Is there a Role of Intravenous Immunoglobulin in Immunologic Recurrent Pregnancy Loss?

Recurrent pregnancy loss (RPL) commonly refers to three or more miscarriages that occur before 20 weeks of pregnancy. The immunological cause of RPL could be either an auto- or alloimmune-related event or both. Because of the discovery of immunological abnormalities in RPL patients in clinical practice, several immunomodulatory therapies were introduced to maintain the immune balance at the maternal-fetal interface. Intravenous immunoglobulin (IVIg) is one of the immunomodulators. In recent years, several studies have analyzed the therapeutic effect of IVIg on RPL patients with antiphospholipid syndrome (APS) or unexplained RPL. However, their results are controversial. IVIg can be used in RPL patients with APS who have previously failed in other treatments. It is recommended that IVIg infusion could be considered used before conception in RPL patients who have cellular immune abnormalities such as increased natural killer (NK) cell counts, NK cell cytotoxicity, or increased T helper (Th)1/Th2 ratio, depending on the cut-off values of each hospital. The aim of this review was to summarize the mechanisms, efficacy, pharmacokinetics, and side effects associated with passive immunization using IVIg in immunologic RPL, according to the literature published in recent years. We hope that more obstetricians will be able to understand the timing and indication of IVIg properly in immunologic RPL patients and effectively enhance pregnancy outcomes for mothers and neonates.

PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation.

BACKGROUND AND OBJECTIVES: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted. DESIGN AND SETTING: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites). PARTICIPANTS AND INTERVENTIONS: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks). MAIN OUTCOME MEASURES: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use. METHODS: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth. RESULTS: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. CONCLUSIONS: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. LIMITATIONS: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. FUTURE WORK: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

Assessment of sub-endometrial blood flow parameters following dydrogesterone and micronized vaginal progesterone administration in women with idiopathic recurrent miscarriage: a pilot study.

AIM: To evaluate differences in uteroplacental blood flow and pregnancy outcome in women with idiopathic recurrent spontaneous miscarriage (IRSM) following administration of micronized vaginal progesterone and oral dydrogesterone. METHODS: One hundred and thirty-three women (aged 23-40 years) who had had early miscarriages and spontaneous conception participated. Oral dydrogesterone (group A, n = 51) and micronized vaginal progesterone (group B, n = 50) were administrated for luteal support and compared. Pregnant women without history of recurrent miscarriage served as controls (group C, n = 32). The outcome measures consisted of endometrial blood flow parameters by Doppler indices and ongoing pregnancy rate. RESULTS: Before progesterone supplementation, resistivity index (RI) and pulsatility index (PI) were found to be significantly higher in groups A and B as compared to controls. Although statistically not significant, end diastolic velocity (EDV) and systolic/diastolic (S/D) ratio was found to be superior in controls than IRSM women. Peak systolic velocity (PSV) was comparable between IRSM and non-IRSM groups. Following progesterone supplementation, groups A and B showed a highly significant reduction in RI, PI and an increase in EDV. A relative increase in the value of PSV was observed in group A as compared to group B. There was remarkable difference in S/D in both groups. Although not statistically significant, group C showed reduction in RI, PI, PSV, EDV and S/D ratio. Pregnancy salvage rates were higher in group A (92.0%) as compared to group B (82.3%). CONCLUSION: Progesterone supplementation appears to lower vascular resistance in women with IRSM. Oral dydrogesterone appears to be equally effective in improving endometrial blood flow as compared with micronized progesterone.

Immunomodulatory effects of intravenous immunoglobulins as a treatment for autoimmune diseases, cancer, and recurrent pregnancy loss.

Intravenous immunoglobulin (IVIG) is a safe preparation, made of human plasma of thousands of healthy donors. The fascinating history of gamma globulin therapy begins in 1930 when Finland treated pneumococcal pneumonia patients with equine serum, which prolonged their survival from pneumonia. Since then, significant breakthroughs were achieved by Cohn, Bruton, Imbach, and others, whose clinical contribution to the world of medicine was of great importance. Originally IVIG was used to treat immunodeficiencies. Later on the use of IVIG extended to autoimmune diseases as well. The efficacy of IVIG has been established only in several autoimmune diseases; clinical reports of trials, series, and case reports indicate significant improvement in many more autoimmune diseases. IVIG have also showed antimetastatic effects in a variety of cancer cell lines, as well as in a few case reports. The efficiency of IVIG has also been observed in recurrent pregnancy loss (RPL), either as a result of an autoimmune disease or spontaneous. Several attempts were made to discover the immunomodulatory effects of IVIG, but it is still not fully understood. Clearly IVIG has multiple mechanisms of actions, which are thought to cooperate synergistically. One of the main mechanisms of actions of IVIG is its ability to neutralize pathogenic autoantibodies via anti-idiotypic antibodies within IVIG preparation. The ability of IVIG to neutralize pathogenic autoantibodies is of great importance in many autoimmune diseases, as well as in RPL. In cancer cell lines, IVIG modulates the immune system in a few ways, including the induction of IL-12 secretion, which consequently activates natural killer cells, and the induction of expression of proapoptotic genes only in cancer cells. Side effects from IVIG are rare and mostly mild and transient. More importantly adverse effects can be minimized by administration to a selective patient population in a proper way: slow infusion rate of 0.4 g/Kg body weight IVIG for 5 consecutive days, given in monthly cycles. The only downside of IVIG therapy is its high price. Therefore, clinicians should balance efficiency versus cost in deciding whether or not to treat certain conditions with IVIG.

Corpus luteum dysfunction: serum progesterone levels in diagnosis and assessment of therapy for recurrent and threatened abortion.

These studies were designed to show that properly timed measurements of serum progesterone (P) can be conveniently used in the diagnosis and treatment of patients with recurrent and threatened abortion. Luteal phase serum P levels between 2 and 10 ng/ml and serum P levels below 15 ng/ml in the first 10 weeks of gestation were considered diagnostic of corpus luteum (CL) dysfunction. Patients were treated with clomiphene, gonadotropins, and/or progesterone suppositories in order to correct serum P levels, thus elevating the serum P into the normal range. When treatment of patients with subnormal P levels resulted in normalization of serum P, successful pregnancies occurred. CL dysfunctions, either before or after conception, were found in eight of the nine patients with histories of recurrent spontaneous abortions. Correction of serum P was associated with successful pregnancy in these eight patients. Twelve patients with threatened abortion were also found to have subnormal serum P levels. Progesterone suppositories corrected the serum P levels in nine of the eleven patients treated, and none of these patients aborted. Serum P measurements provide a means for evaluation of CL function during early gestation. Management of patients with CL dysfunction can also be monitored with serial serum P measurements, provided that progesterone is the therapeutic agent rather than synthetic progestins.