Targeting a higher plasma VWF level at time of delivery in pregnant individuals with von Willebrand disease: Outcomes at a single-institution cohort study.

INTRODUCTION: Guidelines on the management of pregnant individuals with von Willebrand disease (VWD) at the time of delivery recommend that von Willebrand factor (VWF) and factor VIII:C (FVIII:C) levels be ≥50% to prevent postpartum haemorrhage (PPH). Yet, high PPH rates persist despite these levels or with prophylactic factor replacement therapy to achieve these levels. AIMS: The current practice at our centre has been to target peak plasma VWF and FVIII:C levels of ≥100 IU/dL at time of delivery. The objective of this study was to describe obstetric outcomes in pregnant individuals with VWD who were managed at our centre. METHODS: Demographics and outcomes on pregnant individuals with VWD who delivered between January 2015 and April 2023 were collected. RESULTS: Forty-seven singleton deliveries (among 41 individuals) resulting in 46 live births and one foetal death were included. Twenty-one individuals had at least one prior birth by the start date of this study, of which 11 (52.4%) self-reported a history of PPH. Early PPH occurred in 12.8% (6/47) of deliveries. Two individuals required blood transfusion, of which one also had an unplanned hysterectomy and transfer to ICU. There were no thrombotic events reported. CONCLUSION: The strategy of targeting higher peak plasma VWF and FVIII:C levels (≥100 IU/dL) at the time of delivery may be effective in reducing the risk of delivery-associated bleeding complications in VWD patients. Yet, the rate of early PPH remains unsatisfactory compared to the non-VWD population.

Deciphering the clinical significance of longitudinal antiphospholipid antibody titers.

In antiphospholipid syndrome (APS), the risk of clinical manifestations increases with higher titers of antiphospholipid antibodies (aPL). Despite the adoption of aPL titers in the classification approach to aPL-positive subjects, the value of longitudinal monitoring of those titers in the follow-up is still debated, being well studied only in systemic lupus erythematosus (SLE). The literature suggests that the rate of aPL positivity decreases during follow-up in primary APS, estimating that seroconversion occurs in between 8.9 and 59% of patients over time. Negativisation of aPL occurs more frequently in asymptomatic aPL carriers than in patients with full-blown APS as well as in subjects with single aPL positivity or low aPL antibody titers. In patients with SLE, aPL typically behave fluctuating from positive to negative and back again in the course of follow-up. The few studies assessing the longitudinal course of aPL positivity with no associated systemic connective tissue disease reported a progressive decrement of aPL titers over time, in particular of antibodies against ß2 glycoprotein I (antiß2GPI) and cardiolipin (aCL) of IgG isotype. After a thrombotic event, aPL titers tend to decrease, as emerged from cohorts of both primary and secondary APS. Hydroxychloroquine has been identified as the most effective pharmacological agent to reduce aPL titers, with multiple studies demonstrating a parallel reduction in thrombosis rate. This review addresses available evidence on the significance of aPL titer fluctuation from clinical, therapeutic and pathogenic perspectives.

Thrombosis recurrence and major bleeding in non-anticoagulated thrombotic antiphospholipid syndrome patients: Prospective study from antiphospholipid syndrome alliance for clinical trials and international networking (APS ACTION) clinical database and repository ("Registry").

BACKGROUND: Long-term anticoagulant therapy is generally recommended for thrombotic antiphospholipid syndrome (TAPS) patients, however it may be withdrawn or not introduced in routine practice. OBJECTIVES: To prospectively evaluate the risk of thrombosis recurrence and major bleeding in non-anticoagulated TAPS patients, compared to anticoagulated TAPS, and secondly, to identify different features between those two groups. PATIENTS/METHODS: Using an international registry, we identified non-anticoagulated TAPS patients at baseline, and matched them with anticoagulated TAPS patients based on gender, age, type of previous thrombosis, and associated autoimmune disease. Thrombosis recurrence and major bleeding were prospectively analyzed using Kaplan-Meier method and compared using a marginal Cox's regression model. RESULTS: As of June 2022, 94 (14 %) of the 662 TAPS patients were not anticoagulated; and 93 of them were matched with 181 anticoagulated TAPS patients (median follow-up 5 years [interquartile range 3 to 8]). The 5-year thrombosis recurrence and major bleeding rates were 12 % versus 10 %, and 6 % versus 7 %, respectively (hazard ratio [HR] 1.38, 95 % confidence interval [CI] 0.53 to 3.56, p = 0.50 and HR 0.53; 95 % CI 0.15 to 1.86; p = 0.32, respectively). Non-anticoagulated patients were more likely to receive antiplatelet therapy (p < 0.001), and less likely to have more than one previous thrombosis (p < 0.001) and lupus anticoagulant positivity (p = 0.01). CONCLUSION: Fourteen percent of the TAPS patients were not anticoagulated at recruitment. Their recurrent thrombosis risk did not differ compared to matched anticoagulated TAPS patients, supporting the pressing need for risk-stratified secondary thrombosis prevention trials in APS investigating strategies other than anticoagulation.

Oxytocin is not associated with postpartum hemorrhage in labor augmentation in a retrospective cohort study in the United States.

BACKGROUND: Previous studies reported conflicting results on the relationship between oxytocin use for labor augmentation and the risk of postpartum hemorrhage, probably because it is rather challenging to disentangle oxytocin use from labor dystocia. OBJECTIVE: This study aimed to investigate the independent association between oxytocin use for augmentation and the risk of postpartum hemorrhage by using advanced statistical modeling to control for labor patterns and other covariates. STUDY DESIGN: We used data from 20,899 term, cephalic, singleton pregnancies of patients with spontaneous onset of labor and no previous cesarean delivery from Intermountain Healthcare in Utah in the Consortium on Safe Labor. Presence of postpartum hemorrhage was identified on the basis of a clinical diagnosis. Propensity scores were calculated using a generalized linear mixed model for oxytocin use for augmentation, and covariate balancing generalized propensity score was applied to obtain propensity scores for the duration and total dosage of oxytocin augmentation. A weighted generalized additive mixed model was used to depict dose-response curves between the duration and total dosage of oxytocin augmentation and the outcomes. The average treatment effects of oxytocin use for augmentation on postpartum hemorrhage and estimated blood loss (mL) were assessed by inverse probability weighting of propensity scores. RESULTS: The odds of both postpartum hemorrhage and estimated blood loss increased modestly when the duration and/or total dosage of oxytocin used for augmentation increased. However, in comparison with women for whom oxytocin was not used, oxytocin augmentation was not clinically or statistically significantly associated with estimated blood loss (6.5 mL; 95% confidence interval, 2.5-10.3) or postpartum hemorrhage (adjusted odds ratio, 1.02; 95% confidence interval, 0.82-1.24) when rigorously controlling for labor pattern and potential confounders. The results remained consistent regardless of inclusion of women with an intrapartum cesarean delivery. CONCLUSION: The odds of postpartum hemorrhage and estimated blood loss increased modestly with increasing duration and total dosage of oxytocin augmentation. However, in comparison with women for whom oxytocin was not used and after controlling for potential confounders, there was no clinically significant association between oxytocin use for augmentation and estimated blood loss or the risk of postpartum hemorrhage.

Damage measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in antiphospholipid antibody-positive patients included in the APS ACTION registry.

OBJECTIVES: Our primary objective was to quantify damage burden measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in aPL-positive patients with or without a history of thrombosis in an international cohort (the APS ACTION cohort). Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients. METHODS: In this cross-sectional study, we analysed the baseline damage in aPL-positive patients with or without APS classification. We excluded patients with other autoimmune diseases. We analysed the demographic, clinical and laboratory characteristics based on two subgroups: (i) thrombotic APS patients with high vs low damage; and (ii) non-thrombotic aPL-positive patients with vs without damage. RESULTS: Of the 826 aPL-positive patients included in the registry as of April 2020, 586 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 174 non-thrombotic). In the thrombotic group, hyperlipidaemia (odds ratio [OR] 1.82; 95% CI 1.05, 3.15; adjusted P = 0.032), obesity (OR 2.14; 95% CI 1.23, 3.71; adjusted P = 0.007), aß2GPI high titres (OR 2.33; 95% CI 1.36, 4.02; adjusted P = 0.002) and corticosteroid use (ever) (OR 3.73; 95% CI 1.80, 7.75; adjusted P < 0.001) were independently associated with high damage at baseline. In the non-thrombotic group, hypertension (OR 4.55; 95% CI 1.82, 11.35; adjusted P = 0.001) and hyperlipidaemia (OR 4.32; 95% CI 1.37, 13.65; adjusted P = 0.013) were independent predictors of damage at baseline; conversely, single aPL positivity was inversely correlated with damage (OR 0.24; 95% CI 0.075, 0.77; adjusted P = 0.016). CONCLUSIONS: DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. Selected traditional cardiovascular risk factors, steroids use and specific aPL profiles may help to identify patients more prone to present with a higher damage burden.

How I diagnose and treat antiphospholipid syndrome in pregnancy.

ABSTRACT: Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by arterial, venous, or microvascular thrombosis, pregnancy morbidities, or nonthrombotic manifestations in patients with persistently positive antiphospholipid antibodies. These antibodies bind cellular phospholipids and phospholipid-protein complexes resulting in cellular activation and inflammation that lead to the clinical features of APS. Our evolving understanding of APS has resulted in more specific classification criteria. Patients meeting these criteria should be treated during pregnancy according to current guidelines. Yet, despite treatment, those positive for lupus anticoagulant have at least a 30% likelihood of adverse pregnancy outcomes. Patients with recurrent early miscarriage or fetal death in the absence of preeclampsia or placental insufficiency may not meet current classification criteria for APS. Patients with only low titer anticardiolipin or anti-ß(2)-glycoprotein I antibodies or immunoglobulin M isotype antibodies will not meet current classification criteria. In such cases, clinicians should implement management plans that balance potential risks and benefits, some of which involve emotional concerns surrounding the patient's reproductive future. Finally, APS may present in pregnancy or postpartum as a thrombotic microangiopathy, a life-threatening condition that may initially mimic preeclampsia with severe features but requires a very different treatment approach.

Thrombotic Markers in Pregnant Patients with and without SARS-CoV-2 Infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities and increased risk for venous and arterial thrombi. This study aimed to evaluate D-dimer levels and lupus anticoagulant (LAC) positivity in pregnant individuals with and without Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. STUDY DESIGN: This was a prospective cohort study of pregnant individuals delivering at a single academic institution from April 2020 to March 2022. Individuals with a positive SARS-CoV-2 result during pregnancy were compared with a convenience sample of those without a positive SARS-CoV-2 result. For individuals with SARS-CoV-2 infection, severity was assessed based on the National Institutes of Health classification system. The primary outcome was D-dimer level measured during delivery admission. The secondary outcomes were LAC positivity and thromboembolic events. Outcomes were compared between individuals with and without a positive SARS-CoV-2 result, and further by disease severity. RESULTS: Of 98 participants, 77 (78.6%) were SARS-CoV-2 positive during pregnancy. Among individuals with SARS-CoV-2 infection, severity was asymptomatic in 20 (26.0%), mild in 13 (16.9%), moderate in 4 (5.2%), severe in 38 (49.4%), and critical in 2 (2.6%). The D-dimer concentration at delivery did not significantly differ between those with a SARS-CoV-2 positive result compared with those without (mean 2.03 µg/mL [95% confidence interval {CI} 1.72-2.40] vs. 2.37 µg/mL [95% CI 1.65-3.40]; p = 0.43). Three individuals (4%) with SARS-CoV-2 infection and none (0%) without infection were LAC positive (p = 0.59). There were no clinically apparent thromboses in either group. D-dimer concentrations and LAC positive results did not differ by COVID-19 severity. CONCLUSION: Thrombotic markers did not differ in pregnant individuals by SARS-CoV-2 infection; however, high rates of LAC positivity were detected. KEY POINTS: · Thrombotic markers did not differ in pregnant individuals by SARS-CoV-2 infection.. · Higher than expected rates of LAC positivity were detected.. · There were no clinically apparent thromboses..

Excluding pregnancy-associated deep vein thrombosis with whole-leg ultrasound.

Background: Deep vein thrombosis (DVT) is common in pregnancy, yet data are limited on the best diagnostic strategies in pregnant patients suspected of DVT. Objectives: We conducted a prospective cohort study to evaluate the rate of symptomatic DVT in the 90 days after a negative whole-leg compression ultrasound (CUS) in pregnant women presenting with DVT symptoms. Methods: In this prospective cohort study, we enrolled pregnant patients suspected of DVT between 2011 and 2019 who were referred to the vascular imaging laboratory at a tertiary care center and had anticoagulation held after a negative whole-leg CUS. Primary outcome was objectively confirmed DVT or pulmonary embolism or death due to venous thromboembolism (VTE). Results: Whole-leg CUS yielded normal results in 186 patients (97.9%) and identified DVT in 4 (2.1%). The mean age was 30 and 164 were White. Among the 186 patients with a negative, initial whole-leg CUS who did not receive anticoagulation, there were 2 DVT events identified over the 90-day follow-up period, for an overall rate of 1.1% (95% CI: 0.2-3.4%). The study was terminated before full planned accrual for administrative reasons. Conclusion: The rate of symptomatic DVT is low in pregnant patients who have a single, negative whole-leg CUS and did not receive anticoagulation. Adequately powered studies should prospectively assess whole-leg CUS in a larger population alone and in combination with pre-test probability scores and/or D-dimer to determine its role in the evaluation of suspected DVT in pregnancy.

The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Fetal and maternal morbidity in pregnant patients with Lupus: a 10-year US nationwide analysis.

OBJECTIVE: To evaluate and quantify the indicators of fetal and maternal morbidity in deliveries for patients with systemic lupus erythematosus (SLE) compared with deliveries in patients without SLE. METHODS: We used retrospective data from the National Inpatient Sample (NIS) to identify all delivery related hospital admissions of patients with and without SLE from 2008 to 2017 using ICD-9/10 codes. Fetal morbidity indicators included pre-term delivery and intrauterine growth restriction (IUGR). 21 indicators of severe maternal morbidity were identified using standard Centers for Disease Control and Prevention (CDC) definitions. Descriptive statistics, including 95% confidence intervals, were calculated using sample weights from the NIS dataset. RESULTS: Among the 40 million delivery-related admissions, 51 161 patients were reported to have SLE. Patients with SLE had a higher risk of fetal morbidity, including IUGR (8.0% vs 2.7%) and pre-term delivery (14.5% vs 7.3%), than patients without SLE. During delivery, mothers with SLE were nearly four times as likely to require a blood transfusion or develop a cerebrovascular disorder, and 15 times as likely to develop acute renal failure than those without SLE. CONCLUSION: Our study demonstrates that fetal morbidity and severe maternal morbidity occur at a higher rate in patients with SLE compared with those without. This quantitative work can help inform and counsel patients with SLE during pregnancy and planning.

Associations Among Antiphospholipid Antibody Types, Isotypes, and Titers: An AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Study.

Several antiphospholipid antibody (aPL) profiles ("triple" and lupus anticoagulant [LA] positivity) are associated with a higher risk for clinical manifestations of antiphospholipid syndrome (APS). Further risk is correlated with higher levels of anticardiolipin antibody (aCL) and anti-ß2 glycoprotein-I antibody (aß2GPI), and with aPL persistence. Given that the 3 aPL tests detect partially overlapping sets of antibodies, the primary goal of this study was to characterize the associations among aPL tests using AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) core laboratory data. The APS ACTION Registry includes annually followed adult patients with positive aPL based on the Revised Sapporo Classification Criteria. We analyzed baseline and prospective core laboratory data of the registry for associations among aPL tests using the Spearman rank correlation with Bonferroni-adjusted significance level for multiple comparisons. An aPL Load was calculated based on 6 tests (aCL IgG/IgM/IgA and aß2GPI IgG/IgM/IgA); a receiver operating characteristic curve was used to evaluate the diagnostic performance of the aPL Load in predicting LA positivity. In 351 patients simultaneously tested for LA, aCL, and aß2GPI, the frequency of moderate-to-high (≥40 U) titers of aCL and aß2GPI IgG/IgM/IgA was higher in patients who were positive for LA vs those who were negative. An aPL Load was calculated for each patient to assess the overall aPL burden. For every 1-point increase in the aPL Load, the possibility of a positive LA test increased by 32% (odds ratio, 1.32; 95% CI, 1.2-1.5; P < .001). Based on core laboratory data from a large international registry, most aPL enzyme-linked immunosorbent assay ≥40 U and a high calculated aPL Load combining 6 aPL enzyme-linked immunosorbent assays were predictive of a positive LA. These data suggest that the combined quantitative burden of aPL may provide a mechanistic explanation of a positive LA.

Anti-Neutrophil Extracellular Trap Antibodies in Antiphospholipid Antibody-Positive Patients: Results From the Antiphospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking Clinical Database and Repository.

OBJECTIVE: This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti-neutrophil extracellular trap (anti-NET) antibodies in a multinational cohort of antiphospholipid (aPL) antibody-positive patients who did not have lupus. METHODS: Anti-NET IgG/IgM levels were measured in serum samples from 389 aPL-positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n = 214), we profiled autoantibodies using an autoantigen microarray platform. RESULTS: We found elevated levels of anti-NET IgG and/or IgM in 45% of the aPL-positive patients. High anti-NET antibody levels are associated with more circulating myeloperoxidase (MPO)-DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti-NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti-NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti-NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti-NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO-DNA complexes, and nucleosomes. Anti-NET IgM positivity was associated with autoantibodies targeting single-stranded DNA, double-stranded DNA, and proliferating cell nuclear antigen. CONCLUSION: These data reveal high levels of anti-NET antibodies in 45% of aPL-positive patients, where they potentially activate the complement cascade. While anti-NET IgM may especially recognize DNA in NETs, anti-NET IgG species appear to be more likely to target NET-associated protein antigens.

Ultrasonography of the Explanted Uterus in Placenta Accreta Spectrum: Correlation With Intraoperative Findings and Gross Pathology.

OBJECTIVE: To better understand placenta accreta spectrum (PAS) by correlating postoperative ultrasonographic findings of the explanted uteroplacental interface with intraoperative findings and gross pathology. METHODS: We enrolled consecutive pregnant patients aged 18 years and older with a prior cesarean delivery and antenatal diagnosis of lower uterine segment PAS who planned to undergo hysterectomy into this prospective, descriptive study. All underwent cesarean hysterectomy with standardized intraoperative photography. Ultrasonography of explanted postsurgical uteruses was performed by expert radiologists to obtain standard detailed images of the myometrial-placental interface and other areas of interest. Sagittal views of the gross pathologic specimen were photographed. We correlated the intraoperative, ultrasonographic, and gross pathologic findings as a study team and report four consistent patterns that emerged from this systematic evaluation. RESULTS: Thirty-four consecutive eligible patients were enrolled. The following consistent observations emerged: 1) The uteroplacental interface in the explanted specimen was smooth and distinct. At the point of maximal placental protrusion, the myometrium was imperceptible, but the placenta was confined by a smooth thin echogenic line of uterine serosa (the scar shell) unless surgically disrupted. 2) Every specimen of PAS grade 2-3 showed placenta bulging through the lower uterine segment in the region of prior hysterotomy. 3) Placentas extended to, but not through, the uterovesical interface or scar shell. Dense adhesive disease was found between the placenta and bladder. There were no cases of true bladder invasion. 4) Placental extension beyond the serosa (invasion) has a distinct appearance on postoperative ultrasonography with irregular frond-like protrusion of placental tissue. This appearance was always the result of surgical manipulation and was not present before delivery of the neonate. CONCLUSION: These findings suggest that PAS severity is likely mediated by progressive scar dehiscence and uterine remodeling, not placental invasion. This challenges the existence of in situ invasive percreta as it is currently described.

Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study.

One to two percent of couples suffer recurrent pregnancy loss and over 50% of the cases are unexplained. Whole genome sequencing (WGS) analysis has the potential to identify previously unrecognized causes of pregnancy loss, but few studies have been performed, and none have included DNA from families including parents, losses, and live births. We conducted a pilot WGS study in three families with unexplained recurrent pregnancy loss, including parents, healthy live births, and losses, which included an embryonic loss (<10 weeks' gestation), fetal deaths (10-20 weeks' gestation) and stillbirths (≥ 20 weeks' gestation). We used the Illumina platform for WGS and state-of-the-art protocols to identify single nucleotide variants (SNVs) following various modes of inheritance. We identified 87 SNVs involving 75 genes in embryonic loss (n = 1), 370 SNVs involving 228 genes in fetal death (n = 3), and 122 SNVs involving 122 genes in stillbirth (n = 2). Of these, 22 de novo, 6 inherited autosomal dominant and an X-linked recessive SNVs were pathogenic (probability of being loss-of-function intolerant >0.9), impacting known genes (e.g., DICER1, FBN2, FLT4, HERC1, and TAOK1) involved in embryonic/fetal development and congenital abnormalities. Further, we identified inherited missense compound heterozygous SNVs impacting genes (e.g., VWA5B2) in two fetal death samples. The variants were not identified as compound heterozygous SNVs in live births and population controls, providing evidence for haplosufficient genes relevant to pregnancy loss. In this pilot study, we provide evidence for de novo and inherited SNVs relevant to pregnancy loss. Our findings provide justification for conducting WGS using larger numbers of families and warrant validation by targeted sequencing to ascertain causal variants. Elucidating genes causing pregnancy loss may facilitate the development of risk stratification strategies and novel therapeutics.

Antiphospholipid syndrome: advances in diagnosis, pathogenesis, and management.

Antiphospholipid syndrome (APS) is a thrombo-inflammatory disease propelled by circulating autoantibodies that recognize cell surface phospholipids and phospholipid binding proteins. The result is an increased risk of thrombotic events, pregnancy morbidity, and various other autoimmune and inflammatory complications. Although antiphospholipid syndrome was first recognized in patients with lupus, the stand alone presentation of antiphospholipid syndrome is at least equally common. Overall, the diagnosis appears to affect at least one in 2000 people. Studies of antiphospholipid syndrome pathogenesis have long focused on logical candidates such as coagulation factors, endothelial cells, and platelets. Recent work has shed light on additional potential therapeutic targets within the innate immune system, including the complement system and neutrophil extracellular traps. Vitamin K antagonists remain the mainstay of treatment for most patients with thrombotic antiphospholipid syndrome and, based on current data, appear superior to the more targeted direct oral anticoagulants. The potential role of immunomodulatory treatments in antiphospholipid syndrome management is receiving increased attention. As for many systemic autoimmune diseases, the most important future direction is to more precisely identify mechanistic drivers of disease heterogeneity in pursuit of unlocking personalized and proactive treatments for patients.

Fluctuation of Anti-Domain 1 and Anti-ß2 -Glycoprotein I Antibody Titers Over Time in Patients With Persistently Positive Antiphospholipid Antibodies.

OBJECTIVE: The present study was undertaken to longitudinally evaluate titers of antibodies against ß2 -glycoprotein I (anti-ß2 GPI) and domain 1 (anti-D1), to identify predictors of variations in anti-ß2 GPI and anti-D1 titers, and to clarify whether antibody titer fluctuations predict thrombosis in a large international cohort of patients who were persistently positive for antiphospholipid antibodies (aPL) in the APS ACTION Registry. METHODS: Patients with available blood samples from at least 4 time points (at baseline [year 1] and at years 2-4 of follow-up) were included. Detection of anti-ß2 GPI and anti-D1 IgG antibodies was performed using chemiluminescence (BIO-FLASH; INOVA Diagnostics). RESULTS: Among 230 patients in the study cohort, anti-D1 and anti-ß2 GPI titers decreased significantly over time (P < 0.0001 and P = 0.010, respectively). After adjustment for age, sex, and number of positive aPL tests, we found that the fluctuations in anti-D1 and anti-ß2 GPI titer levels were associated with treatment with hydroxychloroquine (HCQ) at each time point. Treatment with HCQ, but not immunosuppressive agents, was associated with 1.3-fold and 1.4-fold decreases in anti-D1 and anti-ß2 GPI titers, respectively. Incident vascular events were associated with 1.9-fold and 2.1-fold increases in anti-D1 and anti-ß2 GPI titers, respectively. Anti-D1 and anti-ß2 GPI titers at the time of thrombosis were lower compared to titers at other time points. A 1.6-fold decrease in anti-D1 titers and a 2-fold decrease in anti-ß2 GPI titers conferred odds ratios for incident thrombosis of 6.0 (95% confidence interval [95% CI] 0.62-59.3) and 9.4 (95% CI 1.1-80.2), respectively. CONCLUSION: Treatment with HCQ and incident vascular events in aPL-positive patients predicted significant anti-D1 and anti-ß2 GPI titer fluctuations over time. Both anti-D1 and anti-ß2 GPI titers decreased around the time of thrombosis, with potential clinical relevance.

Interpregnancy Body Mass Index Change and Offspring Mortality Risk following the Second Pregnancy.

OBJECTIVE: The aim of the study is to examine the impact of maternal interpregnancy body mass index (BMI) change on subsequent offspring mortality risk. STUDY DESIGN: This is a retrospective cohort study of women who had two consecutive live singleton deliveries of at least 20 weeks' gestation from the Utah Population Database. Our exposure was defined as interpregnancy BMI change from the date of first delivery to the conception date of subsequent pregnancy. We categorized BMI change as: < - 1, -1 to 0, 0 to <1 (reference), 1 to 2, 2 to 4, ≥4 kg/m2. Our primary outcome was all-cause age-specific mortality during four time periods: neonatal (≤28 days), infant (29 days to <1 year old), childhood ((≥1 to <5 years old), and late childhood (5 to <18 years old). We also examined mortality specifically attributed to congenital anomalies. Analyses used Cox proportional hazard models stratified by full term (≥37 weeks) and preterm (<37 weeks) deliveries. All models were adjusted for relevant confounders. RESULTS: Of 266,752 women, among full-term deliveries, women with a BMI increase of 4 kg/m2 or more had an increased risk of neonatal mortality in their subsequent pregnancy (hazard ratio or HR = 1.72, 95% confidence interval or CI: 1.23-2.41) Women who lost 1 kg/m2 or more between deliveries also had increased neonatal mortality (HR = 1.46, 95% CI: 1.04-2.05). There were no differences in infant, early, or late childhood mortality by interpregnancy BMI change. Maternal interpregnancy interval weight loss of 1 kg/m2 or more and weight gain of ≥4 kg/m2 also had increased risk of mortality associated with congenital anomalies or conditions arising during the neonatal period following their subsequent delivery. CONCLUSION: Women with significant interpregnancy weight gain and modest weight loss have a significant increased risk of neonatal mortality following their subsequent pregnancy. KEY POINTS: · Significant weight gain between deliveries increases the risk of neonatal death.. · Modest weight loss between deliveries increases the risk of neonatal death.. · This risk may be partially explained by increased risk of congenital malformations..

Prediction and Prevention of Preterm Birth: A Prospective, Randomized Intervention Trial.

OBJECTIVE: The study aimed to determine if a program of mid-trimester serum proteomics screening of women at low risk for spontaneous preterm birth (sPTB) and the use of a PTB risk-reduction protocol in those whose results indicated an increased risk of sPTB would reduce the likelihood of sPTB and its sequelae. STUDY DESIGN: Prospective comparison of birth outcomes in singleton pregnancies with mid-trimester cervical length ≥2.5 cm and at otherwise low risk for sPTB randomized to undergo or not undergo mid-trimester serum proteomics screening for increased risk of sPTB (NCT03530332). Screen-positive women were offered a group of interventions aimed at reducing the risk of spontaneous PTB. The primary outcome was the rate of sPTB <37 weeks, and secondary outcomes were gestational age at delivery, total length of neonatal stay, and NICU length of stay (LOS). Unscreened and screen-negative women received standard care. The adaptive study design targeted a sample size of 3,000 to 10,000 women to detect a reduction in sPTB from 6.4 to 4.7%. Due to limited resources, the trial was stopped early prior to data unblinding. RESULTS: A total of 1,191 women were randomized. Screened and unscreened women were demographically similar. sPTB <37 weeks occurred in 2.7% of screened women and 3.5% of controls (p = 0.41). In the screened compared with the unscreened group, there were no between-group differences in the gestational age at delivery, total length of neonatal stay, and NICU LOS. However, the NICU LOS among infants admitted for sPTB was significantly shorter (median = 6.8 days, interquartile range [IQR]: 1.8-8.0 vs. 45.5 days, IQR: 34.6-79.0; p = 0.005). CONCLUSION: Mid-trimester serum proteomics screening of women at low risk for sPTB and the use of a sPTB risk-reduction protocol in screen-positive patients did not significantly reduce the rate of sPTB compared with women not screened, though the trial was underpowered thus limiting the interpretation of negative findings. Infants in the screened group had a significantly shorter NICU LOS, a difference likely due to a reduced number of infants in the screened group that delivered <35 weeks. KEY POINTS: · Mid-trimester serum proteomics screening of women at low risk for sPTB and the use of a sPTB risk-reduction protocol in screen-positive patients did not significantly reduce the rate of sPTB, though the trial was underpowered.. · NICU LOS following sPTB was significantly shortened among women who underwent screening and risk-reduction management.. · The use of serum biomarkers may contribute to a practical strategy to reduce sPTB sequelae..