive disorders: A critical review. Am J Obstet Gynecol 1992; 167: 1844-1851. Daya et al 1994 Daya S, Gunby J, Aoki K, Carp HJA, Cauchi MN, Lim D et al. The effectiveness of allogeneic leukocyte immunization in unexplained primary recurrent spontaneous abortion. Am J Reprod Immunol 1994; 32/4: 294-302. Fraser 1993 Fraser EJ, Grimes DA, Schultz KF. Immunization as therapy for recurrent spontaneous abortion: A review and meta-analysis. Obstet Gynecol 1993; 82: 854-859. Hill 1990 Hill JA. Immunological mechanisms of pregnancy maintenance and failure: A critique of theories and therapy. Am J Reprod Immunol 1990; 22: 33-42. Johnson 1992 Johnson PM. Pregnancy immunology. Fetal Matern Med Rev 1992; 4: 1-14. Scott 1987 Scott JR, Rote NS, Branch DW. Immunologic aspects or recurrent abortion and fetal death. Obstet Gynecol 1987; 70: 645-656. Scott 1989 Scott JR. Habitual abortion - Recommendations for a reasonable approach to an enigmatic problem. In Soules M (ed); : Controvers-. Scott 1995 Scott JR, Branch WD. Potential alloimmune factors and immunotherapy in recurrent miscarriage. Clin Obstet Gynecol 1995; 37: 761-7. Smith 1988 Smith JB, Cowchock FS. Immunological studies in recurrent spontaneous abortion: Effects of immunization of women with paternal monouclear cells on lymphocytotoxic and mixed lymphocyte reaction blocking antibodies and correlation with sharing of HLA and pregnancy outcome. J Reprod Immunol 1988; 14: 99-113. van Leeuwan 1993 Van Leeuwan I, Branch DW, Scott JR. First trimester ultrasound findings in women with a history of recurrent pregnancy loss. Am J Obstet Gynecol 1993; 168: 111-114. Previously published versions Coulam 1994 Coulam CB, Clark DA, Collins J, Scott JR: Worldwide collaborative observational study and meta-analysis on allogenic leukocyte immunotherapy for recurrent spontaneous abortion. Am J Reprod Immunol. 1994; 32: 55-72. Jeng 1995 Jeng GT, Scott JR, Burmeister LF. A comparison of meta-analytic results using literature vs individual patient data: Paternal cell immunization for recurrent miscarriage. JAMA 1995; 274: 830-836. Extramural sources of support to the review Intramural sources of support to the review Fig 02 DONOR WHITE CELL IMMUNIZATION Fig 03 TROPHOBLAST MEMBRANE IMMUNIZATION Fig 04 INTRAVENOUS IMMUNE GLOBULIN Ober C: A double-blinded randomized multicenter clinical trial of paternal cell immunization in US funded by NIH. (9016)
Reviewer(s) Scott JR Date of most recent amendment 21 February 1999 Date of most recent substantive amendment 28 July 1996 Contact address Prof James R Scott
Department of Obstetrics and Gynaecology
University of Utah Medical Center
50 North Medical Drive
Salt Lake City
Utah 84132
USA
Telephone: +1 801 581 7279
Facsimile: +1 801 649 7074
E-mail: jscott@hsc.utah.eduCochrane Library number CD000112 Editorial group Cochrane Pregnancy and Childbirth Group Editorial group code HM-PREG This review should be cited as :
Scott JR. Immunotherapy for recurrent miscarriage (Cochrane Review). In: The Cochrane Library, Issue 2, 1999. Oxford: Update Software.Sources of support
Comment, Reply and Editorial notes
Please note that, in line with the Cochrane Pregnancy and Childbirth Group s policy of keeping reviews up-to-date, this review was last checked by the reviewer on 27 March 1998. This check did not result in any new data being contributed to the review and, therefore, the review has not been flagged as a substantial update.Keywords
ABORTION-HABITUAL / therapy; IMMUNOTHERAPY; LEUKOCYTES / immunology; PREGNANCY; HUMAN; FEMALE; BIRTH-RATE; RANDOMIZED-CONTROLLED-TRIALS; FATHERS; TISSUE-DONORS; TROPHOBLAST / immunology; IMMUNIZATION; IMMUNOGLOBULINS-INTRAVENOUS / therapeutic-use; TREATMENT-OUTCOMEList of comparisons
Fig 01 PATERNAL WHITE CELL IMMUNIZATION VS PLACEBO
Tables of other data
Tables of other data are not available for this review
| Study | Method | Participants | Interventions | Outcomes | Notes |
|---|---|---|---|---|---|
| Cauchi 1991 | Women were allotted to one or the other treatment group using a computer generated list of numbers. Neither the treating physician nor the women knew whether they were injected with cells or placebo. | Women with three or more consecutive first trimester miscarriages with the same partner, and after exclusion of other known causes of recurrent miscarriage. Assessment included full physical gynecological examination for evidence of fibroids, excluding other abnormalities of the uterus, by hysterosalpingogram and/or hysteroscopy, endocrinological tests including thyroid function tests, hemoglobin A1C, and chromosomal abnormalities. Standard coagulation tests (including APTT, KCT), auto-antibody tests (including anti-nuclear antibody, anti-DNA antibody) as well as anti-cardiolipin antibody were performed, and women were excluded if the results were abnormal. Women were also excluded from this study if they were rhesus negative or had cytotoxic antibodies. | Mononuclear cells (10-100 million) were prepared from 100-150 ml of heparinized blood taken from the partner, separated by density centrifugation and concentrated to 2 ml, half of which was injected intravenously and the rest injected into multiple sites intra-dermally and subcutaneously. Control women were given 2 ml of normal saline, injected in the same manner. | Live births after paternal white cell immunization or placebo. | |
| Christiansen 1994 | Women were randomly allocated to the treatment or control group in a 2:1 ratio. Neither the couple nor the woman s obstetrician knew whether active treatment or placebo was provided. | Women with at least three consecutive miscarriages documented by pregnancy tests or ultrasound scans, a maximum of one pregnancy loss after 14th week of gestation, and not consanguinous with spouse. Women included in the trial proved normal for other causes of miscarriage by hysterosalpingography or hysteroscopy, midluteal serum progesterone, serum thyroxine, parental karyotypes, lymphocytotoxic antibodies, lupus anticoagulant, ANA titer, and anti-DNA. | Immunization with intravenous infusions of 150 ml buffycoat (leukocyte enriched blood) from erythrocyte compatible third party donors or 150 ml of the woman s autologous blood (control). The women were given one repeated infusion of third party buffycoat (from two donors) or autologous blood every fifth month until conception. | Live births after donor leukocytes vs placebo (autologous leukocytes). | |
| Christiansen 1995 | Women were randomized to the treatment or control group. | Women with three or more miscarriages and no more than one live birth or one fetal death after 14 weeks gestation. All had a negative evaluation for other causes of miscarriage including hysterosalpingography or hysteroscopy, parental karyotypes, luteal phase progesterone level, and systemic lupus erythematosus. Women were eligible if they had no IgA deficiency. | Intravenous immune globulin or human albumin (placebo) given at week 5-8, then every other week. Intravenous immune globulin was adjusted according to weight: 1) 60-80 kg: 35 g in week 5-6; 25 g weeks 7-26; 30 g weeks 28, 30 32 and 34. 2) >80 kg: 5 g more at each infusion. | Live births after intravenous immune globulin vs placebo. | |
| Coulam 1995 | Women were randomized to the treatment or control group. | Women between ages 18-45 with two or more miscarriages and a normal evaluation for other causes of miscarriage which included hysterosalpingography or hysteroscopy, parental karyotypes, luteal phase endometrial biopsy or progesterone level, anticardiolipin antibody, and activated partial thromboplastin time. No history of IgA deficiency or hypersensitiviy to immune globulin. | 500 mg/kg vs 0.5% albumin given in the follicular phase of the cycle and every 28 days until pregnancy was achieved and then continued until 28-32 weeks gestation. | Live births after immune globulin or placebo. | Only women with three or more miscarriages included in this review. |
| Gatenby 1993 | Multicenter trial, randomized to paternal white cell immunization or autologous white cell immunization (control) using random number tables. Neither the women, the treating obstetrician, nor the staff were aware of the source of cells the women received. | Women with three or more consecutive miscarriages prior to 20 weeks gestation with one sexual partner and no more than one previous live birth. All other known causes of miscarriage were excluded by gynecological examination, hysterogram, parental chromosome analysis, thyroid function tests, blood glucose, premenstrual endometrial biopsy, serum copper, TORCH titers, serum creatinine, anticardiolipin antibodies, lupus anticoagulant, and ANA. Women with lymphocytotoxic antibodies were also excluded. | 400 million paternal or maternal (placebo) peripheral blood mononuclear leukocytes were injected intravenously, intradermally, and subcutaneously. | Live births after paternal white cell immunization or placebo. | |
| German RSA/IVIG | Multicenter trial with randomization carried out centrally in blocks of four into treatment or control groups. | Women with three or more miscarriages <16 weeks gestation and no live children with the following inclusion criteria: age <40 years, exclusion of known gynaecological, genetic or endocrinologic causes, no history of leukocyte treatment or blood transfusion, no IgA deficiency, gestational age of present pregnancy not beyond 8 weeks gestation. | 30 g of intravenous immune globulin or 5% albumin (control) initiated at <8 weeks gestation and 20 g given thereafter every three weeks until 25 weeks gestation. | Live births after immune globulin or placebo. | |
| Ho 1991 | Women were randomly assigned to paternal white cell immunization or immunization with autologous white cells (control). | Women with three or more consecutive miscarriages with the same husband and no other cause found for miscarriage with the following tests: parental chromosome analysis, hysterosalpingography and hysteroscopy, serum prolactin, testosterone, T3, T4, TSH, fasting and postprandial blood glucose, midluteal phase progesterone levels x2, C3, C4, ANA, anti-ENA, anti-DNA, aPTT, anticardiolipin antibody. | 100-200 million paternal or autologous (control) peripheral blood lymphocytes injected intradermally. Women who did not seroconvert by lymphocytotoxic assays were given a further dose of lymphocytes prepared from 50 ml of blood. Women who did not conceive within six months and did not have lymphocytotoxic antibodies were reimmunized. | Live births after paternal cell immunization or placebo. | |
| Johnson 1991 | Women were randomized ""by an individual without any knowledge of patients names or history"" into a group treated with trophoblast membrane infusion or a group given a 1:600 dilution of intralipid emulsion that was visually identical to the trophoblast membrane preparation (control). | Women with at least three consecutive confirmed miscarriages by the same partner and no more than one live birth with other chromosomal, anatomic, microbiological, and hormaonal causes of miscarriage ruled out. Women were also excluded if the following tests were positive or abnormal: lymphocytotoxic antibodies, anti-erythrocyte antibodies, tissue-reactive antibodies, antiphocardiolipin antibodies, blood coagulation times, and serum IgE. | A slow intravenous infusion of a sterile preparation of isolated placental syncytiotrophoblast plasma membrane preparation suspended in 250 ml saline or 250 ml intravenous infusion of the intralipid (placebo) solution. | Live births after trophoblast membrane or placebo infusion. | |
| Kilpatrick 1994 | This study was part of a multicentered trial, and randomization was organized centrally. A numbered envelope was obtained, and the blood bank techician prepared the appropriate cells which were injected by the investigator. Neither investigators, women, or physicians were aware of the treatment. | Women with at least three miscarriages and no more than one live birth and all non-immunologic causes ruled out. Women were excluded if they has a positive test for lupus anticoagulant, anticardiolipin, ANA, or lymphocytotoxic antibodies. | Paternal leukocytes from 100 ml blood or autologous leukocytes from 40-60 ml blood given intravenously, intradermally, and subcutaneously and boosted once in early pregnancy. | Live births after paternal white cell immunization or placebo. | |
| Mowbray 1985 | A computer-generated list of pseudo-randomized numbers was used to allot the woman to receive either her husband s or her own lymphocytes. Neither the obstetrician nor the couple knew which cells were used until after completion of the next pregnancy. | Women with at least three miscarriages with the same partner and no more than one live birth who had no detectable antibody against paternal lymphocytes and no cause found for miscarriages who were rhesus positive and were UK residents. The screening procedure to rule out other causes included antibodies for brucella and toxoplasmosis, cultures for cytomegalovirus, chlamydia, and herpes simplex, serum thyroxine, random blood sugar, ""evidence"" for cervical incompetence, fibroids or septate uterus, parental chromosome analysis, and lymphocytoxic antibody. | 5 ml of buffycoat paternal or autologous (control) peripheral blood lymphocytes injected intravenously, intradermally, and subcutaneously. | Live births after paternal white cell immunization or placebo. | |
| Parazinni 1994 | Women were randomized by telephone to the physician (multicenter study) from a computer-generated randomization list to paternal cell or no treatment groups. The treatment and control groups were not blinded to investigators, patients or physicians. | Women with at least three miscarriages and no live births who had all nonimmunologic causes ruled out. Women were also excluded if they had a positive test for lupus anticoagulant, anticardiolipin, or ANA test, a positive MLR, or she matched with her husband at the DR3 HLA locus. | Paternal leukocytes from 400 m. blood (200 million cells) injected intravenously, intradermally, and subcutaneously or no treatment. | Live births after paternal white cell immunization or no treatment. | |
| Reznikoff 1994 | Sealed envelopes with paternal or autologous group were opened in the blood bank (laboratory) where the appropriate cells were prepared and administered. Physicians and women were unaware of which treatment was given. | Women with at least three miscarriages with the same partner and no live births who were less than 36 years of age, had all other nonimmunologic causes ruled out, and had no lymphocytotoxic antibodies. Women were also excluded if they did not achieve a pregnancy within six months. | Approximately 400 million (range 146-1075 million) paternal or autologous leukocytes were injected intravenously, intradermally, and subcutaneously. | Liver births after paternal white cell immunization or placebo. | |
| Scott 1994 | A computer-generated list was used to randomize women into paternal versus saline control groups. The alloted groups were obtained by the project nurse who informed the blood bank, gave the appropriate cells, and kept all records. Neither investigators, women or physicians were aware of the treatment given. | Woment with at least three consecutive miscarriages and no more than one live birth who had all non-immunologic causes ruled out. | Paternal leukocytes or donor leukocytes from one unit of blood (400-900 million cells) or saline were given intravenously in a blinded fashion. | Live births after paternal or donor white blood cell immunization or placebo. | |
| Stray-Pederson 1994 | ""Randomization was performed at the Institute of Transplantation Immunology."" Treatment was blinded to the investigator, physicians and women. | Women with at least three verified first trimester miscarriages with the same partner who had all non-immunologic causes ruled out and who had a negative test for lymphocytotoxic antibodies. | Immunization with 100-150 million paternal or autologous leukocytes injected intravenously, intradermally, and subcutaneously. | Live births after paternal or autologous white cell immunization. |
| Study | Reason for exclusion |
|---|---|
| Redman 1996 | The data from this multicentered trial were never analyzed. |