Monitorización inmunológica en mujeres con aborto recurrente / Immunological monitoring in women with recurrent spontaneous abortions

Para evaluar la prevalencia de alteraciones inmunológicas en pacientes con aborto espontáneo recurrente realizamos un estudio retrospectivo transversal. Las mujeres estudiadas habían sido evaluadas previamente mediante cariotipo de pareja y ecografía para investigar alteración anatómica. La monitorización inmunológica de rutina incluyó anticuerpos antifosfolípidos (in = 333), anticuerpos anticardiolipina (ACA), anticoagulante lúpico], anticuerpos anti-beta-2 glucoproteína-I (n = 139) [anticuerpos antinucleares (n = 333), anticuerpos antitiroideos (n = 180) y evaluación del porcentaje de células natural killer (NK) en sangre periférica (n = 189) en 333 pacientes consecutivas con 2 o más (intervalo 2-12) abortos espontáneos recurrentes. Se detectaron anticuerpos antifosfolípidos (ACA a valor moderado-alto o anticoagulante lúpico) en un 15,9% de pacientes. Un 6% de las pacientes tuvo anticuerpos antinucleares a título 1:160 o mayor. Se observó un porcentaje elevado de linfocitos CD56+/CD16+CD3­ (> 18%) en el 11,1% de las pacientes. Se documentó positividad de anticuerpos antitiroideos en el 4% de las mujeres. Globalmente, un 28,5% de las mujeres tuvo al menos una alteración inmunológica de las estudiadas. En un estudio realizado en mujeres con aborto espontáneo recurrente se observaron alteraciones autoinmunitarias y aloinmunitarias que involucran distintos autoanticuerpos y células NK de sangre periférica (AU)

We performed a retrospective cross-sectional study to ascertain the prevalence of immunological abnormalities in women with recurrent spontaneous abortions (RSA). The women had previously undergone karyotyping of the couple and ultrasonography to investigate anatomic uterine anomalies before immunological study. Routine immunologic monitoring for circulating antiphospholipid antibodies (aPL, n=333) [anticardiolipin antibodies (aCL), lupus anticoagulant (LA)], anti-beta-2 glycoprotein-I antibodies (n=139), antinuclear antibodies (n=333), antithyroid antibodies (n=180) and percentages of natural killer (NK) cells in peripheral blood (n=189) was carried out in 333 consecutive patients with two or more (range 2-12) RSA. aPL positivity (mean-high value aCL or LA) was 15.9%. The frequency of positive antinuclear antibody tests at a titer of 1:160 or higher was 6%. Elevated levels of CD56+/CD16+CD32 lymphocytes (>18%) were observed in 11.1% of the patients studied. Anti-thyroid antibody positivity was found in 4% of women. Overall, 28.5% of women had at least one immunological abnormality. Women with RSA had significant autoimmune and alloimmune alterations involving functionally distinct autoantibodies and peripheral blood NK cells (AU)

Predictors of vaginal bleeding during the first two trimesters of pregnancy.

This study evaluates maternal age, race, cigarette smoking, prior spontaneous abortion, prior induced abortion, and prior preterm birth in relation to vaginal bleeding during the first two trimesters of pregnancy. Information on vaginal bleeding and predictors came from the Pregnancy, Infection, and Nutrition Study, which enrolled 2806 pregnant women at 24-29 weeks' gestation during 1995-2000 in central North Carolina, USA. Generalised estimating equations were applied to take into account repeated episodes of vaginal bleeding during pregnancy. Women with advanced maternal age and passive smoking exposure were more likely to experience more intense vaginal bleeding during pregnancy, as were women with prior preterm birth. More intense bleeding was also more likely to be reported among women with multiple prior spontaneous abortions or multiple prior induced abortions, but not among women with a single prior spontaneous or induced abortion. The combination of prior spontaneous and induced abortion showed a dose-response association with the occurrence of vaginal bleeding during pregnancy.

Antiphospholipid antibody profiles and their clinical associations in Chinese patients with systemic lupus erythematosus.

OBJECTIVE: Different prevalences of antiphospholipid antibodies (aPL) have been reported in different populations of patients with systemic lupus erythematosus (SLE). Chinese are generally believed to have lower risk of vascular thrombosis. We examined the prevalence of aPL including lupus anticoagulant (LAC), anticardiolipin (aCL) and anti-beta2-glycoprotein I (anti-beta2-GPI) antibodies, the level of thrombotic risk, and the association of aPL with thrombotic and pregnancy outcomes in a Chinese cohort with SLE at the university lupus clinic during the period 1986-2003. METHODS: aPL were measured in 272 SLE patients, and medical records were reviewed for vascular thrombosis and pregnancy outcomes. RESULTS: The prevalence of LAC, IgG aCL, and IgG anti-beta2-GPI antibodies was 22.4%, 29.0%, and 7.7%, respectively. There were 38 episodes of thrombosis after a mean duration of followup of 11.0 +/- 6.8 SD years, giving a thrombotic rate of 1.26/100 patient-years. All aPL were shown to be associated with vascular thrombosis. IgG anti-beta2-GPI antibodies were found to be associated with recurrent thrombosis [8.0/100 patient-years or 25.0% (7/28)]. Patients taking hydroxychloroquine were found to have fewer thrombotic complications than those who were not (OR 0.17, 95% CI 0.07-0.44; p < 0.0001). LAC was the strongest factor associated with recurrent miscarriages [relative risk 12.3, 95% CI 1.22-123.31; p = 0.03). The diagnosis of secondary antiphospholipid syndrome was satisfied in 8.9% of patients. CONCLUSION: The lifetime and recurrent thrombotic rates in our patients with aPL were not particularly different from those in the literature. However, the lower prevalence of aPL in our cohort may suggest a role of other prothrombotic factors in predisposition to thrombosis.

Recurrent miscarriage and long-term thrombosis risk: a case-control study.

BACKGROUND: Recurrent miscarriage has been associated with antiphospholipid syndrome (APS) and other prothombotic conditions. We tested the hypothesis that women diagnosed as having APS as an aetiological factor for their miscarriages were at higher risk of thrombosis than those with idiopathic recurrent miscarriage. METHODS: A retrospective case-control study was performed using validated questionnaires. A total of 141 women with recurrent miscarriage and APS alone were matched with 141 women with idiopathic recurrent miscarriage for age, number and type of pregnancy loss and number of years of follow-up. A subgroup of eight women included those who initially presented with recurrent miscarriage, thrombosis and APS. RESULTS: The mean length of follow-up was 7.3 years and response rate 74%. The incidence of thrombosis was similar in the recurrent miscarriage and APS women (6/1000 women-years) and in the idiopathic recurrent miscarriage women (2/1000 women-years) (P = 0.18). All eight women who presented with recurrent miscarriage, APS and thrombosis reported further thrombotic events. CONCLUSIONS: Both idiopathic and APS-associated recurrent miscarriage were associated with a similar long-term risk of thrombosis.

Manejo actual del aborto espontáneo / Current management of spontaneous abortion

Hoy en día se puede optar por una conducta más conservadora en el caso de los abortos espontáneos que ocurren antes de las 12 semanas de gestación gracias a un buen seguimiento sonográfico por vía vaginal. El aborto espontáneo es la complicación más común temprana del embarazo. Aproximadamente 10 a 20 por ciento de los embarazos clínicamente reconocidos, bajo las 20 semanas de gestación, sufrirá de un aborto espontáneo; 80 por ciento de aquellos ocurrirá en las primeras 12 semanas de gestación. Del total de abortos espontáneos, un tercio de estos ocurre antes de las 8 semanas de gestación, presentándose en su gran mayoría como huevos anembrionados. El uso de ultrasonido transvaginal ayuda al médico y al paciente para comprender la complicación de un embarazo causada por un sangrado temprano, asimismo orienta el manejo a seguir, el cual puede ser quirúrgico, médico o espectante. El manejo espectante es una alternativa para mujeres con falla temprana del embarazo menor de 12 semanas de gestación con signos vitales normales y sin evidencia de infección.

Pregnancy outcome in patients with a history of recurrent spontaneous miscarriages and documented thrombophilias.

The aim of this study was to evaluate the effect of treatment in patients analyzed for recurrent spontaneous miscarriage with a diagnosis of a hereditary thrombophilia, the presence of antiphospholipid and/or autoimmune antibodies, and/or hyperhomocystinemia (HHC) with or without methylenetetrahydrofolate reductase (MTHFR) polymorphisms. In total, 76 women with 2 or more embryonic or fetal losses were analyzed. Of these, 49 (64.4%) women were found to have one or more thrombophilias and/or autoimmune antibodies, and 33 (43.4%) women were found to have a MTHFR polymorphism and/or HHC. Since completion of the recurrent miscarriage analysis, 39 women conceived again. All women with a thrombophilia were treated with low-dose aspirin plus low molecular weight heparin. All women with previously diagnosed HHC and/or MTHFR polymorphisms were treated with folate and vitamin B(6) and B(12) supplementation. In the thrombophilia group, 27 women conceived resulting in 20 successful pregnancies (74.1%) and 7 pregnancy losses (2 trisomy 16, 1 ectopic pregnancy and 4 unexplained miscarriages), i.e. an unexplained pregnancy loss rate of 14.8%. In the HHC/MTHFR group 22 women conceived, resulting in 17 successful pregnancies (77.3%) and 5 pregnancy losses (1 trisomy 16, 1 Turner syndrome and 3 unexplained miscarriages), i.e. an unexplained pregnancy loss rate of 13.6%.

Estudo das alterações placentárias de gestantes com síndrome antifosfolípide: correlações anátomo-clínicas / Placental changes study in pregnant women with antiphospholipid syndrome: anatomic clinic correlation

A sindrome antifosfolípide é caracterizada pela ocorrência de eventos clínicos tromboembólicos associados a persistência laboratorial de anticorpos antifosfolípides. Na gravidez, está associada à perda fetal de repetição atribuída às tromboses placentárias e aumento de morbidades materno-fetais. Este estudo centrado numa amostra de gestantes com síndrome antifosfolípide, submetidas a protocolo terapêutico de anticoagulação, teve como objetivo avaliar as lesões placentárias encontradas nas placentas resultantes dessas gestações e correlacionar com as intercorrências maternas e repercussões perinatais./The antiphospholipid syndrome is characterized by the occurrence of clinical events thromboembolic associated with the persistence laboratorial of antiphospholipid antibodies. In the pregnancy it is associated with the fetal loss attribuited by the placental thromboses and increase of fetal-maternal complications. This study centered in a sample of pregnant women with the antiphospholipid syndrome, submitted to a therapeutic protocol of anticoagulation, it has as an objective to evaluate the in these pregnant women and correlate with the maternal morbidity and pre-birth repercutions...

La donación de ovocitos / Donation of ovules

Se analizan las indicaciones de la donación de óvulos tanto en los casos de fallo ovárico como en aquellos otros en los que la mujer mantiene su función ovárica pero presenta problemas. Se analizan también los requisitos para ser receptora y para ser donante, los aspectos legales sobre este tema y el procedimiento seguido para la donación (AU)

Factor XII deficiency is strongly associated with primary recurrent abortions.

OBJECTIVE: To evaluate factor XII deficiency in women with primary and secondary recurrent abortion. DESIGN: Prospective case-control study. SETTING: University hospital. PATIENT(S): Sixty-seven women with primary and 33 women with secondary recurrent abortion of unexplained nature and 49 healthy controls with no history of thrombotic disease or adverse pregnancy outcomes. MAIL OUTCOME MEASURE(S): Plasma factor XII activity, activated protein C resistance, factor V Leiden mutation analysis, protein C, protein S, antithrombin III, karyotyping, and anticardiolipin antibodies. RESULT(S): Ten of 67 women with primary recurrent abortion (14.9%) and 4 of 33 women (12.1%) with secondary recurrent abortion had reduced factor XII activity (<60%). These results are highly significant in the former group and showed a tendency toward significance in the latter group. All controls had normal factor XII activity. CONCLUSION(S): Factor XII deficiency is strongly associated with primary recurrent abortion, and women with secondary recurrent abortion show a tendency toward factor XII deficiency.

A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first trimester miscarriage.

BACKGROUND: The true impact of congenital uterine anomalies on reproductive outcomes is unknown. The aim of this study was to examine differences in the morphology of uterine anomalies found in women with and without a history of recurrent miscarriage. METHODS: A total of 509 women with a history of unexplained recurrent miscarriage and 1976 low risk women were examined for the presence of congenital uterine anomalies by three-dimensional ultrasound. The anomalies were classified according to the American Fertility Society classification. In addition, the size of fundal distortion (F) and the length of the remaining uterine cavity (C) were measured to calculate a distortion ratio (F/F+C). The findings were compared with the measurements obtained in low risk women with an incidental finding of uterine anomaly. RESULTS: In all, 121 anomalies were detected in the recurrent miscarriage group and 105 in low risk women. There was no significant difference in relative frequency of various anomalies or depth of fundal distortion between the two groups. However, with both arcuate and subseptate uteri, the length of remaining uterine cavity was significantly shorter (P < 0.01) and the distortion ratio was significantly higher (P < 0.01) in the recurrent miscarriage group. CONCLUSION: The distortion of uterine anatomy is more severe in congenital anomalies, which are found in women with a history of recurrent first trimester miscarriage.

Acquired and inherited thrombophilia in women with unexplained fetal losses.

OBJECTIVE: The purpose of this study was to investigate the possible role of inherited and acquired thrombophilia in women with unexplained abortions and intrauterine fetal death. STUDY DESIGN: We included 75 women with >/=1 unexplained fetal loss, and 75 control subjects with at least 1 healthy term infant and without gestational complications. All of these women were tested for mutations of factor V Leiden, methylenetetrahydrofolate reductase, and prothrombin gene; deficiencies of antithrombin-III, protein C, and protein S; and the presence of antiphospholipid antibodies and fasting homocysteine concentration. A placental histologic study was also carried out. RESULTS: Thirty-five percent of the 75 patients had thrombophilia (control subjects, 16%; P =.008; odds ratio, 2.78). This prevalence was more prominent in second and third trimesters (P =.0002; odds ratio, 6.3), and the presence of combined genetic defects was associated with intrauterine fetal death (P =.04; odds ratio, 12; 95% CI, 1.44-102). When we analyzed the overall gestations of the patients, we observed an increase of intrauterine fetal death in patients with thrombophilia (P =.01) and early pregnancy loss in patients without thrombophilia (P =.02). The analysis of the correlation between extensive placental infarctions and thrombophilic defects rendered values in the boundaries of significance (P =.05). CONCLUSION: The significant high prevalence of biologic causes in patients with late fetal loss suggests that a study of thrombophilia should be carried out, together with an assessment of a preventive treatment.

[Role of antiphospholipid antibodies in 147 patients with spontaneous abortions and stillbirths: a retrospective and prospective analysis]. / Rolia na antifosfolipidnite antitela pri 147 patsientki sus spontanni aborti i murtvorazhdaniia: dvugodishen retro- i prospektiven analiz.

UNLABELLED: Antiphospholipid antibodies (aPL) are a family of autoantibodies including lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and ect. That appear to react with negatively charged phospholipids. These antibodies induce thrombosis and pregnancy complications including recurrent spontaneous abortions (RSA), recurrent stillbirth (SB), preeclampsia and intra-uterine growth retardation, although their exact pathogenic mechanisms remain poorly defined. The aim of this study was to investigate the frequency and the role of a aPL women with a history of RSA and SB due to positive aPL. The study included 147 women with a history of RSA and 48 women with a history of SB and to investigate the histological changes in the heams and stillborn fetuses in aCL positive women. We established that: 1, aCL were significantly increased in 62.2% (n = 92) in women with history of RSA and in 71% (n = 34) in women with history of SB; 2. aTr antibodies were positive in 22.7% (n = 5) in women with history of SB; 3. Tr activation status was increased in 77.3% (n = 17) in women with history of SB. CONCLUSION: The investigation of aPL in women with history of RSA and SB provides new insights into the disease and offers promise for prophylaxis and treatment in subsequent pregnancies.

Hereditary thrombophilias are not associated with a decreased live birth rate in women with recurrent miscarriage.

OBJECTIVE: To assesses the live birth rate without treatment in women with hereditary thrombophilia who have recurrent miscarriage and women without thrombophilia who have recurrent miscarriage. DESIGN: Prospective observational study. SETTING: Tertiary referral unit in university hospital. PATIENT(S): One hundred twenty women with thrombophilia and 65 women without thrombophilia. MAIN OUTCOME MEASURE(S): Number of live births or repeated miscarriages. RESULTS: Of the 185 patients, 44 with thrombophilia and 26 without thrombophilia have conceived. Nineteen of the 44 pregnancies (43.2%) in thrombophilia patients have terminated in live births, compared with 8 of 26 pregnancies (30.8%) in patients without thrombophilia. This difference is not statistically significant. CONCLUSIONS: Hereditary thrombophilia did not seem to affect the live birth rate in women with recurrent miscarriage.

Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss.

BACKGROUND: The genetic predispositions to venous thrombosis such as factor V Leiden (FVL) mutation (Arg 506 Gln), prothrombin (FII) gene mutation (G20210A), and mutation of the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) have been reported to be associated with recurrent pregnancy loss. This paper examines the prevalence of markers for genetic thrombophilias in women with recurrent miscarriage. METHODS: The prevalence of FVL, FII G20210A and MTHFR C677T was compared in 108 women with three or more pregnancy losses either exclusively in the first trimester, or mixed first and second trimester losses, with the prevalence found in 82 fertile parous control women without miscarriages. Markers for the thrombophilias were assessed by PCR analysis. RESULTS: Twenty-three of the 108 patients (21.3%), had thrombophilia markers, which was similar to the proportion of patients in the control group (20.7%) with these markers. The prevalences of FVL and FII G20210A were lower in the study group than in the control group (3.7 versus 6.1% for FVL and 4.6 versus 6.1% for FII respectively); however, the difference was not statistically significant. In contrast, the prevalence of MTHFR C677T was higher in the study group than the control population (13 versus 8.5% respectively), but this difference was not statistically significant. There was no statistically significant prevalence of any particular thrombophilia in patients with previous first and second trimester pregnancy losses compared with patients with first trimester losses alone. CONCLUSION: Thrombophilia was not found to be associated with recurrent pregnancy loss.

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.

Antibodies to factor XII and recurrent fetal loss in patients with the anti-phospholipid syndrome.

Forty female patients with either primary anti-phospholipid syndrome (n = 26) or systemic lupus erythematosus (anti-phospholipid syndrome positive) (n = 14) were investigated for levels of factor XII, the presence of lupus anticoagulant and antibodies to cardiolipin, beta 2-glycoprotein I and factor XII. Twenty-one patients had a history of recurrent fetal loss (> 2, mean = 2.6). Lupus anticoagulant positivity showed a weak association with recurrent fetal loss (odds ratio = 1.1). While there was no association between the presence of antibodies to cardiolipin or beta 2-glycoprotein I with recurrent fetal loss, antibodies to factor XII showed a strong and statistically significant association (odds ratio = 5.4, P = 0.025).

[A case of inflammatory myopathy worsened by miscarriage with autoimmune disorder-associated disease].

The patient was 42-year-old woman who had exhibited elevated levels of serum creatine kinase(CK) and intermittent weakness of proximal muscles since her thirties. She had a history of palmoplantar pustulosis, Mondor's disease and recurrent miscarriages. Basedow's disease, which had been treated with antithyroid drugs since 37 years of age, recurred during the fourth pregnancy. After the pregnancy was terminated in the sixth week, weakness and grasp pain in the proximal muscles developed. The biopsy of biceps brachii muscle showed necrosis and reconstruction of muscle fibers with equivocal inflammatory cells, which was compatible with the findings for inflammatory myopathy such as polymyositis(PM). She was treated with prednisolone and the weakness and grasp pain in the proximal muscles were resolved. PM beginning during a woman's reproductive period is rare, and few studies have examined the association between PM and pregnancy. In this case, pregnancy and her past diseases were considered to be linked to an autoimmune abnormality that might have contributed to the inflammatory myopathy.

Effect of thrombophylaxis on uterine and fetal circulation in pregnant women with a history of pregnancy complications.

PURPOSE: The aim of this study was to investigate the effect of thromboprophylactic therapy on fetal and maternal Doppler flow parameters in pregnant women with severe complications in previous pregnancies and evidence of acquired or congenital thrombophilia in the current pregnancy. METHODS: Sixty-five patients with a history of recurrent abortions, intrauterine fetal death, intrauterine growth restriction (IUGR), and severe early-onset preeclampsia were tested for the presence of acquired or congenital thrombophilia. Those with positive findings were prescribed low-dose aspirin plus low-molecular-weight heparin (LMWH) (enoxaparin); the remainder received low-dose aspirin only. A Doppler flow study was performed before and after treatment and in the third trimester of pregnancy. RESULTS: Of the 65 pregnancies, four ended in spontaneous abortion and were excluded from the analysis. Of the 61 women with completed pregnancies, 37 (61%) had evidence of acquired or congenital thrombophilia: 22 (36%) protein S deficiency; 1 (2%) protein C deficiency; 2 (3%) activated protein C resistance (APC-R); 2 (3%) IgG for antiphospholipid antibodies; 1 (2%) circulating anticoagulant; and 9 (15%) a combined defect. This group showed a significant decrease in mean uterine artery pulsatility index (PI) before and after treatment (1.32+/-0.36 vs. 1.04+/-0.23, P=.006), whereas the remaining 24 patients treated with low-dose aspirin only had nonsignificant changes. Pearson's correlation test yielded no correlations of the pregnancy outcome parameters with Doppler flow values in the umbilical or uterine arteries. CONCLUSIONS: Thromboprophylactic therapy transiently improves maternal circulation parameters in patients with thrombophilia at risk of fetal loss and other severe complications of pregnancy, but not in correlation with their pregnancy outcome. Therefore, Doppler examination of maternofetal circulation in the second trimester is not predictive of pregnancy outcome.