Diagnostic criteria for antiphospholipid syndromea
Diagnosis requires at least one clinical and one laboratory criterion
Clinical criteria
1. Vascular thrombosis: ≥1 clinical episodes of arterial, venous, or small vessel thrombosis (confirmed by imaging or histopathology), excluding superficial venous thrombosis
2. Pregnancy morbidity
(a) ≥1 unexplained fetal deaths at or beyond the tenth week of gestation
(b). ≥1 premature births before the 34th week of gestation because of preeclampsia, eclampsia, or placental insufficiency
(c) ≥3 unexplained consecutive spontaneous abortions before the tenth week of gestation
Laboratory criteria – the presence of one or more of the following antibodies (at medium to high titers) on two or more occasions at least 12 weeks apart
1. Lupus anticoagulant (LA)
2. Anticardiolipin antibody (aCL)
3. Anti-beta-2-glycoprotein-1 antibody (anti- β2GP1)
The procoagulant effect of antiphospholipid (aPL) antibodies on endothelial cells and monocytes that disrupt the coagulation cascade, form placental clots, and therefore block maternal-fetal blood exchange is the most recognized mechanism of APS-associated pregnancy complications. The majority of aPL antibodies bind to β2-glycoprotein-1 (β2GP1), which is a protein that binds to anionic phospholipid membranes. Other ligands include prothrombin, protein C, protein S, and annexin A2, which participate in the coagulation cascade. While thrombosis remains a major mechanism in APS pregnancy morbidity, evidence shows that inflammation induced by the complement cascade plays a large role in aPL-induced fetal loss [23, 24]. Specifically, aPL bound to trophoblasts causes an unregulated activation of the classical complement pathway that leads to subsequent activation of the alternative pathway and a potent inflammatory response that directly inhibits placental trophoblastic growth and differentiation, resulting in placental injury and decreased B-human chorionic gonadotropin release [25]. Other pathogenic mechanisms include platelet activation and aggregation by β2GP1 directly as well as through an antiβ2GP1 antibody-β2GP1 complex that binds to platelet thrombi [26, 27].
Lupus Nephritis and Pregnancy
Lupus nephritis is one of the most serious complications of SLE, despite recent improvements in long-term prognosis. Patients with a history of LN have been shown to have a higher incidence of having a disease flare in all trimesters of pregnancy, as well as postpartum [6, 28, 29]. An increased SLE flare risk of up to 8% has been reported even with quiescent lupus at the onset of pregnancy [6]. In a meta-analysis of 37 studies (from 1980 to 2009) including 1842 women with LN, overall disease flares occurred in 26% (29), and LN flares occurred on average in 16% of patients.
History of LN has been shown to significantly affect pregnancy outcomes [12] with an incidence of approximately 16–30% [3, 13], even if nephritis is in remission at the beginning of pregnancy. In the PROMISSE trial, the largest lupus pregnancy cohort to date with stable or inactive SLE, the risk of adverse pregnancy outcomes was increased by 9% in patients with any renal involvement prior to conception [3]. This could be linked to the observation of LN being a significant predictor of hypertension, preeclampsia, and HELLP, in the absence of active disease [30–33]. In a meta-analysis of 37 studies, the risk of developing hypertension was 16.3% and preeclampsia 7.6% in women with a history of LN [34].
Based on multiple cohorts, an average of 25% patients with a history of LN and approximately 40% with active LN have preterm delivery [33, 35, 36]. As expected, patients with active LN during pregnancy have a higher rate of fetal loss, occurring in up to half of women with active LN, compared to 11–25% with inactive LN and 9% in lupus patients without renal disease [33, 37].
Focal proliferative (Class III) and diffuse proliferative (Class IV) LN portend the worst prognosis with a high risk for maternal and fetal complications, either directly or as a result of hypertension, preeclampsia, or eclampsia [38].
Mortality has been reported in pregnant LN patients, occurring in less than 1%, and observed only in patients with active disease at onset or during pregnancy. Opportunistic infections related to immunosuppressive use (glucocorticoids primarily) have been found to be the leading cause of death, followed by disease flares, pulmonary emboli and pregnancy-associated cardiomyopathy [39].
Antiphospholipid Syndrome and Renal Complications During Pregnancy
APS can occur independently (primary APS) or in the context of SLE (secondary APS), and pregnancy represents a significant risk for spontaneous abortions (35%), fetal deaths (17%), premature births (10%), small for gestational age (17%), preeclampsia (9.5%), eclampsia (4%), and HELLP (10–12%) [23, 40]. Of the APS antibodies, lupus anticoagulant has been found to be the strongest predictor of adverse pregnancy outcomes [3, 4, 41].
APS nephropathy can occur in a tenth of patients with primary APS [42] or concomitantly in patients with LN and can be characterized by acute thrombosis in arterioles and glomeruli and chronic fibrotic vascular lesions in interlobular arteries [43–46]. Although clinically indistinguishable, the findings of microvascular thrombi (thrombotic microangiopathy, TMA) and fibrous intimal hyperplasia on renal biopsy are pathognomonic features of APS nephropathy.
Thrombotic microangiopathy (TMA): comparing APS nephropathy vs. pregnancy-associated TTP vs. pregnancy-associated aHUS
APS nephropathy | Pregnancy-associated TTP | Pregnancy-associated aHUS | Lupus nephritis | |
|---|---|---|---|---|
Histopathology | Arteriolar and capillary thrombosis, fibrin deposition of vessel walls | Complex deposition | ||
Differentiating features | ||||
Neurological symptoms | + | |||
Proteinuria | +/− | − | − | ++ |
Hematuria | − | − | − | ++ |
MAHA | + | ++ | + | +/− |
Thrombocytopenia | + | ++ | + | +/− |
ADAMTS13 | ++ | >5% | ||
Hypocomplementemia | + | <10% | − | ++ |
aPL | +++ | − | − | |
Timing | At any time | 2nd to3rd trimester | Postpartum | At any time |
Treatmenta (First-line) | ASA and anticoagulation | PLEX | Supportive | Glucocorticoids |
PLEX | AZA | |||
Treatment (Second-line) | Glucocorticoids, immunosuppressive therapy | (Eculizumab) | CYC | |
Preeclampsia in SLE/APS Pregnancy
Preeclampsia is estimated to occur in 3.4% of pregnancies in the United States [48, 49]. In patients with SLE and APS, this risk is further increased and is estimated to be between 8% and 35% [8, 21, 50, 51]. This wide variation in the incidence of preeclampsia in the SLE/APS population is likely attributable to disease severity in the presence of LN. Studies have estimated that patients with a history of lupus nephritis are at a tenfold increased risk of preeclampsia [32]. Furthermore, a meta-analysis of 12 studies demonstrated that there was a 3-fold risk for preeclampsia and 11-fold risk for severe preeclampsia in the presence of antiphospholipid antibodies and/or lupus anticoagulant [51, 52].
Comparison of clinical and laboratory features of preeclampsia and lupus nephritis
Features | Preeclampsia | Lupus nephritis |
|---|---|---|
Hypertension | After week 20 | Anytime during pregnancy |
Other organ involvement | HELLP, CNS involvement with eclampsia | Extrarenal active SLE |
Response to corticosteroids | No | Yes |
Urinary sediment | Bland | Activea |
Serum uric acid | Increased | Normal |
24-h urinary calcium | Low | Normal |
Anti-dsDNA | Unchanged or absent | Increased |
Complement | Low-normal | Low |
Assessing SLE Activity and Flare During Pregnancy
Assessing SLE flares in pregnancy can be a challenge as sometimes the changes that occur in normal pregnancy are also indicative of disease flare in lupus. For example, clinical signs and symptoms that can occur in pregnancy can be misinterpreted as a SLE flare, such as arthralgias (mechanical hip/knee pain); myalgias; erythema on the malar eminences and palms of the hand; transient facial blush; melasma; chloasma; hair loss; swelling of the face, hands, and lower extremities; and carpal tunnel syndrome. While elevated ESR and new-onset anemia are clues to disease flare in SLE, it cannot be used reliably in pregnancy because pregnancy itself could lead to rise in ESR and a decrease in hemoglobin due to hemodilution. Similarly, serum creatinine cannot be used reliably in assessing LN flare because physiological vasodilatation of maternal systemic circulation and a subsequent 50–60% increase in glomerular filtration rate lead to a decrease in serum creatinine levels.
Serum levels of C3 and C4 increase by 10–50% throughout pregnancy due to increased liver synthesis induced by estrogens [55]. In inactive SLE patients, C3 and C4 will increase in pregnancy, as in pregnancies of healthy subjects. Therefore, in a pregnant patient with SLE, C3 and/or C4 values within normal range cannot exclude the possibility of lupus activity.
Most studies to date looking at serological predictors of flares and adverse pregnancy outcomes have found that hypocomplementemia and increased anti-dsDNA antibody titers in the second trimester predict LN flares throughout the remainder of pregnancy and moreover predict fetal loss and preterm birth [3, 28, 56–60]; however, there was no correlation of APO with elevated anti-dsDNA in PROMISSE trial. Proteinuria has mostly been found to be a poor prognostic factor of APO [3, 61].
Although not predictive of flares, other independent predictors of poor pregnancy outcomes in SLE patients that are worth mentioning include history of hypertension and thrombosis and history of prior fetal death (above 10 weeks), thrombocytopenia (decrease of 50 × 109 cells/L from baseline), positive LAC (lupus anticoagulant), BMI >30, and African American and Hispanic-white ethnicities [3, 32, 35, 61, 62].
Management
Preconception Planning and Monitoring in SLE/APS
Preconception risk factor stratification in SLE/APS patients
General risk factors | APS-related risk factors | SLE-related risk factors |
|---|---|---|
Maternal age | aPL profile | SLE flares within 6–12 months or at conception |
Hypertension | Previous adverse pregnancy outcomes | History of lupus nephritis |
Diabetes mellitus | History of vascular thrombosis | Serological SLE activity |
Obesity | SLE diagnosis | Presence of anti-Ro and anti-La antibodies |
Thyroid disease | ||
Tobacco and alcohol use |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
