Early Recurrent Miscarriage Research Articles

Aktuelles zur rationellen Diagnostik und Therapie habitueller Frühaborte

Habituelle Frühaborte, also mehr als zwei aufeinander folgende Fehlgeburten, betreffen etwa 1 - 2 % aller Partnerschaften. Traditionell werden chromosomale, anatomische, hämostaseologische, endokrine, autoimmunologische, infektionsbedingte sowie fraglich alloimmunologische Pathologien mit solchen habituellen Frühaborten assoziiert; jedoch wird bei fast 50 % der untersuchten Paare keine zugrunde liegende Abortursache gefunden. Die vorliegende Übersichtsarbeit soll einerseits Ansatzpunkte zur rationellen Diagnostik bei Paaren mit wiederholten Fehlgeburten liefern, zum anderen sollen verschiedene, zum Teil sehr umstrittene Therapieansätze auf dem Hintergrund aktueller Studien und Metaanalysen kritisch diskutiert werden.

Association between antiphospholipid antibodies and recurrent early miscarriage - Does a syndrome actually exist?

Association between antiphospholipid antibodies and recurrent early miscarriage - Does a syndrome actually exist?

Antibodies to β2-glycoprotein I and annexin V in women with early and late idiopathic recurrent spontaneous abortions

Anti-phospholipid antibodies (APA) are heterogeneous group of autoantibodies that target phospholipid or phospholipid-binding proteins. APAs were previously shown to induce several thrombotic states, including idiopathic recurrent spontaneous abortion (RSA). Unlike the contribution of the classical lupus anticoagulant (LAC) and anticardiolipin antibodies (ACA), the contribution of anti-beta2 glycoprotein 1 (beta2GPI) and anti-annexin V antibodies to RSA risk remain poorly understood. We assessed anti-beta2GPI and anti-annexin V IgM and IgG antibodies as RSA risk factors for RSA in 172 Tunisian women with >3 consecutive idiopathic pregnancy losses, together with 173 matched control women. The prevalence of anti-beta2GPI IgG (P=0.41, OR=1.64) and IgM (P=0.50, OR=1.70) were comparable between cases and controls. Higher anti-annexin V IgG (P=0.02, OR=5.28), but not IgM (P=0.25, OR=1.78), levels were seen in cases. Regression analysis showed that anti-beta2GPI IgM (OR=8.90; 95% CI=1.23-64.63) was associated with early RSA, while anti-annexin V IgG (OR=9.35, 95% CI=1.44-60.86) was associated with late RSA. For combined early + late RSA, the only variable selected was BMI (OR=0.93; 95% CI=0.87-0.99), and neither anti-annexin V nor anti-beta2GPI IgM and IgG were associated with early + late RSA. Anti-annexin V and anti-beta2GPI appear to be independent risk markers of RSA.

Primary Antiphospholipid Syndrome in Pregnancy: An Analysis of Outcome in a Cohort of 33 Women Treated With a Rigorous Protocol

Early recurrent miscarriage, placental insufficiency, intrauterine growth restriction (IUGR), and late fetal death all are possible consequences of primary antiphospholipid syndrome (APS). The authors undertook a prospective study of how best to manage APS pregnancies in 33 affected women who were pregnant. Nearly 80% of patients had a history of pregnancy-related morbidity and 36% had had thrombotic events. Four very premature live-born infants had died. One third of women had had three or more consecutive first-trimester miscarriages. A first-trimester ultrasound study was done to confirm viability and for accurate dating. Uterine artery Doppler waveform studies were done at 20 and 24 weeks gestation, and growth scans at monthly intervals starting at 24 to 26 weeks. The timing of delivery was individualized. Induction was recommended at 38 to 40 weeks gestation, although pregnancies were allowed to go beyond this if there were no complications. Operative delivery was done on obstetric indications. Aspirin and low-molecular-weight (LMW) heparin were given until labor began or until the day before planned delivery. Women taking warfarin were admitted 10 to 14 days before planned delivery and converted to either full-dose LMW heparin or intravenous unfractionated heparin up to the time of delivery. LMW heparin was continued after delivery when there was a history of venous thrombosis. The live birth weight in this series was 91%; there were only three failed pregnancies. Mean birth weight was 2853 g, and mean gestational age was 36.7 weeks. Complications included four cases of IUGR (two with concurrent preeclampsia), transient ischemic attacks in five women receiving LMW heparin, and one case of placental abruption. Renal function declined in one patient who had glomerular thrombotic microangiopathy. Lupus anticoagulant was the strongest predictive factor for a thrombotic event in pregnancy. Levels of anticardiolipin antibody were less predictive, but a past thrombotic event was a strong risk factor. A history of IUGR or fetal death predicted IUGR in the current pregnancy. The operative delivery rate in this series was 59%. This study shows that a very high live birth rate is achievable in women with primary APS who have a history of significant pregnancy-related morbidity and/or thrombosis.

Primary antiphospholipid syndrome in pregnancy: an analysis of outcome in a cohort of 33 women treated with a rigorous protocol

Women with primary antiphospholipid syndrome (APS) can experience early recurrent miscarriage, placental insufficiency leading to intrauterine growth restriction (IUGR), late fetal death, pre‐eclampsia, placental abruption or premature delivery [1]. Because evidence‐based recommendations are flawed by lack of qualitative studies, we undertook a prospective study of the management of APS pregnancies in a dedicated clinic following the introduction of a standard protocol.

Genetic thrombophilia has pleiotropic effects in pregnancy.

Genetic thrombophilia has been established as a risk factor for pregnancy-associated disorders, such as thrombosis, early and late miscarriage, and pre-eclampsia. Associations between the factor V (F5) Leiden G1691A and the prothrombin/factor II (F2) G20210A SNPs and pre-eclampsia have been evaluated in over 50 association studies. A pooled analysis of 23 and 11 studies demonstrates that carriage of the F5 Leiden G1691A (p < 0.001; odds ratio [OR] 2.0; 95% confidence interval [CI] 1.6-2.5) and the F2 G20210A (p < 0.001; OR 1.8; 95% CI 1.1-2.9) SNPs is significantly associated with pre-eclampsia. Besides pre-eclampsia, genotyping for the F5 Leiden G1691A and the F2 G20210A SNPs is also useful for individual risk assessment regarding pregnancy-associated thrombosis. Carriers of the F5 Leiden G1691A SNP will develop this condition in 6.4% of heterozygotes and in 8.9-16.7% of homozygotes. A total of 6.2% of women with the F2 G20210A SNP and 17.8% of women with simultaneous carriage of the F5 Leiden G1691A and F2 G20210A SNPs will develop pregnancy-associated thrombosis. Both the F5 Leiden G1691A and F2 G20210A SNPs are also risk factors of early recurrent, late recurrent and late spontaneous miscarriage based on a published meta-analysis of 31 studies. These women may benefit from prophylactic heparinization. Six case-control and cohort studies of 687 women with genetic thrombophilia document live birth rates of 82% (181/221) using low-molecular-weight heparin or fractionated heparin compared with 20% (95/466) without therapy (p < 0.001, OR 17.7; 95% CI 12.2-25.5). Based on the data in the literature, including association studies and meta-analyses of these association studies, it can be concluded that genetic thrombophilia due to carriage of the F5 Leiden G1691A and F2 G20210A SNPs is a significant and clinically relevant risk factor for pre-eclampsia, pregnancy-associated thrombosis, and early and late miscarriages.

Assoziationsstudien von Polymorphismen zur Risikoevaluierung in der Schwangerschaft - Literaturübersicht und Metaanalyse

Ein potenziell wirksames Instrument zur Erkennung der individuellen Physiologie und individueller Risikoprofile von Schwangeren stellt die Kenntnis von Polymorphismen dar. Mittlerweile wurden in über 70 Assoziationsstudien die Effekte der Trägerschaft bestimmter Polymorphismen auf die Schwangerschaft und schwangerschaftsassoziierte Erkrankungen wie Präeklampsie und Thrombose untersucht. Eine Metaanalyse von 22, 11 und 10 Studien weist die Trägerschaft des F-V-Leiden G1691A- (OR 1,9; 95 %-KI 1,6 - 2,5), des F II G20210A- (OR 1,8; 95 %-KI 1,1 - 2,9) und des AGT Met235Thr-Polymorphismus (OR 1,6; 95 %-KI 1,4 - 1,8) als signifikante Risikofaktoren für Präeklampsie aus, während die Trägerschaft des MTHFR C677T-Polymorphismus in einer Metaanalyse von 24 Assoziationsstudien nicht mit einem erhöhten Präeklampsierisiko assoziiert ist (OR 1,1; 95 %-KI 0,9 - 1,3).

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

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. 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. 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]. Obesity is associated with increased risk of first trimester and recurrent miscarriage.

Elevated plasma levels of factor VIII in women with early recurrent miscarriage

Inherited and acquired thrombophilia have been found to be associated with recurrent pregnancy loss. This paper examines whether or not elevated factor (F)VIII:C plasma levels, which have been demonstrated to be an independent risk factor for venous thromboembolism, are a risk factor for early recurrent miscarriages also. Consecutive women referred to our clinic with a history of early recurrent abortion (at least three pregnancy losses before week 13 of gestation) were eligible for the study. Exclusion criteria were endocrine, immunological, anatomical and genetic causes of embryo demise, as well as any thrombophilic abnormality, either congenital or acquired, or a personal or familial history of venous thromboembolism. FVIII:C plasma levels were determined in 51 cases and in 51 controls matched for age, ethnicity and blood group. The mean FVIII:C level in the control subjects was 106.8 IU dL-1, compared with 128.2 IU dL-1 in the patients group (P = 0.0002). Thirteen (25.5%) of the 51 patients had FVIII:C values exceeding the 90th centile of the control population (145 IU dL-1), compared with four subjects in the control group (chi2 = 4.52; P = 0.033; odds ratio = 4.02, 95% confidence interval 1.09, 16.05). No cases with increase in FVIII:C levels attributable to an acute-phase reaction, as assessed by C-reactive protein plasma concentration, were found. We found FVIII:C levels significantly higher in women with early recurrent miscarriage compared with controls. This finding suggests a possible association between this thrombophilic condition and early reproductive failures.

Anti-annexin A5 antibodies in reproductive failures in relation to antiphospholipid antibodies and phosphatidylserine.

The presence of IgG anti-annexin A5 (IgGalphaA5) and/or antiphospholipid antibodies (aPL) are risk factors associated with recurrent spontaneous abortion. Problems are whether IgA antiannexin A5 (IgAalphaA5) is pathogenic, and how IgGalphaA5 works. Blood samples from 238 patients with early recurrent spontaneous abortion, 48 patients with recurrent in vitro fertilization-embryo transfer failure, 179 non-pregnant women and 120 pregnant controls were tested for IgAalphaA5 by enzyme-linked immunosorbent assay. We also determined if IgGalphaA5 appeared coincident with aPL. The antigenic epitope(s) recognized by IgGalphaA5 was investigated. We observed no difference between patients and controls for IgAalphaA5. The prevalence of IgGalphaA5 was not different statistically between patient samples with or without aPL. Patient IgGalphaA5 bound annexin A5 when the latter was free/unbound but not when annexin A5 was associated with phospholipid. The IgAalphaA5 does not appear to be pathogenic. IgGalphaA5 works to make a complex with annexin A5 without relation to aPLs, which may reduce annexin A5 available for binding to trophoblast.

Increased sperm DNA damage in partners of women with unexplained recurrent miscarriages: preliminary report

Objective: The objectives of our study were to (I) investigate the level of sperm DNA damage in partners of patients with unexplained recurrent miscarriages and compare them with fertile controls (ii) attempt to correlate sperm DNA damage with gestational age of miscarriages.Design: Prospective observational study in a teaching hospital setting.10 male partners of women attending the recurrent miscarriage clinic were recruited.Controls consisted of 5 volunteers with proven fertility and 2 sperm donors.Materials/Methods: Standard semen analysis(WHO, 1992) was performed in all patients (n=10) and controls(n=7). Sperm DNA damage was assessed using the single cell gel electrophoresis (modified comet assay). Comet moment was used to measure the level of sperm DNA damage. SPSS package(version 11.01) was used for statistical analysis.Results: Significantly increased levels of sperm DNA damage was detected in partners of patients with unexplained recurrent miscarriage compared to controls (p <0.032). The level of sperm DNA damage(comet moment) was found to correlate significantly with the number of early miscarriages (anembryonic and less than eight weeks gestation miscarriages);(r=0.788;p <0.008). A significant correlation between sperm morphology by strict criteria with early miscarriages was also detected(r=0.89;p <0.001).Conclusions: Male partners of patients suffering from unexplained recurrent miscarriages have significantly higher sperm DNA damage than controls and the level of DNA damage may be more significant in women who suffer from recurrent early miscarriages.Supported by: Central Sheffield University Hospital Trust, Sheffield, UK. Objective: The objectives of our study were to (I) investigate the level of sperm DNA damage in partners of patients with unexplained recurrent miscarriages and compare them with fertile controls (ii) attempt to correlate sperm DNA damage with gestational age of miscarriages. Design: Prospective observational study in a teaching hospital setting.10 male partners of women attending the recurrent miscarriage clinic were recruited.Controls consisted of 5 volunteers with proven fertility and 2 sperm donors. Materials/Methods: Standard semen analysis(WHO, 1992) was performed in all patients (n=10) and controls(n=7). Sperm DNA damage was assessed using the single cell gel electrophoresis (modified comet assay). Comet moment was used to measure the level of sperm DNA damage. SPSS package(version 11.01) was used for statistical analysis. Results: Significantly increased levels of sperm DNA damage was detected in partners of patients with unexplained recurrent miscarriage compared to controls (p <0.032). The level of sperm DNA damage(comet moment) was found to correlate significantly with the number of early miscarriages (anembryonic and less than eight weeks gestation miscarriages);(r=0.788;p <0.008). A significant correlation between sperm morphology by strict criteria with early miscarriages was also detected(r=0.89;p <0.001). Conclusions: Male partners of patients suffering from unexplained recurrent miscarriages have significantly higher sperm DNA damage than controls and the level of DNA damage may be more significant in women who suffer from recurrent early miscarriages. Supported by: Central Sheffield University Hospital Trust, Sheffield, UK.

Regulated Expression of Signal Transducer and Activator of Transcription, Stat5, and its Enhancement of PRL Expression in Human Endometrial Stromal Cells in Vitro

Differentiation of human endometrium during the secretory phase of the menstrual cycle is characterized by expression of a variety of genes implicated in the establishment and maintenance of pregnancy. An increased abundance of signal transducers and activators of transcription (Stats) in the secretory phase suggests Stat5 as a component of the differentiation of endometrium in response to ovarian hormone stimulation in vivo. Decidualization is initiated in a subset of endometrial stromal cells (ESC) in vivo during the secretory phase, but it is unclear whether regulated expression of Stat5 is a feature of these cells. Here, therefore, the abundance and subcellular distribution of Stat5 in ESC after a decidualization stimulus of cAMP plus medroxyprogesterone acetate (MPA) has been investigated in vitro. Western blotting revealed an increase in the apparent abundance of Stat5a and Stat5b, in the cytosolic and nuclear fractions, at 2, 3, and 4 d after stimulation. The potential functional relevance of this increase in Stat5 is suggested by the ability of transiently transfected Stat5a or Stat5b to significantly enhance the response of the decidual PRL promoter to cAMP/MPA and attenuation of the response to cAMP/MPA by dominant negative Stat5. Recent evidence suggests endometrial differentiation, including PRL production, as a possible target of antiphospholipid antibodies (aPL) prevalent in recurrent miscarriage. Monoclonal antibody, ID2, which has similar reactivity as human aPL, significantly decreased the apparent abundance of nuclear Stat5b in response to cAMP/MPA and was associated with decreased decidual PRL promoter activation and PRL secretion. Regulated expression of Stat5 is therefore a component of decidual differentiation of human ESC and contributes significantly to activation of the decidual PRL promoter. Alteration of this process by an aPL component suggests decidual differentiation as a potential clinical target in recurrent early miscarriages.

Factor V Leiden and recurrent miscarriage-prospective outcome of untreated pregnancies.

Some cases of recurrent miscarriage and later pregnancy complications have a thrombotic basis. Factor V Leiden is a common thrombophilic mutation. The prospective outcome of untreated pregnancies amongst 25 women heterozygous for the Factor V Leiden allele who had a history of either recurrent early miscarriages only (three or more miscarriages at <12 weeks gestation; n = 19) or of late miscarriage (>12 weeks gestation; n = 9) was studied. Control groups of women with a similar pregnancy history but who had a normal Factor V genotype were also studied. The live birth rate was significantly lower amongst women with a history of recurrent early miscarriage who carried the Factor V Leiden allele (6/16; 37.5%) compared with that amongst those with a normal Factor V genotype (106/153; 69.3%; odds ratio 3.75, 95% confidence intervals 1.3-10.9). The live birth rate was 11.1% (1/9) amongst those with a history of late miscarriage carrying the Factor V Leiden allele and 48.9% (22/45) amongst those with a normal Factor V genotype. Attention should be directed at screening women with recurrent miscarriage associated with placental thrombosis for Factor V Leiden and a policy of targeted thromboprophylaxis during future pregnancies should be assessed in the form of a randomized controlled trial.

Factor V Leiden and G20210A prothrombin mutations are risk factors for very early recurrent miscarriage.

To determine whether there is an association between early recurrent miscarriage (before 10 weeks of pregnancy) and Factor V Leiden and G20210A prothrombin mutations. A prospective study. Department of Gynaecology and Obstetrics, Saint Antoine Hospital, Paris, France. Two groups of women: those with early unexplained recurrent miscarriage before 10 weeks of pregnancy (n = 260) and control healthy women without a previous history of thromboembolism (n = 240). Screening for defects in the protein C anticoagulant pathway was performed using the anticoagulant response to agkistrodon confortrix venom (ACV test). Protein C and Factor V Leiden mutation testing was performed for each low ACV level. Each sample was tested for the G20210A prothrombin mutation. Factor V Leiden and G20210A mutations were found to be associated with early recurrent spontaneous miscarriage before 10 weeks of pregnancy, the odds ratios being 2.4 (95% CI 1-5) and 2.7 (95% CI 1-7), respectively. Similar results were found whether or not women had had a previous live birth. Early recurrent miscarriage before 10 weeks of pregnancy is significantly associated with Factor V or G20210A prothrombin mutations. These results indicate a possible role for anticoagulant prevention in these early miscarriages.

Factor V Leiden and G20210A prothrombin mutations are risk factors for very early recurrent miscarriage

Objective To determine whether there is an association between early recurrent miscarriage (before 10 weeks of pregnancy) and Factor V Leiden and G20210A prothrombin mutations. Design A prospective study. Setting Department of Gynaecology and Obstetrics, Saint Antoine Hospital, Paris, France. Population Two groups of women: those with early unexplained recurrent miscarriage before 10 weeks of pregnancy ( n=260) and control healthy women without a previous history of thromboembolism ( n=240). Methods Screening for defects in the protein C anticoagulant pathway was performed using the anticoagulant response to agkistrodon confortrix venom (ACV test). Protein C and Factor V Leiden mutation testing was performed for each low ACV level. Each sample was tested for the G20210A prothrombin mutation. Results Factor V Leiden and G20210A mutations were found to be associated with early recurrent spontaneous miscarriage before 10 weeks of pregnancy, the odds ratios being 2.4 (95% CI 1–5) and 2.7 (95% CI 1–7), respectively. Similar results were found whether or not women had had a previous live birth. Conclusions Early recurrent miscarriage before 10 weeks of pregnancy is significantly associated with Factor V or G20210A prothrombin mutations. These results indicate a possible role for anticoagulant prevention in these early miscarriages.

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.

Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorphometric study.

Endometrial natural killer (NK) cells were compared in luteal-phase endometrial samples from women with recurrent miscarriage and from normal subjects. Cryostat sections were labelled using a monoclonal antibody to CD56 using an avidin-biotin complex method and a morphometric study performed. Increased mean numbers of CD56+ cells were documented in the endometrium of women with recurrent early miscarriage only. These findings suggest a possible role for NK cells in the pathogenesis of recurrent early pregnancy loss.

Inherited thrombophilia and adverse pregnancy outcome: has the time come for selective testing?

Inherited thrombophilia and adverse pregnancy outcome: has the time come for selective testing?

The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss

We have investigated the potency of the C677T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene as a genetic risk factor in women with a history of early (</=12 weeks gestation) and/or late (>12 weeks gestation) recurrent miscarriage (three or more consecutive pregnancy losses). Fifty-seven of the total 173 (32. 9%) patients were heterozygous for the MTHFR mutation, 14/173 (8.1%) were homozygous (allele frequency 0.25). The prevalence of the MTHFR mutation in these women did not differ significantly from that in the control group of parous women with uneventful pregnancies, where 30/67 (44.8%) were heterozygous and 6/67 (9.0%) homozygous for the mutation (allele frequency 0.31; odds ratio for homozygous T/T 0.90, 95% CI 0.30-2.4). There was no association between the trimester of pregnancy loss and MTHFR genotype. We conclude that the C677T MTHFR mutation is not a risk predictor in women with a history of early or late recurrent miscarriage.

Beta2-glycoprotein I-dependent anticardiolipin antibody in early recurrent spontaneous abortion.

The objective of this study was to assess the clinical significance of autoimmune anticardiolipin antibody that can react with cardiolipin only in the presence of beta2-glycoprotein I (beta2-glycoprotein I-dependent anticardiolipin antibody) in the pathogenesis of early recurrent abortion. A total of 72 early recurrent spontaneous aborters and 175 normal healthy women were analysed for the occurrence of beta2-glycoprotein I-dependent anticardiolipin antibody in serum samples by an enzyme-linked immunosorbent assay specific for the detection of beta2-glycoprotein I-dependent anticardiolipin antibody. The incidence of beta2-glycoprotein I-dependent anticardiolipin antibody in the early recurrent spontaneous aborters was essentially the same as that of normal women. Thus, the beta2-glycoprotein I-dependent anticardiolipin antibody seemed to have little, if any, implication in the pathogenesis of early recurrent spontaneous abortion.