Antiphospholipid syndrome in pregnancy: a randomized,controlled trial of treatment

OBJECTIVE: To compare the efficacy of low-dose aspirin alone versus low-dose aspirin plus low molecular weight heparin in pregnant women with antiphospholipid syndrome and recurrent miscarriage as prophylaxis against pregnancy loss.METHODS: From a regional miscarriage clinic, 119 consecutive women with persistently positive tests for lupus anticoagulant and/or anticardiolipin immunoglobulin G and M antibody were invited to participate in a randomized, controlled trial between 1997 and 2000. After ethical approval and adherence to a written protocol, 12 women were unwilling to participate, five failed exclusion/inclusion criteria, and four were nonpregnant. Laboratory analysis was performed by Sheffield University Coagulation Department, electronically generated randomization by Manchester University Centre for Cancer Epidemiology, and data collection and analysis by a research officer at Leeds University. Viability ultrasound every 2 weeks was provided until 12 weeks' gestation before transfer to the pregnancy support antenatal clinic.RESULTS: Ninety-eight women were randomized before 12 weeks' gestation. Forty-seven received low-dose aspirin 75 mg daily (group A), and 51 received low-dose aspirin plus low molecular weight heparin 5000 U subcutaneously daily (group B) throughout pregnancy. There were 13 pregnancy losses and 34 live births in group A and 11 losses and 40 live births in group B. The live-birth rate was 72% in group A and 78% in group B (odds ratio 1.39, 95% confidence interval 0.55, 3.47). There were no cases of maternal thrombosis in either group.CONCLUSION: A high success rate is achieved when low-dose aspirin is used for antiphospholipid syndrome in pregnancy. The addition of low molecular weight heparin does not significantly improve pregnancy outcome.     

Anticoagulant therapy and pregnancy

Low dose aspirin therapy is one of the anticoagulant treatments used during pregnancy. Anticoagulant agents may be useful for several disorders, such as recurrent miscarriage, pre-eclampsia, fetal growth restriction and infertility. However, it is unclear whether anticoagulant therapy can increase the live birth rate in all of these cases. Recent data suggest that a low-dose aspirin and heparin combination therapy is effective in the prevention of recurrent pregnancy loss in women with antiphospholipid syndrome. Thrombogenic diseases, for example, protein C deficiency, protein S deficiency, factor XII deficiency and hyperhomocysteinemia, may cause pregnancy loss. The etiology of recurrent miscarriage is often unclear and may be multifactorial, with much controversy regarding diagnosis and treatment. Although 70% of recurrent pregnancy losses are unexplained, anticoagulant therapy is effective in maintaining pregnancy without antiphospholipid antibody syndrome. We conclude that a low-dose aspirin and heparin combination therapy can be useful for unexplained cases of recurrent pregnancy loss without antiphospholipid antibody syndrome. (Reprod Med Biol 2008; 7 : 1–10)     

Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin.

OBJECTIVE: To study the obstetric course of women with a history of recurrent miscarriage associated with antiphospholipid antibodies, lupus anticoagulant and anticardiolipin antibodies, treated with low dose aspirin and low dose heparin. DESIGN: Prospective observational study. SETTING: University based tertiary referral clinic. POPULATION: One hundred and fifty pregnant women with a history of recurrent miscarriage associated with persistently positive tests for antiphospholipid antibodies. METHODS: Lupus anticoagulant was detected using the dilute Russell's viper venom time together with a platelet neutralisation procedure. IgG and IgM anticardiolipin antibodies were detected using a standardised enzyme linked immunosorbent assay. An IgG anticardiolipin level > or = 5 per litre units and an IgM anticardiolipin level > or = 3 per litre units was considered positive. Aspirin (75 mg daily) was commenced at the time of a positive pregnancy test and heparin (5000 units subcutaneously 12 hourly, or enoxaparin 20 mg daily) was started when fetal heart activity was demonstrated on ultrasound. Treatment was stopped at the time of miscarriage or at 34 weeks of gestation. RESULTS: One hundred and seven pregnancies (71%) resulted in a live birth. Forty-one pregnancies (27%) miscarried, the majority in the first trimester. One woman had a stillbirth, and one a premature baby who died in the neonatal period. One pregnancy was terminated for a fetal anomaly. Gestational hypertension complicated 17% (18/108) of ongoing pregnancies and antepartum haemorrhage 7% (8/108). Twenty-six babies (24%) were delivered before 37 weeks of gestation. Fifty women (46%) were delivered by caesarean section. The median birthweight of all live born infants was 3069 g (range 531-4300); however 15% (16/108) of the infants were small for gestational age. CONCLUSION: Combination treatment with aspirin and heparin leads to a high live birth rate among women with recurrent miscarriage and antiphospholipid antibodies. However, successful pregnancies are prone to a high risk of complications during all trimesters. Close antenatal surveillance and planned delivery of these pregnancies in a unit with specialist obstetric and neonatal intensive care facilities are indicated.     

Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial

OBJECTIVE: This pilot investigation was undertaken to assess the efficacy of low-dose aspirin therapy for the treatment of women with antiphospholipid antibodies when recurrent miscarriage is the only sequela. STUDY DESIGN: A double-blind, randomized, placebo-controlled trial was conducted in the setting of the recurrent miscarriage clinic of a tertiary referral obstetric hospital. The participants were 50 women with a history of recurrent miscarriages (>/=3) and antiphospholipid antibodies. Women with systemic lupus erythematosus or a history of thrombosis were excluded. Women were recruited after full investigative screening at the recurrent miscarriage clinic. Women with >/=3 fetal losses and persistently positive results for antiphospholipid antibodies were randomly allocated to receive either aspirin (75 mg daily) or placebo. Investigators, clinicians, and patients were blinded to the treatment. Rates of live births, antenatal complications, and delivery and neonatal outcomes were recorded prospectively. Data were compared by chi(2) analysis with Yates' correction, the Fisher exact test, or the Student t test as appropriate. RESULTS: There were 10 exclusions after random assignment because of inappropriate inclusion. Eighty-five percent of the placebo (17/20) group and 80% of the aspirin-treated group (16/20) were delivered of live infants. This difference was not significant. There were no significant differences in antenatal complications or neonatal morbidity between the groups. CONCLUSIONS: This preliminary study suggests that low-dose aspirin has no additional benefit when added to supportive care for women for whom recurrent early fetal loss is the only sequela of the antiphospholipid syndrome. This live birth rate with supportive care alone exceeds the published live birth rates for women with antiphospholipid antibody-mediated recurrent fetal loss who were treated with heparin or corticosteroids. This trial, like all other trials in this field, is small, but its results bring into question the need for pharmacologic intervention for women with antiphospholipid syndrome for whom recurrent fetal loss is the only sequela. Our results highlight the need for a large randomized controlled trial to identify the optimal treatment for this group of women and justify the inclusion of a placebo arm in any such trial.     

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%.     

Recurrent miscarriage associated with antiphospholipid antibodies: prophylactic treatment with low-dose aspirin and fish oil derivates

PROBLEM: The aim of this study was to evaluate the effects of two different prophylactic protocols, low-dose aspirin and fish oil derivates, in the treatment of patients with recurrent pregnancy loss associated with antiphospholipid antibodies (APA) syndrome. METHODS: A prospective study included 30 patients who were alternately assigned to treatment. Each patient had had at least two consecutive spontaneous abortions, positive antiphospholipid antibodies on two occasions, and a complete evaluation. RESULTS: Among patients treated with low-dose aspirin, 12 out of the 15 (80%) pregnancies ended in live births. In the fish oil derivate group 11 out of the 15 (73.3%) ended in live births (p > 0.05). There were no significant differences between the low-dose aspirin and the fish oil derivates groups with respect to gestational age at delivery (39.9 +/- 0.4 vs 39 +/- 1.5 weeks), fetal birth weight (3290 +/- 200g vs 3560 +/- 100 g), number of cesarean sections (25% vs 18%), or complications. CONCLUSION: There were no significant differences in terms of pregnancy outcome between women with recurrent pregnancy loss associated with APA syndrome treated with low-dose aspirin or fish oil derivates.     

Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study

OBJECTIVE: To compare the use of enoxaparin alone with combination therapy of prednisone, aspirin and progesterone in the treatment of women with idiopathic recurrent miscarriage (IRM) in terms of live births and pregnancy outcome. METHODS: A prospective, randomized, single-blinded, placebo-controlled trial was conducted at a tertiary referral obstetric hospital. The participants were 170 women with a diagnosis of IRM. Women were recruited after full investigative screening. Women with > or =3 fetal losses and after exclusion of all known causes of recurrent miscarriage were randomly allocated to receive either enoxaparin alone, combination treatment consisting of prednisone, aspirin, and progesterone or placebo. Rates of live births, antenatal complications, delivery and neonatal outcomes were recorded prospectively. Data were statistically analyzed as appropriate. RESULTS: Ten patients were dropped out after random assignment. Eighty-one percent of the enoxaparin (46/57) group and 85% of the combination-treated group (45/53) were delivered of live infants compared to 48% (24/50) of the placebo (P < 0.05). Women who were treated with combination therapy had a 4.2% higher live birth rate than enoxaparin group. This difference was not significant. Miscarriage rates were significantly lower in the treated groups compared with placebo (P < 0.05). There were no significant differences in late obstetric complications or neonatal mortality between groups. CONCLUSIONS: A combination treatment consisting of high-dose, low-duration prednisone, progesterone and aspirin might be an effective treatment as enoxaparin alone. Both regimens were associated with a good pregnancy outcome.     

Enoxaparin and aspirin therapy for recurrent pregnancy loss due to anti-phospholipid syndrome (APS)

BackgroundRecurrent miscarriage affects 1–2% of women. Thrombophilia included antiphospholipid syndrome has been identified in about 50% of women with recurrent miscarriage. Aspirin and heparin therapy is frequently prescribed for APS, yet there is no robust evidence for the most efficacious regime.ObjectiveTo determine maternal and foetal outcomes in women with APS managed with aspirin or enoxaparin plus aspirin during pregnancy.DesignProspective non randomized study.SettingHigh-risk pregnancy unit-Benha University Hospital.MethodsSeventy selected patients during pregnancy with clinical and/or serological findings of antiphospholipid syndrome were divided into two Groups: Group A (n = 47) had received aspirin (81 mg once daily orally) plus LMWH enoxaparin (40 mg subcutaneously/day) while Group B (n = 23) had received low-dose aspirin (81 mg day orally).Main outcome measuresMaternal outcomes included thromboembolic, haemorrhagic complications and pregnancy-induced hypertension. Prematurity, intrauterine growth restriction and neonatal death were considered as foetal complications.ResultsThere were significant differences between Groups A and B in the rate of miscarriages (4 in Group A (9%) versus 8 in Group B (35%); p = 0.02), number of live births (43/47(91%) versus 15/23(65%); p = 0.02), mean gestational age (37.86 ± 1.8 versus 36.13 ± 2.39 weeks; p = 0.005), neonatal birth weight (3252 ± 459 versus 2907 ± 618 g; p = 0.03) and rate of pre-eclampsia (3/43 (7%) versus 6/15 (40%); p = 0.009). Although not statistically significant, women in Group A tended to have lower rates of preterm births (6/43 (14%) versus 3/15 (20%); p = 0.89) and IUGR (5/43 (12%) versus 5/15 (33%); p = 0.13) than in Group B.ConclusionsUse of low dose aspirin and enoxaparin 40 mg subcutaneously daily in patients with RPL due to antiphospholipid syndrome resulted in higher live birth rates compared to low dose aspirin alone. Solid conclusions from this study are limited due to the small number of patients, non-randomization of groups and discrepancy in number between groups because the choice of the interventional drug was left to patient’s preference after counselling. A larger RCT is needed.     

妊娠合并抗磷脂综合征13例临床分析

目的探讨妊娠合并抗磷脂综合征患者的孕期治疗与母儿结局。方法回顾性分析北京大学人民医院1990年1月至2013年7月妊娠合并抗磷脂综合征患者的临床资料。结果妊娠期共13例患者符合抗磷脂综合征的诊断。其中,按诊断时间分孕前诊断10例,孕期诊断3例;按类型分原发性抗磷脂综合征12例,继发性抗磷脂综合征1例。13例患者中3次以上胎停育或胎死宫内病史者8例。孕期治疗以小剂量阿司匹林治疗2例,以低分子肝素治疗3例,以小剂量阿司匹林联合强的松治疗3例,以小剂量阿司匹林联合低分子肝素治疗3例,由于血小板减少以糖皮质激素及丙种球蛋白治疗1例,单独丙种球蛋白1例。母儿结局：13例患者均获活产新生儿,围产死亡率0%。足月分娩11例,早产2例,平均体重（2 921.43±1326.6）g。胎儿宫内生长受限2例。重度子痫前期1例,妊娠高血压1例。结论孕期适当的干预治疗可改善妊娠合并抗磷脂综合征患者的妊娠结局,应重视并提高对妊娠期出现的抗磷脂综合征的及时诊断及必要的治疗。     

Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience.

OBJECTIVE: To determine the outcome of treated pregnancies in women with well-characterized antiphospholipid syndrome. METHODS: We reviewed 82 consecutive pregnancies in 54 women with antiphospholipid syndrome who were treated during pregnancy with the following: 1) prednisone and low-dose aspirin; 2) heparin and low-dose aspirin; 3) prednisone, heparin, and low-dose aspirin; or 4) other combinations of these medications or immunoglobulin. RESULTS: The overall neonatal survival rate was 73%, excluding spontaneous abortions, but treatment failures (fetal and neonatal deaths) occurred in all treatment groups. Patients with successful treated pregnancies had fewer previous fetal deaths than those with unsuccessful treated pregnancies. There were no significant differences in outcome among the four treatment groups. Preeclampsia and fetal distress occurred in half of all pregnancies, and fetal growth impairment occurred in nearly one-third. Preterm delivery due to maternal or fetal indications was required in 37% of the pregnancies. Four pregnancies were also complicated by postpartum thrombosis during treatment. CONCLUSIONS: Pregnancy in women with antiphospholipid syndrome appears to be improved by treatment, but fetal loss may occur despite treatment. Preeclampsia, fetal distress, fetal growth impairment, and premature delivery are common. Because of the clinically significant risk of thrombotic episodes, thrombosis prophylaxis should be considered in these patients.     

Aspirin and reproductive outcomes

In the late 1980s and early 1990s, researchers hypothesized that aspirin could be used to prevent or delay the onset of preeclampsia. This hypothesis was tested in numerous trials which showed limited, but positive results. Subsequently, aspirin has been used in an attempt to improve pregnancy outcomes in women who have both antiphospholipid antibodies and a history of recurrent loss, and has also been used in an attempt to improve the success of in vitro fertilization. In theory, aspirin has both positive and negative effects on reproduction. Aspirin, which suppresses cyclooxygenase, has the potential to interfere with implantation, but also has the potential to support the maintenance of pregnancy. Aspirin is prescribed with increasing frequency to reduce the risk of maternal thrombosis and reduce the risk of miscarriage and poor pregnancy outcome. Aspirin alone, however, is not considered sufficient to prevent thrombosis and even in women with the antiphospholipid syndrome, the question as to whether low-dose aspirin improves pregnancy outcomes has not been answered affirmatively. Aspirin has potential risks. Aspirin inhibits platelet function and can contribute to maternal and fetal bleeding. Aspirin crosses the placenta. Although aspirin has not been associated with other congenital anomalies, it has been associated with an increased risk of vascular disruptions, particularly gastroschisis and possibly premature closure of the ductus arteriosus. Nonetheless, large trials demonstrate low-dose aspirin's relative safety and generally positive effects on reproductive outcomes.     

An analysis of the pattern of pregnancy loss in women with recurrent miscarriage

OBJECTIVE: To describe the pattern of pregnancy loss in women with a history of recurrent miscarriage (RM). DESIGN: Retrospective, observational study. SETTING: A tertiary referral center for RM. PATIENT(S): Five hundred thirty-eight subjects with RM. INTERVENTION(S): Women with antiphospholipid syndrome were treated with clexane and aspirin; some patients with uterine anomalies underwent corrective surgery, and some cases of retarded endometrium were treated with hMG. MAIN OUTCOME MEASURE(S): Pregnancy outcome, including the stage of pregnancy at which pregnancy loss occurred. RESULT(S): In women with a prothrombotic state, the miscarriage rate before the detection of fetal heart activity (early loss) in the untreated group (50%) was significantly higher than in the treatment group (17.5%). In women with a uterine anomaly, the early loss rate and the later loss rate (after detection of fetal heart activity) were both increased. Women with retarded endometrium, women with >/=6 losses, and older women (>/=41 years) are more likely to have a further early loss but not a later loss. CONCLUSION(S): An understanding of the patterns of pregnancy loss provides further insight into the mechanism of the reproductive failure, which has implications for treatment.     

A favorable outcome of pregnancies in women with primary and secondary recurrent pregnancy loss associated with antiphospholipid syndrome

Objective:To study the outcome of pregnancies in women with primary and secondary recurrent pregnancy loss associated with antiphospholipid syndrome treated with the standard treatment regimes including intravenous immunoglobulin (IV Ig). Methods: Forty three patients with recurrent pregnancy loss associated with antiphospholipid syndrome diagnosed before pregnancy and subdivided into primary (18) and secondary (25) subgroups were closely monitored all through pregnancy with serial blood tests and ultrasonography until the pregnancy ended in miscarriage or delivery. The patients were treated with low-dose aspirin and heparin and or steroids and IV Ig given to some selected patients. The maternal and fetal outcomes were analysed. Results: The mean age of the patients in the primary sub group (24.60±4.30) years was significantly lower than the mean age of the secondary recurrent pregnancy loss group (31.50±4.50) years, (p<0.0001). 85.00% of all the previous miscarriages were in the first trimester. There was no significant difference in the incidence of live births in the primary (77.80%) and secondary (84.00%) groups, (p>0.05); the babies were of normal birth weight. The incidence of caesarean section in the primary and secondary groups, 22.23% and 12.00% respectively, were not significantly different (p>0.05). Intravenous immunoglobulin added to the standard therapy resulted in 100% live births. Maternal complications were negligible. Conclusions: The fetal and maternal outcome of pregnancies in patients with primary and secondary recurrent pregnancy loss associated with antiphospholipid syndrome were virtually identical and quite satisfactory. Intravenous immunoglobulin added to the standard therapy resulted in excellent fetal and maternal outcome, although its definitive role will have to wait for the outcome of randomised trials. Received: 22 November 2000 / Accepted: 19 February 2001     

Treatment outcome in women suffering from recurrent miscarriages and antiphospholipid syndrome

OBJECTIVE: To evaluate the outcomes of treatment in patients suffering from recurrent spontaneous abortion and antiphospholipid syndrome. MATERIALS AND METHODS: 148 observed women suffering from recurrent abortion with presence of lupus anticoagulant antibodies (LA) and/or high moderate concentration of anticardiolipin antibodies (ACA) have been divided randomly into followed three treated groups: I--56 patients treated by low-dose of acetylsalicylic acid (LDA, 75 mg daily); II--39 patients treated by low molecular weight heparin (applied in dose of 20 g daily); III--53 patients treated by LDA and low molecular weight heparin simultaneously. RESULTS: It has been affirmed that coincidental application of low-dose of acetylsalicylic acid and low molecular weight heparin statistically more often increase the percentage of successful pregnancy in comparison with application of low molecular weight heparin or acetylsalicylic acid alone. In the group where only low-dose of acetylsalicylic acid was applied the success of pregnancy equaled 89.3%, in the group where only low molecular weight heparin was applied the successful pregnancy equaled 81.1% and in the group with acetylsalicylic acid and low molecular weight heparin being applied together the successful pregnancy equaled 92.5%. In has simultaneously been affirmed that the percentage of pregnancy loss is statistically higher in the women suffering from isolated occurrence of lupus anticoagulant antibodies (21.2%) in comparison with the women suffering from occurrence of anticardiolipin antibodies (6.7%) and anticardiolipin antibodies with lupus anticoagulant antibodies simultaneously. CONCLUSION: 1. Simultaneous application of low-doses of acetylsalicylic acid and low molecular weight heparin seems to be the best solution in patients suffering from recurrent spontaneous abortion and antiphospholipid syndrome. 2. The occurrence of anticardiolipin antibodies in the serum of blood in patients suffering from antiphospholipid syndrome is a better foretelling factor for the future pregnancy outcome than the occurrence of lupus anticoagulant antibodies.     

Prednisolone plus low-dose aspirin improves the implantation rate in women with autoimmune conditions who are undergoing in vitro fertilization

Objective: To evaluate the effect of prednisolone plus low-dose aspirin (PSL/LDA) in women with autoimmune conditions who were enrolled in an IVF-ET program.

Design: A retrospective clinical study.

Setting: In vitro fertilization unit, Niigata University Hospital, Niigata, Japan.

Patient(s): Three hundred seven women who underwent IVF-ET between January 1996 and December 1997.

Intervention(s): Prednisolone (10 mg/d) and aspirin (81 mg/d) were administered to the women with autoantibodies who chose to participate.

Main Outcome Measure(s): Pregnancy and implantation rates with IVF-ET.

Result(s): Women undergoing IVF who had positive antinuclear antibodies, with or without antiphospholipid antibodies, had significantly lower pregnancy and implantation rates than did women without autoantibodies (14.8% versus 21.7% and 6.8% versus 10.4%, respectively). The administration of PSL/LDA to women with antinuclear antibodies significantly improved the outcome of IVF-ET (40.6% pregnancy rate and 20.3% implantation rate).

Conclusion(s): A high proportion of women who are undergoing IVF-ET have autoantibodies, which are associated with poor IVF outcomes. The administration of PSL/LDA to these women may improve their implantation rate.     

Enoxaparin treatment in women with mechanical heart valves during pregnancy

OBJECTIVE: This prospective audit reports pregnancy outcomes, anticoagulation complications, and anti-Xa levels in women with mechanical heart valves who were treated with therapeutic enoxaparin plus aspirin during pregnancy. STUDY DESIGN: Between 1997 and 1999, 11 women with mechanical heart valves were treated with enoxaparin, 1 mg/kg twice daily, and aspirin, 100 to 150 mg daily during 14 pregnancies. Predose and 4-hour postdose anti-Xa levels were monitored monthly. RESULTS: There were 9 live births, 3 miscarriages, and 2 terminations. In 48 months of enoxaparin treatment, one woman who had a documented valve thrombosis when she presented at 8 weeks' gestation also had a valve thrombosis at 20 weeks' gestation. There were no enoxaparin-related hemorrhagic complications. Mean (SD) anti-Xa levels were 0.46 (0.12) U/mL predose and 0.89 (0.22) U/mL 4 hours postdose. CONCLUSION: Successful pregnancy outcome may be achieved with therapeutic subcutaneous enoxaparin, but its efficacy at preventing valve thrombosis remains uncertain. Further data are required before use of enoxaparin during pregnancy in women with mechanical heart valves can be recommended.     

Recurrent miscarriage: pathophysiology and outcome

PURPOSE OF REVIEW: This article reviews new concepts in the aetiology of recurrent miscarriage, presents new outcome data and evaluates new modalities of treatment for unexplained recurrent miscarriage. RECENT FINDINGS: Preimplantation genetic diagnosis has been considered an option for couples who have structural chromosomal abnormalities or unexplained recurrent miscarriage. The association between thrombophilias and adverse pregnancy outcome is further reviewed. In relation to this, there is increasing support for the use of thromboprophylaxis in improving pregnancy outcome in women with inherited thrombophilias. Nonrandomized studies have shown that the reduction in insulin levels with metformin in insulin-resistant individuals may reduce miscarriage risk by restoring normal haemostasis and improving the endometrial milieu. With respect to immunological concepts there is now evidence to suggest that, in addition to a suppression of maternal cell-mediated immunity, some elements of the innate immune system are activated in successful pregnancies. SUMMARY: With the exception of aspirin and heparin for the prevention of recurrent miscarriage in women with the antiphospholipid syndrome, no other suggested therapies for this heterogeneous group of patients have been evaluated in randomized controlled trials. These include thromboprophylaxis for inherited thrombophilias and use of insulin sensitizers in women with insulin resistance and/or polycystic ovarian syndrome. The role of the innate immune system in pregnancy was recently highlighted, and use of nonspecific therapies to suppress the maternal immune response to pregnancy should be reassessed.     

A randomized,double-blind,placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies

OBJECTIVE: To investigate whether heparin and low-dose aspirin increase the pregnancy rate in antiphospholipid antibody or antinuclear antibody-seropositive women with IVF implantation failure. DESIGN: A double-blind, randomized, transfer-by-transfer of fresh or cryopreserved embryos, crossover trial.A hospital infertility clinic and associated IVF service. PATIENT(S): Women seropositive for at least one antiphospholipid (APA), antinuclear (ANA), or beta(2) glycoprotein I autoantibody and >or=10 embryos transferred without achieving pregnancy (n = 143). INTERVENTION(S): Subcutaneous unfractionated heparin (5000 IU b.i.d.) and aspirin (100 mg daily) (158 transfers of 296 embryos) or placebo (142 transfers of 259 embryos) from the day of embryo transfer. MAIN OUTCOME MEASURE(S): Fetal heart per embryo transferred (implantation rate). RESULT(S): There was no significant difference in pregnancy rates or implantation rates between treated and placebo cycles; for example, fetal hearts per embryo transferred implantation rates were 6.8% (20/296) and 8.5% (22/259), respectively, and the generalized estimating equation covariate adjusted relative pregnancy rate was 0.65 (95% confidence interval, 0.33-1.28). The implantation rate for seropositive trial participants (42/555, 7.6%) compared favorably with that for IVF implantation-failure patients continuing treatment outside the trial (147/3237, 4.5%). CONCLUSION(S): Heparin and aspirin did not improve pregnancy or implantation rates for APA-positive or ANA-positive patients with IVF implantation failure.     

Lupus anticoagulant as a marker of autoimmunity in recurrent pregnancy loss; a case report

We present a patient with primary antiphospholipid syndrome, as defined by nine pregnancy losses, the presence of lupus anticoagulant (LAC), and the absence of clinical signs and symptoms of autoimmunity. A successful pregnancy was achieved by treatment with low-dose prednisone (15 mg daily) and aspirin (100 mg daily). The patient was followed-up throughout her two last pregnancies and a 6 months postpartum period. Our data indicate that LAC serves as a marker of disease in women with previous pregnancy wastages, and that aspirin-prednisone therapy is beneficial in carefully selected patients.     

Antiphospohlipid syndrome in obstetrics

Antiphospholipid syndrome is characterised by a variety of clinical and immunological manifestations. The clinical hallmarks of this syndrome are thrombosis and poor obstetric outcomes, including miscarriages, fetal loss and severe pre-eclampsia. The main antiphospholipid antibodies include lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I. The combination of aspirin and heparin is considered the standard of care for women with antiphospholipid syndrome and embryo-fetal losses; however, aspirin in monotherapy may have a place in women with recurrent early miscarriage. A good benefit-risk ratio of low-molecular-weight heparin in pregnancy thrombosis treatment has been reported. Warfarin must be avoided if possible throughout the first trimester of pregnancy. Adequate pregnancy management of women with antiphospholipid syndrome should include co-ordinated medical-obstetrical care, a close follow-up protocol and a good neonatal unit. Close blood pressure control and early detection of proteinuria, together with Doppler studies of the utero-placental circulation should be included in the management protocol.