A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage

BACKGROUND: Previous trials of intravenous immunoglobulin (IvIg) treatment of women with recurrent miscarriage (RM) have provided diverging results. This may be due to different inclusion criteria and suboptimal treatment protocols in some trials. METHODS: According to a computer-generated list, 58 women with at least four unexplained miscarriages were randomly assigned to receive infusions of high doses of IvIg or placebo starting as soon as the pregnancy test was positive. RESULTS: In the intention-to-treat analysis, a 45% live birth rate was found in both allocation groups. In patients with secondary RM, 50% in the treatment group and 23% in the placebo group had successful pregnancies (P = not significant). When data from the present and a previous placebo-controlled trial of the same treatment were combined, 15/26 (58%) of the patients with secondary RM in the treatment group versus 6/26 (24%) in the placebo group had successful outcomes (P < 0.02). Only 7% of the karyotyped abortuses were abnormal. CONCLUSIONS: IvIg may improve pregnancy outcome in patients with secondary RM. A new placebo-controlled trial focusing on this subgroup should be conducted to confirm the results.     

Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study

The aim of this study was to evaluate the therapeutic efficacy of intravenous immunoglobulin (IVIG) in the prevention of recurrent spontaneous abortion (RSA). In a double-blind, randomized, placebo-controlled study, 41 women with a history of unexplained recurrent spontaneous abortion were treated with IVIG or saline infusions during pregnancy. The birth of a child was considered a successful outcome. The overall success rate was 77% in the IVIG group compared with 79% in the placebo group. For women with primary RSA the success rates were 82 (IVIG) and 89% (placebo), and for women with secondary RSA the rates were 73 (IVIG) and 70% (placebo). We found no statistically significant difference in treatment results between IVIG and placebo.     

Thromboelastography, whole-blood haemostasis and recurrent miscarriage

BACKGROUND: Some cases of recurrent miscarriage have a thrombotic basis. Thromboelastography is a rapid, reproducible test of whole-blood haemostasis. METHODS: Thromboelastography was performed in 494 consecutive, non-pregnant women (median age 35 years; range 21-48) with a history of miscarriages at <12 weeks gestation (median 4; range 3-12) and 55 parous women (median age 33 years; range 20-41) with no history of pregnancy loss. The prospective outcome of untreated pregnancies amongst 108 women with recurrent miscarriage was studied. RESULTS: The maximum clot amplitude (MA) (median 66.0 mm; range 48.0-76.0) was significantly higher and the rate of clot lysis (LY30) (median 2.5%; range 0.5-7.8) significantly lower amongst women with recurrent miscarriage compared with controls (MA 61.5 mm; range 50.0-67.0; P = 0.01; LY30 4.9%; range 2.9-9.7; P = 0.01). The pre-pregnancy MA was significantly higher amongst women who subsequently miscarried (median 66.0 mm; range 54.0-73.0) compared with those whose had a live birth (median 61.7 mm; 48.0-71.5; P < 0.01). A pre-pregnancy MA >or=64 mm has a sensitivity of 68% and specificity of 82% to predict miscarriage. CONCLUSIONS: Thromboelastography identifies a subgroup of women with recurrent miscarriage to be in a prothrombotic state outside of pregnancy. Women in such a state are at increased risk of miscarriage in future untreated pregnancies.     

Further experience with intravenous immunoglobulin in women with recurrent miscarriage and a poor prognosis

PROBLEM: Women with three or more unexplained miscarriages have a 60% chance of a subsequent live birth. Intravenous immunoglobulin (IVIG) has not been conclusively shown to improve this prognosis. This study assessed the effect of IVIG in patients expected to have a poor outcome if untreated, i.e. women with five or more abortions, who have aborted after paternal leukocyte immunization or who continue to abort despite expressing anti-paternal complement dependent antibody. METHODS: Seventy-six women received IVIG in a dose of 400 mg/kg body weight, in one day (total 30-45 g) in the follicular phase of a cycle in which pregnancy was planned. A booster dose was administered when pregnancy was diagnosed. Their results were compared to an untreated control group of 74 women. RESULTS: Thirty-five (49%) pregnancies in treated women have resulted in live births or passed their previous stages of abortion compared to 23 (31%) in control patients (P = 0.04). CONCLUSIONS: These figures indicate that IVIG may prevent further miscarriages in this poor prognosis population. These figures are especially significant considering the doubt concerning the efficacy of IVIG in patients with three miscarriages and therefore a relatively good prognosis.     

Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study

BACKGROUND: Obesity has become a major health problem worldwide and is also associated with adverse pregnancy outcome. The aim of this study was to assess the impact of obesity on the risk of miscarriage in the general public. METHODS: This was a nested case-control study. The study population was identified from a maternity database. Obese [body mass index (BMI) >30 kg/m2] women were compared with an age-matched control group with normal BMI (19-24.9 kg/m2). Only primiparous women were included in the study to avoid including the subject more than once, and to be able to correctly identify recurrent miscarriages. The prevalence of a previous history of early (6-12 weeks gestation), late (12-24 weeks gestation) and recurrent early miscarriages (REM) (more than three successive miscarriages <12 weeks) was compared between the two groups. RESULTS: A total of 1644 obese and 3288 age-matched normal weight controls with a mean age of 26.6 years [95% confidence interval (CI) 26.5-26.7] were included in the study. The risks of early miscarriage and REM were significantly higher among the obese patients (odds ratios 1.2 and 3.5, 95% CI 1.01-1.46 and 1.03-12.01, respectively; P = 0.04, for both]. CONCLUSIONS: Obesity is associated with increased risk of first trimester and recurrent miscarriage.     

Intrauterine haematomas in a recurrent miscarriage population

BACKGROUND: This study examines the effect of intrauterine haematomas (IUH) discovered during early pregnancy ultrasound scanning in patients with recurrent miscarriage. Previous studies of IUHs have reported conflicting findings, and none studied women with recurrent miscarriage. METHODS: A total of 341 women with a viable pregnancy was included. Women with an IUH (n = 41) were compared with those without (n = 300). RESULTS: An IUH was identified by ultrasound in 12% (41/341) women. There were no differences in the number of live births between the two groups (25/41, 61% in the IUH group compared with 169/300, 56% without an IUH) or the number of miscarriages (6/41, 15% with an IUH compared with 72/300, 24% without an IUH). Anti-phospholipid antibodies were more common in the IUH group (21/31, 68% compared with 103/244, 42% P < 0.01). More women with haematomas experienced vaginal bleeding (16/31, 52% compared with 47/244, 19%, P < 0.01). These associations did not affect pregnancy outcome. Also, no increase in the rate of pregnancy complications was observed in the IUH group. CONCLUSIONS: The presence of an IUH in this potentially high risk patient group does not have a deleterious effect on pregnancy outcome.     

The Euro-Team Early Pregnancy (ETEP) protocol for recurrent miscarriage

The underlying causes and rationale for treatment of recurrentabortion are not entirely clear. The Euro-Team early pregnancyprotocol was developed as a diagnostic work-up based on theevaluation of risk factors. Possibilities for therapy can bebased only on the expectancy that elimination of some risk factorsmay improve the prognosis.     

Management of recurrent miscarriage: evaluating the impact of a guideline

BACKGROUND: Little is known on the actual diagnostic and therapeutic management of recurrent miscarriage and the impact of introducing guidelines on this topic. The objective of this study was to evaluate any changes in the management of recurrent miscarriage among Dutch gynaecologists after the introduction of the Dutch guideline 'Recurrent Miscarriage' in 1999. METHODS: Questionnaires were sent to all practices for obstetrics and gynaecology in the Netherlands. Data concerned definition, diagnosis and treatment of recurrent miscarriage. Results were compared with a similar study conducted before the introduction of the guideline and with the recommendations in the guideline. RESULTS: The response rate was 83%. Regarding gestational age, only 3% of the respondents used the definition as advised in the guideline. After the introduction of the guideline, thrombophilia factors were tested more frequently, anticoagulants were prescribed more frequently and more respondents reported to correct uterine malformations. Therapies not described in the guideline, e.g. donor insemination and oocyte donation, were still applied. CONCLUSIONS: The adherence to the Dutch guideline 'Recurrent Miscarriage' was rather poor, presumably due to guideline-related as well as physician-related barriers. Too many diagnostic tests and ineffective therapeutic interventions were performed. This study demonstrates the importance of appropriate implementation and revision.     

Intravenous immunoglobulin treatment of pregnant patients with unexplained recurrent abortions

Intravenous immunoglobulins, first given to recurrent aborterswith anti-phospholipid syndrome, have been administered to unexplainedaborters since 1986. They probably have immunomodulatory propertiesbeyond supplying blocking antibodies. When pregnancy was confirmed,women were started with a loading dose which was repeated every3–4 weeks until the second trimester. Dosages were empirical.Pregnancy rates ranged between 50 and 82%. The main maternalcomplications, i.e., allergic reactions and infections, wererare.     

Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage

Recurrent miscarriage (RM; > or =3 consecutive early pregnancy losses) affects around 1% of fertile couples. Parental chromosomal anomalies, maternal thrombophilic disorders and structural uterine anomalies have been directly associated with recurrent miscarriage; however, in the vast majority of cases the pathophysiology remains unknown. We have updated the ESHRE Special Interest Group for Early Pregnancy (SIGEP) protocol for the investigation and medical management of RM. Based on the data of recently published large randomized controlled trials (RCTs) and meta-analyses, we recommend that basic investigations of a couple presenting with recurrent miscarriage should include obstetric and family history, age, BMI and exposure to toxins, full blood count, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), parental karyotype, pelvic ultrasound and/or hysterosalpingogram. Other investigations should be limited to particular cases and/or used within research programmes. Tender loving care and health advice are the only interventions that do not require more RCTs. All other proposed therapies, which require more investigations, are of no proven benefit or are associated with more harm than good.     

The one-stop recurrent miscarriage clinic: an evaluation of its effectiveness and outcome

BACKGROUND: Couples with recurrent miscarriages make several visits to specialized clinics for investigations before treatment is offered. Consequently, 'the interval' between receipt of referral and advice to try for a pregnancy is often lengthy. The objectives of this study were to examine the effect of a 'one-stop' clinic on 'the interval', throughput and the outcome from this clinic. METHODS: The processes for investigation, management and outcomes of 189 couples seen in our Recurrent Miscarriage Clinic (RMC) and their records were reviewed. RESULTS: The one-stop clinic reduced the interval and number of visits by 36% (206.6 to 130.4 days, P < 0.001) and by 60% (2.5 to 1, P < 0.002) respectively. The prevalence and frequency of aetiological factors were similar in those with two and three or more miscarriages (41% versus 45%, P > 0.05). The commonest aetiological factors were thrombophilias (14%) and antiphospholipid syndrome (11%). No cause was identified in 54% of cases. The pregnancy and live birth rates were best in the idiopathic group (75%), those with thrombophilias (64%) and autoimmune antibodies (83%). Older couples had the worse pregnancy rates and outcome. CONCLUSION: A one-stop clinic significantly shortens 'the interval' between referral and initiation of treatment. Investigations should be initiated in women after two consecutive miscarriages.     

Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study

BACKGROUND: Reproductive loss carries immeasurable human costs as well as being costly to the health care system. The objectives of this study were to determine the frequency and distribution of cytogenetically abnormal miscarriages from couples with recurrent miscarriage and to compare the results with the general population. METHODS: A total of 420 specimens, including 29 pre-clinical, 237 embryonic and 154 fetal, were successfully karyotyped from 285 couples with recurrent miscarriage. The results were stratified according to maternal age and compared with controls. RESULTS: In all, 225 specimens (54%) were euploid. A total of 195 specimens (46%) were cytogenetically abnormal, of which 131 (66.5%) were trisomic, 37 (19%) were polyploid, 18 (9%) were monosomy X, eight (4%) were unbalanced translocations and one was a combination of trisomy 21 and monosomy X. The frequency of euploid miscarriages was significantly higher in women <36 years of age with recurrent miscarriage compared with controls. The distribution of cytogenetic abnormalities in the recurrent miscarriage group was not significantly different from controls, when stratified by maternal age. CONCLUSIONS: Women <36 years of age with recurrent miscarriage have a higher frequency of euploid miscarriage. When stratified for maternal age, there is no difference in the distribution of cytogenetically abnormal miscarriages in couples with recurrent miscarriage compared with controls.     

Immunology: Intravenous immunoglobulin for in-vitro fertilization failure

The aim of this study was to determine the effectiveness ofintravenous (i.v.) immunoglobulin (Ig) for treatment of individualsexperiencing failure after in-vitro fertilization (IVF) andembryo transfer. A total of 29 women with unexplained infertilitywho failed to become pregnant after IVF/embryo transfer weredivided into two groups based on performance in previous IVFcycles: 16 women had fertilization of 50%of oocytes retrievedand/or produced 3 embryos each cycle and 13 had fertilizationof<50% of oocytes retrieved and/or produced <3 embryoseach cycle. Each woman had received at least 12 transferredembryos (95th percentile for successful IVF patients) or hadexperienced two or more biochemical pregnancies without ultrasonicconfirmation of implantation during previous IVF/embryo transferattempts. All women received i.v. Ig 500 mg/kg prior to thenext embryo transfer. Only one of the 13 (8%) women with suboptimalfertilization and embryo yield became pregnant in the treatmentcycle. Of 16 women who had previously had fertilization of atleast 50% of oocytes retrieved and produced at least three embryos,nine (56%) became pregnant in the treatment cycle. The differencein pregnancy rates between the two groups is significant (P=0.02).Intravenous Ig is useful in the treatment of unexplained IVFfailure in women who have oocyte fertilization rates 50% andgenerate at least three embryos per cycle.     

Chromosomal abnormalities and embryo development in recurrent miscarriage couples

BACKGROUND: Chromosomal abnormalities are an important cause of spontaneous abortion and recurrent miscarriage (RM). Therefore, we have analysed the incidence of chromosomal abnormalities and embryo development in patients with RM. METHODS: Preimplantation genetic diagnosis (PGD) was performed on 71 couples with RM and 28 couples undergoing PGD for sex-linked diseases (control group). Chromosomes 13, 16, 18, 21, 22, X and Y were analysed by fluorescence in-situ hybridization. RESULTS: The implantation rate in RM patients was 28% and three patients (13%) miscarried. The percentage of abnormal embryos was significantly increased (P < 0.0001) in RM patients compared with controls (70.7 versus 45.1%). All of the embryos were abnormal in 19 cycles (22.1%) and repeated PGD cycles yielded similar rates of chromosomal abnormalities in 14 couples. Anomalies for chromosomes 16 and 22 were significantly higher (P < 0.01) in RM cases. In the RM population, euploid embryos reached the blastocyst stage more frequently than abnormal embryos (61.7 versus 24.9%; P < 0.0001). CONCLUSIONS: RM is associated with a higher incidence of chromosomally abnormal embryos, of which some are able to develop to the blastocyst stage. IVF plus PGD is an important step in the management of these couples, but the technique has to move towards a full chromosome analysis.     

Role of cathepsins and cystatins in patients with recurrent miscarriage

In the implantation, trophoblasts penetrate maternal decidua by secreting proteases. It has been reported that cathepsins are highly expressed in the mouse villi, and play an important role in normal embryonal growth and decidualization. In this study, we evaluated cathepsins and their endogenous inhibitors, cystatins, in tissue and serum of patients with recurrent miscarriage. Decidua and villi were surgically collected from 22 patients and 12 healthy women. Immunohistochemistry was performed with antibodies against cathepsins, stefin A (cystatin A), stefin B (cystatin B) and cystatin C. The concentrations of cathepsins, stefins and cystatin C were measured by Enzyme-linked immunosorbent assay. In addition, we measured the serum level of cystatin C in 85 Japanese women with recurrent miscarriage. Staining of cathepsin B, D, H, L, stefin B and cystatin C was observed in the cytoplasm of epithelial cells in decidua. Stefin A was expressed on the surface of the trophoblast. The concentration of cathepsin B and H in patients' decidua was significantly higher than in control individuals. The serum level of cystatin C was significantly lower in patients than in control individuals. Our findings suggest that the regulation of the cathepsin-cystatin system may play an important role in patients with recurrent miscarriage.     

Microchimerism in recurrent miscarriage

Maternal-fetal cell exchange during pregnancy results in acquisition of microchimerism, which can durably persist in both recipients. Naturally acquired microchimerism may impact maternal-fetal interaction in pregnancy. We conducted studies to ask whether microchimerism that a woman acquired from her own mother is detectable before or during pregnancy in women with recurrent miscarriage. Fetal microchimerism was also assayed. Women with primary idiopathic recurrent miscarriage （n=23） and controls （n=31） were studied. Genotyping was conducted for probands, their mothers and the fetus, a non-shared polymorphism identified and quantitative polymerase chain reaction performed to measure microchimerismin peripheral blood mononuclear cells. Preconception comparisons were made between recurrent miscarriage subjects and controls, using logistic regression and Wilcoxon rank sum. Longitudinal microchimerism in subsequent pregnancies of recurrent miscarriage subjects was described. There was a trend toward lower preconception detection of microchimerism in recurrent miscarriage versus controls, 6% vs. 19% （1/16 vs. 6/31, P=0.2）. During pregnancy, 3111 （27%） of recurrent miscarriage subjects who went on to have a birth had detection of microchimerism from their own mother, whereas neither of two subjects who went on to miscarry had detection （0/2）. This initial data suggest that microchimerism from a woman＇s own mother, while detectable in women with recurrent miscarriage, may differ from controls and according to subsequent pregnancy outcome. Further studies are needed to determine the cell types,quantities and any potential functional role of microchimerism in recurrent miscarriage.     

Thyroid autoimmunity and recurrent miscarriage

Citation Ticconi C, Giuliani E, Veglia M, Pietropolli A, Piccione E, Di Simone N. Thyroid autoimmunity and recurrent miscarriage. Am J Reprod Immunol 2011; 66: 452–459 Problem To investigate the role of antithyroid autoantibodies (ATA) in recurrent miscarriage (RM). Methods In this case‐control study, a total of 160 women with RM and 100 healthy women were investigated for the presence of serum ATA directed against thyreoglobulin (TG‐Ab), thyroid peroxidase (TPO‐Ab) and TSH receptor (TSHr‐Ab), which were determined by either chemiluminescence or radioimmunoassay. Results Antithyroid autoantibodies were detected in 46 (28.75%) women with RM and in 13 (13%) women of the control group (P < 0.05). The frequencies for TG‐Ab and TPO‐Ab were higher in RM than in control women. Among the women of RM group, 91.3% of ATA+ women were positive also for other autoantibodies. The majority of study women were euthyroid. Conclusions Antithyroid autoantibodies, particularly TG‐Ab, are associated with RM and could be an expression of a more general maternal immune system abnormality leading to RM. ATA could have a role in RM irrespective of thyroid hormone status.     

Depression as a potential causal factor in subsequent miscarriage in recurrent spontaneous aborters

BACKGROUND: Unexplained miscarriage is speculated to be due to a Th1/Th2 cytokine imbalance at the feto-maternal interface and immunological functions are known to be under the influence of various psychological factors. Indeed, the psycho-neuro-immuno-endocrine network has been proposed to contribute to miscarriage. To assess whether psychological disorders might induce spontaneous abortion we carried out a prospective study to determine if any psychological parameter influenced risk in those patients with a history of recurrent miscarriages. METHODS: A prospective study was carried out on 61 patients with a history of two consecutive first-trimester miscarriages. A battery of self-report questionnaires including Symptom Checklist-90 Revised and the NEO Five Factor Index and semi-structured interviews were conducted before a subsequent pregnancy. We investigated whether or not these parameters predicted subsequent miscarriages. RESULTS: Ten (22.2%) of the 45 patients who conceived miscarried again. Baseline depressive symptoms influenced subsequent miscarriage (P = 0.004). This statistically significant effect remained when we corrected with Bonfferoni adjustment (P = 0.036). CONCLUSIONS: A high depression scale is associated with a high miscarriage rate in those patients suffering recurrent miscarriage.     

Progestagen therapy for recurrent miscarriage

BACKGROUND: Recurrent pregnancy loss (RM) affects 0.5-1% of couples. The pathophysiology of RM is complex. The suggested causes include anatomical, genetic and molecular abnormalities, endocrine disorders, thrombophilias and anti-phospholipid syndrome. In approximately 50% of the cases neither of the above can be identified. We aimed at examining the evidence on the role of progesterone in the pathophysiology of RM, and the clinical evidence on effectiveness of progestogen treatment. METHODS: We searched PubMed and the Cochrane database covering the period of 1968-2007. The search terms progestogens and recurrent miscarriage, NK cells and recurrent miscarriage as well as cytokines and recurrent miscarriage were used. RESULTS: Progesterone is indispensable for creating a suitable endometrial environment for implantation. RM may be due to subnormal progesterone secretion and retarded endometrial development in the peri-implantation period. Progesterone also acts on the immune system, mainly by affecting cytokine synthesis and the function of NK cells. A recent meta-analysis showed that though progesterone treatment did not affect pregnancy outcome in women with miscarriages in general, separate analysis of three small and dated studies including altogether 91 patients with RM revealed a small but significant effect. It is noteworthy that the design of these 40 years old studies does not meet modern requirements. CONCLUSION: Standardized laboratory protocols for identifying potential targets of progestogen treatment as well as implementation of well-designed randomized studies are needed to establish the usefulness of progesterone supplementation in the treatment of RM.     

Hypersecretion of luteinizing hormone and ovarian steroids in women with recurrent early miscarriage

Polycystic ovary syndrome is associated with hypersecretionof luteinizing hormone (LH) which has been implicated in theaetiology of early pregnancy loss. Although 82% of women withrecurrent early loss have polycystic ovaries on ultrasound imaging,random serum LH concentrations are normal. In the present study,we have obtained further information from serial samples concerningthe cyclical patterns of gonadotrophin and sex steroid secretionin these women. Twenty-one women with recurrent early pregnancyloss and 10 multiparous controls were investigated; 81% of themand one of ten control subjects had polycystic ovaries. Meanmid-follicular and mid-luteal serum LH and follicle stimulatinghormone (FSH) levels were similar in both groups. Seventeenwomen with pregnancy loss had either raised urinary LH excretionor a premature LH surge; one control subject had a prematureLH surge. Total LH excretion during the cycle and mean follicularphase serum testosterone was significantly greater with earlypregnancy loss than in the control group, the difference inLH being greatest in the early luteal phase. Urinary oestrone-3-glucuronideexcretion was raised in the early luteal phase of the cyclein the group with early pregnancy loss; there was no differencebetween the groups in pregnanediol-3-glucuronide excretion.These data demonstrate abnormalities in LH secretion in 81%of women with recurrent fetal loss. Inappropriately raised LHlevels may have adverse effects on the developing oocyte orendometrium either directly, or indirectly by causing an elevationin testosterone and oestrogen levels.