The relation between antiphospholipid syndrome-related pregnancy morbidity and non-gravid vascular thrombosis: A review of the literature and management strategies

The antiphospholipid syndrome (APS) is associated with pregnancy morbidity and vascular thrombosis in the presence of circulating antiphospholipid (aPL) antibodies. Clinical manifestations of aPL antibodies represent a spectrum (asymptomatic, pregnancy events, vascular events, or both pregnancy and vascular events), and APS should not be considered a single disease with a predictable outcome. Patients with aPL antibodies are at increased risk of vascular thrombotic events during pregnancy, the postpartum period, and even during long-term follow-up after an APS-related pregnancy event. Therefore, the purpose of this paper is to review the relation between APS-related pregnancy morbidity and vascular thrombosis, and to address the importance of prophylactic therapy during and after APS pregnancies to prevent maternal thrombotic complications. During pregnancy, low-dose aspirin (LDA) should be considered for all patients with aPL antibodies and heparin should be added to LDA in patients fulfilling the Sapporo criteria for definite APS. During delivery, especially with caesarian section, periods without anticoagulation should be kept to an absolute minimum. Some data suggest that LDA might be effective against future non-gravid vascular thrombosis in patients with APS and a history of only pregnancy morbidity.     

Laboratory diagnosis and management challenges in the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is characterized by recurrent arterial and/or venous thrombosis and pregnancy morbidity manifested by early or late losses. Laboratory diagnosis ofAPS relies on the demonstration of a positive test for antiphospholipid antibodies (aPL). In clinical practice, the gold standard tests are those that detect anticardiolipin antibodies (aCL) and/or the lupus anticoagulant (LA). Although other specificities for aPL have been described their clinical utility and standardization has still to be established. Persistence of aPL positive tests must be demonstrated, and other causes and underlying factors considered. Although it is universally recognized that the routine screening tests (aCL and/or LA) might miss some cases, careful differential diagnosis and repeat testing are mandatory before the diagnosis of 'seronegative APS' can be made. Correct identification of patients with APS is important, because prophylactic anticoagulant therapy can prevent thrombosis from recurring, and treatment of affected women during pregnancy can improve fetal and maternal outcome.     

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.     

Neonatal antiphospholipid syndrome associated with heterozygous methylentetrahydrofolate reductase C677T and prothrombin G20210A gene mutations

SIR, Neonatal antiphospholipid syndrome (APS) is a rare clinicalentity characterized by neonatal thrombotic disease due to thetransplacental passage of maternal antiphospholipid antibodies(aPL) [1]. While women with aPL show a high incidence of obstetricand fetal complications, the aPL-related thrombosis in theiroffspring seems to be exceedingly rare. The low     

Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies

OBJECTIVE: Our aim was to assess the outcome of pregnancy in a cohort of patients with SLE and to evaluate clinical and laboratory markers for fetal outcome and maternal flares. METHODS: Sixty patients with 103 pregnancies were evaluated prospectively between 1984 and 1999. RESULTS: There were 68 live births, 15 spontaneous abortions, 12 stillbirths and eight therapeutic abortions. Of liveborn infant births, 19 were premature, 24 had suffered intrauterine growth restriction and one had neonatal lupus. Maternal lupus flares occurred in 33% of pregnancies, mostly in the second trimester (26%) and in the post-partum period (51%). Flares during pregnancy showed a statistically significant association with discontinuation of chloroquine treatment, a history of more than three flares before gestation, and a SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score of >or=5 in these flares. Antiphospholipid antibodies, C3 hypocomplementaemia and hypertension during pregnancy were significantly associated with fetal loss, prematurity and intrauterine growth restriction. CONCLUSIONS: Patients with more active SLE and those with aPL antibodies and hypertension should be monitored and managed carefully during pregnancy.     

Pregnancy outcomes in women with childhood-onset and adult-onset systemic lupus erythematosus: a comparative study

To compare the maternal and fetal outcomes between childhood-onset and adult-onset systemic lupus erythematosus (SLE), we reviewed the medical records of SLE pregnant women treated from January 2005 to August 2013. For comparison, patients were allocated to one of the two groups, those pregnant patients with SLE onset before 18 years of age (childhood-onset) and ≥18 years (adult-onset). The patients were evaluated at least once in each trimester and postpartum. Relevant maternal and fetal outcomes were extracted, such as lupus flare, preeclampsia/eclampsia, rate of liveborns, fetal loss (spontaneous abortion and stillbirth), term delivery, preterm birth, neonatal death, low birth weight, low birth weight at term, and congenital malformations. We studied 186 pregnancies (in 180 women), 58 of them had childhood-onset SLE, and the remaining 128 had adult-onset SLE. The rate of maternal and fetal complications was similar in both groups. Multivariate analysis showed that active SLE before pregnancy, primigravida, renal flare, preeclampsia, lupus flare, anticardiolipin antibodies, and low serum complement were associated with an increased risk of poor maternal and fetal outcomes. The diagnosis of childhood-onset had no impact on maternal–fetal outcome. The maternal and fetal outcome in women with childhood-onset SLE is similar to that reported in women with adult-onset SLE. Pregnancy in women with childhood-onset SLE should not be contraindicated if the disease is well controlled.     

Pregnancy, lupus and antiphospholipid syndrome (Hughes syndrome)

Autoimmune diseases (AD) occur frequently in women during their childbearing years and may influence pregnancy outcome and neonatal health. Patients with systemic lupus erythematosus (SLE) can experience a disease flare-up during pregnancy with potential negative effects on the product of conceptus, especially if the disease is active. Recurrent pregnancy loss is now considered as a treatable clinical condition associated with the presence of circulating antiphospholipid antibodies (aPL). The neonatal lupus syndromes (NLS), caused by the transplacental passage of maternal IgG anti-Ro/SS-A and anti-La/SS-B antibodies to the fetus, carry significant morbidity and mortality in case of cardiac manifestations. Immunosuppressive agents are often administered during pregnancy in order to control maternal disease and to ensure a better pregnancy outcome. Nowadays, owing to our increasing knowledge of the disease pathophysiological mechanisms and the development of combined medical-obstetric clinics, pregnancy outcome in patients with AD has notably improved.     

Embryonic Stage of Congenital Zika Virus Infection Determines Fetal and Postnatal Outcomes in Mice

Zika virus (ZIKV) infection during pregnancy causes a wide spectrum of congenital abnormalities and postnatal developmental sequelae such as fetal loss, intrauterine growth restriction (IUGR), microcephaly, or motor and neurodevelopmental disorders. Here, we investigated whether a mouse pregnancy model recapitulated a wide range of symptoms after congenital ZIKV infection, and whether the embryonic age of congenital infection changed the fetal or postnatal outcomes. Infection with ZIKV strain PRVABC59 from embryonic day 6.5 (E6.5) to E8.5, corresponding to the mid-first trimester in humans, caused fetal death, fetal resorption, or severe IUGR, whereas infection from E9.5 to E14.5, corresponding to the late-first to second trimester in humans, caused stillbirth, neonatal death, microcephaly, and postnatal growth deficiency. Furthermore, 4-week-old offspring born to dams infected at E12.5 showed abnormalities in neuropsychiatric state, motor behavior, autonomic function, or reflex and sensory function. Thus, our model recapitulated the multiple symptoms seen in human cases, and the embryonic age of congenital infection was one of the determinant factors of offspring outcomes in mice. Furthermore, maternal neutralizing antibodies protected the offspring from neonatal death after congenital infection at E9.5, suggesting that neonatal death in our model could serve as criteria for screening of vaccine candidates.     

Livedo reticularis and pregnancy morbidity in patients negative for antiphospholipid antibodies

BACKGROUND: Livedo may be an independent risk factor for pregnancy morbidity, additional to the known risks associated with the presence of antiphospholipid antibodies (aPL). OBJECTIVE: To determine the prevalence of pregnancy related morbidity in patients with widespread livedo reticularis who are persistently negative for aPL. PATIENTS AND METHODS: 52 patients with widespread livedo reticularis were studied: 31 fulfilled ACR criteria for SLE, 21 had a lupus-like illness; all were negative for aPL. All patients had livedo (racemosa or reticularis type) on their extremities, trunk, and/or buttocks. RESULT: 33 (63%) patients had pregnancy related morbidity. 22 patients had up to 9 miscarriages, 15 patients had >3 miscarriages, 2 had 2 miscarriages, 4 had a fetal death (>10 weeks), 17 had pre-eclampsia, and 4 patients had premature delivery. 19 patients had no pregnancy related morbidity. Overall morbidity was similar in the patients with lupus and lupus-like disease. CONCLUSION: Pregnancy related morbidity in lupus is known to be associated with the presence of aPL. This study suggests that pregnancy loss may also be independently associated with widespread livedo reticularis in patients who are aPL negative. A larger study is needed.     

Pregnancy in lupus.

Patients with systemic lupus erythematosus with established disease have poorer pregnancy outcomes than do women with later onset disease. Active renal disease and maternal hypertension are important predictors of fetal loss and premature birth, respectively. Placental pathology in SLE patients is characterized by decidual vasculopathy and infarction, and in APLS patients, infarction can be extensive. Maternal anti-52 kD SSA/Ro by immunoblot continues to be an important risk factor for having a child with heart block. The risk of having a subsequent child with congenital heart block ranges between 12-16%. Childhood morbidity with heart block is high, with 63% eventually requiring pacemakers. In APLS, antiB2GP-I antibodies can have a significant role in the diagnosis, especially when the traditional assays for aCL antibodies and LAC are negative. Some obstetricians have found that IVIG improves the birthrate in aPL positive women who have recurrent spontaneous abortions after IVF.     

Neonatal effects of maternal antiphospholipid syndrome

Antiphospholipid antibodies (aPL) can impair the physiologic development of a fetus during pregnancy not only by causing thrombosis of the placental vessels, but also by directly binding throphoblast cells and modifying their functions. Consequently, the presence of aPL in pregnant women is linked to an increased rate of pregnancy complications. These include recurrent early miscarriages, late fetal losses, and hypertensive disorders of gestation. In this clinical setting, preeclampsia is usually early and severe and can be complicated by the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). The close association between aPL and obstetric pathology supports the inclusion of these manifestations in the clinical classification criteria of antiphospholipid syndrome. About 30% of children born to mothers with aPL passively acquire these autoantibodies; fortunately, the occurrence of thrombosis seems extremely rare in these babies. The prospective ongoing studies of children born to antiphospholipid syndrome patients reassure us about their general good health; however, some data suggest that learning difficulties might occur, possibly related to in utero exposure to aPL.     

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.     

Primary prevention in antiphospholipid antibody carriers

The discovery of antiphospholipid antibodies (aPL) positivity in individuals who have never experienced thrombosis or pregnancy complications is not a rare event, and is one of the unresolved issues in the field of antiphospholipid syndrome (APS). This paper focuses on primary prophylaxis for thrombotic events in aPL carriers. In our view, patients with high risk aPL profiles and/or other cardiovascular risk factors, concomitant diagnosis of systemic lupus erythematosus (SLE) and patients with an history of obstetric APS (OAPS) should be offered thromboprophylaxis. Chronic thromboprophylaxis with low-dose aspirin and hydroxychloroquine in aPL positive SLE patients should be prescribed both to prevent thrombosis and to avoid early organ damage.     

Anti-beta 2-glycoprotein I antibodies: a useful marker for the antiphospholipid syndrome

We studied anti-beta 2-glycoprotein I antibodies (a beta 2GPI) in autoimmune disease patients to evaluate their relationship to clinical findings. Seventy-nine systemic lupus erythematosus (SLE) patients [44 with antiphospholipid antibodies (aPL)], 21 with primary antiphospholipid syndrome (APS), eight asymptomatic individuals with aPL and 60 controls were studied. Sixteen SLE patients (14 with aPL and two without aPL) and six with primary APS had a beta 2GPI. A significant relationship was found between a beta 2GPI and aPL (P < 0.01). In SLE, a significant correlation was found between previous thrombosis or thrombocytopenia and a beta 2GPI or a beta 2GPI + aPL, but not between fetal losses and a beta 2GPI. These data suggest that a beta 2GPI may be useful in the study of APS.      

Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury

Fetal loss in patients with antiphospholipid (aPL) antibodies has been ascribed to thrombosis of placental vessels. However, we have shown that inflammation, specifically activation of complement with generation of the anaphylotoxin C5a, is an essential trigger of fetal injury. In this study, we analyzed the role of the procoagulant molecule tissue factor (TF) in a mouse model of aPL antibody-induced pregnancy loss. We found that either blockade of TF with a monoclonal antibody in wild-type mice or a genetic reduction of TF prevented aPL antibody-induced inflammation and pregnancy loss. In response to aPL antibody-generated C5a, neutrophils express TF potentiating inflammation in the deciduas and leading to miscarriages. Importantly, we showed that TF in myeloid cells but not fetal-derived cells (trophoblasts) was associated with fetal injury, suggesting that the site for pathologic TF expression is neutrophils. We found that TF expression in neutrophils contributes to respiratory burst and subsequent trophoblast injury and pregnancy loss induced by aPL antibodies. The identification of TF as an important mediator of C5a-induced oxidative burst in neutrophils in aPL-induced fetal injury provides a new target for therapy to prevent pregnancy loss in the antiphospholipid syndrome.     

Risk of thrombosis in patients with antiphospholipid antibodies and factor V Leiden mutation

OBJECTIVE: Antiphospholipid antibodies (aPL) are thrombophilic risk markers in patients with systemic lupus erythematosus (SLE) or primary antiphospholipid syndrome (APS). The risk factors for recurrent venous or arterial thrombosis and indications for longterm anticoagulation therapy are debated. We hypothesized that carrying a second thrombophilic defect, factor V Leiden mutation, would increase the risk for thrombosis in patients with aPL. METHODS: Seventy-five patients with primary APS and 83 with SLE and aPL with or without thrombosis followed at 2 university hospitals were studied. Factor V mutation rate was analyzed in patients and in 200 healthy blood donors by polymerase chain reaction analysis. RESULTS: The prevalence of factor V Leiden mutation in patients with SLE and aPL or primary APS was similar to controls. Patients with deep vein thrombosis or arterial thrombosis did not have a significantly increased rate of factor V mutation compared to controls or to patients with aPL without thrombosis. CONCLUSION: Factor V Leiden mutation is not significantly associated with vein thrombosis in patients with aPL. However, due to the sample size we cannot rule out synergy between both factor V Leiden and aPL. A trend toward increased risk for thrombosis was detected in patients with the mutation and this should be analyzed in a larger study.     

Reduced placental growth and hCG secretion in vitro induced by antiphospholipid antibodies but not by anti-Ro or anti-La: studies on sera from women with SLE/PAPS

Systemic lupus erythematosus (SLE) and primary anti-phospholipid syndrome (PAPS) are autoimmune diseases causing recurrent pregnancy loss. We hypothesized that anti-phospholipid antibodies (aPL), but not anti-Ro and anti-La antibodies, might have a role through direct placental damage. We cultured human placental explants in sera from women with SLE/PAPS with different antibodies. These sera were found to reduce placental growth and increase trophoblastic apoptosis. No effect was found on estradiol or progesterone secretion, but inhibition in betahCG secretion was detected. BetahCG was reduced in women with a history of recurrent pregnancy loss or thromboembolic events, and was also the most sensitive marker when examining the effects of specific antibodies. High titers of aPL were found to cause the largest reduction in betahCG. Anti-Ro and anti-La did not induce placental damage. A strong correlation was found between the rise in the number of different antibodies in the sera and the incidence of recurrent pregnancy loss, which was also accompanied by a decline in the betahCG levels. In conclusion, aPL, but not anti-Ro or anti-La, may cause placental damage in vitro. Thus betahCG levels might constitute a predictive marker for the risk of placental damage and pregnancy loss in women with SLE/PAPS.     

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.     

Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia

The aim of this study was to examine the pregnancy outcomes in patients with systemic lupus erythematosus (SLE) and the effect of SLE flare and treatment on pregnancy outcomes. We performed a retrospective evaluation of all pregnancies occurring in patients with SLE during the 27-year period from 1980 to 2006. Of the 319 women with SLE planning pregnancy after SLE onset, 176 (55.2%) conceived resulting in 396 pregnancies. Live births were significantly lower in proportion (70.2% vs. 85.7%) and more likely to end in fetal deaths (29.7% vs. 14.2%) and preterm births (26.7% vs. 5.8 %) in pregnancies occurring after SLE onset than in pregnancies occurring before SLE onset (p < 0.0001). With respect to different disease manifestations, we found that fetal loss was significantly higher in patients with antiphospholipid (aPL) antibodies than without (p < 0.001). Preterm deliveries were significantly more frequent in patients with lupus nephritis, anti-Ro/SSA antibodies, hypertension, history of intravenous cyclophosphamide treatment and aPL than those without these features (p < 0.05). Neonates with intrauterine growth retardation (IUGR) neonates were more common in hypertensive and Raynaud's-positive pregnancies (p < 0.05). SLE flares occurred in 30.8% pregnancies. There was increased risk of fetal loss, preterm births and IUGR in pregnancies with SLE exacerbations than without (p < 0.05). Prednisolone was found to improve the rate of live births, although it was also a predictor of prematurity. The predictors of pregnancy loss were lupus nephritis (odds ratio (OR) 7.3), aPL (OR 3.9), and SLE flares in pregnancy (OR 1.9). There was higher risk of preterm deliveries in patients with lupus nephritis (OR 18.9), anti-Ro antibodies (OR 13.9), hypertension (OR 15.7) and SLE flares (OR 2.5). IUGR was found to be associated with hypertension (OR 37.7), Raynaud's (OR 12.3), and SLE flares (OR 4.2). In conclusion, pregnancies in SLE patients with active lupus nephritis, anti-Ro/SSA antibodies, aPL, hypertension, Raynaud's phenomenon, active disease at conception and SLE exacerbations are at a higher risk of adverse pregnancy outcomes. It is important to carefully plan pregnancy, and experienced rheumatologists and obstetricians should monitor SLE patients in pregnancy and postpartum.     

Antiphospholipid antibodies in pediatric systemic lupus erythematosus and the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is recognized increasingly as the most common acquired hypercoagulation state of autoimmune etiology and may occur as an isolated clinical entity (primary APS) or in association with an underlying systemic disease, particularly systemic lupus erythematosus (SLE). The major differences between pediatric and adult APS include absence of common acquired risk factors for thrombosis, absence of pregnancy-related morbidity, increased incidence of infection-induced antibodies, differences in cut-off values for determination of aPL and specific factors regarding long-term therapy in children. APS in children has been largely reported in patients with arterial or venous thromboses and less frequently in association with neurological or hematological manifestations. The presence of aPL in pediatric SLE can modify the disease expression and may be an important predictor of the development of irreversible organ damage. Two recently established international registries of neonates and children with APS provide a good opportunity to conduct large, prospective studies on the clinical significance of aPL and long-term outcome of pediatric APS.