INTRODUCTION
Antiphospholipid syndrome (APS) is a chronic autoimmune disease with main clinical features that include recurrent thrombosis of the arteries, veins, microvasculature, or/and obstetric complications. The main characteristics of the disease are the presence of antiphospholipid autoantibodies (aPL): anticardiolipin antibodies (aCL) directed against membrane anion phospholipids, antiβ2 glycoprotein 1 antibody (aβ2GPI) directed against β2 glycoprotein I (a cardiolipin binding factor), and circulating lupus anticoagulant (LA) (1).
The estimated incidence of the disease is around 2 cases per 100,000, and prevalence is around 45 per 100,000. The prevalence of aPL with obstetric complications is 6–9%, and with vascular complications it is 9–10% (2).
The prevalence of aPL in seemingly healthy individuals is around 5% and it is more likely to be found in elderly patients (3).
Traditionally, APS is subcategorized into 1.) Primary (PAPS), in which no associated systemic autoimmune disease exists, 2.) Secondary (SAPS), which is accompanied by systemic autoimmune disease, such as systemic lupus erythematosus (SLE), and 3.) Catastrophic APS (CAPS) in which thrombosis affects multiple organs in a short period of time (4).
DIAGNOSIS
For the diagnosis of APS to be established, a clinical criterion, such as venous, arterial, or microvasculature thrombosis and/or obstetric complications, in combination with persistently circulating aPL, must be present (5).
The Sapporo criteria were established in 1998 and updated in 2006 as the Sydney criteria. Patients were classified as having APS if they had a clinical event (vascular thrombosis and/or pregnancy morbidity) along with laboratory criteria that were defined as at least double positive aPL (LA, aCL IgG/IgM in medium to high titer, or aβ2GPI IgG/IgM higher than the 99th percentile), and they were tested 12 weeks apart (6).
For the diagnosis of obstetric APS, the clinical criteria defining pregnancy morbidity included a) one or more unexplained deaths of a morphologically normal fetus at/beyond the 10th week of gestation; b) one or more premature births at/before the 34th week of gestation due to severe preeclampsia (PEC)/eclampsia, or severe placental insufficiency; (PI) c) three or more unexplained consecutive spontaneous abortions before the 10th week of gestation (other possible reasons such as chromosomopathy, hormonal or anatomy abnormalities were excluded) (6).
The 2023 ACR/EULAR APS criteria require an entry criterion of at least one positive aPL test within three years of identification of clinical criterion, followed by additive weighted criteria (1–7 points each) divided 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 aCL and aβ2GPI. For the established diagnosis, at least 3 points in the laboratory domain and 3 points in the clinical domain are needed (7).
When defining pregnancy morbidity, the following clinical criteria are included: a) three or more consecutive pre-fetal (<10th week) and/or early fetal (10w 0d – 15w 6d) deaths, which is weighted as 1 point, b) fetal death (16w 0d – 33w 6d) in the absence of PEC or PI with severe features — 1 point; c) PEC or PI with severe features (<34w 0d) with/without fetal death — 3 points; d) PEC and PI with severe features (<34w 0d) with/without fetal death — weighted the most as 4 points (7).
OBSTETRIC ANTIPHOSPHOLIPID SYNDROME
Obstetric complications are one of the significant manifestations of APS that have a direct effect on maternal and fetal morbidity, causing recurrent pregnancy miscarriages, fetal death, and signs of placental insufficiency, such as preeclampsia, intrauterine growth restriction, and HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelets) syndrome (8).
PATHOPHYSIOLOGY OF OBSTETRIC ANTIPHOSPHOLIPID SYNDROME
Thrombosis, the most prominent feature of vascular APS (vAPS), was once thought to be the primary mechanism in the pathophysiology of obstetric APS.
Pathological examinations of the placentas in patients with APS have revealed changes beyond just thrombosis. These changes include impaired spiral artery remodeling, inflammation of the decidua with neutrophil infiltration, local production of tumor necrosis factor (TNF)-α, deposition of complement split product, and placental infarction. All these findings suggest that thrombo-inflammation is the primary cause of the condition. (9, 10).
Additionally, it is important to note that not all patients with oAPS will develop vAPS, and vice versa. This understanding has helped distinguish vAPS from oAPS as a distinct pathophysiological mechanism.
In 2017. Taraborelli et al. performed a multicentric, retrospective study that included 115 women diagnosed with primary APS. During the 18-year follow-up period, 19% (6/31) of patients with a history of pregnancy morbidity but without a prior history of thrombosis developed thrombosis during the follow-up period, and 12% of patients (6/49) with a history of thrombosis developed an obstetrical adverse outcome during the follow-up period (11).
A retrospective multicentric study conducted in Israel revealed that among primary APS patients, 21.2% of patients with oAPS developed arterial thrombosis and 6% of them developed venous thrombosis during the 15-year follow-up period (12).
To facilitate understanding of the pathophysiology of oAPS, it is important to comprehend placental development during a normal pregnancy.
A fertilized egg rapidly undergoes multiple mitotic cleaves and reaches the uterine cavity. There, it is differentiated into blastomere, and then morula until the blastocyst stage is reached.
Blastocystis comprises the inner cell mass (ICM)-embryonic stem cells, and cells surrounding and protecting ICM- trophectoderm cells. From the trophectoderm, cytotrophoblast arises (13). One part of the cytotrophoblast is developed in syncytiotrophoblast by fusing and growing towards the placenta primed for implantation through decidualization. Syncytiotrophoblast has multiple roles: the role of connecting to the uterus by covering the surface of the villi, secreting hormones like progesterone, leptin, lactogen, and human chorionic gonadotropin which are essential to maintain early pregnancy, forming intervillous space by secreting protease in the decidua. One part of the cytotrophoblast is differentiated in extravillous trophoblasts that invade the uterine spiral arteries and remodel them into non-vasoactive large-bore conduits (14). This process is essential for future fetal development because impaired spiral artery remodeling is one of the main culprits in the pathology of placental insufficiency, leading to preeclampsia and fetal growth restriction (15).
In oAPS, antiphospholipid antibodies have a major role in the pathophysiology of the disease. In vitro studies have demonstrated that they directly affect the proliferation and growth of trophoblasts and lead to the loss of trophoblast-endothelium interactions. There is a reduced invasion of extravillous trophoblast with impaired spiral artery remodeling. aPL antibodies also trigger the production of pro-inflammatory cytokines (interleukin (IL)-1, IL-7, IL-8) that attract monocytes and neutrophils, leading to macrophage activation and release of neutrophil extracellular traps (NETosis), which results in inflammation around trophoblast and apoptosis. Additionally, they activate macrophages and complement deposition, thus promoting inflammation around trophoblasts and apoptosis. Complement activation leads to local TNF-α production and secretion, adding to a vicious inflammation circuit. (14, 16, 17)
Animal models and in vitro research showed the direct embryotoxic activity of aPL. Antibodies taken from women with APS directly affect the growth and viability of animal embryos. (18, 19)
In 2013, Gardiner and the authors conducted research that included around 190 women with APS with vascular and obstetric manifestations. Interestingly, over 50% of women with oAPS, but no known thrombosis had low-titre aCL and/or aβ2GPI in the absence of LA. The researchers suggested that low-titer aCL and aβ2GPI should be included in the criteria for the diagnosis of oAPS (20). One possible explanation is that decidual cells and cytotrophoblast usually exhibit high basal levels of β2GPI and represent easily accessible targets for aβ2GPI. This might also explain why a second hit, such as trauma, surgery, infection, primary autoimmune disease or another proinflammatory stimulus needed for developing thrombosis in vAPS is not required to develop oAPS (21).
The different effects of aPL in vAPS and oAPS leading to divergent pathophysiological mechanisms were also confirmed by two in vitro studies. In the first study, aPLs from vAPS and oAPS were observed to activate the monocyte signaling pathway. aPL against β2GPI from vAPS patients were the only ones to induce thrombin factor (TF) production by monocytes, while antibodies from the patient with obstetric manifestations failed to do this. In the second study, purified IgG from patients with obstetric APS, but not the one from non-obstetric APS, inhibited trophoblast invasion (10, 22, 23).
Clinical manifestations:
1.) Early miscarriages (>10th week of gestation)
Early miscarriages are the most common clinical finding in aPL-positive patients with pregnancy morbidity and were included in the 2006 revised Sapporo classification criteria (6).
According to the 2023 ACR/EULAR classification criteria, it is no longer sufficient to have three or more early miscarriages to fulfill the clinical domain of APS diagnosis. Nonetheless, the authors emphasize that they still remain a part of the high-priority research agenda to guide the future update of the 2023 ACR/EULAR APS classification criteria (7).
Carvera et al. published a multicentric observational study that included 1000 APS patients (820 women). During the 10-year follow-up period, 127 (15.5%) women got pregnant. The most common obstetric complication was early pregnancy loss (16.5% of pregnancies) (24).
Alijotas-Reig et al. analyzed obstetric outcomes in 1000 patients with oAPS using the European Registry of oAPS. They found that the most prevalent manifestations were miscarriages in 38.6% of the pregnancies (25).
In another study that included 183 patients with oAPS during a 10-year follow-up, recurrent early abortions were found in 58.6% of patients (26).
2.) Stillbirth (loss of a baby at or after 20 weeks of pregnancy)
When assessing maternal sera in 582 stillbirth deliveries, elevated levels of aCL and aβ2GPI were associated with a threefold increased odd of stillbirth (27).
A retrospective French study that included 65 women with APS and intrauterine fetal death (IUFD), found that IUFD was the first APS clinical manifestation in 74% of women (28).
3.) Preeclampsia and fetal growth restriction
When assessing the European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS), PE was found to be present in 18.1% and fetal growth restriction in 16.1% of cases (25).
The prevalence of aPL is twice as high in pregnant women who develop PE compared to those who have healthy pregnancies. (29).
In a prospective case-control study that compared the frequency of aPL positivity in women who delivered their baby in the period before the 36th week due to PE or placental insufficiency and women with normal pregnancies, it was found that aPL was present in 11.5% of women with PE or placental insufficiency, which was significantly higher compared to 1.4% of women with uncomplicated pregnancies (30).
Carvera et al. found that intrauterine growth restriction (26.3% of live births) and prematurity (48.2%) were the most frequent fetal morbidities.
The observational study of patients with pregnancy loss showed that patients with oAPS who were treated with low-molecular-weight heparin (LMWH) plus low-dose aspirin (LDA) had a lower rate of pregnancy losses but a higher rate of PE than the others, and the study confirmed the greater risk of PE in the oAPS group. (31).
THROMBOTIC EVENTS IN PATIENTS WITH OBSTETRIC ANTIPHOSPHOLIPID SYNDROME
Pregnancy itself carries a risk of thrombotic events; for example, the risk of venous thromboembolism is five times higher in a pregnant woman than in a non-pregnant woman of similar age (32).
A retrospective study on 200 APS patients divided into four groups based on previous medical history (obstetric, thrombotic, non-criteria antiphospholipid syndrome, and aPL carriers) showed that 2.5% of patients experienced thrombotic events during pregnancy and puerperium. Most cases were reported in the thrombotic group with prior thrombotic events. Unfortunately, in 85% of these cases, the thrombotic event occurred despite the use of adequate antithrombotic therapy (33).
RISK FACTORS FOR ADVERSE OUTCOMES IN PREGNANCY
Various studies were conducted in search of risk factors for the adverse outcomes in oAPS and found, for example, SLE or hypocomplementaemia to be an additional risk factor (33, 34).
The 2021 meta-analysis, that included 27 eligible records, identified previous thrombosis, double and triple aPL positivity, and lupus anticoagulant positivity as the most important predictors of adverse pregnancy outcomes in APS (35).
These findings should be utilized routinely in preconception counseling and pregnancy follow-up to guide individualized risk assessment for adverse pregnancy outcomes.
MANAGEMENT OF OBSTETRIC ANTIPHOSPHOLIPID SYNDROME
1.) Standard therapy: low-molecular-weight heparin and low-dose aspirin
Anticoagulant therapy plays an essential role in the treatment of APS. In patients with thrombotic APS, vitamin K antagonists (VKAs), such as warfarin, should be included in therapy. Due to warfarin teratogenicity, especially in the first trimester, in pregnant patients with prior thrombosis, warfarin should be discontinued (36).
There is a rising interest in using direct oral anticoagulants (DOACs) in APS patients with vascular manifestations of the disease. Current guidelines recommend that warfarin should be the first-choice treatment in APS, especially in patients with triple aPL positivity and with previous arterial thrombosis due to increased rates of recurrent thrombosis treated with DOAC compared with VKAs (37). Although DOACs may be effective in single/double aPL-positive patients with an exclusively venous thrombotic event, there is no adequate data for the use of DOACs in pregnancy. Limited real-world data and animal studies raised concern for embryo-fetal safety, with a higher rate of miscarriages and possible fetal anomalies, so the current guidelines recommend against DOAC use throughout pregnancy (38).
In pregnant patients with prior thrombosis, therapeutic doses of LMWH and LDA are recommended in therapy. For pregnant patients with purely obstetric morbidity and no prior thrombosis, prophylactic dose LMWH and LDA until six weeks postpartum is recommended (36).
Since early recurrent miscarriages are one of the prominent features of oAPS, it is necessary to emphasize the importance of starting the treatment promptly.
In patients with recurrent miscarriages, a prophylactic dose of LMWH should be included since the positive pregnancy test and LDA at least one month before starting attempts for a new pregnancy. For the patients who are in the process of assisted reproductive technique (ART), a prophylactic dose of LMWH should be included since estrogens are started in the substituted cycle or 14 days before the transfer, combined with LDA, at least one month before starting ART (10).
2.) Management of refractory oAPS
Approximately 20–30% of oAPS patients do not benefit from standard treatment (LMWH+LDA), and additional therapeutic options are necessary in those refractory cases (39).
In pregnant patients who receive prophylactic doses of LMWH but still experience recurrent fetal loss, therapeutic doses of LMWH can be administered to prevent adverse events.
Other therapeutic options include small doses of prednisolone, hydroxychloroquine, plasmapheresis, immunoglobulins, tumor necrosis factor (TNF)-α inhibitors, e.g., certolizumab-pegol, statins (pravastatin), and eculizumab, with promising results (36, 39–48).
CONCLUSION
Pregnant women with APS must have frequent follow-up visits with both gynecologists and rheumatologists. During these visits, detailed check-ups should be performed, and risk factors for pregnancy morbidity should be screened for. A better understanding of the pathophysiology of the disease will enable the use of new therapeutic options, which can help improve outcomes in oAPS for both the mother and the child.
Acknowledgments: The author report no acknowledgments.
Funding: For this work author did not receive any funding.
Conflict of interest statement: The author declare no conflict of interest.
REFERENCES / LITERATURA
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<jrn>34. Tao JJ, Adurty S, D’Angelo D, DeSancho MT. Management and outcomes of women with antiphospholipid syndrome during pregnancy. J Thromb Thrombolysis. 2023;55(4):751–9.PubMedhttps://doi.org/10.1007/s11239-023-02789-8</jrn>
<jrn>38. Lameijer H, Aalberts JJJ, van Veldhuisen DJ, Meijer K, Pieper PG. Efficacy and safety of direct oral anticoagulants during pregnancy; a systematic literature review. Thromb Res. 2018;169:123–7.PubMedhttps://doi.org/10.1016/j.thromres.2018.07.022</jrn>