Why low-dose aspirin persists in recurrent pregnancy loss without APS: cognitive bias and system design

This guidance updates and replaces the previous guideline on the investigation and management of antiphospholipid syndrome (APS) published in 2000 (Greaves et al, 2000), though where there have not been changes we refer back to them when appropriate. The guidance is updated with reference to relevant publications since 2000. Publications known to the writing group were supplemented with additional papers identified by searching PubMed for publications in the last 11 years using the key words: lupus anticoagulant, anticardiolipin, antiphospholipid, b2–glycoprotein I, antiprothrombin and limits (clinical trial, randomized control trial, meta-analysis, humans, core clinical journals, English language). The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the Royal College of Obstetricians and Gynaecologists (RCOG), and the British Committee for Standards in Haematology (BCSH) Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMEN DATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with antiphospholipid syndrome though individual patient circumstances may dictate an alternative approach.

Objective: To determine whether treatment with low dose aspirin and heparin leads to a higher rate of live births than that achieved with low dose aspirin alone in women with...

Low dose aspirin rescues subsequent pregnancies of the patients with two consecutive miscarriages associated with antiphospholipid antibodies and/or hypercoagulability

Study objectiveTo compare the live birth rate of women presented with recurrent miscarriages in the first trimester due to antiphospholipid antibody syndrome (APS), randomized to either low molecular weight heparin (Bemiparin) or low dose aspirin (LDA) and to determine the maternal and fetal adverse effects in both treatment groups.Patients and methodsA clinical comparative study was conducted in Maternity teaching Hospital, Erbil city, north of Iraq, Kurdistan region from 15th of September 2007 to the 1st of August 2010 on 141 women presented with 2 or more consecutive miscarriages due to APS, the women randomized to receive either prophylactic dose of Bemiparin with the diagnosis of pregnancy or LDA started preconceptioally and until 36 weeks gestation. The primary outcome was live birth rate in both treatment groups, the secondary outcomes were maternal and fetal complications in both trial groups.ResultThere was no statistically significant difference between the two groups regarding demographic characters (age groups, parity, gestational age and history of previous abortion), and mode of delivery of the viable newborns.There was a statistically significant difference between the two treatment groups regarding live birth rate. The proportions of women who gave birth to a live infant were 72.13% in the LDA group and 86.25% in the Hibor group, the mean difference between the live birth rate in both group was 0.141 (95% Confidence interval of the difference, 0.08, 0.274). The average birth weight for women received LDA was significantly lower than women who received Bemiparin.ConclusionThe use of the new second generation LMWH (Bemiparin) in comparison to LDA during pregnancy for prevention of recurrent miscarriage in women with APS is a safe, reliable method with a high live birth rate and no maternal and fetal complications.

A comprehensive network meta-analysis was designed to clarify contradictions and offer valuable clinical guidance in the treatment of recurrent spontaneous abortion (RSA). The included clinical trials were selected from the relevant medical journal databases and screened. Treatments were ranked by the surface under the cumulative ranking curve. Heat plots were constructed to analyze the inconsistency between direct data and network results, and adjusted funnel plots were constructed to assess publication bias. Forty-nine randomized controlled trials involving a total of 8496 RSA patients were selected. With placebo as control, corticosteroid plus low dose aspirin (LDA) plus unfractionated heparin (UFH), granulocyte colony-stimulating factor (G-CSF) alone, and LDA plus low molecular weight heparin (LMWH) all demonstrated effectiveness in increasing successful live birth rates and reducing the incidences of miscarriage. However, no treatment was demonstrably superior to placebo in terms of pregnancy success. For all 3 endpoints (live birth, abortion and success pregnancy), the adjusted funnel plots were symmetric to zero and indicated no publication bias. In terms of live birth and abortion rates, no treatment outperformed placebo in patients with antiphospholipid syndrome. In consideration of live birth and abortion rates, corticosteroid plus LDA plus UFH appeared to be the optimum treatment strategy; G-CSF was second, followed by LDA with LMWH, LDA plus LMWH plus intravenous immunoglobulin, corticosteroid with LDA and others. Subgroup analysis demonstrated no benefit of antithrombotic therapy in patients with antiphospholipid syndrome.

Risk of stratified therapies for antiphospholipid antibody syndrome (APS) in pregnancy: is tailored treatment ready for prime time?

Treatment of recurrent miscarriage and antiphospholipid syndrome with low-dose enoxaparin and aspirin

Heparin and aspirin (HA) therapy is used for antiphospholipid syndrome (APS)-associated recurrent pregnancy loss (RPL). Low-dose aspirin (LDA) is recommended for thrombophilic predispositions, such as antiphospholipid antibodies that do not completely meet the Sydney classification criteria for APS, protein S deficiency, factor XII deficiency and increased platelet aggregation. However, no established strategy exists for cases where LDA is ineffective. Therefore, this study aimed to identify the characteristics of RPL cases unresponsive to LDA and to determine whether HA is more effective than LDA in such cases. A total of 913 LDA-treated pregnancies were categorized into live births and miscarriages, and their characteristics were retrospectively analyzed. The live birth rates following one, two, or three or more LDA therapies were 78.5%, 61.5% and 16.7%, respectively. Live birth rates were significantly lower when lupus anticoagulant (LAC) aPTT was positive but did not qualify as obstetric APS following LDA therapy (birth rates: 33.3%, p = 0.048). Three or more LDA therapies decreased the live birth rate, whereas HA therapy significantly increased the live birth rate (p = 0.0019). HA therapy is recommended over repeated LDA treatment, particularly when LAC aPTT is positive but does not qualify as obstetric APS.

Antiphospholipid syndrome (APS) is one of the treatable causes for pregnant women with recurrent pregnancy loss (RPL). This review compares the efficacy of a few treatment interventions (low-dose aspirin (LDA), aspirin plus low molecular weight heparin (LMWH), or unfractionated heparin (UFH)) in preventing complications during pregnancy and miscarriages for women with RPL and APS, and the potential differences in therapeutic effects of UFH and LMWH when combined with aspirin. We searched randomized controlled trials (RCTs) in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials and performed a systematic review and a Bayesian network meta-analysis (NMA). Finally, we found aspirin alone had a lower live birth rate compared to LMWH plus aspirin (OR=0.37; 95% CrI, 0.17, 0.71), and UFH plus aspirin showed a higher live birth rate than aspirin alone (OR=2.63; 95% CrI, 1.04, 5.39) in NMA, treating with UFH plus aspirin or LMWH plus aspirin did not have difference on live birth. Furthermore, LDA alone resulted in a lower birthweight compared to heparin plus aspirin, while higher birthweight was found when compared UFH plus aspirin to LMWH plus aspirin (MD=895.40; 95% CrI, 817.40, 988.57) in NMA. Additionally, in women with RPL and APS and without a prior thrombosis, heparin plus aspirin improved birthweight but could not promote live birth rate compared to aspirin alone. In conclusion, heparin plus aspirin is recommended for women with RPL and APS. Notably UFH plus aspirin demonstrates the most significant therapeutic efficacy among these interventions in improving birthweight.

Recurrent spontaneous abortion (RSA) was defined as three or more failed clinical pregnancies before 28 weeks with the same sexual partner, and the definition differs from areas and races. Factors associated with RSA are numerous, and the cause of most patients is still unknown. Clinical diagnosis and treatment are very difficult. RSA caused by anatomical abnormalities usually requires surgical treatment to help patients recover anatomy and function of uterus, endomembrane, cervix, etc., especially in patients with intrauterine adhesions, hysteroscopic adhesiolysis can effectively improve the pregnancy outcome of patients. Currently, there is no adequate evidence suggests that preimplantation genetic diagnosis can improve the live birth rate of RSA patients. For thyroid dysfunction in RSA patients, thyrotropin should be controlled to a certain level. Metformin can improve insulin resistance in RSA patients, but the efficacy to improve pregnancy outcome remains to be feather verified. There is insufficient evidence that progesterone supplement can improve live birth rate of RSA patients with luteal insufficiency. RSA patients with typical antiphospholipid syndrome (APS) should be treated with low molecular weight heparin (LMWH) and low dose aspirin. Whether LMWH, granulocyte colony-stimulating factor or lymphatic immunotherapy can effectively improve pregnancy outcome in patients with unexplained RSA is still unproven. This article reviewed the treatment of RSA according to different causes. Key words: Recurrent spontaneous abortion (RSA); Unexplained recurrent spontaneous abortion(URSA); Treatment

The significance of heritable thrombophilia in pregnancy failure is controversial. We surveyed all UK Early Pregnancy Units and 70% responded. The majority test routinely for heritable thrombophilias; 80%, 76% and 88% undertook at least one screening test in late miscarriage, recurrent miscarriage and placental abruption, respectively. The range of thrombophilias sought is inconsistent: testing for proteins C and S deficiency and F5 R506Q (factor V Leiden) is most prevalent. Detection of heritable thrombophilia frequently leads to administration of antithrombotics in subsequent pregnancies. Thus, thrombophilia testing and use of antithrombotics are widespread in the UK despite controversies regarding the role of heritable thrombophilia in the pathogenesis of pregnancy complications, and the lack of robust evidence for the efficacy of antithrombotic therapy.

Background As hypercoagulability may result in recurrent miscarriages, anticoagulants (clexane) and aspirin (aspocid) could potentially increase live-birth rate in subsequent pregnancies in women with either inherited thrombophilia or unexplained recurrent miscarriages. Patients and methods This randomized trial included 120 pregnant women who were recruited by the closed-envelope method from the outpatient clinics of El-Hussien University Hospital and El-Galaa Maternity Teaching Hospital with history of at least three recurrent miscarriages. The trial was designed to compare the effects of low-dose aspirin (aspocid 75 mg tab) and low-molecular-weight heparin (LMWH) (clexane) on pregnancy outcome and live-birth rate. Pregnant women were divided into two groups: group 1 (60) was administered oral, low-dose aspirin (aspocid 75 mg tab) daily, and group 2 (60) was administered LMWH (clexane) 1 mg/kg subcutaneously daily. Results Regarding primary outcome (live-birth rate), the two groups did not differ significantly. Both drugs increased live-birth rate with an incidence of 81.7% in group 1 and 83.3% in group 2. Conclusion Low-dose aspirin (aspocid 75 mg tab) and LMWH (clexane 1 mg/kg) improve pregnancy outcome and increase live-birth rate, with no significant differences between the two drugs in patients with history of recurrent miscarriages without antiphospholipid antibody syndrome.

Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications – Yes

Antiphospholipid syndrome and recurrent miscarriages

Hydroxychloroquine (HCQ) is a novel medication for women suffering from autoimmune-related recurrent pregnancy loss. Many autoimmune disorders have been related to poor obstetric outcomes; anti-phospholipid syndrome (APS) is the only autoimmune disorder in which pregnancy loss is a diagnostic requirement. The goal of this study is to see how beneficial it is to provide hydroxychloroquine (HCQ) in addition to low-molecular-weight heparin (LMWH) and low-dose aspirin (LDA) to females having a record of autoimmune-related recurrent pregnancy loss and refractoriness to low-dose aspirin and LMWH in previous pregnancies, both during preconception and gestation. Patients and methods. Between January 2019 and January 2021, 120 females with a history of autoimmune recurrent pregnancy loss at Ain Shams University Maternity Hospital were examined. Participants were divided into two classes using computer-based randomization procedures. During preconception and gestation, class A (60 cases) received hydroxychloroquine (HCQ), while class B (60 cases) received a placebo. Also, they received LDA and LMWH. The primary outcome measure in this study was the rate of live births. Secondary outcomes included gestational age at delivery, birth weight, mode of delivery, Apgar score at 5 minutes, neonatal morbidity, rate of neonatal intensive care unit (NICU) admission, and postneonatal mortality rate. Results. The live birth rate was 66% in class A and 42.3 % in class B. So, it was significantly higher in class A than in class B (p-value = 0.016). Additionally, gestational age at delivery was substantially greater in class A than in class B. In terms of live births, C-section was slightly less common in class A than in class B (p-value = 0.015). Notably, the mean birth weight was 2.509 kg in class A and 1.972 kg in class B, indicating that neonatal birth weight was substantially greater in class A than in class B (p-value = 0.003). Finally, NICU admission was significantly less common in class A than in class B (p-value = 0.044). Conclusion. HCQ is a potent, safe, and cost-effective medication used to prevent adverse obstetric outcomes in females with a history of autoimmune-related recurrent pregnancy loss with refractoriness to LDA and LMWH in previous pregnancies. This randomized controlled trial (RCT) provided additional evidence to support previous studies (non-criteria or seronegative APS), in which the diagnosis of APS is made solely based on the medical history, regardless of laboratory findings for antiphospholipid antibodies (aPL). Trial registration: Pan African Clinical Trial registration number is: PACTR2021104858485905. Key words: hydroxychloroquine; anti-phospholipid syndrome; heparin; low dose aspirin; autoimmune recurrent pregnancy loss