Progestogens in luteal support.

Progestational agents are often prescribed to increase the clinical pregnancy rate in assisted reproduction. Progestogens affect implantation, cytokine balance, natural killer cell activity, arachidonic acid release and myometrial contractility. Progesterone production from the corpus luteum is essential for reproduction, but assisted reproductive technologies (ART) can impair luteal function. ART cycles can be classified into three, fresh cycles in which there may or may not be luteal insufficiency, agonist or antagonist cycles in which there is luteal insufficiency, and luteal support is essential, and donor cycles, in which there is no corpus luteum, and a luteal phase has to be created. However, there is no adequate diagnostic test for luteal insufficiency. This article summarises the effect of various progestogens, progesterone itself whether administered vaginally, intra-muscularly, rectally or subcutaneously, and the effect of the progestogen, dydrogesterone. The time of commencement and cessation of therapy are also discussed. Progestogens are also often used to treat threatened and recurrent miscarriage. In these patients progestogen supplementation may need to be prolonged. In threatened miscarriage, until after all bleeding stops, and in recurrent miscarriage, at least as long as the luteo-placental shift.

Progestogens in the prevention of miscarriage.

Progestational agents are often prescribed to prevent threatened miscarriage progressing to miscarriage, and subsequent miscarriages in recurrent pregnancy loss. Progestogens affect implantation, cytokine balance, natural killer cell activity, arachidonic acid release and myometrial contractility. A recent Cochrane review reported that progestogens were effective for treating threatened miscarriage with no harmful effects on mother or fetus. The results were not statistically different when vaginal progesterone was compared to placebo, (RR=0.47, 95% CI 0.17-1.30), whereas oral progestogen (dydrogesterone) was effective (RR=0.54, CI 0.35-0.84). The review concluded, that the small number of eligible studies, and the small number of the participants, limited the power of the metaanalysis. A later metaanalysis of five randomised controlled trials of threatened miscarriage comprised 660 patients. The results of 335 women who received dydrogesterone were compared to 325 women receiveing either placebo or bed rest. There was a 47% reduction in the odds ratio for miscarriage, (OR=0.47, CI 0.31-0.7). There was a 13% (44/335) miscarriage rate after dydrogesterone administration compared to 24% in control women. Recurrent miscarriage affects approximately 1% of women of child bearing age. A metaanalysis of progestational agents shows a 26% increase in the live birth rate. Again, dydrogesterone was associated with a more significant increase in the live birth rate than the other progestogens included in the metaanalysis.

Intradermal sex hormone desensitization for relief of premenstrual symptoms may improve the obstetric outcome of women with recurrent pregnancy loss.

The aim of this study was to determine whether women with recurrent pregnancy loss (RPL) and concurrent premenstrual syndrome (PMS) who underwent desensitization with sex hormones had an improved obstetric outcome. This manuscript summarizes a 10 year open label prospective follow up study of 26 women with RPL, aged 25-42 with 3-8 previous miscarriages and PMS, who had hormone hypersensitivity on skin testing. Skin testing was positive to estradiol in 23 women, progesterone in 20 women and to both estrogen and progesterone in 17 women. Amelioration of the symptoms of PMS (according to the VAS) was seen in 21 of 26 patients after desensitization with small doses of sex hormones intradermally. There was long term and stable reduction of severe PMS in 21 of 26 patients after desensitization. Five women conceived after skin testing, prior to desensitization. Sixteen of 26 women (61%) had subsequent live births. Five women had two subsequent live births in the subsequent pregnancy. There were no obstetric complications. Five women had two subsequent pregnancies with live births. It seems that correction of sex hormone hypersensitivity was accompanied by relief of persistent PMS, may have a positive effect on the chances of a successful pregnancy.

Recurrent pregnancy loss - beyond evidence based medicine.

Patients with five or more unexplained recurrent pregnancy losses (RPL) have a poor prognosis for a subsequent delivery compared to patients with two to three RPL. Treatment guidelines are needed to address this select group of patients.

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.

Steroid hormone hypersensitivity: clinical presentation and management.

Hypersensitivity to estrogens and progestogens is often undiagnosed. The condition has many manifestations, including premenstrual syndrome, dysmenorrhea, and impaired fertility. Diagnosis is confirmed by skin testing for inflammatory responses to small doses of the hormone, and desensitization with small doses of the hormone is the most appropriate form of management.

Recurrent pregnancy loss and inappropriate local immune response to sex hormones.

PROBLEM: The cause of recurrent miscarriage is often unknown. Recurrent miscarriage may be associated with inappropriate responses to progesterone and estrogen. We examined whether the condition may be diagnosed by skin testing. METHOD OF STUDY: In a longitudinal prospective study, the weal and flare reaction after intradermal injection of estradiol and progesterone was compared in 29 women with recurrent miscarriage to the response in 10 healthy women. Reactions were evaluated after 20 min, 24, and 48 hr and 5 days later. RESULTS: Estrogen hypersensitivity was found in 23 patients, and progesterone hypersensitivity in 20 patients. No patient in the control group demonstrated sex hormone hypersensitivity. CONCLUSION: Recurrent pregnancy loss may be associated with inappropriate local immune responses to sex hormones. Further research is necessary into the mechanisms of hypersensitivity to estrogen and progesterone and their interactions with other systems.

Autoantibodies and prediction of reproductive failure.

PROBLEM: To determine which autoantibodies are associated with reproductive failure. METHOD OF STUDY: Sera from 269 patients with autoimmune disease and/or reproductive failure were analyzed for anti-phospholipid (aPL), anti-annexin-V, anti-lactoferrin, anti-thyroglobulin, anti-thyroid peroxidase, anti-prothrombin, anti-nuclear, and anti-saccharomycetes cerevisiae antibodies (ASCA), by enzyme-linked immunosorbent assay. Patients were classified as: recurrent pregnancy loss (RPL), infertility, and autoimmune diseases. The results were compared with those of 120 healthy volunteers. RESULTS: In autoimmune diseases, the prevalence of anti-prothrombin, anti-annexin, anti-phospholipid and anti-nuclear antibodies was significantly higher than in the control group, OR 11.0 [CI, 3.5-35.2], 33 [CI, 7.2-174.2], 13 [CI, 1.4-309.7], and 16.1 [CI 2.4-122], respectively. In infertility, the antibodies with significantly higher levels than controls were: aPL OR, 5.11 [CI 1.2-25.4], and anti-prothrombin antibodies, OR, 5.15 [CI, 2.1-12.7]. In RPL, ASCA, anti-prothrombin and aPL were more prevalent than in controls, OR 3.9 [CI, 1.5-10.6], 5.4 [CI, 2.4-12.5] and 4.8[CI, 1.2-22.2] for each antibody, respectively. Anti-prothrombin antibodies and aPL were more significantly associated with late pregnancy losses than early losses. CONCLUSION: ASCA antibodies have not previously been described in RPL. Nor are anti-prothrombin antibodies usually assessed in infertility or RPL. If these results are confirmed in further studies, these antibodies might be assessed routinely in reproductive failure.

Thrombophilia and recurrent pregnancy loss.

Many unanswered questions regarding thrombophilia and recurrent pregnancy loss exist. For example, does a true association exist? Are thrombotic mechanisms relevant? Is a second messenger necessary to cause the manifestation of thrombosis? At present it seems that thrombophilia are associated with and may even cause some cases of pregnancy loss. The role of treatment remains to be determined. Although the aim of physicians working in this field is entirely laudable, to allow childless couples to have children, it is necessary to have good evidence of effect before treatment is given to all patients. A serious ethical dilemma remains, however, namely should treatment that may be effective be denied to patients who have prior pregnancy losses? Denial of treatment is extremely distressing for the patient and the physician. The author's own practice is to offer treatment after a full explanation, particularly because treatment is generally prescribed in the antiphospholipid syndrome and justified in hereditary thrombophilias according to the report of Carp and colleagues, showing a 25% improvement in live birth rates in treated patients. When treatment fails, however, the embryo should be karyotyped to exclude chromosomal aberrations.

Intravenous immunoglobulin and recurrent pregnancy loss.

Intravenous immunoglobulin (IVIg) has been used to prevent pregnancy loss, in unexplained recurrent miscarriage, and in antiphospholipid syndrome (APS). When used on an unselected population with recurrent miscarriage, IVIg has not been shown to improve the live birth rate. However, when patients are selected for poor prognosis or autoimmune phenomena, IVIg has been shown to be effective. This article discusses the possible immune mechanisms by which IVIg may act and the effect of confounding factors such as embryonic chromosomal aberrations or anti-beta2-glycoprotein I antibodies in APS. Hence, there may be an impression of futility, when IVIg may be highly effective in saving those pregnancies that can be saved. Additionally, in an unselected population with recurrent miscarriage, there is a relatively good prognosis for a subsequent live birth (60%). Therefore, the spontaneous prognosis must be taken into account, which has not been the case in previous trials.

Antiphospholipid syndrome in pregnancy.

PURPOSE OF REVIEW: Antiphospholipid syndrome is widely recognized as a risk factor for numerous obstetric complications including miscarriage, intrauterine growth restriction, preeclampsia, fetal death and preterm labour. The many recent changes in concept regarding this syndrome, the role of the relevant antibodies, mechanism of action, diagnosis and treatment are assessed in this review. RECENT FINDINGS: In recent years, our understanding of antiphospholipid syndrome has grown. The antigen has become better defined and is now thought to be beta2 glycoprotein 1. The 'classical' antibodies, lupus anticoagulant and anticardiolipin antibody are known to be pathogenic even when passively transferred to animal hosts. It seems, however, that the pathogenic antibodies are those directed towards beta2 glycoprotein 1, and that those which are directed to phospholipids without binding to beta2 glycoprotein 1 may not be pathogenic, but merely epiphenomena. The treatment of this condition has also been changed due to the influence of randomized trials in which heparin or low molecular weight heparin has replaced the use of steroids. SUMMARY: There are numerous pitfalls in managing this condition. As beta2 glycoprotein 1 antibodies are not usually tested, the condition may be over diagnosed or misdiagnosed. Similarly, the results of treatment are not usually corrected for confounding factors such as fetal chromosomal aberrations. In the absence of other confounding factors low molecular weight heparins are probably the treatment of choice.

The pathogenic role of anti-thyroglobulin antibody on pregnancy: evidence from an active immunization model in mice.

BACKGROUND: The presence of antibodies to thyroglobulin (Tg) is associated with fetal loss even in the absence of thyroid dysfunction. The aim of this study was to examine whether active immunization with Tg could elicit anti-Tg autoantibodies and reproductive failure without interfering with thyroid function. METHODS: BALB/c mice that were immunized with human Tg in complete Freund's adjuvant (CFA) or injected with only CFA were studied for the development of antibodies to Tg, T4, dsDNA, ssDNA and cardiolipin. Total T4, free T4 and thyroid-stimulating hormone (TSH) levels were also assessed before and during pregnancy. Percentages of resorbed fetuses (the equivalent to human missed abortion) were compared and autoantibody presence on the placentae and fetuses was examined. RESULTS: Following immunization, high levels of anti-Tg were observed in mice immunized with Tg, compared with mice injected with CFA [0.83 +/- 0.23 versus 0.012 +/- 0.016 respectively; mean +/- SD optical density (OD) at 405 nm; P < 0.001]. The specificity of binding to Tg was confirmed by competition assay. Although total T4 levels were increased in comparison with control mice, this was associated with the presence of antibodies to T4. Indeed, free T4 levels and TSH were similar to control mice. Mice were killed after 14 days of pregnancy. The thyroid function and the histology of the thyroid glands were normal. Increased fetal wastage was found among the Tg-immunized mice compared with the CFA-injected mice (P = 0.04), with lower fetal and placental weights (fetal weights: 194 +/- 4 mg versus 240 +/- 6 mg; placental weights: 105 +/- 2 mg versus 130 +/- 3; P < 0.001 for both). Antibodies to Tg were demonstrated only on the placentae of Tg-immunized mice. CONCLUSION: Immunization with Tg results in the production of Tg antibodies and fetal resorption. These effects occur in the absence of thyroid dysfunction.

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.