Update on immunotherapy for recurrent pregnancy loss

Results of recent, randomized, placebo-controlled clinical trials have raised questions about the efficacy of immunotherapy for recurrent spontaneous abortion (RSA). Most of the clinical trials have shown a 70% successful pregnancy rate with immunotherapy. The controversy comes from variations in success rates in the control populations, which have ranged from 29% to 76%. Explanations for these variations includes small sample sizes and heterogeneity by the populations studied as well as cointervention by the placebo. A meta-analysis has been proposed to investigate these explanations. Because the trials have largely used husband's leukocytes for immunization, alternative forms of immunotherapy have been sought. Two treatments that have been proposed but have not completed testing a randomized, placebo-controlled trials are intravenous immunoglobulin (IVIG) and immunization with seminal plasma. A safe and efficacious method is needed to treat recurrent spontaneous abortion; it is hoped that results of proposed studies will answer this controversy.     

Efficacy of methotrexate and misoprostol for early abortion

BACKGROUND: Medical termination of pregnancy (medical abortion) as an alternative to surgical abortion has many advantages since it does not require anesthetics and there is no risk of cervical laceration or uterine perforation. In the present study, we evaluated the efficacy of methotrexate and intravaginally administered misoprostol for early abortion. METHODS: The study population consisted of 32 women seeking abortion of a normal intrauterine pregnancy of 8 weeks or less documented by ultrasound. The dose of methotrexate was 50 mg/m2 intramuscularly and the dose of misoprostol was 800 micrograms intravaginally. The final outcome of treatment was evaluated on day 14 or 16, and an abortion was considered successful if pregnancy was terminated without a surgical procedure. RESULTS: Abortion occurred in only 23 (71.8%) of 32 women. There were 9 failures (28.1%); 3 were ongoing pregnancies (9.3%) and 6 were incomplete abortions (18.7%) requiring suction curettage. After the exclusion of treatment failures, the mean duration of vaginal bleeding was 16.3 +/- 2 days. No serious side effects occurred as a result of methotrexate and misoprostol treatment. CONCLUSION: The use of methotrexate and intravaginal misoprostol for the termination of pregnancy requires larger studies to determine the safety and efficacy of this medical abortion, a comparison with RU 486 in prospective controlled randomized trials is necessary.     

Lyophilized pig bladder as a partial bladder wall substitute (author''s transl)

Removing abortion from the Criminal Code in Canada will mean that more and more abortions will be performed for nonmedical reasons which will result in an abortion-on-demand situation similar to that in Japan. Early complications of abortion include death, hemorrhage, shock, cervical injury, and infection. Later complications include premature births, spontaneous abortions, ectopic pregnancies, pelvic inflammation, and infertility. Legalized abortion does not seem to reduce the incidence of illegal abortion. There are also psychological, moral, and sociological consequences of legalized abortion. It would seem that liberal abortion makes bad medicine and leads to far-reaching consequences.     

Sequence analysis of the terminal protein precursor coding regions from bovine adenovirus serotypes 2 and 3

The acceptability of medical abortion (mifepristone and misoprostol) among US women was investigated in a 1995 survey of 262 women seeking this method of pregnancy termination at 3 clinics in Oregon, Washington, and Vermont. The abortion patients' mean age was 27 years; mean gestational age was 49.5 days. 51.1% of respondents had experienced at least one prior abortion. Women completed a questionnaire at their initial clinic visit and again two weeks after the procedure. Participants chose medical abortion to avoid surgery (62.8%) or because they perceived it to be less invasive (56.3%), more natural (40.5%), and associated with a lesser risk of infection or damage to the uterus (35.1%) than vacuum aspiration, and could be performed earlier in pregnancy (27.2%). 49.8% indicated they preferred to wait for abortion to occur with a partner, friend, or family member, while 30.6% preferred to be alone; only 17.6% wanted to wait with other women undergoing the same procedure. Comparison of pre- and post-abortion questionnaires indicated women expected significantly more discomfort than they actually experienced and underestimated the number of days of bleeding. 72.8% of respondents were very satisfied with their medical abortion and 15.5% were somewhat satisfied. Women in the somewhat satisfied group had experienced significantly more abortion-related discomfort and anxiety than those who were very satisfied. Prior abortion experience and demographic characteristics did not influence satisfaction. 94% stated they would recommend medical abortion to a friend and 87% would select medical abortion if they had to terminate another pregnancy. Medical abortion has the potential to increase access to abortion among underserved groups of US women. Appropriate educational materials should be developed to help women choose between abortion methods.     

Antiprogestin drugs: ethical issues

Ethical issues of RU-486 in the US are the same as those of any new medical technology, but the politics of abortion can tempt us to believe that antiprogestins pose new ethical hazards. Good facts are needed to have good ethics. Risk-benefit assessments reveal medical facts and begin with clinical trials, evaluating RU-486's effectiveness and the degree and likelihood it causes harm, discomfort, and side effects. They should also consider social and psychological risks and benefits. Clinical trails in Los Angeles show that women who had previously undergone a surgical abortion method found RU-486 to be a less violent abortion method. Antiabortion proponents misconstrue this benefit to be a disadvantage, because they believe women undergoing abortion should suffer from pain and suffering. Even though an international convention ensures reproductive freedom for women, women must be informed about and have access to all family planning services in order to exercise this right. Ethics and the law require voluntary, informed consent. Yet, the US prevents workers at federally-funded family planning programs from providing clients any information on abortion, thereby violating this ethical requirement. Ethical precepts are also violated by denying women their right to privacy and by the punitive actions taken against women undergoing abortion by physicians, other health workers, and antiabortion proponents. Ru-486 allows women to undergo an abortion in private. Abortion opponents consider this privacy a disadvantage, because they lose targets for picketing, harassment, and violence. They believe that the improved access to abortion awarded by RU-486 would make abortion emotionally easier for women, leading to an increase in the number of abortions. Yet, there is no empirical evidence to support this. Again they see a benefit (decreased psychological stress) as a disadvantage. Ethical arguments show that RU-486 provides women greater health benefits, fosters their right to reproductive freedom, and improves the prospects for expanded social justice.     

Abortion incidence and services in the United States, 1995-1996

CONTEXT: In the 1980s, the number of abortion providers in the United States began to decline, and more recently, so has the number of abortions performed. Whether the decline in service providers, which was last documented in 1992, is continuing and whether this influences the availability and number of abortions is of public interest. METHODS: In 1997, the Alan Guttmacher Institute conducted its 12th survey of all known abortion providers in the United States. The number and location of abortion providers and abortions were tabulated for 1995 and 1996, and trends were calculated by comparing these data with those from earlier surveys. Limited data were also gathered on types of abortion procedures. RESULTS: Between 1992 and 1996, the number of abortions fell from 1,529,000 to 1,366,000, and the abortion rate decreased from 26 to 23 per 1,000 women aged 15-44. The number of providers fell 14%, to 2,042, with the greatest decline among hospitals and physicians' offices rather than clinics. Eighty-six percent of counties had no known abortion provider, and 32% of women aged 15-44 lived in these counties. Of the country's 320 metropolitan areas, 89 had no known abortion provider, and for an additional 12, fewer than 50 abortions each were reported. Seventy percent of abortions were performed in specialized clinics and only 7% in hospitals. In the first half of 1997, early medical abortions were being offered in about 160 facilities, virtually all of which were also providers of surgical abortions. CONCLUSIONS: While abortion services in some areas of the country have declined since 1992 and many women continue to have limited access to providers, other factors have probably had more influence on the level of abortions performed. Early medical abortion methods are too new to be a measurable factor in abortion access.     

The ontological basis of strong artificial life

In 1973, the United States Congress enacted legislation requiring physicians to initiate Peer Review Organizations to monitor utilization and quality of hospital and physician services in the federally funded Medicare program. A hardly noticed provision of the statute intimated the desirability of formulating guidelines for medical treatment. What was originally intended to simplify and universalize general standards by which quality of care could be objectively measured has more recently escalated into formalized projects, subsidized by government, to create "practice parameters". The impetus to define clinical conditions and methods of treatment for specific medical conditions (practice parameters) and standards of practice to avoid or defend malpractice claims (risk management protocols) are part of the movement in the United States for tort reform. If the vague "reasonable man" standard of care in negligence law can be supplanted by a scientifically developed, particularized medical practice standard, it is anticipated that spurious claims and defensive medical practice will be discouraged, quality improved, iatrogenic injury and malpractice litigation diminished. Many U.S. states undertook tort reform in the last decade. A few have embarked on medical-legal reform. One state is conducting a five-year medical liability project that calls for the development of practice parameters and risk management protocols in four medical specialties. The parameters will have the effect of law and may be introduced as evidence in medical malpractice trials. How the parameters are established, their effect on the strategies of litigation, the resultant trial problems in the introduction of evidence and in the burden of proof and their potential for acceptance by a significant number of jurisdictions-are the issues to be explored in this paper.     

Randomized controlled trial of omeprazole or endoscopy in patients with persistent dyspepsia: a cost-effectiveness analysis

BACKGROUND: Cost-effectiveness analysis, Helicobacter pylori research and the development of proton pump inhibitors are having an increasing impact on the management of dyspepsia. However, clinical trials have not always included both H. pylori diagnosis and proton pump inhibitors in their protocols. METHODS: Patients who were referred for upper gastrointestinal endoscopy by their general practitioner were randomized to either prompt endoscopy followed by directed medical treatment (conventional group, n=38), or to empirical treatment with omeprazole and, in the case of symptom relapse, serological screening for H. pylori infection followed by eradication therapy in seropositive patients (empirical group, n=42). The study lasted for up to 1 year. RESULTS: In the empirical group, only 13 patients (31%) underwent endoscopy. The average number of days for which the patients kept records of their dyspeptic symptoms was 266 (95% CI: 226-307) in the empirical group, of which 166 (95% CI: 128-204) were symptom-free. In the conventional group, 159 (95% CI: 119-198) out of 255 days (95% CI: 209-302) were recorded as symptom-free. The average medical cost in the empirical group was $284 (95% CI: 218-350) and in the conventional group $491 (95% CI: 383-600). In the empirical group, two malignancies were found, whereas in the conventional group one malignancy was found. CONCLUSIONS: The empirical drug treatment strategy in patients with persistent dyspeptic symptoms resulted in 69% fewer diagnostic endoscopies with lower medical costs and equal effectiveness in the first year, compared to prompt endoscopy followed by directed medical treatment.     

Surgical procedures and devices should be evaluated in the same way as medical therapy

This paper is a personal essay that starts and ends with the message that surgical procedures and devices should be evaluated in the same way as medical therapies, namely, by randomized clinical trials (RCTs). I discuss, with particular attention to surgical procedures and devices, the objections raised against RCTs in medical decision-making, a schema for utilizing the traditional phases of RCTs in the evaluation of surgical procedures and devices, the importance of RCTs to FDA approval, financial compensation, and health care costs, the impact of RCTs on clinical practice, the role of RCTs in academia, teaching, and research, and the surgeon's obligation to participate in a leadership role in RCTs. The belief is expressed that national funding of health care should mandate allocations for RCTs and that such expenditures, as well as the spending of health care dollars on the basis of the outcomes of such trials, will not only improve patient management in the shortest time but will eventually reduce health care costs. The RCT, by selecting effective and safe surgical procedures and devices, as well as diets and drugs, is the best means science has to assess the validity of patient management.     

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.     

Managing anxiety and depression in alcohol and drug dependence

Previous research has highlighted the high prevalence (30-60%) of comorbid anxiety and mood disorders in clients with substance misuse disorders and, equivalently, a third of those with affective disorder report a history of substance use disorder (Kessler et al., 1994; Regier et al., 1990; Robins & Regier, 1991). This article reviews the management of such cases and identifies key issues in the assessment process, as well as potential avenues for treatment. Other articles have highlighted the increased service utilisation and the cost of care and treatment of comorbidity. This article will primarily focus on the management of individual cases and will briefly refer to issues of service organisation. Although antidepressant or anxiolytic pharmacotherapy may have a role in the treatment of severe disorders, the benefits of using these medications must be balanced against the increased risk of side-effects or adverse reactions in individuals who continue to engage in substance misuse or who have medical complications associated with drug or alcohol dependency. Effective psychosocial approaches largely focus on brief, empirically tested manualised therapies such as cognitive therapy (Carroll, 1998a). However, modifications are required to such approaches to ensure that the interventions are tailored to the needs of clients exhibiting comorbidity. The data available demonstrate some evidence for the benefits of structured psychological approaches, but more sophisticated randomized controlled trials are required to evaluate the efficacy of both psychological and pharmacological approaches.     

Morphologic findings in fetuses and placentas of late abortion in the 2nd trimester

To investigate possible causes of abortion (and intrauterine foetal death) we reviewed clinical and morphological data of foetuses and placentas morphologically from 830 spontaneous abortions seen during a 12 years period (1978-1989) at the Institute of Pathology, University of Leipzig, and the Pathological Institute of Hoyerswerda. Our review showed that definite and possible causes of foetal death and abortion could be classified as placental, foetal maternal, and clinical. Placental changes, which included infection of the foetal membranes, disturbances of the uteroplacental circulation (abruptio placentae with bleeding) and placental dysmaturity, were the most important causes and accounted for 73.8% of the cases. Foetal causes mainly comprised multiple twin pregnancies and foetal malformations. In 20 cases (2.4%) we found malformations as a cause of foetal death and consecutive abortion. Overall, malformations were found in 7.5% of the cases examined. Maternal and obstetric complications of pregnancy were less frequent. In 16.5% of our cases, the cause of the abortion or intrauterine death remained obscure. However, since 1989, genetic analysis and prenatal diagnostic procedures have improved, bringing a greater knowledge on the spectrum and aetiology of possible developmental disorders in the foetus. This should reduce the number of unexplained abortions.     

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.     

Habitual abortion: endocrinological aspects

Endocrine disorders are among the potential causes of repeated spontaneous abortion although their role is uncertain. These disorders most frequently associated with repeated spontaneous abortion are corpus luteum insufficiency, polycystic ovary syndrome, diabetes mellitus, and hypo- and hyperthyroidism. The best method of diagnosing corpus luteum insufficiency has not yet been established. It seems that treatment for this condition cannot be based on simple supplementation with progesterone, but ovulation induction preceded by pituitary suppression and human chorionic gonadotropin administration might be more successful. There is increasing evidence that polycystic ovary syndrome is a cause of repeated spontaneous abortion, but possibly only in the presence of oligomenorrhea and luteinizing hormone hypersecretion. Diabetes, if well controlled by treatment, and thyroid dysfunction, probably play a minor role.     

Structures and policy of nosocomial infection prevention: France is speeding up the process

For the past 10 years France has tried to set up a programme to prevent and survey nosocomial infections and antibiotic resistance. A series of recommendations have been made available for hospitals. Hygiene, nosocomial infections, and resistance to antibiotics are recognized by medical doctors, nurses and administrative people as pertinent and logical quality indicators. Those indicators will probably be proposed by the French agency for accreditation and evaluation. We still need to define which events are preventable, which should be declared to the official agencies, and how to integrate infection control in a broader programme coordinating different systems of surveillance (drug, blood, ...) and risk management. We have also to make those informations available to the public in a more transparent mind.     

Trends since 1989, in France, of induced abortions by mifepristone (RU486) combined with a prostaglandin analogue

In 1989 the French Ministry of Health gave its agreement to the utilisation of the combination mifepristone + a prostaglandin analogue for abortion up to 49 DA. Since then, research activities have been carried out to improve this method. Research to define the best prostaglandin analogue: sulprostone and gemeprost were dropped out; misoprostol was authorized in 1992 following very convincing trials, it is now commonly used and has never generated any major problem. Research to extend the application time limit to 63 DA: it showed a significant drop in efficiency (86.8% instead of 95.4%) as well as an increase of the rate of haemorrhages (2.25% instead of 0.3%). Therefore the method currently used reads as follows. Day 1: mifepristone 600 mg, day 3: misoprostol 400 micrograms, day 10-15: control visit. The efficiency rate is 95.4%; an additional dose of 400 micrograms of misoprostol 3 hours after the first dose if no expulsion has occurred, increases the rate up to 98.5%. This method is well accepted by women as it enables an early abortion and avoids surgery and anesthies. The arrangements required to implement the method are not easy to make as they call for a change of habits by the institutions as well as by medical teams. CONCLUSION: Since the use of misoprostol, the abortion by mifepristone using. 400 micrograms + 400 micrograms of misoprostol has become a method which is safe, efficient and much appreciated by women, but it implies a change in the usual practice of abortion.     

Breast cancer and pregnancy

Breast cancer treatment during pregnancy involves a host of psychosocial, ethical, religious, and even legal considerations, as well as medical multidisciplinary decisions, since the effect of treatment on the fetus must be considered. For example, breast or chest wall radiotherapy should be avoided. The absorbed fetal dosage is at least 5 cGy early in pregnancy and increases to several hundred cGy late in pregnancy to the fetal part immediately below the diaphragm. In the second and third trimesters, chemotherapy is associated with intrauterine growth retardation and prematurity in about half of the babies; the risk of birth defects is a concern in the first several weeks. Typical anesthetic agents readily reach the fetus but are not known to be teratogenic. Although abortion will allow full and comprehensive treatment to the mother, it is not known whether the procedure itself is therapeutic. Early in pregnancy, abortion deserves strong consideration, since the effects of treatment on the fetus will not be a consideration. The poor prognosis of pregnancy-associated breast cancer in the past is probably attributable to a combination of initial delay of diagnosis and possibly to unfavorable biologic characteristics of the hormonal milieu of pregnancy. When pregnant patients are matched stage for stage with controls, survivals seem equivalent, although pregnant patients present with more advanced disease.     

Pleural disease and acquired immune deficiency syndrome

Patients with acquired immune deficiency syndrome (AIDS) do not frequently have pleural complications. However, pneumothorax is a troublesome complication of patients with AIDS. At some medical centres, more than 50% of patients with spontaneous pneumothorax have AIDS. Most patients with spontaneous pneumothorax and AIDS have Pneumocystis carinii infection and necrotic subpleural blebs. The pneumothoraces in these patients usually cannot be managed with tube thoracostomy alone. Patients who do not respond to tube thoracostomy are best managed with a Heimlich valve or with thoracostomy with stapling of blebs and pleural abrasion. Approximately 2% of human immunodeficiency virus (HIV)-positive individuals will have a pleural effusion. Parapneumonic effusions or empyema, tuberculosis and Kaposi's sarcoma are the three leading causes. P. carinii infection is frequently responsible for pulmonary infections, but is only occasionally responsible for a pleural effusion. Pleural effusions may also develop from non-Hodgkin's lymphoma (NHL). There is one relatively rare NHL that is associated with the Kaposi's sarcoma associated virus that produces a lymphoma confined to the body cavity.     

Ergot alkaloids. Current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology

Ergot alkaloids are well known preparations. Ergot alkaloids used in obstetrics and gynaecology are ergometrine (ergonovine; EM), methylergometrine (methergine; ME) and bromocriptine. The pharmaceutical properties of ME EM) are critical. To guarantee stability, ME and EM ampoules should be stored in a cool, dark place. ME and EM tablets are unstable in all conditions and they show an unpredictable bioavailability, which prevents oral use of the drugs for any purpose. ME and EM are known for their strong uterotonic effect and, compared with other ergot alkaloids, for their relatively slight vasoconstrictive abilities. ME and EM do have a place in the management of the third stage of labour as they are strong uterotonics. They act differently from oxytocin and prostaglandins, and have different adverse effects. Oxytocin should be used as prophylaxis or a the drug of first choice; next, ME or EM should be used, and if none of these drugs produce the desired effects, prostaglandins should be used to control bleeding. Ergot alkaloid use in gynaecology has been limited and today is discouraged even in essential menorrhagia. It is suggested that EM and ME be used (parenterally) only in first trimester abortion curettage, to reduce blood loss. Bromocriptine has been used for lactation suppression. However, alternatives such as cabergoline, which possess fewer adverse effects, are now available and therefore preferred for this indication. In sum, there is no place for the prophylactic use of ME and EM in obstetrics or gynaecology. They can be used for therapeutic purposes in the third stage of labour. During use, the practitioner must be alert for adverse effects.