Systemic Autoimmune Diseases and Recurrent Pregnancy Loss: Research Progress in Diagnosis and Treatment
Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies before 24 weeks of gestation, affecting approximately 1% to 2% of couples. The etiology of RPL is multifactorial, encompassing metabolic/endocrinological abnormalities, genetic factors, anatomical factors, immune disorders, thrombophilia, male factors, and psychological factors. Among these, systemic autoimmune diseases such as antiphospholipid syndrome (APS), undifferentiated connective tissue disease (UCTD), and systemic lupus erythematosus (SLE) have emerged as significant contributors to RPL in recent years. Understanding the associations between these autoimmune diseases and RPL, along with advancements in diagnosis and treatment, is crucial for improving pregnancy outcomes.
Antiphospholipid Syndrome (APS) and Recurrent Pregnancy Loss
APS is a systemic autoimmune disease characterized by vascular and obstetric manifestations associated with thrombotic and inflammatory mechanisms mediated by antiphospholipid antibodies (aPL). Obstetric antiphospholipid syndrome (OAPS) is a subset of APS that presents with adverse pregnancy outcomes, including fetal losses at or after 10 weeks of gestation and spontaneous miscarriages before 10 weeks. These pregnancy losses are integral to the clinical diagnostic criteria for OAPS. Additionally, the presence of lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-beta-2 glycoprotein I antibodies (ab2GPI) in serum is necessary for the diagnosis of OAPS. According to the European Alliance of Associations for Rheumatology (EULAR) recommendations, the diagnosis of OAPS with pregnancy loss requires one clinical criterion and one laboratory criterion.
However, some RPL patients may not meet the diagnostic criteria for OAPS, leading to the concept of non-criteria obstetric antiphospholipid syndrome (NOAPS). Patients who meet one non-classical clinical or laboratory criterion and one classical laboratory or clinical criterion can be diagnosed with NOAPS. The non-classical criteria related to pregnancy loss are also outlined in the EULAR recommendations. A novel nomenclature proposal for non-criteria APS, published in 2020, further categorizes non-criteria APS into seronegative APS, clinical non-criteria APS, incomplete laboratory APS, and laboratory non-criteria APS. This classification includes two or more unexplained in vitro fertilization failures and two unexplained spontaneous abortions before 10 weeks as non-classical clinical criteria, and non-criteria aPL as non-classical laboratory criteria. Despite these advancements, the diagnostic criteria for NOAPS remain imperfect and require further refinement.
Given the complexity of diagnosing APS or NOAPS, risk stratification methods have been developed to guide clinical practice. High-risk aPL profiles include the presence of LA on two or more occasions at least 12 weeks apart, double or triple aPL positivity, or persistently high aPL titers above the 99th percentile. Conversely, isolated aCL or ab2GPI antibodies at low- to mid-level titers, particularly if transiently positive, are considered low-risk. A history of SLE, thrombosis, or pathological pregnancy also increases the risk of adverse pregnancy outcomes.
Treatment Strategies for APS and NOAPS
The treatment of APS and NOAPS is relatively well-defined. According to EULAR recommendations, women with a high-risk aPL profile but no history of thrombosis or pregnancy complications should consider low-dose aspirin (LDA) during pregnancy. For women with a history of OAPS but no prior thrombotic events, a combination of LDA and low molecular weight heparin (LMWH) at prophylactic dosages is recommended. In cases of NOAPS without prior thrombotic events, treatment with LDA alone or in combination with LMWH may be considered based on individual risk profiles. Women with a history of thrombotic APS should receive a combination of LDA and LMWH at therapeutic dosages during pregnancy. For those with recurrent pregnancy complications despite prophylactic doses of LDA and LMWH, increasing the LMWH dose to a therapeutic level or adding hydroxychloroquine (HCQ) and/or low-dose prednisone during the first trimester may be considered.
Despite these treatment guidelines, many aPL-positive patients do not meet the diagnostic criteria for NOAPS. While basic scientific studies support a causative relationship between aPL and RPL, human studies have not consistently confirmed this link. Nevertheless, these patients may still develop NOAPS or even OAPS in the future, necessitating careful management. The tools for identifying and determining risk in these patients are limited, and there is no consensus on whether aPL should be assessed during pregnancy. However, monitoring coagulation indicators during pregnancy is advisable. More evidence-based studies are needed to guide the management of pregnancy in aPL-positive patients.
Undifferentiated Connective Tissue Disease (UCTD) and Recurrent Pregnancy Loss
UCTD is a heterogeneous group of autoimmune diseases characterized by at least one symptom of connective tissue disease and a positive antinuclear antibody (ANA) test. The diagnostic criteria for UCTD are not universally agreed upon, but the generally accepted criteria require both the presence of at least one symptom of connective tissue disease and a positive ANA test with titers of 1:80 or higher. UCTD is the most common autoimmune disease in pregnant women, with a prevalence of up to 2.5%, and it has been associated with a 9% to 21% risk of pregnancy loss. ANA positivity has also been significantly associated with RPL in women without defined autoimmune diseases, suggesting that both UCTD and ANA positivity are potential etiologies of RPL.
RPL is considered a symptom of connective tissue diseases, and managing unexplained RPL combined with positive ANA as pregnancy loss–associated undifferentiated connective tissue disease (PLUCTD) is recommended. This concept helps standardize the clinical management of such cases. Although there is no consensus on the diagnostic criteria for PLUCTD, the impact of UCTD and ANA on RPL warrants greater attention.
Treatment Strategies for PLUCTD
There is no consensus on the treatment of PLUCTD, but UCTD is not considered a contraindication for pregnancy. According to Chinese experts, HCQ treatment starting 3 to 6 months before planned pregnancy can benefit patients with PLUCTD. Low-dose prednisone should be used throughout pregnancy and up to 3 months postpartum in patients prone to conversion to other autoimmune diseases. Coagulation indicators should be monitored during pregnancy, and LDA and LMWH at prophylactic or therapeutic doses may be used in patients prone to thrombosis based on individual risk profiles. Patients who experience pregnancy loss despite this treatment are considered to have refractory PLUCTD, for which no effective treatment strategy is currently available. Exploratory therapy for research purposes is encouraged in such cases. The significance of monitoring ANA titers or the autoantibody profile during pregnancy remains uncertain, and further clinical studies are needed to confirm the prognostic value of anti-extractable nuclear antigen antibodies or other autoantibodies.
Systemic Lupus Erythematosus (SLE) and Recurrent Pregnancy Loss
SLE primarily affects women of childbearing age and is associated with high-risk pregnancies due to maternal risks such as lupus flare-ups, diabetes, and preeclampsia, as well as adverse pregnancy outcomes including RPL, intrauterine fetal demise, preterm birth, fetal intrauterine growth restriction, and fetal congenital heart block. Disease activity prior to conception, the onset of SLE during pregnancy, and underlying renal disease are risk factors for RPL in SLE patients. The presence of aPL is the most recognized risk factor, and many SLE women with RPL also have OAPS or NOAPS, establishing a mechanistic link between SLE, OAPS/NOAPS, and RPL. ANA, a classical immunological marker of SLE, may also play a role in the pathogenesis of RPL in SLE patients.
For RPL patients with SLE, stabilizing the condition before the next pregnancy is essential, particularly if SLE is active or if there is active nephritis or hypertension. Teratogenic immunosuppressive drugs should be discontinued at least 6 months before pregnancy and replaced with pregnancy-safe immunosuppressants such as HCQ and cyclosporine A (CsA). During pregnancy, disease activity should be assessed regularly, including renal function parameters and serological markers such as serum C3/C4 and anti-dsDNA titers, to monitor for adverse obstetrical outcomes and disease flare-ups. HCQ is recommended preconceptionally and throughout pregnancy for RPL patients with SLE, and low-dose prednisone should be added if disease activity increases. If HCQ and low-dose prednisone fail to control lupus activity, relatively safe immunosuppressants such as azathioprine (AZA), CsA, or tacrolimus may be considered. Collaboration between obstetricians and rheumatologists is essential for managing SLE patients during pregnancy.
Conclusion
In summary, OAPS/NOAPS, UCTD, and SLE are important etiologies of RPL. The diagnosis and treatment of RPL associated with systemic autoimmune diseases remain challenging due to limited basic and clinical research. Further studies are needed to explore the mechanisms by which systemic autoimmune diseases and antibodies cause RPL and to evaluate different treatment strategies for these conditions. Advances in understanding and managing these diseases will significantly improve pregnancy outcomes for women with RPL.
doi.org/10.1097/CM9.0000000000001691
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