Howard Carp

Anti-inflammatory and immunosuppressive drugs and reproduction

Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given.

Karyotype of the abortus in recurrent miscarriage.

Abstract Objective: To assess the chromosomal aberrations in the abortus in recurrent miscarriage and the live birth rate after a euploid or aneuploid miscarriage. Design: Retrospective analysis. Setting: Tertiary referral unit in university hospital. Patient(s): One hundred sixty-seven patients with 3 to 16 miscarriages before 20 weeks. Intervention(s): Material collected at curettage from 167 abortuses was analyzed by standard G-banding techniques. Main Outcome Measure(s): The incidence of aberrations and the outcome of the subsequent pregnancy were assessed according to the embryonic karyotype. Result(s): In this study 125 specimens were successfully karyotyped. Of these, 29% (36 of 125) had chromosome aberrations; 94% of the aberrations were aneuploidy, and 6% were structural. The most prevalent anomalies were chromosome 16, 18, and 21 trisomies, triploidy, and monosomy X. After an aneuploid miscarriage, there was a 68% subsequent live birth rate (13 of 19) compared to the 41% (16 of 39) rate after a euploid abortion. Conclusion(s): The low (29%) incidence of aberrations indicates that alternative mechanisms may be responsible for the majority of recurrent miscarriages. These figures provide a basis for assessing the efficacy of therapy for recurrent miscarriage. If further studies confirm that patients with karyotypically abnormal fetuses have a good prognosis, an informed decision can be made as to whether further investigations and treatment should be undertaken.

Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia

Summary.  The effect of thromboprophylaxis with low molecular weight heparin (LMWH), on the subsequent live birth rate, in thrombophilic women with recurrent miscarriage has not been sufficiently assessed. The present study is a cohort study undertaken to assess the effect of enoxaparin on the subsequent live birth rate in women with hereditary thrombophila. Eighty‐five patients with three or more consecutive pregnancy losses and a hereditary thrombophilia subsequently conceived. Thirty‐seven were treated with daily subcutaneous injections of enoxaparin 40 mg and 48 were not treated. The outcome of the subsequent pregnancy was assessed in both groups of patients in terms of live births or repeat miscarriage. Forty‐seven of the 85 patients were subsequently delivered, 38 have miscarried. Twenty‐six of the 37 pregnancies in treated patients (70.2%) resulted in live births, compared with 21 of 48 (43.8%) in untreated patients (P < 0.02, OR 3.03, 95% CI 1.12–8.36). The beneficial effect was seen mainly in primary aborters, i.e. women with no previous live births (P < 0.008, OR 9.75, 95% CI 1.59–52.48). This benefit was also found in patients with a poor prognosis for a live birth (five or more miscarriages), where the live birth rate was increased from 18.2% to 61.6%. However, the benefit was not statistically significant, probably due to the small number of patients. If the beneficial effects of enoxaparin are confirmed by additional studies, thromboprophylaxis can be recommended for patients with hereditary thrombophilia and recurrent pregnancy loss.

The role of apoptosis in normal and abnormal embryonic development.

Programmed cell death or apoptosis is a widespread biological phenomenon. Apoptosis is characterized by typical cell features such as membrane blebbing, chromatin condensation, and DNA fragmentation. It involves a number of membrane receptors (e.g., Fas, TNFR) and a cascade of signal transduction steps resulting in the activation of a number of cysteine proteases known as caspases. Disordered apoptosis may lead to carcinogenesis and participates in the pathogenesis of Alzheimer disease, Parkinson disease, or AIDS. Programmed cell death plays an important role in the processes of gamete maturation as well as in embryo development, contributing to the appropriate formation of various organs and structures. Apoptosis is one of the mechanisms of action of various cytotoxic agents and teratogens. Teratogen-induced excessive death of embryonic cells is undoubtedly one of the most important events preceding the occurrence of structural abnormalities, regardless of their nature. Therefore understanding the mechanisms involved in physiological as well as in disturbed or dysregulated apoptosis may lead to the development of new methods of preventive treatment of various developmental abnormalities. The present review summarizes data on the mechanisms of programmed cell death and concentrates on apoptosis involved in normal or disturbed gametogenesis and in normal and abnormal embryonic development.

Treatment of pregnant patients with antiphospholipid syndrome

Antiphospholipid Syndrome (APS) has been widely recognized as a risk factor for the recurrence of both thrombosis and pregnancy losses; however the optimal treatment of patients is debatable. The aim of this paper was to establish a consensus among experts on the treatment of APS in pregnancy. A questionnaire that described possible different clinical situations was sent to the International Advisory Board of the 10th International Congress on AntiphospholipidAntibodies. Sixteen experts from different medical branches and different geographic areas sent their replies. The consensus was that treatment for APS pregnant patients should be low molecular weight heparin (LMWH) and low dose aspirin (LDA). The dosage, and frequency of LMWH depends on different situations, including the body weight and past history. Patients with previous thromboses usually receive two injections per day. Warfarin can also be used from 14 to 34 weeks, for patients with previousstroke or severe arterial thromboses. The use of intravenous immunoglobulin (IVIG) seems to be restricted to patients with pregnancy losses despite conventional treatment. The experts usually advised barrier methods of contraception, intrauterine device (if the patient is not taking corticosteroids) or progestins. Oral contraception with oestrogens was usually avoided.

The autoimmune bases of infertility and pregnancy loss

Several lines of evidence suggest that autoimmune mechanisms may influence the reproductive life and fertility of both sexes, commonly manifesting as infertility or pregnancy loss. Part of the controversy that characterizes this assumption derives from the overlooked suspect of autoimmune conditions in the absence of symptoms or the limited physician awareness in a gynecological setting. Numerous autoimmune diseases, including but not limited to systemic lupus erythematosus and anti-phospholipid syndrome, may be associated with infertility and pregnancy loss through different putative mechanisms. First, serum autoantibodies such as anti-phospholipid, anti-thyroid, or antinuclear antibodies may be directly associated with infertility, regardless of the presence of a clinically overt autoimmune disease. Second, autoimmunity may affect all stages of fertility, via ovarian failure, testicular failure, implantation failure, and pregnancy loss. Third, infertility may also be secondary to vasculitis associated with other conditions such as systemic lupus erythematosus and diabetes mellitus. This review article will illustrate and critically discuss the available data on the link between the breakdown of tolerance that characterizes autoimmune diseases and the changes in reproductive life that affect patients in real clinical setting and that often constitute the iatrotropic stimulus.

TNF-α in pregnancy loss and embryo maldevelopment: A mediator of detrimental stimuli or a protector of the fetoplacental unit?

AbstractPurpose: Tumor necrosis factor alpha (TNF-α), a multifunctional cytokine, has been identified in the ovary, oviduct, uterus, and placenta, and is expressed in embryonic tissues. For many years TNF-α was mainly considered to be a cytokine involved in triggering immunological pregnancy loss and as a mediator of various embryopathic stresses. However, data collected during the last decade has characterized TNF-α not only as a powerful activator of apoptotic, but also antiapoptotic signaling cascades, as well as revealed its regulatory role in cell proliferation. This review summarizes and conceptualizes the studies addressing TNF-α-activated intracellular signaling and the possible functional role of TNF-α in embryonic development. Methods: Studies addressing the role of TNF-α in intercellular signaling, in vivo studies addressing the functional role TNF-α in spontaneous and induced pregnancy loss, and studies addressing the role of TNF-α in fetal malformations were reviewed. Comparative studies in TNF-α knockout and TNF-α positive mice were performed to evaluate embryonic death, structural anomalies in fetuses, the degree of apoptosis and cell proliferation, and the activity of molecules such as caspases 3 and 8, the NF-κB, (RelA), IκBα in some target embryonic organs shortly after exposure to embryopathic stresses. Results: It is proposed that the possible essential function of TNF-α may be to prevent the birth of offspring with structural anomalies. Conclusions: TNF-α will boost death signaling to kill the embryo if initial events (damages) triggered by detrimental stimuli may culminate in structural anomalies, and stimulate protective mechanisms if the repair of these damages may prevent maldevelopment.

Pregnancy and reproduction in autoimmune rheumatic diseases

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on children.

Pregnancy Outcome after Laparoscopy or Laparotomy in Pregnancy

STUDY OBJECTIVE To assess obstetric performance and fetal outcomes after laparoscopy or laparotomy performed during pregnancy. DESIGN Nationwide, multicenter, retrospective chart review (Canadian Task Force classification II-2). SETTING Seventeen hospitals throughout Israel: 12 university or university-affiliated hospitals and 5 general hospitals. PATIENTS Three hundred eighty-nine pregnant women. INTERVENTION Laparoscopy or laparotomy for various indications. MEASUREMENTS AND MAIN RESULTS Of 192 laparoscopies performed, 141 were during the first, 46 during the second, and 5 during the third trimester; respective figures for 197 laparotomies were 63, 110, and 24. No intraoperative complications were reported for either procedure. Six and 25 women had complications after laparoscopy and laparotomy, respectively. There was no significant difference in abortion rates between groups. Mean gestational age at delivery and mean birthweight were comparable between groups. No significant difference was found in frequency of fetal anomalies between groups or when compared with the Israel register of anomalies. CONCLUSION Operative laparoscopy seems to be as safe as laparotomy in pregnancy.

Intravenous immunoglobulin in the prevention of recurrent miscarriage

adrenal insufficiency in a study of 71 fetuses of asthmatic mothers receiving predntsolone. The adrenocortical reserve of six newborns whose mothers had received steroids long term was assessed and the response to exogenous ACTH found to be normal (Arad & Landau 1984). Chan and Wilson draw attention to a recognised complication of prolonged or high dose steroid therapy. We accept that avascular necrosis in their patient is likely to have been related directly to the use of steroids to treat her hyperemesis. However, the dose of steroids used was extremely high; 24 mg dexamethasone is equivalent to 640 mg hydrocortisone. Their patient therefore received a dosage of glucocorticoid equivalent to 160-640 mg hydrocortisone (40-160 mg prednisolone) for a total of six to seven weeks. In our experience lower initial doses (200-300 mg hydrocortisone, 50-75 mg prednisolone) have been sufficient. After control of symptoms is achieved, patients can usually be weaned to a dose of 30-40 mg prednisolone per day within a few days, and thereafter to 20 mg per day within four weeks of starting treatment. In addition, avascular necrosis may rarely occur as a complication of pregnancy itself (Kay et al. 1972; Zolla-Pazna et a/ . 1980). It is important, and part of our practice, to discuss the possible risks of steroid therapy with the pregnant woman as Oladipo suggests. Since our original case report was accepted for publication, we have treated (or recommended the treatment of via telephone consultation) an additional six women with severe hyperemesis gravidarum with corticosteroid therapy. All 10 patients in this series had complete remission of their symptoms within 48 hours of starting treatment. We accept that parenteral steroid therapy may be required as Wong and Daniel suggest, and six out of ten women in our series required intravenous steroids. However, we fail to see the advantage of dexamethasone over hydrocortisone, and there are theoretical disadvantages since relatively more dexamethasone reaches the fetus. These pilot data support a beneficial role for corticosteroids in the treatment of severe hyperemesis gravidarum, but a definitive, randomised, double-blind, placebo-controlled trial is now in progress. Since the natural history of hyperemesis gravidarum is of gradual improvement with increasing gestation, the design of this multicentre study incorporates strict inclusion criteria. An intravenous arm to the study will ensure that steroids receive a fair trial.