Manifestations in Lupus Pregnancy

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)

From Miyakis et al. [22], with permission

aCL of IgG and/or IgM in medium or high titer (i.e., >40GPL or MPL or >99th percentile) and anti-β2GP1 of IgG and/or IgM (in titer >99th percentile)

aAdapted from the Sydney criteria [22]

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 [3033]. 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 [4346]. Although clinically indistinguishable, the findings of microvascular thrombi (thrombotic microangiopathy, TMA) and fibrous intimal hyperplasia on renal biopsy are pathognomonic features of APS nephropathy.

APS nephropathy shares similar clinical and histological features of thrombotic microangiopathy with renal involvement in thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS); therefore, differentiating these conditions could be challenging (Table 5.2) [44].

Table 5.2

Thrombotic microangiopathy (TMA): comparing APS nephropathy vs. pregnancy-associated TTP vs. pregnancy-associated aHUS


APS nephropathy

Pregnancy-associated TTP

Pregnancy-associated aHUS

Lupus nephritis


Arteriolar and capillary thrombosis, fibrin deposition of vessel walls

Complex deposition

Differentiating features

Neurological symptoms
































At any time

2nd to3rd trimester


At any time

Treatmenta (First-line)

ASA and anticoagulation






Treatment (Second-line)

Glucocorticoids, immunosuppressive therapy



Adapted from Thomas et al. [47], with permission

MAHA microangiopathic hemolytic anemia, aPL antiphospholipid antibodies, ASA aspirin, PLEX plasma exchange, CYC cyclophosphamide

aReference [47]

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].

It is often difficult to distinguish preeclampsia from lupus nephritis as they share similar clinical manifestations and may frequently overlap. Although renal insufficiency, proteinuria, and hypertension are hallmark features of both conditions, there are unique clinical attributes that can help differentiate the two (Table 5.3). In the general population, preeclampsia most commonly occurs late in the third trimester; however, in LN patients, it tends to occur several weeks earlier [31, 32, 53, 54].

Table 5.3

Comparison of clinical and laboratory features of preeclampsia and lupus nephritis



Lupus nephritis


After week 20

Anytime during pregnancy

Other organ involvement

HELLP, CNS involvement with eclampsia

Extrarenal active SLE

Response to corticosteroids



Urinary sediment



Serum uric acid



24-h urinary calcium




Unchanged or absent





aActive sediment: RBC >5/hpf, WBC >5/hpf in absence of infection, presence of cellular RBC or WBC casts

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, 5660]; 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].


Preconception Planning and Monitoring in SLE/APS

Management of lupus pregnancy starts well before conception and includes a careful review of general and disease-specific risk factors (Table 5.4) and comprises of disease activity assessment and medication adjustment. We recommend that pregnancy should be delayed 6–12 months after remission of active LN (preferably with proteinuria <300 mg/24 h and GFR >50 mL/min). Ideally, teratogenic immunosuppressive medications should be discontinued 3 months preconception to reduce the risk of congenital malformations and early pregnancy loss. Patients should be transitioned from medications such as cyclophosphamide (CYC) or mycophenolate (MMF) to azathioprine (AZA), as studies have shown that switching to AZA in patients with inactive LN on MMF prior to pregnancy did not result in an increase in renal flares or adverse pregnancy outcomes [64]. Though classified as a Class D drug, it is considered safe in pregnancy up to doses of 2 mg/kg [65]. Rituximab increases the risk of neonatal B-cell depletion, and therefore pregnancy should be avoided 6–12 months after rituximab exposure [66].

Table 5.4

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


Previous adverse pregnancy outcomes

History of lupus nephritis

Diabetes mellitus

History of vascular thrombosis

Serological SLE activity


SLE diagnosis

Presence of anti-Ro and anti-La antibodies

Thyroid disease


Tobacco and alcohol use


Adapted from EULAR’s (European League Against Rheumatism) recommendations for family planning in patients with SLE and/or APS

Adapted from Andreoli et al. [63], with permission

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Nov 3, 2020 | Posted by in Uncategorized | Comments Off on Manifestations in Lupus Pregnancy
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