Recurrent abortion and leukocyte therapy--long-term benefits?
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Biomedical subjects
Publications and source records attributed to H J Carp.
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Between January 1984 and August 1991, 511 cases of extrauterine pregnancies were diagnosed by laparoscopy in our department. In 374 cases salpingectomy was performed: 184 by explorative laparotomy, and 190 by operative laparoscopy. Patients were scheduled for salpingectomy if one or more of the following criteria were fulfilled: (i) a ruptured tube which was surgically unsuitable for conservation; (ii) no interest in future fertility; (iii) tubes with ectopic gestation previously operated on; (iv) a previous tubal pregnancy on the same side, which was treated expectantly. Salpingectomy was performed via operative laparoscopy with bipolar diathermy forceps and laparoscopic scissors. Pregnancy rates, i.e. intra-uterine and repeat extra-uterine, were evaluated. The reproductive performance following salpingectomy did not differ significantly, whether by laparotomy or laparoscopy: the intra-uterine pregnancy rate was 78 and 64%, respectively and the repeat ectopic pregnancy rate was 12 and 6%, respectively. Salpingectomy via laparoscopy can be performed safely with a low incidence of complications, with subsequent reproductive performance comparable to laparotomy.
The present study was performed to evaluate whether the effect of environmental teratogens can be modified by maternal immunostimulation. Two chemicals, cyclophosphamide (CP) and 2,3-quinoxalinedimetanol,1,4-dioxide (QD) were used as the reference teratogens (RT). The response to these RT was investigated in two animal models: (i) primigravid C57Bl/6 mice who underwent intrauterine immunization with allogeneic paternal (CBA/J), third-party (BALB/c) or syngeneic male splenocytes 21 days before mating; (ii) C57Bl/6 and CBA/J mice who were treated with RT during the second pregnancy only, after a different mating combination (syngeneic or allogeneic) in the first and the second pregnancy. Different doses of CP and QD were injected on days 12 and 9 of pregnancy, respectively. On day 19 of pregnancy implantation sites, resorptions, live and dead fetuses were recorded and live fetuses were examined for external and internal malformations with methods routinely used in teratological study. It was shown that intrauterine immunopotentiation with allogeneic paternal splenocytes clearly enhances the tolerance of F1 embryos to RT. Thus, in CP-treated females the resorption rate and the proportion of malformed fetuses were significantly reduced. It was followed by an almost two-fold increase in fetal weight. The protective effect of such immunization in QD-treated females was manifested as a dramatic decrease of the proportion of malformed fetuses and the resorption rate. Syngeneic splenocytes could not significantly influence an embryo's sensitivity to RT. The response to RT was also significantly weaker in the second pregnancy of female mice mated twice allogeneically than that observed in allogeneically mated primigravid mice. These results show that the embryo's response to environmental teratogens may be influenced by fetomaternal immune interactions.
The risk of congenital malformations as assessed in infants born to women who underwent immunotherapy for habitual abortion. One hundred and eighty women were immunized with paternal mononuclear cells and 85 were not. Of 135 pregnancies in immunized patients, 27 (20%) were miscarriages, and 4 of the remaining 108 had congenital malformations. Two (encephalocele and common AV canal) were diagnosed in the 20th and 21st week of gestation. A case of esophageal atresia and Fallot's tetralogy were diagnosed at birth. Of 65 pregnancies in the non-immunized group 38 (58.5%) were miscarriages, and of the remaining 27, 1 case of Down's syndrome occurred. In a subgroup of 7 habitually aborting couples with parental balanced chromosomal anomalies, the balanced translocation was transferred to the infant in 1 case. No other congenital anomalies were found in either group. Consequently, these anomalies are probably not the result of abnormal pregnancies retained as a result of immunization.
Therapy with steroids and aspirin has been reported to benefit pregnancies in patients with lupus anticoagulant (LA). In this study, habitual first-trimester aborters with LA using steroids and aspirin were compared to a control group of untreated habitual aborters without LA. In habitual aborters with LA, 12 of 24 (50%) pregnancies reached the second trimester as compared to 8 of 22 pregnancies (36%) in the control group. Since the treated group did no better than the control group, LA probably is not a cause of first-trimester abortion. However, once the second trimester is reached, a 50% incidence of growth retardation was found, and 42% of fetuses died in the second or third trimester in treated LA patients. Treatment with steroids and anti-platelet aggregating agents may be necessary despite the attendant risks to prevent those sequelae in the second and third trimesters. There was a 29% live birth rate in treated LA patients; the rate was 36% in control patients. However, this rate was produced only by early intervention, which was unnecessary in the control patients.
Four women with the antiphospholipid syndrome associated with lupus anticoagulant and a poor obstetric history were treated with a combination of glucocorticosteroids, anticoagulants and platelet inhibitor therapy. All patients had at least one previous miscarriage while receiving prednisone and low-dose aspirin. The treatment regimen included: aspirin, dipyridamole, prednisone, and warfarin or heparin. This treatment resulted in a successful pregnancy outcome in all cases, without preeclampsia or recurrence of thrombosis. One patient developed a vertebral compression fracture while receiving heparin and prednisone. Two pregnancies required cesarean delivery for fetal distress at 32 and 34 weeks. All four infant birth weights were appropriate for the gestational age. This regimen may be a therapeutic option for patients with the antiphospholipid antibody syndrome, especially if they have failed other commonly used treatments.
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There are no reports on the subsequent anatomic findings in women with intrauterine adhesions who conceived and delivered after therapy, but our experience indicates that most of these women menstruate and conceive normally. The recurrence of intrauterine adhesions, together with preserved fertility in this patient, suggest that fertility, while usually correlated with subsequent resumption of normal menstruation and anatomy, may sometimes be independent of these features.
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After potentiation of the immune response in habitual aborters 75-85% of subsequent pregnancies are claimed to result in healthy term infants. However, all publications to date have either been based on the authors concept of the immune processes involved or an attempt to demonstrate the efficacy of treatment either empirically or by matched trials. As immunization is coming into wider clinical use, it is necessary to determine which patients will benefit from this form of treatment. This paper presents our experience with paternal leucocyte immunization over the period 1985-1988. 207 patients were classified on a clinical basis and by immunological testing. 143 patients have been immunised, 129 pregnancies have occurred in 108 patients. The vast majority of our patients have recurrent missed abortions. Only six women habitually aborted live fetuses. Two had subsequent live births. Secondary aborters seem to do well in subsequent pregnancies, whether immunized or not. The patient most likely to benefit from immunization is the Primary missed aborter who does not possess antipaternal antibody (APCA), but is induced to produce APCA by immunization. Using these criteria, 75% success rates are observed in the subsequent pregnancy. This success rate is irrespective of HLA antigen sharing or in-vitro mixed lymphocyte reactivity.
We briefly present our experience with trial labour in the presence of a Caesarean section scar and review some of the literature on the management of such patients.
Habitual abortion is a difficult clinical problem, as no cause can be found for abortion in over 50% of patients. At the habitual abortion clinic of the Sheba Medical Center, immunological activity is tested and patients who are considered suitable are offered immunopotentiation with paternal leukocytes. Patients are only treated if they have no other cause for habitual abortion, no lupus anticoagulant and no antipaternal complement-dependent antibodies (APCA). Immunization is thought to potentiate the maternal immune response to paternal antigens encountered on the trophoblast. The production of APCA antibody indicates that an immune response has occurred. Of the 156 patients so far immunized, 109 have developed these antibodies. To date, 79 of these 156 patients have become pregnant. Sixty-seven patients (with 3-12 miscarriages each) belong to the antibody-positive group. Sixty-four of the 89 subsequent pregnancies have been carried past their previous dates of abortion. Forty-seven live births have occurred. By contrast, 12 patients have been pregnant in the antibody-negative group, of the 16 subsequent pregnancies only 6 were successful. A control group is available for comparison. This consists of patients suitable for immunization, but not immunized. Of these patients, only 11 of 30 pregnancies have been carried to term.
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There are many reports in the literature associating lupus anticoagulant with fetal death. Successful pregnancies have been reported following suppression of the antibody by prednisone and the addition of antiaggregants and possibly anticoagulants. This report describes our experience treating such patients and the outcome of subsequent pregnancies. The results are less successful than the figures in the literature, 13 live births out of 27 pregnancies in 19 patients. This may be due to lupus anticoagulant being diagnosed as the cause for a wide variety of clinical presentations including habitual first trimester abortion, mid trimester fetal death, intrauterine growth retardation and placental dysfunction in the third trimester. Our experience shows that steroids and antiaggregants have a definite place in cases of second and third trimester fetal death and in cases of clinical systemic lupus erythematosus. However, lupus anticoagulant is one of a spectrum of autoantibodies whose pathophysiology has not been fully elucidated. It is questionable whether this regimen of treatment has a place in patients with no previous fetal loss or in cases of primary habitual abortion.
Recent evidence suggests that decidualization can be considered a modified inflammatory reaction. In this work we intended to determine whether the prostaglandin inhibitor diclofenac could affect implantation. Rat blastocysts were cultured in diclofenac in vitro, then implanted to host mothers on day 5 of pseudopregnancy. Large doses of diclofenac in culture were toxic. Smaller doses had a profound effect on implantation. Another group of host mothers received diclofenac i.p., one hour prior to transfer of untreated blastocysts. The results were compared to parallel controls without diclofenac treatment. Control animals had a 72% implantation rate, whereas there was only a 35-41% implantation rate after in vitro diclofenac treatment. In the treated host mothers only 7% of embryos were normal, while 34% were growth-retarded. More normal embryos were found when the blastocysts were cultured with diclofenac. The observations indicate that diclofenac administered to the mother inhibits the ongoing process of implantation and placentation, whereas following in vitro exposure the embryo can recover from the insult. The implications for a better understanding of the process of implantation are discussed.