Immunotherapy for recurrent pregnancy loss: analysis of results from clinical trials

PROBLEM: Up to 80% of unexplained recurrent spontaneous abortions (RSA) are thought to have an immunologic mechanism. Yet clinical trials using immunotherapy to treat women experiencing RSA have low treatment effects. The present study was undertaken to explain the low treatment effects. METHODS: Results of clinical trials using allogeneic leukocyte immunization and intravenous (IV) immunoglobulin (Ig) are compared. The mechanisms of pregnancy loss are reviewed in light of data on frequency of karyotype abnormalities in trophoblast of failing pregnancies. RESULTS: Results of two independent analyses using allogeneic leukocyte immunization as immunotherapy for all women with RSA revealed live birth ratios of 1.16 (P = 0.03) and 1.21 (P = 0.02). When the analysis was limited to primary aborters, the live birth ratio increased to 1.46 (P = 0.006). Live birth ratio after immunotherapy for all RSA using IVIg was 1.88 (P = 0.04). Because of low treatment effects, confounders to treatment success of maternal age and number of previous abortions were studied. Chromosomal abnormalities have been identified in 55% of concepti from RSA. The frequency of chromosomal abnormalities remained constant for up to six pregnancy losses. Women with a history of primary compared to secondary RSA had a higher frequency of karyotypically abnormal concepti (chi 2 = 4.54, P < 0.05). Risk factors for RSA also include number of previous losses. CONCLUSION: Chromosomal abnormalities are a significant confounder when evaluating efficacy of immunotherapy for treatment of RSA. Some women with RSA have a high risk of recurrent chromosomal problems.     

Comparative study of the enzyme activities of Borrelia burgdorferi and other non-intestinal and intestinal spirochaetes

Recurrent pregnancy loss is a healthcare concern. Safe and effective treatments are necessary. Since women experiencing recurrent pregnancy loss are a heterogeneous population, specific markers are necessary to identify those who will respond to various treatments. The presence of antiphospholipid antibodies identifies women with recurrent pregnancy loss who are most likely to respond to heparin and aspirin treatment. An elevated concentration of NK cells in maternal blood and a loss of karyotypically normal embryos after detection of cardiac activity on ultrasonographic examination identify women who are most likely to respond to IVIg treatment. An obstetric history of recurrent primary abortion with an absence of maternal antipaternal lymphocytotoxic antibodies and anti-phospholipid antibodies predicts women who are most likely to respond to allogeneic leukocyte immunization. However, the treatment effect is low, with a livebirth rate of 60% which represents an enhancement over no treatment in the range of 8-10%. The difference in livebirth rates between women receiving IVIg therapy as compared to placebo was 28%. Women experiencing recurrent spontaneous abortion who have high, as opposed to low levels of leukocyte antibody do not respond to leukocyte immunization therapy. They do, however, respond to treatment with IVIg--the overall success rate of IVIg being 70%. It is important to be able to identify women likely to respond to various forms of immunotherapy. Chromosomal abnormalities are evident in 60% of recurrent aborters. Women experiencing recurrent aneuploidy in their abortus would not be expected to respond to immunotherapy. At the present time, the only way to identify such women is to have the results of chromosome analysis of previous pregnancy losses available. Having access to this information will require a change in current obstetric practice regarding obtaining karyotyping of all pregnancy losses. The cost-effectiveness of chromosome studies from abortuses is apparent when costs of evaluation and treatment are considered.     

Authors'' experience with transvaginal administration of progestagens]

Prognostic value of some clinical factors on the course of subsequent pregnancy in 117 women with unexplained recurrent spontaneous abortion undergoing immunization with paternal lymphocytes were evaluated in the study. The results allow to conclude that high efficiency of alloimmunization in preventing consecutive abortions (87.2% in our own study) does not seem to depend significantly on: the woman's and her partner's age, number, type (primary vs. secondary), and time of previous miscarriages, coexistence of subfertility, time from immunization to the fertilization and the number of lymphocytes used for the procedure (as far as it concerns the number of lymphocytes isolated from 100 ml of blood). In our results, alloimmunization is most effective in preventing a missed abortion (in comparison with "live" spontaneous abortion).     

Localized in vivo 1H nuclear MR spectroscopy for evaluation of human uterine cervical carcinoma

Spontaneous abortion occurs in 15% to 20% of all human pregnancies. Since the late 1800s, the management of incomplete spontaneous abortion has focused on using curettage to empty the uterus as quickly as possible. This practice began to reduce blood loss and infection and has been unquestioned for 4 decades. In today's medical climate, few spontaneous abortions are the resuslt of illegal manipulation, given the availability of legal pregnancy termination. Antibiotics and transfusions are available, should complications arise in conservatively managed cases. Two prospective randomized trials suggest that conservative management may be advantageous for women who have stable vital signs without evidence of infection. They will have fewer perforations and, possibly, fewer infections and uterine synechiae with expectant or medical management. Larger trials should be undertaken to critically assess surgical evacuation compared to medical management, factoring in the psychologic impact of treatment. We believe that medical management will prove to be the most appropriate treatment for uncomplicated spontaneous incomplete abortion in the 21st century.     

Altered interface adhesion molecules in oral lichen planus

Recurrent spontaneous abortion is a frustrating problem for clinicians and their patients. Fortunately, a reasonable amount of research is being conducted to try and identify the causes of this disorder and develop appropriate and effective diagnostic tests and therapies. This review focuses on some of the factors that have been associated with recurrent abortion, such as cell-mediated immune responses to trophoblast antigens, the effect of oxidative stress, and the immunomodulatory properties of placental protein. The risk of recurrence is particularly high when the length of the embryo in early pregnancy is less than the 50th centile, even though cardiac activity may be present. Also, the risk is directly related to the number of previous abortions. Efficacy has been shown for treatment of unexplained recurrent abortion with allogeneic leukocyte immunization and possibly with intravenous immunoglobulin. Patients with oligomenorrhoea may benefit from treatment with human chorionic gonadotropin.     

Anesthetic implications for implantation of a left ventricular assist device: a case study

Restenosis after coronary angioplasty is a major limitation of an otherwise highly effective and safe procedure for the treatment of atherosclerotic coronary artery disease. Although the advent of coronary stenting has reduced restenosis rates for selected patients, an overall restenosis rate of 20% to 25% remains. Despite numerous trials, no effective pharmacologic therapy has been found. Intracoronary irradiation is a new technique proposed to prevent restenosis after angioplasty. In animal models of restenosis after balloon injury, there is marked reduction of neointimal proliferation when the injured vessel is irradiated, using a variety of radiation sources and delivery systems. Early human trials have underscored the importance of careful source calibration and dosimetry. A small, randomized, double-blind, placebo-controlled study of intracoronary irradiation to prevent recurrent restenosis recently reported striking reductions in angiographic restenosis as well as clinical event rates. A number of important issues remain unresolved, such as defining which component of the arterial wall serves as the target tissue for radiation, the minimal effective dose, the maximum tolerable dose, and user-friendly radiation delivery systems. Further studies are needed to define the safety, efficacy and the ultimate usefulness of intracoronary irradiation as an adjunct to current procedures in interventional cardiology.     

Chemotherapy, biologics, and chemoprevention as systemic therapies for head and neck cancer

The role of chemotherapy in the management of patients with head and neck carcinoma is actively being investigated. Currently, chemotherapy is considered the standard of care for patients with recurrent or metastatic disease. Several single-agent and combination regimens have been used, demonstrating a partial response rate of 30% or less. The role of chemotherapy in the neo-adjuvant and adjuvant setting is less clearly defined. Concomitant chemoradiotherapy and rapid sequence alternating combined therapy have demonstrated a survival advantage in randomized trials. The degree of toxicities associated with these regimens, however, currently limits their use to clinical trials. Biologic therapy has been evaluated neo-adjuvantly and in recurrent and metastatic disease. Additional trials are needed before definitive conclusions can be made regarding its effectiveness and indications. The role of chemoprevention is rapidly expanding, with new agents and combinations currently in clinical trials.     

Immunotherapy in metastatic cancer of the kidney

Evidence accumulated over the last 15 years has clearly demonstrated that metastatic renal cell cancer is an excellent model of the effect of immunotherapy for the treatment of cancer. To date, at least 2 cytokines, interleukin-2 and alpha-interferon have been found to be effective. Objective response is obtained in 15 to 30% of the patients treated with interleukin-2 and 10 to 30% with interferon. Complete response can be achieved in 5% of the cases. Clinically, the best results are seen in patients in good general health and lung metastasis. Complete response for more than 5 years is often observed. Combination protocols with both cytokines and other combinations with infusion of activated lymphocytes have not shown to be more effective than one cytokine alone. It may be possible to obtain higher response rates by combining cytokines with chemotherapy protocols. Surgery still has a role to play however, particularly in patients with an isolate accessible metastasis. Among the perspectives for new immunotherapies, interleukin-12, a strong stimulator of the natural killer population is in phase II trials. Other possibilities include the use of selective populations of lymphocytes as adoptive immunotherapy or combinations using immunotherapy and surgery. Despite the enthusiasm generated by these new techniques, it is imperative to continue rigorous clinical trials in order to develop immunotherapy as a reliable routine treatment.     

A meta-analytic review of the preventive treatment of recurrences of febrile seizures

OBJECTIVE: To assess the efficacy of various medications in the prevention of recurrent febrile seizures. STUDY DESIGN: A meta-analysis of all published randomized, placebo-controlled trials of the preventive treatment of febrile seizures published in English; 45 articles were found, but only 9 trials were randomized and placebo-controlled--4 using phenobarbital; 3, diazepam; 1, pyridoxine; and 1, phenytoin. In one of the phenobarbital trials, valproate was also compared with placebo. RESULTS: The risk of recurrences was significantly lower in children receiving continuous phenobarbital therapy than placebo (odds ratio 0.54, 95% confidence intervals 0.33 to 0.90, p = 0.017). The odds ratio for recurrences in the valproate group was 0.09, 95% CI 0.01 to 0.78, p = 0.011. No difference in the risk was found for recurrences between children receiving intermittent diazepam and placebo (odds ratio 0.81, 95% CI 0.54 to 1.22, p = 0.31). The risk for recurrences in children receiving pyridoxine or phenytoin did not differ from the risk among children receiving placebo. Four children would have to be treated with valproate (95% CI 2 to 11) or eight children would have to be treated with phenobarbital (95% CI 5 to 27), continuously, to prevent one febrile seizure. CONCLUSIONS: Because both agents found to be effective in prevention of recurrent febrile seizures have known adverse effects, prophylaxis of febrile seizures cannot be recommended.     

Bereavement, grieving and psychological morbidity after first trimester spontaneous abortion: comparing expectant management with surgical evacuation

Early pregnancy loss is a profound adverse life event for many women, and increased psychiatric morbidity has been shown to occur after spontaneous abortion. Dilatation and curettage (D&C) has been the cornerstone in the treatment of first trimester spontaneous abortion over the last few decades. During recent years the possibility of conservative management has, however, been increasingly discussed. In a prospective randomized trial, we compared psychological reactions and morbidity, after either expectant management or D&C, for miscarriages of < 13 weeks gestation in which a transvaginal ultrasound examination showed intrauterine tissue and/or blood clots with an antero-posterior diameter of between 15 and 50 mm. Of the 86 patients included, 58 were randomized to expectant management and 28 to primary D&C. In patients randomized to expectant management, pregnancy products shown by transvaginal ultrasound disappeared within 3 days in 43 cases (74%), whereas 15 patients (26%) underwent D&C owing to retained products of conception after 3 days. At 2 weeks after inclusion, all patients answered self-administered questionnaires, including visual analogue scales, concerning their experience of the pregnancy loss, the present situation and concerns about the future. A brief anxiety status inventory was included. This study showed no increase in anxiety or depressive reactions 2 weeks after a first trimester spontaneous abortion when these patients were compared with non-pregnant healthy working females 19-39 years of age. Moreover, there were no significant differences in psychological reactions between patients managed either expectantly or by D&C.     

Polyethylenimine-mediated transfection of human monocytes with the IFN-gamma gene: an approach for cancer adoptive immunotherapy

Human monocytes (Mo) and monocyte-derived macrophages (MdM) are major effectors in host defense systems against cancer. Their antitumoral activity is dependent upon two processes: recruitment and activation. One of the most powerful activators for these cells is recombinant human IFN-gamma (rhIFN-gamma). However, when the potential of activated rhIFN-gamma was evaluated in clinical trials by ex vivo adoptive cellular immunotherapy protocols, the major problem was the short duration of ex vivo activation by rhIFN-gamma. Thus repeated injections were required to obtain a clinical response. To overcome this limitation we have developed a gene transfer protocol with IFN-gamma cDNA and polyethylenimine so as to obtain an efficient, long-lasting autocrine cytocidal activation in transfected human Mo/MdM. We show, by clonogenic assays, that efficient transfection and tumoricidal activity can be obtained by this method in human monocyte populations. Although the proposed model must be improved before clinical use, IFN-gamma producing monocytes have potential for adoptive immunotherapy.     

Placement of retrograde nephroureteral stents through ileal conduits

Preeclampsia is a multisystem disorder of unknown etiology. During the past 2 decades, numerous clinical reports and randomized trials described the use of various methods to prevent or reduce the incidence and severity of preeclampsia. These methods were used in an attempt to correct certain abnormalities such as biochemical imbalance, a pathophysiologic mechanism, or a dietary deficiency. There are at least 15 randomized trials evaluating the use of various antihypertensive drugs including diuretics for the prevention of preeclampsia. Results of these trials reveal no such benefit. There are few randomized trials evaluating magnesium (n = 2), zinc (n = 2), or fish oil supplementation (n = 3) to prevent preeclampsia. The majority of these trials had limited sample size; however, results reveal minimal-to-no benefit. There are 7 placebo-controlled trials evaluating calcium supplementation during pregnancy. Findings of these trials reveal that calcium supplementation does not reduce the incidence of preeclampsia in healthy nulliparous women. The majority of randomized trials for the prevention of preeclampsia have used low-dose aspirin. Results of early single-center trials demonstrated an average reduction of preeclampsia of 70% with low-dose aspirin. However, results of recent large multicenter trials (n = 7) that included >27,000 women revealed minimal-to-no benefit. Until the pathogenesis of preeclampsia is well defined, prevention of this syndrome with any modality remains unlikely.     

Anticardiolipin antibody in recurrent spontaneous aborting and fertile women

OBJECTIVE: To determine the association between the presence of anticardiolipin antibody and a history of recurrent spontaneous abortion. STUDY DESIGN: Clinical controlled study. LOCATION: Department of Gynecology and Obstetrics-University of Campinas (UNICAMP). SUBJECTS: 52 individuals with recurrent spontaneous abortion were included in Group 1 and 104 individuals with at least one live born child in Group 2. Elapsed time from last delivery to blood sampling varied from six months to two years. METHOD: Between November 1993 and November 1994, patients' blood samples were screened for anticardiolipin antibody by ELISA, as described by Triplett, Barna and Unger (1993). ANALYSIS: Chi-square and Fisher's Exact tests were used for statistical analysis. Student's "t" test was used to compare the means. RESULTS: There was no statistical difference in the presence of the anticardiolipin antibody between Group 1 (zero and 2.9%) and Group 2 (7.7 and 5.8%). CONCLUSION: There was no association between the presence of anticardiolipin antibody and recurrent spontaneous abortion.     

Benefits of screening mammography: a review for the primary care physician

BACKGROUND: Screening mammography, particularly for women in their 40s, has become a confusing issue for many physicians. Recent scientific and political controversies regarding screening guidelines have added to this confusion. METHODS: Many randomized clinical trials have shown the benefits of mammographic screening for women over the age of 50, and recent studies show a statistically significant benefit for women in their 40s as well. Understanding the screening controversy requires an understanding of the principle of screening for disease, the epidemiology of breast cancer, and the results of the many randomized clinical trials, particularly recent data from the Swedish two-county trials. An appreciation of the improvements in mammographic quality in recent years, and in the education of the radiologists who interpret these studies, will also heighten clinical acceptance of this screening technique. RESULTS: Both the American Cancer Society and American College of Radiology endorse annual mammographic screening for women over age 40, and there is compelling evidence to support these recommendations. CONCLUSION: Radiologists, primary care providers, surgeons, and pathologists should work together to enhance the benefits of and access to screening mammography.     

Strategies for blocking the systemic effects of cytokines in the sepsis syndrome

OBJECTIVES: To review and evaluate animal and human data regarding strategies to intervene in the pathogenesis of the sepsis syndrome by specifically blocking the action of single cytokines. DATA SOURCES: The English language medical literature was reviewed, including reports of human clinical trials, animal experiments, and in vitro studies elucidating cellular and molecular interactions. STUDY SELECTION: Emphasis was placed on controlled experimental studies that elucidated the effectiveness of antibodies, soluble receptors, and receptor antagonists in intervening in the pathogenesis of the sepsis reaction. DATA EXTRACTION: This review focuses on data that directly involve the induction and regulation of protein mediators of sepsis, especially tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, and interleukin-8. DATA SYNTHESIS: Information concerning the potential of cytokine blockers in modulating the sepsis reaction is presented in a logical, clinically oriented fashion. The purpose is to emphasize the potential role of these agents by focusing on the actual existing data. CONCLUSIONS: The pathophysiology of the sepsis reaction appears to involve the sequential release of cytokines. Interventions designed to specifically block the biological effects of single cytokines appear to have a role in the management of sepsis syndrome, but well-designed, prospective, randomized, placebo-controlled clinical trials in well-defined clinical populations are necessary to define this role. These trials require the cooperation of clinical and basic scientists.     

Caries prediction: a review of the literature

Since Jenner and Pasteur, various vaccines have been developed and administered in immunization program conducted by WHO in order to diminish the circulation of pathogenic agents and eradicate some diseases. Risks associated with immunization are revealed by the collection and assessment of adverse events reported after the use of these drugs. They vary according to the type of vaccines. With high rates of immunization and a low incidence of infectious diseases, adverse events receive increasing attention. Frequent and mostly expected adverse events are reported in clinical trials. Unexpected rare adverse events are reported after marketing authorization by spontaneous reporting and post marketing surveillance studies. Post marketing surveillance should be adapted to vaccines (vaccino-vigilance) and should take into account the risk linked to the disease they may protect against. Adverse events are often temporally associated with vaccines, that does not mean they are causally related. Specific studies should be conducted to assess the causal relationship between vaccines and post immunization adverse events. In order to reduce the risk associated with immunization, a strict follow-up of recommendations, warnings and contraindications in addition to appropriate information being delivered to both vaccinees and physicians are required.     

Surgical treatment of degenerative mitral regurgitation

Karyotypes were prepared from peripheral blood leukocytes in 77 couples in whom there was no apparent cause for recurrent spontaneous abortion. In addition to conventional staining, chromosomes were stained by the new technics for Q-, G-, or C-banding. Translocations were found in 5 of 154 persons (3.25% or 1:31 individuals). The frequency of translocations in the general adult population is 0.4% (1:255). Two translocations were apparent only with the new technics for banding. The incidence of chromosomal microanomalies was 7.79% (2.6% in the general population). Karyotyping of couples with recurrent abortion is recommended, with use of the new staining technics.     

A look through the new therapeutic window: irbesartan

Although an impressive array of efficacious antihypertensive agents are available to treat hypertension, the optimal use of these agents is limited by dose-related side-effect profiles. This is particularly the case for widely used first-line antihypertensive agents such as diuretics, beta-blockers, calcium antagonists, and alpha1-blockers; this represents a major therapeutic dilemma in treating hypertension. With the development of the angiotensin II receptor antagonists (AIIRAs), this dilemma might have been solved. Irbesartan is a long-acting AIIRA that provides dose-related efficacy with placebo-like tolerability at all clinical doses. The results of placebo and active-control trials of irbesartan have demonstrated that the agent is as effective as the leading members of major antihypertensive classes with respect to blood pressure control, while having superior tolerability. Pooled data from nine multicenter, randomized, placebo-controlled trials with irbesartan have documented no adverse events caused by dose-response. This feature could widen the traditionally narrow therapeutic window in the treatment of hypertension and point to the use of AIIRAs such as irbesartan as first-line therapy in the management of hypertension.     

A cytogenetic study of 514 Chinese couples with recurrent spontaneous abortion

OBJECTIVE: To study the role of chromosomal aberration in the causation of recurrent spontaneous abortion (RSA) in Chinese population. METHODS: A total of 514 Chinese couples with 2 or more spontaneous abortions at less than 24 weeks of gestation were included. For each proband, a minimum of 13 metaphases were analyzed by G-banding. Additional cells (usually 50-100 cells) were screened when mosaicism was suspected. Chi 2 test was used to compare the number and frequency of couples with and without balanced translocation with respect to whether liveborn was present or absent. Chi 2 test for trend was used to show whether a correlation existed between the occurrence of balanced translocation and the number of spontaneous abortions at ascertainment. RESULTS: The overall incidence of chromosome anomaly was 51 out of 514 (9.92%). Chi 2 test for trend analysis showed that the chance of one member of a couple being a balanced carrier increased with the number of spontaneous abortions. The chance of finding translocation in couples with liveborn was higher than that in couples without liveborn, but the difference was not statistically significant. We also found that pericentric inversion 9 did not play an important role in the causation of recurrent abortion. CONCLUSIONS: Cytogenetic analysis is indicated in couples with 2 or more spontaneous abortions and the chance of finding chromosomal aberration increases with the number of abortions at the time of ascertainment.     

Endocrine factors associated with recurrent spontaneous abortion

The role of endocrine factors as a cause of recurrent spontaneous abortion is controversial. Diabetes mellitus and thyroid disease do not represent a significant risk factor for recurrent pregnancy loss. Luteal-phase defect has been questioned because there are no accurate methods for diagnosis and no convincing evidence of correction with treatment exists. The corpus luteum is an unusual endocrine gland, highly diverse in function and important for successful reproduction in all mammalian species. Much controversy exists about the luteal function in humans and how defects in luteal function affects reproduction. Disagreement has been due to lack of accurate diagnosis and controlled studies to determine whether correction of the luteal-phase defect is worthwhile when treating female reproductive problems. The donor egg recipient model from assisted reproductive technology programs has shown that corpus luteum function can be replaced by estrogen and progesterone administration. The mechanism by which these steroids stimulate a uterus to be receptive to implantation of the embryo is not known. Several proteins produced by the endometrium are candidate markers for uterine receptivity. Further work needs to be done to correlate these markers with subsequent pregnancy outcome. A noninvasive marker for uterine receptivity is ultrasonographic evaluation of the endometrium. Although the sensitivity of this test is high (100%), its specificity is low (only 20% to 60%).