First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss

The objective of this study was to assess pregnancy outcome in women with a history of refractory antiphospholipid antibody-associated pregnancy loss(es) who were treated with early low-dose prednisolone in addition to aspirin and heparin. Eighteen women with antiphospholipid antibodies who had refractory pregnancy loss(es) were given prednisolone (10 mg) from the time of their positive pregnancy test to 14 weeks' gestation. Before low-dose prednisolone was given as treatment, 4 (4%) of 97 pregnancies had resulted in live births. Among 23 pregnancies supplemented with prednisolone, 9 women had 14 live births (61%), including 8 uncomplicated pregnancies. The remainder were complicated by preterm delivery, preeclampsia, and/or small-for-gestational-age infants. There were 8 first-trimester miscarriages and 1 ectopic pregnancy. There were no fetal deaths after 10 weeks' gestation and no evidence of maternal morbidity. The addition of first-trimester low-dose prednisolone to conventional treatment is worthy of further assessment in the management of refractory antiphospholipid antibody-related pregnancy loss(es), although complications remain elevated.     

The anti-phospholipid antibody syndrome (Hughes syndrome): therapeutic aspects.

Despite the enormous amount of work focused on the pathogenesis and clinical manifestations of the Hughes or anti-phospholipid syndrome (APS), there is little published on management. Usually, the diagnosis of APS is made after the first thrombotic event, when a thrombophilia screen is performed. These patients have a high risk of recurrent thromboses and current therapy centres on the use of thromboprophylaxis with warfarin. However, a number of clinical questions keep recurring: do arterial and venous thrombosis require the same intensity of anti-coagulation? When should warfarin be stopped? Should patients who develop thrombosis when other risk factors (oral contraceptive pill, prolonged resting etc.) are present be treated like those without any risk factors but the presence of anti-phospholipid antibodies (aPL)? How to manage a patient with recurrent thrombosis despite a high intensity anti-coagulation (International normalized ratio (INR) between 3.0-4.0)? Since many of the patients with aPL are fertile women, a substantial group of patients are diagnosed after recurrent pregnancy loss. Low-dose aspirin for those patients without previous thrombosis and aspirin plus heparin for patients with a history of thrombotic events are the current therapeutic options. However, some questions remain unanswered: does the addition of heparin to low-dose aspirin in women with first trimester recurrent miscarriage but without previous thrombosis improve foetal outcome over and above aspirin alone? Which is the best therapeutic regime during pregnancy for patients with aPL-associated stroke? When should high-dose intravenous gammaglobulin be considered? Finally, very little is known about the risk of thrombosis in individuals positive for aPL but still free of thrombosis. Should these individuals receive any treatment? If so, which one? In this review we attempt to address some of these questions taking into account available data from retrospective and prospective studies and our own clinical experience.     

Postpartum management of women at increased risk of thrombosis--results of a Canadian pilot survey

OBJECTIVE: To determine current practice patterns in the postpartum management of women at increased risk of thrombosis. METHODS: Physicians affiliated with the University of Toronto departments of Obstetrics and Gynecology, Rheumatology, Hematology, and Obstetric Medicine who provide care to pregnant women were mailed a questionnaire that presented 6 clinical scenarios involving postpartum management of a woman at risk for thrombosis, with (1) recurrent pregnancy loss and antiphospholipid antibody syndrome (APS) treated with aspirin (ASA) in the pregnancy; (2) 2 pregnancy losses and a low titer antiphospholipid antibody (aPL) treated with ASA and low molecular weight (LMW) heparin with placental insufficiency; (3) known APS and pregnancy loss treated with LMW heparin and delivered by cesarean section; (4) a previous 17 week fetal death and aPL; (5) a previous deep vein thrombosis while on oral contraception; and (6) systemic lupus erythematosus and secondary APS with a history of a stillbirth. Physicians were asked whether they would recommend postpartum coagulation, and if so to choose from a list of treatment options. RESULTS: Of the 71 questionnaires mailed, 44 were returned (62%). Three physicians replied that their practices do not include patients similar to those presented in the cases and chose not to respond to the clinical scenarios. Percentages of responders recommending treatment in each scenario were 29% for Case 1, 49% for Case 2, 63% for Case 3, 41% for Case 4, 51% for Case 5, and 58% for Case 6. Recommendation for treatment differed among medical specialties, with rheumatologists being less likely to treat in all cases. Prophylactic heparin was selected as the treatment of choice most frequently by those recommending anticoagulation 70% (84/120). CONCLUSION: Postpartum treatment recommendations for women at increased risk of thrombosis are variable across different practitioner specializations demonstrating clinical equipoise regarding therapy. More definitive research is needed and broader study of physicians involved in the care of these patients is planned to more accurately describe and understand the decision to treat these patients.     

Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder

The prospective evaluation of the effect of thromboprophylaxis in women with one unexplained pregnancy loss from the 10th week of amenorrhea was performed. A total of 160 patients with heterozygous factor V Leiden mutation, prothrombin G20210A mutation, or protein S deficiency were given 5 mg folic acid daily before conception, to be continued during pregnancy, and low-dose aspirin 100 mg daily or low-molecular-weight heparin enoxaparin 40 mg was taken from the 8th week. Twenty-three of the 80 patients treated with low-dose aspirin and 69 of the 80 patients treated with enoxaparin had a healthy live birth (odds ratio [OR], 15.5; 95% confidence interval [CI], 7-34, P <.0001). Enoxaparin was superior to low-dose aspirin in each subgroup defined according to the underlying constitutional thrombophilic disorder. An associated protein Z deficiency and/or positive antiprotein Z antibodies were associated with poorer outcomes. The neonate weight was higher in the women successfully treated with enoxaparin, and neonates small for gestational age were more frequent in patients treated with low-dose aspirin. No significant side effects of the treatments could be evidenced in patients or newborns. As there is no argument to prove that low-dose aspirin may have been deleterious, these results support enoxaparin use during such at-risk pregnancies.     

Pregnancy in essential thrombocythaemia: treatment and outcome of 17 pregnancies

OBJECTIVE: To evaluate treatment and outcome of 17 pregnancies in nine patients with essential thrombocythaemia (ET) seen at our institution from 1988 to 1998. METHODS: Treatment and outcome of 17 pregnancies in nine ET patients were retrospectively analyzed. RESULTS: Seventeen pregnancies in nine patients with ET resulted in 11 (65%) live births and ended in six (35%) spontaneous abortions. Abortion could not be predicted from ET-associated complications before (p= 0.23) or during (p = 0.39) pregnancy. Maternal complications occurred during six pregnancies (35%): Three major bleedings in two patients with an acquired von Willebrand disease and two minor bleedings in patients treated with low-dose acetylsalicylic acid (ASA) were observed during pregnancy or at term; one patient suffered from transient visual loss while pausing low-dose ASA. Platelet counts prior to pregnancy were significantly higher as compared to the platelet nadir observed during pregnancy (p = 0.0017). Postpartum clinical course was uneventful in all patients. No specific treatment was given during 11 pregnancies. Six women received low-dose ASA during pregnancy followed by low-molecular-weight heparin until the end of the sixth week postpartum in five cases. This treatment was correlated with a favourable outcome (live birth versus abortion) when compared to no treatment (p=0.04). CONCLUSION: Pregnancy in ET can be complicated by first trimester abortion and/or maternal haemorrhage. Our limited observation suggest a positive impact of low-dose ASA during pregnancy followed by low-molecular-weight heparin postpartum on pregnancy outcome in ET; nevertheless, confirmation by prospective documentation is mandatory.     

The efficacy and safety of second-line treatments of refractory and/or high risk pregnant antiphospholipid syndrome patients. A systematic literature review analyzing 313 pregnancies

ObjectiveThe most efficacious strategy to manage pregnant patients with antiphospholipid syndrome (APS) refractory to conventional heparin/low-dose aspirin treatment or at high risk of adverse pregnancy outcomes has not been determined with any degree of certainty. The study set out to evaluate the efficacy and safety of the second-line treatments most frequently used in addition to conventional therapy, and the data were analyzed to identify which is/are associated to the best pregnancy outcomes.MethodsA systematic review of the literature on studies concerning second-line treatments for refractory and/or high risk pregnant APS women published between February 2006 and February 2020 was conducted. The records were retrieved by searching Medline via Pubmed, the Web of Science platform, the Cochrane library database and clinicaltrials.gov.ResultsFourteen studies met the eligibility criteria of the review: six retrospective cohort studies, one case-control, one case-series and six case reports. The results of single treatment protocols based upon hydroxychloroquine (HCQ), low-dose steroids (LDS), intravenous immunoglobulins (IVIG), plasma exchange (PE) or pravastatin and of combination protocols based upon HCQ+LDS, IVIG+LDS, PE+LDS and PE+IVIG used during 313 pregnancies in 303 APS women were analyzed and compared. The second-line treatments produced 261/313 (83.4%) live births; severe pregnancy complications were registered in 75/313 (24%) pregnancies. Drug side-effects were observed in 3/313 (0.9%) pregnancies. Statistical analysis identified a significantly higher live birth rate and/or a significantly lower number of severe complications in the pregnancies treated with IVIG, HCQ, pravastatin, PE+IVIG and PE+LDS.ConclusionOur results suggest using low-dose IVIG (< 2 g/Kg/month) or HCQ 400 mg/day starting before pregnancy in women with APS refractory to conventional therapy, while high-dose IVIG (2 g/Kg/month) associated with PE or alone in those with high risk±refractory APS.     

Identification of an Fc gamma receptor-independent mechanism by which intravenous immunoglobulin ameliorates antiphospholipid antibody-induced thrombogenic phenotype

OBJECTIVE: Patients with the antiphospholipid antibody syndrome (APS) often experience recurrent arterial and venous thrombosis and pregnancy losses. Intravenous immunoglobulin (IVIG) therapy has prevented pregnancy loss in some women with APS and has reversed fetal resorption rates in murine models of pregnancy loss. Although the basis for these effects is unknown, effector mechanisms of pathogenic antibodies often involve receptors for IgG (Fc gamma receptors [Fc gammaR]). We examined the potential mechanisms of action of WIG in an in vivo murine model of antiphospholipid antibody (aPL)-induced thrombosis and endothelial cell activation. METHODS: Mice infused with IgG containing human anticardiolipin antibodies (aCL) were treated with IVIG (36 microg i.v.), saline, or ovalbumin. Surgically induced thrombus formation and in vivo leukocyte adhesion to endothelial cells were measured. Circulating levels of aCL were measured by enzyme-linked immunosorbent assay. To determine whether Fc gammaR are required for the effects of IVIG, we treated mice deficient in stimulatory Fc gammaR. To examine the effects of IVIG on endogenously generated antibody, we treated mice immunized with beta2-glycoprotein I (beta2GPI). RESULTS: IVIG treatment inhibited aPL-induced endothelial cell activation and enhancement of thrombosis in mice passively infused with human aPL-containing IgG, and this was associated with a decrease in aPL levels. Similarly, IVIG lowered aPL levels and inhibited thrombogenesis in mice immunized with beta2GPI. The thrombophilic effects of aPL were evident in Fc gammaR-deficient mice. CONCLUSION: Treatment with IVIG inhibits the thrombogenic effects of aPL in vivo and reduces the levels of aCL in the circulation. Blockade of stimulatory Fc gammaR on inflammatory cells is not necessary for this effect. The mechanism of action of IVIG is more likely saturation of the IgG transport receptor, leading to accelerated catabolism of pathogenic aPL. These results have implications in the management of thrombosis in APS and may have applications for pregnant patients with a history of APS.     

Incidence of postpartum thrombosis and preterm delivery in women with antiphospholipid antibodies and recurrent pregnancy loss

OBJECTIVE: To determine the frequency of preterm deliveries and postpartum thrombotic events (TE) in pregnancies resulting in live birth in women with antiphospholipid antibodies (aPL) and a history of recurrent pregnancy loss (RPL) but without prior TE. METHODS: We reviewed the pregnancy outcomes of women referred to our clinic with a history of RPL. Prepregnancy investigation of RPL included history of TE and aPL positivity (anticardiolipin IgG and lupus anticoagulant). We recorded use of anticoagulation therapy during and after pregnancy, obstetric outcome, gestational age at delivery, and postpartum course. Included in our study were women with unexplained RPL with no history of TE attending our clinic who subsequently had pregnancies that resulted in a live birth. RESULTS: Over a 5-year period, 260 women with RPL and no history of TE had a live birth at our clinic. Eighty-seven (33.5%) were positive for aPL and 173 (66.5%) were negative for aPL. Twenty-four percent of deliveries in the aPL-positive group occurred before 37 weeks' gestation compared to 9.8% of deliveries in the aPL-negative group (p = 0.004; 95% CI 0.052-0.234). There were no antepartum TE in either group. One woman in the aPL-positive group (1.1%) had a deep vein thrombosis 3.5 weeks postpartum while receiving prophylactic anticoagulant therapy, compared to none in the aPL-negative group. CONCLUSION: A significantly higher proportion of aPL-positive patients had preterm deliveries compared to aPL-negative patients, but pregnancy-related TE was infrequent: 99.0% of aPL-positive women with a history of RPL and no prior TE who had a live birth at our clinic had an uneventful pregnancy, delivery, and postpartum course.     

Management of Philadelphia negative chronic myeloproliferative disorders in pregnancy

The management of pregnancy in Philadelphia negative chronic myeloproliferative disorders (CMPDs) is an increasingly frequent problem. In the literature, most pregnancies are reported for women with essential thrombocythemia (ET) with about 400 pregnancies in about 200 women. In ET, first trimester abortion is the most frequent complication occurring in about one third of pregnancies. Interestingly, the incidence of maternal complications is relatively low with 3% for major thromboembolic and 2% for major bleeding events. The presence of the Jak2 mutation seems to be an independent predictor of pregnancy complications. Pregnancies in ET should be stratified according to underlying risk factors in low, high and highest risk pregnancies. Women with low risk pregnancies are treated with low-dose aspirin, whereas women with high and higher risk pregnancies may benefit from low-dose aspirin plus interferon alpha +/- low molecular weight heparin throughout pregnancy and at least for six weeks post-partum. In polycythemia vera (PV) there is only very few information on pregnancy outcome with 36 pregnancies reported in the literature. According to these data pregnancy in PV is per se a high risk situation. Accordingly, all women with PV should be treated with low-dose aspirin. Some pregnant PV patients may benefit from a more intensive therapy including interferon alpha +/- low molecular weight heparin throughout pregnancy and at least for six weeks post-partum.     

Update on the management of the pregnant patient with antiphospholipid antibody

Management of the pregnant patient with antiphospholipid antibody (aPL) is reviewed, with emphasis on recent randomized controlled clinical trials. These support the use of subcutaneous heparin and low dose aspirin, current standard therapy for women with aPL and a history of fetal loss. Prednisone is rarely used due to high risk of maternal and fetal morbidity. Intravenous immunoglobulin may represent an important additional therapy for women who fail aspirin and heparin. Patients with a history of thrombosis require full, therapeutic anticoagulation during pregnancy. Recommendations are less clear for newly described antibodies to phospholipid-binding protein, for low titer antibodies, and for infertility treatment in the setting of aPL.     

Pregnancy after mechanical mitral valve replacement

BACKGROUND AND AIM OF THE STUDY: Forty-six pregnancies among 32 patients after mitral valve replacement (MVR) were reviewed. Prosthetic valve-related complications, and outcome of pregnancy including feto-maternal mortality and morbidity for different anticoagulation regimens are presented and discussed. METHODS: Among 521 women of fertile age undergoing MVR with a St. Jude Medical mechanical prosthesis, 32 patients developed a total of 46 pregnancies. Average patient follow up was 5 +/- 4 years (range: 10 months-17 years); total follow up was 155 patient years (pt-yr). Follow up commenced at onset of the first pregnancy. RESULTS: Ten-year Kaplan-Meier survival estimate was 94 +/- 6%; 10-year freedom from valve-related events was 33 +/- 14%. Rates for embolism, anticoagulation-related bleeding and mechanical valve thrombosis were 4.5%, 3.2% and 2.6% per pt-yr, respectively. Among 30 patients receiving uninterrupted low-dose oral warfarin plus aspirin throughout pregnancy, three had normal deliveries, two had premature births, one had a low birth weight, seven had spontaneous abortions, and 17 had therapeutic abortions. By contrast, among eight patients who discontinued anticoagulation despite medical advice, seven had normal-term deliveries without thromboembolic complications, and spontaneous abortion occurred in one patient. Of the five women taking low molecular-weight heparin regimen, three had normal deliveries, one had a premature birth, and one an abortion. Two patients taking warfarin replaced by heparin in the first trimester and in the last two weeks, had term deliveries. One of these women developed left atrial thrombus in the third trimester while receiving heparin; after switching back to warfarin, the thrombus dissolved spontaneously. Another patient on heparin throughout the gestation had an uneventful gestation period that resulted in term delivery. There were four cases of prosthetic valve thrombosis during the postpartum period; all of these developed in women who ceased anticoagulation during pregnancy. CONCLUSION: There were no congenital malformations or maternal mortality/morbidity during pregnancy in this series of 20 live births, probably due to the low-dose anticoagulation regimen used. However, anticoagulation cessation was associated with a high prosthetic valve thrombosis rate in the postpartum period, even when a new-generation prosthetic valve of unique design and expected low thrombogenicity was implanted.     

Risk-based secondary prevention of obstetric antiphospholipid syndrome

Treatment of pregnant women with antiphospholipid syndrome (APS) should be set apart from that from thrombotic APS patients. Patients with a history of pregnancy morbidity but no vascular thrombosis are usually treated with a prophylactic dose of heparin plus low-dose aspirin; whereas, those with previous vascular thrombosis alone or associated with previous pregnancy morbidity, are commonly treated with a therapeutic dose of heparin generally combined with low-dose aspirin. However, in about 20% of pregnant APS women these regimens fail. In this context, we conducted a case-control study on a large multicentre cohort of conventionally treated pregnancies to verify whether specific laboratory profiles and/or clinical characteristics are predictive of unsuccessful pregnancy outcome during conventional treatments. Multivariate analysis showed that pregnancy failure during conventional therapies was independently associated with a history of both thrombosis and pregnancy morbidity, the presence of systemic lupus erythematosus (SLE) or other systemic autoimmune diseases and triple antiphospholipid antibody positivity. With the aim to discover the most effective and safe treatments in high-risk pregnant APS women a large-scale multicentre study focusing on the effect of treatments on pregnancy outcome in women with APS and further risk factors for pregnancy failure has been designed.     

Recurrent thrombosis prevention with intravenous immunoglobulin and hydroxychloroquine during pregnancy in a patient with history of catastrophic antiphospholipid syndrome and pregnancy loss

We report a case of a 36-year old patient with prior history of thrombosis in a setting of antiphospholipid antibody syndrome (APS) as well as pregnancy-associated catastrophic antiphospholipid syndrome (CAPS), resulting in multi-organ infarction and pregnancy loss. The episode of CAPS occurred while she was receiving antepartum low-dose aspirin and therapeutic-dose enoxaparin. This patient presented again at 6 weeks gestation and ultrasounds were consistent with fetal growth restriction, concerning for placental insufficiency and thrombosis. This time, hydroxychloroquine and monthly intravenous immunoglobulin (IVIG) infusions were added to her prophylaxis regimen, resulting in a successful delivery. Platelet count and antiphospholipid antibody titers were routinely monitored throughout pregnancy as markers of disease activity for APS. Current thromboprophylaxis guidelines do not address therapeutic options to prevent further pregnancy morbidity in women who develop recurrent episodes of thrombosis or CAPS despite receiving adequate anti-thrombotic treatment. Use of hydroxychloroquine and IVIG has been associated with good outcomes in this subset of patients.     

Identification of an Fcγ receptor–independent mechanism by which intravenous immunoglobulin ameliorates antiphospholipid antibody–induced thrombogenic phenotype

Objective

Patients with the antiphospholipid antibody syndrome (APS) often experience recurrent arterial and venous thrombosis and pregnancy losses. Intravenous immunoglobulin (IVIG) therapy has prevented pregnancy loss in some women with APS and has reversed fetal resorption rates in murine models of pregnancy loss. Although the basis for these effects is unknown, effector mechanisms of pathogenic antibodies often involve receptors for IgG (Fcγ receptors [FcγR]). We examined the potential mechanisms of action of IVIG in an in vivo murine model of antiphospholipid antibody (aPL)–induced thrombosis and endothelial cell activation.

Methods

Mice infused with IgG containing human anticardiolipin antibodies (aCL) were treated with IVIG (36 μg IV), saline, or ovalbumin. Surgically induced thrombus formation and in vivo leukocyte adhesion to endothelial cells were measured. Circulating levels of aCL were measured by enzyme‐linked immunosorbent assay. To determine whether FcγR are required for the effects of IVIG, we treated mice deficient in stimulatory FcγR. To examine the effects of IVIG on endogenously generated antibody, we treated mice immunized with β₂‐glycoprotein I (β₂GPI).

Results

IVIG treatment inhibited aPL‐induced endothelial cell activation and enhancement of thrombosis in mice passively infused with human aPL–containing IgG, and this was associated with a decrease in aPL levels. Similarly, IVIG lowered aPL levels and inhibited thrombogenesis in mice immunized with β₂GPI. The thrombophilic effects of aPL were evident in FcγR‐deficient mice.

Conclusion

Treatment with IVIG inhibits the thrombogenic effects of aPL in vivo and reduces the levels of aCL in the circulation. Blockade of stimulatory FcγR on inflammatory cells is not necessary for this effect. The mechanism of action of IVIG is more likely saturation of the IgG transport receptor, leading to accelerated catabolism of pathogenic aPL. These results have implications in the management of thrombosis in APS and may have applications for pregnant patients with a history of APS.

     

Management of Obstetric Antiphospholipid Syndrome

Recurrent early miscarriages (excluding chromosomal anomalies), late fetal loss, and maternal thrombosis are characteristic of obstetric antiphospholipid syndrome (APS). Obstetric complications such as preeclampsia, fetal growth restriction, premature delivery, and fetal death also occur in higher frequency in APS patients than in the general population. A high-risk obstetric center is needed for proper evaluation of and intervention with pregnant women with APS. Association with lupus carries additional risk of thrombosis when antiphospholipid antibodies (aPLs) are present. Gestational results with live births are improved to about 80% when antithrombotic therapy is used, but failure in 20% to 30% of the cases despite correct treatment with low-dose aspirin with or without heparin reveals new pathways for pregnancy loss in APS and unmet needs. At the moment, there is no recommendation to investigate patients with infertility for the presence of aPLs.     

Antithrombotic Treatment for Recurrent Miscarriage: Bayesian Network Meta-Analysis and Systematic Review

Combined use of heparin and aspirin is frequently prescribed for treatment of recurrent miscarriage (RM) in patients with antiphospholipid syndrome (APS), or in those without apparent cause of RM other than thrombophilia; however, this strategy is largely based on expert opinion and has not been well studied. The option for the use of different antithrombotic therapies to improve live birth remains unclear. In this network meta-analysis, we incorporated direct and indirect evidence to evaluate effects of different antithrombotic treatments on prevention of pregnancy losses.We searched PubMed and Embase for randomized clinical trials comparing effects of at least 2 antithrombotic treatments on live birth in RM patients published from 1965 through the early of May 2015. Potential risk bias of eligible trials was evaluated according to the Cochrane Collaboration guidelines. Bayesian network meta-analysis was used to estimate relative effects on live birth.A total of 19 trials involving 2391 RM patients with or without thrombophilia and 543 with APS were included. No beneficial effect of antithrombotic treatment was observed either in RM patients with or without thrombophilia or in patients with APS; however, for patients with or without thrombophilia, low molecular weight heparin therapy had the greatest probability (61.48%) of being the best option in terms of live birth; for patients with APS, unfractionated heparin plus aspirin was the superior treatment for RM with the highest possibility (75.15%) of being top 2 places for reducing pregnancy losses. Aspirin was inferior in both groups.Our results do not support the use of combined low molecular weight heparin and aspirin for RM treatment, and suggested aspirin may have negative effects for lowering the risk of pregnancy loss.     

Clinical feature and anti-phospholipid antibody profiles of pregnancy failure in young women with antiphospholipid antibody syndrome treated with conventional therapy

Objective: To elucidate clinical feature and anti-phospholipid antibody (aPL) profiles, including lupus anticoagulant (LA), anti-cardiolipin (CL) antibodies and anti-phosphatidylserine/prothrombin (PS/PT) antibodies, of pregnancy failure in patients with antiphospholipid antibody syndrome (APS) already treated with conventional therapy.

Materials and methods: Thirty-four women with a history of pregnancy who were diagnosed with APS between 2008 and 2016 were included in the study. We defined the successful pregnancy group as women who gave birth to a healthy baby over 1500?g after 34 weeks of pregnancy under conventional treatment (heparin and/or low-dose aspirin). The unsuccessful pregnancy group was defined as women whose pregnancy outcomes did not meet the aforementioned criteria despite the conventional therapy. The clinical features and aPL profiles were compared between the two groups.

Results: Fifteen women were classified into the unsuccessful pregnancy group; seven women were in the successful pregnancy group. Having history of both thrombosis and pregnancy morbidity and LA positivity were significantly more prevalent in the unsuccessful pregnancy group than in the successful pregnancy group (p?<.05, respectively). In contrast, single positivity of anti-CL antibody was negatively associated with APS-associated pregnancy morbidity under the conventional treatment (p?<.01). The proportion of anti-PS/PT IgG-positive patients was significantly higher in the unsuccessful pregnancy group (p?=?.02, OR 18.7, 95% CI 1.50, 232.29) with high concordance rate with LA (97% consistence).

Conclusion: History of both thrombosis and pregnancy morbidity and the positivity of LA and/or anti-PS/PT-IgG, not but anti-CL-antibodies were correlated with APS-associated pregnancy morbidity refractory to conventional treatment. Clinical feature and aPL profiles might help us to make risk assessment for adverse pregnancy outcomes in patients with APS.     

Evaluation of an optimal dose of low-molecular-weight heparin for thromboprophylaxis in pregnant women at risk of thrombosis using coagulation activation markers.

There is no consensus on the dose of low-molecular-weight (LMW) heparin for thromboprophylaxis in pregnant women at increased risk of thrombosis. Based upon monitoring with anti-factor Xa activity, the studies showed conflicting results suggesting either fixed dosages throughout the pregnancy or dosages adapted to the gestational age. We tested whether monitoring thromboprophylaxis with D-dimers and thrombin-antithrombin complexes (TAT) would provide additional information on the optimal dose of LMW heparin. Women (165 women and 202 pregnancies) with hereditary or acquired thrombophilia or a history of thrombosis were considered to receive prophylactic LMW heparin therapy. All women received initially 5,000 IU/day of dalteparin s.c. All further dosages were determined solely on the basis of TAT and/or D-dimer values which were determined every 2-3 weeks. As soon as one of these values increased above the normal range, the dose of LMW heparin was adjusted. In 84.6% of all pregnancies, TAT and/or D-dimer values increased above the normal range once or more during the pregnancy. Consequently, the dose of LMW heparin had to be adjusted at least once over the course of the pregnancy. The mean daily dose of LMW heparin increased from 5,000 to 11,200 U between the 6th and 40th week of gestation. Adverse effects included one major bleeding and six local complications, but no thromboembolic event. In conclusion, increasing doses of LMW heparin are needed to keep TAT and D-dimers within the normal range during pregnancy. Hence, to suppress thrombin generation, apparently, the dosage of LMW heparin should be adjusted to the gestational age rather than using fixed doses throughout the pregnancy. However, it remains to be further established whether elevated TAT and D-dimers truly reflect a prothrombotic state during pregnancy.     

Prevention of Recurrent Spontaneous Abortion by Intravenous Immunoglobulin

Intravenous immunoglobulin (IVIG) treatment was attempted as a novel therapeutic approach for unexplained recurrent spontaneous abortions (RSA) occurring in the first trimester of pregnancy. Twenty women with a history of RSA were treated with IVIG during pregnancy. Therapy was commenced at week 5 of gestation with 1 dose of 0.5-0.6 g IVIG/kg body weight. Infusions were repeated every 3 weeks (0.3-0.4 g/kg) and terminated by week 22 to 24. Of 20 women, 11 delivered healthy infants at term. 5 women are still pregnant, 3 in the third trimester. Only 3 patients suffered abortions and 1 presented with ectopic pregnancy. The overall success rate was 82-86%. Thus, the therapeutic effect of IVIG is comparable to that of the conventional transfusion/vaccination regimen with allogeneic leukocytes, but avoids the risk of transmission of infections and/or HLA immunization, has no major adverse effects and is applicable to 'nonresponders'.     

The HELLP syndrome in the antiphospholipid syndrome: retrospective study of 16 cases in 15 women

OBJECTIVE: To study the characteristics of the haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome in the antiphospholipid syndrome (APS) and its influence on the subsequent pregnancies. METHODS: This was a retrospective analysis of 16 episodes of HELLP complicating APS in 15 women. RESULTS: HELLP was complete in 10 cases and partial in six. It occurred during the second trimester in seven cases (the earliest at 18 weeks' gestation), the third trimester in seven cases, and the day following delivery in two cases. Pre-eclampsia was present in six cases and eclampsia in five. Outcome of pregnancies was: live birth (n = 8), stillbirth (n = 2) and fetal death (n = 6). APS was primary in nine women and secondary to systemic lupus erythematosus (SLE) in six. HELLP revealed primary APS in six cases. Seven women were not treated. Low dose aspirin was empirically prescribed in one woman whose APS had been undiagnosed despite a history of two fetal deaths. In the other women, therapy consisted of aspirin (n = 8), low molecular weight heparin with a dose varying between 3000 and 12 000 U daily (n = 5), and high dose immunoglobulin every 4 weeks (n = 2), hydroxychloroquine (n = 4), and prednisone (n = 6). Six women had seven subsequent pregnancies, 3-6 years after the complicated pregnancy. HELLP recurred at 33 weeks' gestation in one woman with SLE treated with prednisone, hydroxychloroquine, aspirin, and enoxaparin, and pregnancy ended in live birth. One woman became pregnant after in vitro fertilisation and embryo transfer, but pregnancy ended in fetal death despite prednisone, hydroxychloroquine, and enoxaparin. Four women had five uneventful pregnancies with 100 mg daily aspirin and heparin. CONCLUSIONS: APS may be revealed by HELLP. In APS, HELLP is associated with pre-eclampsia/eclampsia in most cases and seems to occur earlier than in the general population. Heparin plus aspirin may prevent obstetric complications in the subsequent pregnancies.