Mannan binding lectin concentration and risk of miscarriage.

Recurrent miscarriage is associated with low concentrations of mannan-binding lectin (MBL), but it is not known below which value relative MBL deficiency becomes a significant risk factor. The sera of 397 patients (male and female) suffering from recurrent miscarriage and 376 controls were assayed for MBL and the data analysed. It was found that the lower the cut-off value, the greater the statistical strength of the association. It was concluded that only MBL concentrations 相似文献   

Association between mannan binding protein deficiency and recurrent miscarriage

The distribution of mannan binding protein (MBP) in blood donorsera was determined by enzyme-linked immunosorbent assay toestablish normal concentrations. Abnormally low MBP concentrationswere found in 16% (21 out of 135) of female partners and 14%(15 out of 108) of male partners of couples experiencing recurrentmiscarriage, compared with <5% of obstetrically normal controls(P < 0.005). This relationship was even stronger (9.5 versus1.0%) and more significant (P < 0.002) when only subjectspresumed to be homozygous for the mutant allele responsiblefor MBP deficiency were considered. By immunohistochemistry,MBP could be demonstrated in first trimester placenta. We suggestthat low concentrations of MBP within the feto-placental unitincrease susceptibility to fetal loss, possibly via an infection-inducedplacental cytokine imbalance. mannan binding protein/recurrent miscarriage/recurrent spontaneous abortion/RSA     

Variations in the thrombomodulin and endothelial protein C receptor genes in couples with recurrent miscarriage

BACKGROUND: Recurrent miscarriage (RM) has been suggested to be caused by mutations in genes coding for various coagulation factors resulting in thrombophilia. Mouse models indicate that genes involved in the protein C anticoagulant pathway are essential for normal embryonic development. Loss of function of two of these genes, thrombomodulin (TM) and endothelial protein C receptor (EPCR), causes embryonic lethality in mice. The aim of this study was to determine whether variations in the human TM or EPCR genes are associated with an increased risk for RM. METHODS: Forty-six RM patients and 191 controls were screened for mutations in TM and EPCR using denaturing high-performance liquid chromatography (DHPLC). The partners of 40 RM patients were also screened. RESULTS: One exonic and one intronic variation in TM and two exonic and two intronic sequences in EPCR were detected. Four variants were common in both patients and controls. A previously identified truncating mutation in EPCR, suggested to have a role in pregnancy complications, was identified in two patients and one control. A novel deletion in the 3'UTR region of TM was detected, but its significance remains unsolved. CONCLUSIONS: These data suggest that mutations in the TM or EPCR genes are not a major cause of RM, although they may exert a modifier effect in combination with other variants.     

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.     

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.     

Mannan-binding lectin concentration during normal human pregnancy

Relative deficiency of mannan-binding lectin (MBL) is associated with recurrent miscarriage. To investigate whether MBL concentration alters as a result of pregnancy, serial measurements were made in 14 patients before and during normal early pregnancy. Additionally, a longitudinal study was made of one individual over several years and including two normal pregnancies. Three (20%) subjects experienced a significant increase in MBL concentration during pregnancy. It was concluded that a modest but significant increase in MBL concentration can result from pregnancy, but it is a rare occurrence in the first trimester.     

Impact of the sex of first child on the prognosis in secondary recurrent miscarriage

BACKGROUND: The carriage of a male fetus often initiates maternal immunological reactions against male-specific minor histocompatibility (HY) antigens, which, in theory, could result in subsequent recurrent miscarriage (RM). METHODS: Information about subsequent pregnancy outcome was procured among 182 women with RM after a birth (secondary RM) referred since 1986 using questionnaires, telephone interviews and registers. RESULTS: Significantly more of the women had had a male first-born as compared with a female first-born (110 versus 72; P < 0.02). By January 2002, 58% of those who had a male first-born had given birth to a second live infant compared with 76% of those who previously had had a female first-born (P = 0.01). Women in the former group had a significantly lower chance of having a second child than those in the latter (adjusted hazard ratio 0.59; 95% confidence interval 0.41-0.86). The number of miscarriages after admission and the risk of secondary infertility were significantly greater in women with a male first-born than among those with a female first-born (P < 0.001 and P = 0.02; respectively). CONCLUSIONS: A male first-born seems to be associated with a less favourable reproductive potential among women with secondary RM. Maternal immunization against HY antigens may be responsible for these findings.     

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.     

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.     

Leptin and leptin-binding activity in women with recurrent miscarriage: correlation with pregnancy outcome

BACKGROUND: Previous studies in humans and mice have suggested the importance of leptin in fetal growth. Recurrent miscarriage may be a result of abnormal placental and/or fetal development and therefore abnormal leptin levels may be associated with this form of pregnancy loss. METHODS: Leptin and leptin-binding activity (LBA) were measured in blood obtained from women who had a history of recurrent miscarriage (n = 53) during weeks 5-6 and 7-8 of pregnancy, and the concentrations were correlated with subsequent pregnancy outcome. RESULTS: Concentrations of leptin ranged from 1.4-62.8 ng/ml, but there was a strong correlation (r = 0.825, P < 0.001) between leptin values at weeks 5-6 and 7-8 in the same woman. Women who subsequently miscarried had significantly lower plasma leptin concentrations on both weeks 5-6 (13.34 +/- 2.1 ng/ml) (P < 0.05) and 7-8 (13.71 +/- 2.4 ng/ml) (P < 0.01) of pregnancy, than women who subsequently had a term birth (22.04 +/- 2.43 ng/ml week 5-6, 24.76 +/- 3.66 ng/ml week 7-8). LBA values ranged from 1-8.5% but there was no significant difference in LBA in blood obtained from women who subsequently miscarried or had a live birth. CONCLUSIONS: The significantly lower concentrations of leptin in women who subsequently miscarried suggest that leptin may play a role in preventing miscarriage. However, as there was a considerable overlap between the values of leptin in women who subsequently miscarried, and those that had a live birth, these measurements are of limited use in the prediction of pregnancy outcome in these women.     

Divergence of natural killer cell receptor and related molecule in the decidua from sporadic miscarriage with normal chromosome karyotype

The aim of this cohort study was to investigate immunophenotypic characteristics of natural killer (NK) cells by assessing specific molecules expressed in the decidua of sporadic miscarriages and induced abortions. The deciduae were obtained from 29 consecutively seen women whose pregnancies ended in first trimester miscarriages (MS), and the fetal chromosome karyotype of these MS was analysed. Additionally, 13 deciduae were obtained from induced abortion (IA) with informed consent. The expression of perforin, CD94, CD161, CD158a, CD158b, CD244 on CD3-CD56+NK cells, and perforin on CD3+CD8+ T cells was analysed by flow cytometry. The CD158a (mean+/-SD, 26.2+/-14.7%) and CD94 (50.2+/-25.7%) expressions in MS with normal chromosome karyotype (MSNK; n=11) were significantly decreased as compared with those (41.5+/-19.5%, 71.4+/-20.4%) in MS with abnormal karyotype (MSAK; n=18) and those (44.3+/-21.9%, 80.8+/-17.5%) in IA (n=13). Conversely, the perforin expression on CD3-CD8-CD56+NK cells (76.3+/-11.0%) and CD3+CD8+T cells (30.6+/-9.2%) in MSNK was significantly increased as compared with those (66.8+/-16.6%, 23.6+/-8.7%) in MSAK and those (62.9+/-11.6%, 19.7+/-8.1%) in IA. A positive correlation between CD94 and CD158a expressions on NK cells, negative correlations between CD94 on NK cells and perforin on NK cells/T cells, and between CD158a on NK cells and perforin on T cells were found in the decidua. A divergence of NK cell repertoire in the decidua might be related to aetiology of sporadic MSNK.     

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.     

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.     

Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage

Activated protein C (APC) resistance, both in its congenital form, due to the factor V Leiden mutation, and in its acquired form, are important risk factors for systemic venous thrombosis. In view of the suspected thrombotic aetiology of some cases of recurrent miscarriage, the prevalence of APC resistance was determined among 1111 consecutive Caucasian women with a history of either recurrent early miscarriage (three or more consecutive pregnancy losses at <12 weeks gestation; n = 904) or a history of at least one late miscarriage (>12 weeks gestation; n = 207). A control group of 150 parous Caucasian women with no previous history of adverse pregnancy outcome was also studied. Acquired APC resistance was significantly more common among both women with recurrent early miscarriage (8.8%: 80/904; P = 0.02) and those with late miscarriage (8.7%: 18/207; P = 0.04) compared with controls (3.3%: 5/150). In contrast, the frequency of the factor V Leiden allele was similar among (i) women with recurrent early miscarriage (3.3%:60/1808; 58 heterozygotes and one homozygote), (ii) those with late miscarriage (3.9%:16/414; 14 heterozygotes and one homozygote) and (iii) the control group (4.0%:12/300; 12 heterozygotes). Acquired but not congenital APC resistance (due to the factor V Leiden mutation) is associated with both early and late miscarriage.     

Variations of the Amnionless gene in recurrent spontaneous abortions

Recurrent spontaneous abortions (RSA) are estimated to affect 0.5-1% of couples trying to have a child. The causes of RSA are unknown in the majority of cases. This study aimed to determine whether homozygous mutations in the AMN gene in a fetus cause spontaneous abortions in humans, as they are known to cause spontaneous abortions in mice. The study was conducted by screening 40 couples and 5 women with three or more unexplained spontaneous abortions for heterozygous mutations in the AMN gene using denaturing high-performance liquid chromatography. Altogether, 3 exonic and 11 intronic sequence variations were found. There were no significant differences in the frequencies of the variations between the patients and a control group. One of the exonic variations was non-synonymous, and three of the variations may affect gene splicing. None of the putative phenotype-affecting variations were found in both partners in any couple. These results indicate that RSA in the couples studied cannot be explained by homozygous AMN mutations in the fetus. However, two couples had different, potentially deleterious variations in both partners. If these variations have a phenotypic effect, the RSA experienced by these couples may be caused by mutations in the AMN gene. In addition, birthplaces of the patients' ancestors revealed some clustering, suggesting that some patients may carry a founder mutation in another gene which may contribute to RSA.     

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.     

Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage

BACKGROUND: The natural killer (NK) cells at the site of placentation expresskiller-cell immunoglobulin-like receptors (KIR) that can bindto human leukocyte antigen (HLA)-C molecules on trophoblastcells. Both these gene systems are polymorphic and an associationof particular maternal KIR/fetal HLA-C genotypes has been shownin pre-eclampsia. Pre-eclampsia and recurrent miscarriage (RM)share the pathogenesis of defective placentation and thereforewe have now genotyped couples with RM. METHODS AND RESULTS: DNA was obtained from the male (n = 67) and female (n = 95)partners of couples with three or more spontaneous miscarriagesand genotyped for HLA-C groups and 11 KIR genes using the PCR-sequence-specificprimer method (SSP). The frequency of the HLA-C2 group was increasedin both parents (reaching significance only in the male partners,P = 0.018) compared with a parous control population. The KIRgene frequencies of the male partners were similar to controls,but the women had a high frequency of KIR AA haplotypes thatlack activating KIR. In particular, the activating KIR for HLA-C2groups (KIR2DS1) was significantly lower in these women (P =0.00035, odds ratio 2.63, confidence interval 1.54–4.49). CONCLUSIONS: This is the first report to identify a genetic male factor thatconfers risk in RM. These findings support the idea that successfulplacentation depends on the correct balance of NK cell inhibitionand activation in response to trophoblast.     

Embryo loss pattern is predominant in miscarriages with normal chromosome karyotype among women with repeated miscarriage

OBJECTIVE: The aim of this study was to assess pregnancy loss patterns in women with repeated miscarriage (RM), according to fetal chromosome karyotypes and aetiologies of RM. METHODS: In this cohort study, 168 fetal chromosome karyotypes of miscarriages were investigated. The pregnancy loss patterns were compared between 75 miscarriages from RM women who had a history of two or more consecutive miscarriages and 93 miscarriages from control women whose previous pregnancies ended in live births without a history of RM. By serial ultrasonography, embryo loss (EL) was defined as miscarriage before fetal heat movement was identified and fetal loss (FL) as miscarriage after fetal heat movement was identified. The EL rate was calculated as EL/(EL+FL). RESULTS: The EL rate (66.7%) in miscarriages with normal karyotypes among RM women (n=42) was higher (P<0.05) than that (45.7%) in controls (n=46), while the EL rate (30.3%) in miscarriages with abnormal karyotypes among RM women (n=33) did not differ from that (25.5%) in the controls (n=47). The EL rate (71.4%) in miscarriages with normal karyotypes among unexplained RM women (n=21) was much higher (P<0.05) than that in the controls. CONCLUSIONS: By evaluating fetal karyotypes, we demonstrated for the first time that EL was predominant in miscarriages with normal karyotype among RM women.     

Pregnancy: An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases

A total of 500 consecutive women (mean age 32.9 years; SD 5years) presenting with a history of recurrent miscarriages (median4; range 3–17) were investigated for the presence of antiphospholipidantibodies (APA), polycystic ovaries (PCO), hypersecretion ofluteinizing hormone (LH) and chromosome abnormalities in orderto detect an underlying cause of their pregnancy losses. Allwomen had details of their previous reproductive history, investigationsand treatment documented: 76% of the women had experienced onlyearly pregnancy losses (miscarriage <13 weeks gestation);32% had a history of subfertility; and significant parentalchromosome rearrangements were present in 3.6% of couples. Anultrasound diagnosis of PCO was made in 56% of women, 58% ofwhom were demonstrated to hypersecrete LH, based on early morningurinary LH analysis. Circulating APA were found in 14% of women.An underlying cause of recurrent miscarriage—genetic,endocrine or autoimmune—was found in >50% of couples.Women in the latter two groups are being recruited to randomizedtreatment trials which are discussed.