Loss of opportunities in the diagnosis and treatment of primary obstetric antiphospholipid syndrome (POAPS): from theory to reality.

OBJECTIVES: (I) To identify and measure the clinical consequences of a delayed diagnosis in patients with primary obstetric antiphospholipid syndrome (POAPS), in terms of time and events associated to antiphospholipid syndrome (APS), and (II) to evaluate the impact of their treatment status on perinatal outcomes, before and after diagnosis. METHODS: This retrospective multicentre study included 99 POAPS women who were separated in two groups of timelines based on their diagnostic status: group 1: women who met the clinical criteria for POAPS; group 2: included the same patients from group 1 since they meet the laboratory criteria for APS. In group 1, we assessed the following variables: obstetric events, thrombotic events and time (years) to diagnosis of APS. We also compared perinatal outcomes between patients in group 1 vs. group 2. Women in group 2 were treated with standard of care for POAPS. Simple and multivariable logistic regression analyses were performed. RESULTS: Regarding the impact of the delay on diagnosis, a total of 87 APS-related events were recorded: 46 miscarriages, 32 foetal losses and 9 premature deliveries before the 34th week due to preeclampsia, and one thrombosis. The estimated rate of preventable events was 20.58 per year/100 patients. The mean diagnostic delay time was 4.27 years. When we compared both groups during pregnancy, we found that patients in group 1 (no treatment) had a higher association with pregnancy losses [OR = 6.71 (95% CI: 3.59-12.55), p < 0.0001]. CONCLUSION: Our findings emphasize the negative impact of POAPS underdiagnosis on patient health and the critical importance of a timely intervention to improve pregnancy outcomes. Key Points •Our study shows the relevance of underdiagnosis on primary obstetric antiphospholipid syndrome (POAPS). •These patients presented a high risk of APS-related events with each passing year. •Shorter diagnostic delay time was observed in the reference centres.

Clinical and therapeutic value of the adjusted Global Antiphospholipid Syndrome Score in primary obstetric antiphospholipid syndrome.

OBJECTIVES: (1) To assess the clinical utility of the adjusted global antiphospholipid syndrome score (aGAPSS) to predict new obstetric events during follow-up in primary obstetric antiphospholipid syndrome (POAPS) patients under standard-of-care treatment (SC) based on the use of low-dose aspirin (LDA) + heparin and (2) to study the risk of a first thrombotic event and to evaluate whether stratification according to this score could help to identify POAPS patients who would benefit from long-term thromboprophylaxis. METHODS: This is a retrospective, multicentre study. 169 women with POAPS were evaluated for the presence of a new obstetric event and/or a first thrombotic event during follow-up [time period: 2008-2020, median: 7 years (6-12 years)]. The outcomes of 107 pregnancies from these POAPS patients with SC were studied to evaluate relapses. Simple and multivariable logistic regression analyses were performed. RESULTS: Regarding obstetric morbidity, only triple positivity for antiphospholipid antibodies (aPLs) [OR = 8.462 (95% CI: 2.732-26.210); p < 0.0001] was found to be a strong risk factor independently associated with treatment failure. On the other hand, triple positivity for aPLs [OR=10.44 (95% CI: 2.161-50.469), p = 0.004] and an aGAPSS ≥7 [OR = 1.621 (95% CI: 1.198-2.193), p = 0.002] were independent risk factors associated with a first thrombotic event. LDA was marginally associated with a decrease in the risk of thrombosis only in patients with aGAPSS ≥ 7 (p = 0.048). CONCLUSION: aGAPSS appears to be useful in predicting the occurrence of a first thrombotic event in POAPS patients, and these stratification of patients could be helpful in selecting patients who would benefit from thromboprophylaxis with LDA.

Risk factors for early severe preeclampsia in obstetric antiphospholipid syndrome with conventional treatment. The impact of hydroxychloroquine.

OBJECTIVE: The first aim was to retrospectively identify risk factors for the development of early severe preeclampsia (sPE) in patients with obstetric antiphospholipid syndrome (OAPS) who received conventional treatment (CT). The second aim was to evaluate the impact of hydroxychloroquine (HCQ) in preventing early sPE among a subgroup of patients considered at high risk. METHODS: A total of 102 women diagnosed with OAPS and treated with CT since the diagnosis of pregnancy were selected. At the end of pregnancy, we identified risk factors associated with early sPE. According to these risk factors, we collected a new cohort of 42 patients who presented high-risk factors for developing early sPE and split them into two groups according to the treatment received: group A, CT (30 patients); and group B, CT+HCQ (12 patients). We evaluated and compared pregnancy outcomes in both groups. RESULTS: According to the multivariate analysis, risk factors associated with early sPE and CT were triple positivity for antiphospholipid antibodies (aPL) (OR = 24.70, [4.27-142.92], p < 0.001) and a history of early sPE (OR = 7.11, [1.13-44.64], p = 0.036). A low-risk aPL profile was associated with a good response to CT in preventing early sPE (OR = 0.073, [0.014-0.382], p = 0.002). High-risk patients treated with CT+HCQ had a significantly lower early sPE rate than those treated with CT only (8.3% vs 40.0%; p = 0.03). CONCLUSION: Triple positivity for aPL and a history of early sPE are potential strong risk factors for the development of early sPE. HCQ might be an interesting therapeutic option for patients with high-risk factors for early sPE.

A high-risk laboratory profile of antiphospholipid antibodies and thrombosis is associated with a large number of extra-criteria manifestations in obstetric antiphospholipid syndrome.

Extra-criteria manifestations such as thrombocytopenia and livedo are described associated with antiphospholipid syndrome (APS) but are not included in the current classification criteria. Their clinical expression might be important, as they may be associated with a high-risk profile of antiphospholipid antibodies (aPL) and thrombosis. We evaluated the association between the presence of extra-criteria manifestations in primary obstetric-APS (POAPS) and aPL profiles. We also evaluated whether the presence of extra-criteria manifestations in POAPS patients increases the risk of developing thrombosis during the follow-up period (median follow-up 5 years; range 3-9 years). We selected 79 women who were included in our study only if they were first diagnosed with POAPS (with no history of previous thrombosis) and reevaluated for the presence of thrombosis after the follow-up period. We evaluated the association between the aPL profile and extra-criteria manifestations. We also evaluated the relationship of thrombosis during the follow-up period with extra-criteria manifestations and other risk factors. Patients with three or more extra-criteria manifestations presented high rates of triple positivity for the aPL profile (75%) (p < 0.001). We also found a relationship between the presence of extra-criteria manifestations and the presence of high titers of aPL: 91.7% of patients with three or more extra-criteria manifestations had high titers of aPL (p < 0.01). We further evaluated the group of POAPS patients according to thrombotic events during the follow-up. Among these patients, 6 (7.6%) presented thrombosis. Notably, 100% of patients with a thrombotic event during the follow-up had more than three extra-criteria manifestations. POAPS patients with extra-criteria manifestations might have a high-risk aPL profile and a major risk of developing thrombosis.

Inherited thrombophilia and pregnancy loss. Study of an Argentinian cohort. / Trombofilia hereditaria y pérdidas de embarazo. Estudio de una cohorte de Argentina.

BACKGROUND AND OBJECTIVES: Thrombophilia might increase the risk of suffering from obstetric complications by adversely affecting the normal placental vascular function. Our aim was to study the distributions of five thrombosis-associated genetic variants: factor V Leiden, prothrombin G20210A, -675 4G/5G PAI-1, 10034C/T gamma fibrinogen and 7872C/T factor XI and the frequencies of the deficiencies of protein C, S and antithrombin in Argentinian patients with recurrent pregnancy loss (RPL) and, therefore, to analyse their association with the risk and timing of RPL and the risk of suffering other vascular obstetric pathologies. PATIENTS AND METHODS: We performed a case-control study that included 247 patients with idiopathic RPL (cases), 107 fertile controls and 224 subjects from general population (reference group). Cases were stratified according to the gestational time of the losses (early RPL, n = 89; late losses, n = 158; foetal losses, n = 107) and according to the type of vascular obstetric pathologies. RESULTS: No differences were found in the distribution of the genetic variants among RPL group vs. control/reference group (p >.05). Similarly, no differences were observed in their distributions when analysing RPL patients stratified according to gestational times or vascular obstetric pathologies (p >.05), except for the factor V Leiden carriage in patients with foetal growth retardation vs. controls (11.8%, 4/34 vs. 1.9%, 2/107; p = .04) (OR = 7.11 [1.24-40.93], p = .03). CONCLUSIONS: Factor V Leiden might have a significant impact on certain obstetric pathologies such as foetal growth retardation. The genetic variants, 10034C/T gamma fibrinogen and 7872C/T factor XI, associated with thromboembolic disease, would not have an impact on PRE.

What is the best time to assess the antiphospholipid antibodies (aPL) profile to better predict the obstetric outcome in antiphospholipid syndrome (APS) patients?

Serological risk factors are the most important determinant in predicting unsuccessful pregnancy in obstetric antiphospholipid antibodies syndrome (OAPS) despite conventional treatment. It is not clear if changes in the profile of antiphospholipid antibodies (aPL) during pregnancy modify the risk associated with a poor response to conventional treatment. The aim of our study was to compare the value of a serological tag for aPL obtained before and during the first trimester of pregnancy to predict the response to conventional treatment. We carefully selected 97 pregnancies in women who were included in our study only if they were diagnosed with OAPS prior to a new pregnancy (basal serological risk), retested for aPL during the first trimester of pregnancy (serological risk during pregnancy), and treated with conventional therapy. High baseline serological risk was associated with pregnancy failure in 62.1% of cases (18/29) and predicted 82.5% of pregnancy outcomes with conventional treatment: OR = 16.9, CI = 5.5-52.1, p < 0.001. High serological risk during pregnancy was associated with pregnancy failure in 86.3% of cases (19/22) and predicted 91.8% of pregnancy outcomes with conventional treatment: OR = 88.7, CI = 19.4-404.8, p < 0.001. According to these results, we found that risk categorization performed during pregnancy was better in predicting pregnancy outcome (82.5 vs. 91.8%). Moreover, risk categorization during pregnancy had an increased specificity regarding the prediction: 84.9% at baseline and 95.9% during pregnancy (p = 0.024). Our findings suggest that it is important to perform aPL during the first trimester of pregnancy since that is the best time to establish the serological risk factors.

Maternal carriers of the ANXA5 M2 haplotype are exposed to a greater risk for placenta-mediated pregnancy complications.

PURPOSE: Annexin A5 (ANXA5) is a protein abundantly expressed in normal placenta where it contributes to the healthy outcome of a pregnancy. Lower ANXA5 levels have been observed in M2/ANXA5 haplotype carrying chorion. Consequently, this study aimed to assess the potential association of M2 maternal carrier status with the risk of recurrent pregnancy loss (RPL), the timing of miscarriages, and other obstetric complications, for the first time in a population from Latin America. METHODS: This study was designed as a prospective recruitment of RPL patients with post hoc analysis. The distribution of the M2/ANXA5 haplotype was compared between a group of 229 Argentine women with RPL and 100 parous controls, and was further analyzed in subgroups of patients stratified according to the timing of miscarriages and in relation to other obstetric complications. RESULTS: No significant differences were found in the distribution of M2 haplotype among either RPL patients or the subgroups with embryonic, early fetal, or late fetal losses compared to parous controls. Notwithstanding, maternal M2/ANXA5 was found to be independently associated with a higher risk of suffering intrauterine growth restriction (IUGR) and/or preeclampsia (PE). Simultaneously, the presence of inherited and/or acquired thrombophilia also proved to be an independent risk factor for these. CONCLUSIONS: The association found between the maternal carriage of the M2/ANXA5 haplotype and an elevated risk of IUGR and/or PE supports the hypothesis that carrier status of this haplotype and the consequently reduced placental ANXA5 expression might be responsible, at least partially, for the onset of these gestational vascular complications.