Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Pregnancy and Rheumatic Diseases


Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiorgan involvement characterized by periods of remission and relapse. The clinical presentation varies considerably, but the disease tends to affect the joints, skin, kidneys, serous membranes, hematologic system, and nervous system. The prevalence of SLE among women is approximately 5 to 100 per 100,000 in the United States, and it is two- to fourfold more common among Black Americans than among White Americans. SLE disproportionately affects women of reproductive age, and these women are at increased risk for both maternal and fetal pregnancy complications.

Pathogenesis

The pathogenesis of SLE is complex and involves the loss of immune tolerance and persistent autoantibody production. It is postulated that environmental or infectious factors trigger the onset of disease in genetically susceptible individuals, with sex hormones likely playing at least a permissive role. Dozens of genetic loci have been associated with SLE, including those of the major histocompatibility complex, those encoding complement and complement regulation, and those involved in numerous other immunomodulatory pathways. The concordance rate for SLE is 25% to 50% for monozygotic twins and 2% to 5% for dizygotic twins. Defective clearance of immune complexes and cellular debris, particularly apoptotic cells, promotes an inflammatory milieu. Abnormalities in lymphocyte and B-cell signaling and aberrant production of cytokines, particularly type I interferons, stimulate immune cell differentiation and loss of self-tolerance.

The production of autoantibodies is characteristic of SLE and likely precedes the onset of disease by several years. Autoantibodies found in individuals with SLE include those to nuclear antigens (antinuclear antibodies [ANAs]), cytoplasmic antigens, cell surface antigens, and soluble antigens in the circulation. Subtypes of ANA are useful for establishing a diagnosis and in monitoring the course of the disease. Anti–double-stranded DNA (anti-dsDNA) antibodies are present in over three-fourths of patients with newly diagnosed SLE, and increasing levels precede symptomatic flare in many patients. Autoimmune hemolytic anemia and immune thrombocytopenia, sometimes features of SLE, are caused by autoantibodies to surface antigens on red blood cells and platelets, respectively.

Clinical Presentation, Diagnosis, and Treatment

The initial presentation of SLE includes varying combinations of polyarthralgias, fatigue, photosensitive skin rash, and serositis. Up to one-half of patients present with evidence of lupus nephritis, and renal involvement eventually occurs in a majority of SLE cases. Classification criteria, originally created to facilitate research, are useful in making the clinical diagnosis. New classification criteria from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) were published in 2019 ( Fig. 65.1 ). To be classified as having SLE, a patient must have a positive ANA and an additive point score >10 (that includes at least one clinical criterion) calculated on presence of criteria grouped in seven clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains that are weighted from 2 to 10.

Figure 65.1, Classification criteria for systemic lupus erythematosus.

Therapy of SLE is dictated by both degree of disease activity and specific organ involvement; more serious and extensive inflammation is treated more aggressively. Unless contraindicated, all patients are treated with long-term antimalarial therapy, most commonly hydroxychloroquine (HCQ), which has multiple benefits, including reduction in flare risk and accrual of disease-related damage. Exacerbations are commonly treated with corticosteroids, with dosage depending on flare severity; severe flares are generally treated with 1 mg/kg/d prednisone or, in critical situations, with intravenous “pulse” methylprednisolone 1000 mg/d for 3 days before high-dose oral steroid (e.g., prednisone). Chronic corticosteroid use is avoided whenever possible because of long-term side effects; when disease does not respond to steroids, or when steroids cannot be tapered, steroid-sparing immunosuppressive therapy is initiated. Commonly used steroid-sparing medications include azathioprine, mycophenolate mofetil (MMF), and belimumab (a monoclonal antibody directed against B-lymphocyte stimulator, or BlyS); methotrexate is often used when arthritis is a prominent symptom. Lupus nephritis may be treated initially with cyclophosphamide or MMF, followed by maintenance therapy with MMF or azathioprine. Belimumab and voclosporin have recently been FDA approved as additions to standard nephritis therapy to further improve renal outcomes. Life-threatening disease or central nervous system lupus is treated with intravenous cyclophosphamide. Rituximab, although not proven effective in controlled studies, is often used as a second- or third-line agent.

Immunosuppressive therapy need not be lifelong; if remission is achieved, immunosuppressive medications are often tapered or discontinued. Frequent monitoring of patients, every 3 to 4 months, allows early institution of therapy when recurrent flare occurs. Comorbid conditions such as hypertension and other cardiovascular disease, diabetes, osteoporosis, and infection are significant causes of morbidity and mortality and must be identified and managed in concert with SLE itself to optimize outcome.

Systemic Lupus Erythematosus and Pregnancy

Maternal Risks and the Course of Systemic Lupus Erythematosus in Pregnancy

Women with SLE have long been recognized as having an increased rate of pregnancy complications, and though improvement over time has been noted, they remain at greater risk. A recent meta-analysis of 11 studies published between 2001 and 2016 (including 529,778 women) assessed the impact of SLE on maternal and fetal adverse outcomes. Rates of cesarean delivery (relative risk [RR] = 1.85; 95% confidence interval [CI], 1.63–2.10; P = .00001), hypertension (RR = 1.99; 95% CI, 1.54–2.56; P = .00001), preeclampsia (RR = 1.91; 95% CI, 1.44–2.53; P = .00001), spontaneous abortion (RR = 1.51; 95% CI, 1.26–1.82; P = .0001), thromboembolic disease (RR = 11.29; 95% CI, 6.05–21.07; P = .00001), and postpartum infection (RR = 4.35; 95% CI, 2.69–7.03; P = .00001) were all significantly higher in women with SLE. Similarly, maternal complications occurred in one-half of all SLE pregnancies in a report from the Danish National Registry.

Maternal mortality in SLE pregnancy was estimated to be 20-fold higher than that in the general obstetric population in 2008. A recent National Inpatient Sample database cohort analysis examined SLE and non-SLE pregnancies over 18 years, including 93,820 pregnant women with SLE who were hospitalized in the United States from 1998 to 2015. In-hospital maternal mortality and overall outcomes improved markedly among all women but more among women with SLE. SLE maternal mortality in 2013–15 was twofold higher than that for the non-SLE population.

Active renal disease during pregnancy may increase mortality risk. Systematic review and analysis of maternal SLE deaths in patients with concomitant nephritis showed that death tended to occur in those with active disease. Disease activity/complications and infection were the two major causes of mortality overall. Pregnancy complications may have significant long-term implications for the health of SLE patients. Maternal placental syndromes (defined as any hypertensive disorder in pregnancy, stillbirth, placental abruption, and delivery of a small-for-gestational-age [SGA] infant) and preterm delivery (<34 weeks) have been associated with increased risk for death from cardiovascular causes in women with SLE.

Professional groups have recently published recommendations for assessment, management, and treatment of pregnancy in patients with SLE, emphasizing the importance of preconception counseling. , A pregnancy that is not planned is an important risk factor for both severe adverse pregnancy and neonatal outcomes. Assessment of SLE patients prior to pregnancy is important and should focus on presence of severe disease-related organ damage, current level of lupus disease activity, compatibility of lupus medications with pregnancy, and presence of autoantibodies that can impact pregnancy outcome (antiphospholipid and anti-Ro/SSA and La/SSB antibodies). Rarely, severe manifestations of cardiomyopathy, cardiac valve disease, pulmonary arterial hypertension (PAH), interstitial lung disease, serious neurologic manifestations, and moderate-to-severe renal insufficiency may put women at risk for organ failure. Women with these severe chronic conditions should be discouraged from pursuing pregnancy. In certain circumstances, such patients may be able to have a biological child through in vitro fertilization with a gestational carrier.

All SLE patients should be encouraged to conceive during a period of inactive disease to ensure optimal maternal and pregnancy outcome. Patients with current or recent active disease should be advised to defer pregnancy and pursue appropriate lupus treatment; when disease has been inactive for about 6 months, they may be reassessed. When medications have been changed to those compatible with pregnancy, patients should be observed for a period of several months to ensure that the new medications are both tolerated and effective in maintaining disease control.

Risk for SLE Flare

Pregnancy has long been considered a high-risk state for SLE patients, in part because of concern for increased risk for flare. It was assumed that most patients with SLE would worsen during pregnancy and, as a result, patients were often counseled against becoming pregnant. Current reports suggest that the majority of women with SLE can anticipate a successful pregnancy, although controversy continues as to the extent of flare risk. Conflicting results in older studies were likely due to lack of uniformity in flare definition, differences in populations including level of disease activity at conception, lack of control groups for some studies, and variation in medication use.

In the recent PROMISSE study (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus), a large prospective observational study of over 700 women with SLE, antiphospholipid antibodies (aPLs), and controls, the rate of severe flare was 3% in the second trimester and 3% in the third trimester, and the rate of mild or moderate flare was less than 15%. Importantly, these very favorable outcomes likely relate in part to the fact that the enrolled SLE patients had low-level or inactive disease with normal or near-normal renal function. A follow-up analysis of PROMISSE patients assessed risk of postpartum flare: lupus flares after pregnancy were mild and occurred at similar rates to those in pregnancy.

Overall, patients with active disease during the 6 months before conception are at highest risk for flare during pregnancy. Flare rate in patients with active disease preconception has been estimated to be as high as 60%. In one series of 132 prospectively followed SLE pregnancies in 96 patients, predictors of lupus flares and fetal/obstetric complications during pregnancy were identified using stepwise logistical regression analysis. Maternal lupus flares occurred in 57% of pregnancies and were best predicted by the number of flares before conception. First births may be associated with an increased risk for flare when compared with subsequent pregnancies, and the pattern of previous lupus involvement may be helpful in predicting clinical course: specific flare manifestations during a woman’s pregnancy tend to mirror organ involvement before pregnancy.

Continuation of HCQ during pregnancy reduces risk of lupus flare and improves maternal outcomes. In an updated analysis of the Hopkins Lupus Cohort, the hazard ratio (HR) of flares in pregnancy from 1987 to 2015 compared with nonpregnant/nonpostpartum periods was estimated to be 1.83 (95% CI, 1.34–2.45) for patients with no HCQ use and 1.26 (95% CI, 0.88–1.69) for patients with HCQ use. The risk of flare was similarly elevated among non-HCQ users in the 3months postpartum but not for women taking HCQ after delivery. Patients were not necessarily inactive at time of conception. Though risk of flare likely varies depending on the population studied, these data suggest benefit in reduction of flare risk with ongoing HCQ therapy.

Diagnosing lupus flare during pregnancy may be difficult, because pregnancy-induced thrombocytopenia, proteinuria caused by preeclampsia, and palmar and facial erythema associated with normal pregnancy can resemble the signs of an SLE flare. Flare is most confidently diagnosed when a pregnant patient has new or increasing characteristic rash (not erythema alone), lymphadenopathy, arthritis, fever, or anti-dsDNA antibodies.

Effect of Lupus Nephritis

Lupus nephritis is an important risk factor for pregnancy complications. Meta-analysis of 2751 SLE pregnancies (37 studies published between 1980 and 2009) calculated 25.6% rates of lupus flare, 39.4% of premature birth, and 12.7% of fetal growth restriction (FGR): active lupus nephritis was associated with increased risk for premature birth, and history of nephritis was associated with increased risk for preeclampsia. Overall, about 15%–25% of women with SLE develop preeclampsia during pregnancy, as compared with 5% in the general population. In those women with preexisting renal disease who develop preeclampsia, renal function may not return to its prepregnancy baseline; however, progression to renal failure is unusual. SLE patients with proliferative nephritis on biopsy (classes III/IV) have a higher frequency of adverse maternal outcomes, including disease flare, hospitalization, and cesarean section. In another cohort study, when investigators excluded pregnant SLE patients with active nephritis within 6 months of conception, they found no significant differences in the frequency of maternal and fetal complications between renal and nonrenal SLE pregnancies in the remaining patients. Nephritis history alone, without renal damage or current nephritis, may not be a significant risk factor for adverse pregnancy outcomes.

Prediction of preeclampsia in women with SLE is challenging, especially given the multiple risk factors commonly present in SLE patients. Ten studies involving 6389 SLE patients were included in a recent 2020 meta-analysis. The authors confirmed that pregnant women with SLE have a significantly increased risk of preeclampsia (RR = 2.99; 95% CI, 2.31–3.88; P < .001) compared with healthy controls. Based on demonstration of increased risk, all women with SLE are advised to take low-dose aspirin beginning in the first trimester as preeclampsia prophylaxis. , , Despite increasing recognition of elevated preeclampsia risk in SLE, only 25% of lupus pregnancies followed in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort were treated with low-dose aspirin, and aspirin use did not increase over the years of observation from 2000 to 2017.

Distinguishing a lupus renal flare from preeclampsia is challenging. Laboratory and clinical evidence suggesting active disease support a diagnosis of a lupus flare, whereas preeclampsia is more often associated with stable SLE disease parameters and proteinuria with inactive urine sediment ( Table 65.1 ). Rapid worsening over days suggests preeclampsia. In patients with seizures late in pregnancy, especially if accompanied by hypertension and renal failure, it may not be possible to distinguish between central nervous system SLE and eclampsia. Differentiation between lupus flare and preeclampsia/eclampsia is important when possible, because treatments vary: preeclampsia/eclampsia is managed with delivery, whereas lupus flare is managed with medication. However, clinical management often includes treatment for both, because differentiation may be impossible and disease flare and preeclampsia/eclampsia may coexist.

TABLE 65.1
Common Clinical and Laboratory Characteristics of Lupus Nephritis Versus Preeclampsia
Lupus Nephritis Preeclampsia
White blood cell count Low or normal Normal or high
Platelet count Low or normal May be low (HELLP)
Liver function tests Normal Normal or elevated (HELLP)
Serum creatinine Normal or high Normal or high
Proteinuria Present Present
Urine sediment RBCs and casts Acellular
Urine calcium Normal Usually low
Uric acid Normal or high Usually high
dsDNA antibody Rising or elevated Stable or normal
Complement levels Dropping or low Normal or high
Time of onset Variable, anytime Abrupt, after 20 weeks
Blood pressure Normal or elevated Usually elevated
Abdominal pain Rare May be present (HELLP)
Symptoms of active SLE (rash, arthritis, fever) May be present Not present
HELLP, Hemolysis, elevated liver enzymes, and low platelets; SLE, systemic lupus erythematosus.

Renal biopsy, rarely performed during pregnancy, may aid in therapy decisions. Biopsy results altered management in 10 of 11 cases (including three pregnancy terminations) in one small series of pregnant SLE patients. Median gestational age at time of biopsy was 16 weeks (range, 9–27 weeks). Clearly, not all biopsies were intended to differentiate between preeclampsia and lupus nephritis, because preeclampsia occurs after 20 weeks’ gestation. Renal biopsy may be performed solely to define renal histopathology, degree of activity, and prognosis, as in the nonpregnant patient.

Fetal-Neonatal Outcomes in Lupus Pregnancy

SLE pregnancy outcomes have greatly improved in recent years but are still not equal to those in the non-SLE population. Comparison of one SLE pregnancy cohort ( n = 83) with previous reported SLE pregnancies from 40 years earlier showed that pregnancy loss rates improved dramatically, from 40% to 17%, compared with an estimated general population rate of 16%. However, rate of preterm delivery did not significantly change. It was 37% in the historical lupus cohort and 32% in the current cohort, compared to an estimated general population rate of 9% to 12%. A large Norwegian database study evaluated pregnancies in women with SLE and other connective tissue diseases over the preceding four decades, recorded through the medical birth registry. The number of births to women with connective tissue disease increased progressively over the decades, and rates of cesarean deliveries, preterm deliveries, and low-birth-weight infants decreased. Still, pregnancy complications were more common in SLE patients than in the general population. In the meta-analysis by Bundhun and colleagues (study years 2001–16), SLE was associated with a lower rate of live birth (RR = 1.38; 95% CI, 1.14–1.67; P = .001) and higher rates of premature birth (RR = 3.05; 95% CI, 2.56–3.6; P = .00001) and SGA infants (RR = 3.05; 95% CI, 2.56–3.63; P = .00001). There is clearly still a higher risk for preeclampsia, preterm delivery, fetal loss, and low-birth-weight infants in SLE patients. Examination of placentas in SLE pregnancies suggests that placental vasculopathy, with or without the presence of aPL, may play an important role.

Specific risk factors for adverse pregnancy outcomes in SLE, including pregnancy loss, preterm birth, and FGR, have been confirmed in multiple studies with varied populations. Most factors relate to the degree of renal involvement, presence of current or recent lupus disease activity, or presence of aPL , , ( Table 65.2 ). Activation of complement early in pregnancy has been associated with adverse pregnancy outcomes in the PROMISSE cohort. Other risk factors have also been identified. Risk for adverse outcomes in SLE pregnancy appears to vary depending on race and ethnicity: Black and Hispanic women with lupus have poorer pregnancy outcomes when adjusting for known risk factors. , In particular, for African American women with SLE without aPL, socioeconomic factors are suggested to be important contributors to disparities in adverse pregnancy outcomes.

TABLE 65.2
Systemic Lupus Erythematosus: Risk Factors for Adverse Pregnancy Outcome
Renal Disease Recent/Current Disease Activity Antiphospholipid Antibody
Hypertension High lupus disease activity “Triple-positive” aPL panel a
Prior nephritis Elevated anti-dsDNA antibody Positive lupus anticoagulant
Active nephritis Low complements
Proteinuria (>1 g/24 h) Low platelets
Prednisone use

a Positive anticardiolipin, anti–β 2 -glycoprotein-1, and lupus anticoagulant antibodies.

Like risk for lupus flare, adverse pregnancy outcomes are more common in first births than in subsequent births for women with SLE. Nine of the 10 women with stillbirth or neonatal death in their first pregnancy who were followed in a population-based cohort study of lupus pregnancy had a successful second pregnancy. Whether or not this might have been caused by changes in management or treatment(s) is uncertain.

A predictive risk model for fetal loss based on data from 338 SLE pregnancies in Chinese patients has been formulated. Risk factors selected by stepwise regression included unplanned pregnancy (OR = 2.84; 95% CI, 1.12–7.22), C 3 hypocomplementemia (OR = 5.46; 95%CI, 2.30–12.97), and elevated 24-hour urinary protein level (0.3 ≤ protein< 1.0g/24hours: OR = 2.10; 95% CI, 0.63–6.95; urine protein ≥ 1.0g/24hours: OR = 5.89, 95% CI, 2.30–15.06). Scores were divided into low risk (0–3) and high-risk groups (>3), with a sensitivity of 60.5%, a specificity of 93.3%, positive likelihood ratio of 9.03, and negative likelihood ratio of 0.42. Although preliminary, such models may lead to better predictions for severe adverse SLE pregnancy outcomes.

Neonatal Lupus and Congenital Heart Block

Approximately one-third of patients with SLE and most patients with Sjögren syndrome have anti-Ro/SSA and/or anti-La/SSB antibodies. Infants of mothers with anti-Ro/SSA and anti-La/SSB antibodies are at risk for neonatal lupus erythematosus (NLE). These antibodies confer a roughly 2% risk for the development of congenital complete heart block (CCHB) and an approximately 15% risk for transient noncardiac NLE manifestations. Noncardiac manifestations include reversible thrombocytopenia or leukopenia, transaminitis, and photosensitive rash. Most experts advise antibody-positive women to undergo screening fetal echocardiograms in the second trimester to monitor for the development of CCHB, although the efficacy of this approach for preventing CCHB is uncertain. Because the risk for recurrent CCHB is 15% to 20%, experts recommend that women with a history of a prior child with NLE should have weekly echocardiograms from 16 to 26 weeks to detect early evidence of developing heart block (e.g., first- or second-degree heart block). Even if fetal cardiac conduction abnormalities or new-onset block are found, credible evidence that medical interventions will alter fetal or neonatal outcomes is lacking. Fluorinated glucocorticoids, intravenous immune globulin (IVIG), and even plasmapheresis have been used when first- or second-degree heart block is detected, but their efficacy remains unproven. Treatment with a course of fluorinated glucocorticoids for clear first- or second-degree heart block or cardiac inflammation on echocardiogram may be considered; if isolated CCHB is detected, however, no medical therapy is suggested as no studies report benefit. Severe inflammatory manifestations are infrequent but include myocarditis, heart failure, and hydrops fetalis. CCHB in the newborn usually requires a permanent pacemaker.

Preventive treatments have been the subject of some studies in women at risk for recurrent CCHB. Neither prophylactic glucocorticoids nor IVIG have proven effective. , However, following on a retrospective analysis suggesting benefit for antepartum HCQ therapy, the recent prospective PATCH study (Preventive Approach to Congenital Heart Block with Hydroxychloroquine) supports a significant HCQ-associated reduction in recurrence of CCHB below the historical rate by >50%, suggesting that HCQ be prescribed for secondary prevention of fetal cardiac disease in anti-Ro/SSA-positive pregnancies. The PATCH data indirectly support considering HCQ therapy for primary prevention in pregnant anti-Ro/SSA-positive women without a history of NLE in some cases. Ongoing studies using home monitoring devices may permit more rapid identification of early heart block, allowing trials of early, immediate treatment.

Long-Term Outcomes in Offspring

Other than a slight inherited tendency to develop rheumatic illness, children born to mothers with SLE are generally healthy with normal growth and intelligence levels, and patients should be reassured regarding overall good outcomes for their children. Several studies have suggested an increased but low risk of developmental issues. A recent systematic review of 24 cohort and 4 case-control studies suggested that maternal SLE may be associated with learning disability (specifically dyslexia), autism spectrum disorder, attention deficit, and possible speech problems in offspring. Current data are limited with a low level of evidence, making it difficult to know whether the increased rate of developmental disability is primarily related to maternal SLE, prematurity, or even medications. Compared to children from the general population, children born to women with SLE seem to have a slight increased risk of neurodevelopmental issues; however, in absolute terms, it represents a rare outcome.

Management of Lupus in Pregnancy

Prepregnancy evaluation of women with SLE is strongly advised to establish the degree of pregnancy risk and to define optimal monitoring and management strategies. Assessment should include identification of organ damage, current and recent disease activity, safety of medications during pregnancy, and presence of relevant autoantibodies. All women with SLE, particularly those with a known history of renal involvement, should undergo assessment of renal function.

Review of the current medical regimen is critical. If lupus medications are contraindicated for use in pregnancy (e.g., cyclophosphamide, mycophenolate mofetil, or methotrexate), they may be tapered and discontinued or changed to acceptable medications such as azathioprine or tacrolimus. Patients should be monitored on these new medications to ensure that they remain stable with quiet or low-level disease. Measurement of relevant autoantibodies may help determine specific pregnancy risks and dictate both pregnancy monitoring and need for additional therapy. Every SLE patient should be evaluated for the presence of antibodies, including aPL (lupus anticoagulant, anticardiolipin, and anti–β 2 -glycoprotein-1 [aβ 2 GP-1] antibodies), and for anti-Ro/SSA and anti-La/SSB (Sjögren) antibodies to assess the risk for pregnancy loss and neonatal lupus, respectively. Communicating the pregnancy risk assessment to the patient is a final and important component of the initial evaluation.

Ideally, SLE pregnancy should be comanaged by a rheumatologist and a maternal-fetal medicine (MFM) physician. Patients with active or severe SLE disease should be counseled against pregnancy. Patients should be maintained on antimalarial medication throughout pregnancy, as studies suggest benefit for both mother and neonate. All patients with SLE, and especially those with aPL, hypertension, renal insufficiency, or other risk factors for preeclampsia, are advised to take low-dose aspirin. Patients should have well-controlled disease on low-risk medications for 6 months before attempting conception. Disease flares are managed with nonfluorinated glucocorticoids and, if necessary, the introduction of immunosuppressive agents compatible with pregnancy. Life-threatening disease may be treated with rituximab or, in the latter part of pregnancy, intravenous cyclophosphamide.

Given the fetal risks in lupus pregnancy, serial fetal sonography from 18 weeks forward is recommended to detect abnormalities of fetal growth and amniotic fluid volume. Barring clinical concerns indicating earlier monitoring, fetal surveillance testing (e.g., modified biophysical profile testing and/or fetal movement counts) is usually started at 32 weeks. Frequent prenatal visits, perhaps weekly after the first trimester, might afford early detection of gestational hypertensive disease or lupus flare. We often suggest home blood pressure monitoring in SLE pregnancies after 20 weeks. Finally, we advise visits with a rheumatologist at least once per trimester, or more frequently if the patient is symptomatic. In addition to assessment of clinical signs or symptoms of flare, changes in anti-dsDNA antibodies and complement (C3 and C4) levels may indicate impending flare. A collaborative team approach with MFM, rheumatology, other related medical specialists, and, of course, the patient herself will likely lead to fewer surprises and better outcomes overall.

Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune condition characterized clinically by thrombosis (venous or arterial) and/or several adverse pregnancy outcomes ( Box 65.1 ). The diagnosis is confirmed by the presence of repeatedly positive circulating aPL. aPLs comprise a heterogeneous group of autoantibodies directed against either negatively charged phospholipids or glycoproteins. International consensus holds that there are three relevant aPL: lupus anticoagulant (LA), anticardiolipin antibodies (aCLs), and anti-β2-glycoprotein-I (aβ2-GP-I) antibodies ( Box 65.1 ). The international consensus classification criteria are currently the subject of a combined American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) multiphase, iterative revision that will employ an additive, weighted, multicriteria point system to define a threshold above which experts would classify a case as APS for the purpose of research.

BOX 65.1
Criteria for the Diagnosis of Definite Antiphospholipid Syndrome
Modified from Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost . 2006;4:295–306.
Investigators are strongly advised to classify patients with APS in studies into one of the following categories: I, more than one laboratory criteria present (any combination); IIa, LAC present alone; IIb, aCL antibody present alone; IIc, anti- β2-glycoprotein-I antibody present alone.
aCL , Anticardiolipin; ACOG , American College of Obstetricians and Gynecologists; APS , antiphospholipid antibody syndrome; ELISA , enzyme-linked immunosorbent assay; GPL , reference reagent for IgG; HDL , high-density lipoprotein; Ig , immunoglobulin; LAC , lupus anticoagulant; LDL , low-density lipoprotein.

APS is present if ≥ clinical criteria and ≥ laboratory criteria are met. a

a Classification of APS should be avoided if <12 weeks or >5 years separate the positive aPL test and the clinical manifestation.

Clinical Criteria

  • 1.

    Vascular thrombosis b

    b Coexisting inherited or acquired factors for thrombosis are not reasons for excluding patients from APS trials. However, two subgroups of patients with APS should be recognized, according to (1) the presence and (2) the absence of additional risk factors for thrombosis. Indicative (but not exhaustive) such cases include age (>55 in men and >65 in women) and the presence of any of the established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated LDL or low HDL cholesterol, cigarette smoking, family history of premature cardiovascular disease, body mass index >30 kg/m 2 , microalbuminuria, estimated GFR <60 mL min -1 ), inherited thrombophilias, oral contraceptives, nephrotic syndrome, malignancy, immobilization, and surgery. Thus patients who fulfill criteria should be stratified according to contributing causes of thrombosis.

  • One or more clinical episodes c

    c A thrombotic episode in the past could be considered as a clinical criterion, provided that thrombosis is proved by appropriate diagnostic means and that no alternative diagnosis or cause of thrombosis is found.

    of arterial, venous, or small-vessel thrombosis, d

    d Superficial venous thrombosis is not included in the clinical criteria.

    in any tissue or organ.

    • Thrombosis must be confirmed by objective validated criteria (i.e., unequivocal findings of appropriate imaging studies or histopathology).

    • For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.

  • 2.

    Pregnancy morbidity

    • a.

      One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus.

    • b.

      One or more premature births of a morphologically normal neonate before the 34th week of gestation because of

      • severe preeclampsia or eclampsia according to standard definitions e

        e American College of Obstetricians and Gynecologists. Gestational hypertension and preeclampsia. ACOG Practice Bulletin No. 222. Obstet Gynecol . 2020;135:e237–e260.

        or

      • placental insufficiency. f

        f Generally accepted features of placental insufficiency include (i) abnormal or nonreassuring fetal surveillance test(s) (e.g., a nonreactive nonstress test, suggestive of fetal hypoxemia), (ii) abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia (e.g., absent end-diastolic flow in the umbilical artery), (iii) oligohydramnios (e.g., an amniotic fluid index <5 cm or deepest vertical pocket <2 cm), or (iv) a postnatal birth weight <10th percentile for the gestational age.

    • c.

      Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to a, b, or c above.

Laboratory Criteria

  • 1.

    LAC present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis (Scientific Subcommittee on LAs/Phospholipid-Sependent Antibodies).

  • 2.

    aCL antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e., 40 GPL or MPL, or >99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA.

  • 3.

    Anti-β2-glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th percentile), present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures.

Pathogenesis

Considerable evidence points to aPL as the primary agent of the autoimmune manifestations of APS. However, a full understanding of the molecular and cellular pathophysiologic pathways has yet to be realized, in part due to the different types of aPL used in in vitro and in vivo studies and the different cellular targets employed by various investigators. Despite the moniker, experts agree that pathogenic aPLs do not bind phospholipids per se but bind to antigens expressed by phospholipid-binding proteins. The best studied of these is β 2 -glycoprotein I, a ubiquitous glycoprotein involved in the clearance of apoptotic cells and microparticles, as well as the innate immune response. , A target antigen for pathogenic aPL is a neoepitope expressed in domain 1 of β 2 -glycoprotein I when the glycoprotein binds to phospholipids in disrupted cell membranes. Similarly, this antigen may be expressed when β 2 -glycoprotein I binds other cell receptors, such as ApoER2, or cell membrane–binding complexes, such as annexin A2 or A5. , aPL-mediated interference with trophoblastic annexin A5 or impairment of trophoblastic hormone production or invasion may play important roles. More recently, neutrophil extracellular traps released from activated white blood cells have been shown to play a role in aPL-mediated thrombosis. In mice, passive transfer of aPLs results in clinical manifestations of APS, including fetal loss and reduced fetal weight. , In a murine pinch-induced venous thrombosis model, human polyclonal and murine monoclonal aPLs were associated with larger and more persistent thrombi than in mice treated with control antibodies.

Immune activation plays a key role in APS pathogenesis. Complement activation was required for fetal loss in a murine model. , In these models, aPL antibodies targeted placenta and activated complement via the classical pathway, leading to generation of potent anaphylatoxins, recruitment of neutrophils, and release of proinflammatory mediators, such as tumor necrosis factor-α (TNF-α). , , Inactivation and inhibition of the complement cascade prevented fetal loss and growth restriction that are associated with addition of aPLs. , , TNF-α, a proinflammatory cytokine associated with complement activation, has likewise been implicated in the signaling pathways by T cells that are essential to the pathogenesis of aPL, and pregnant mice lacking TNF-α were protected from pregnancy loss induced by injections of aPLs.

Studies in humans confirm a role for complement activation in the pathogenesis of APS-related pregnancy morbidity, and immunohistochemical analysis of placentas from APS cases with pregnancy morbidities indicates deposition of complement components. In the PROMISSE study, a significant elevation in complement activation products was seen by 12–15 weeks in women with adverse pregnancy outcomes. Findings of angiogenic factor imbalance in early pregnancy in these patients suggest that APS-associated pregnancy complications are related to abnormal placental function, probably secondary to a cascade of events that ultimately lead to poor vascularization of the developing placenta. Abnormal histologic findings in the spiral arteries have included narrowing, intimal thickening, acute atherosis, and fibrinoid necrosis. , In addition, placental histopathology demonstrates extensive necrosis, infarction, and thrombosis.

Laboratory Features of Antiphospholipid Syndrome

The diagnosis of definite APS requires at least one clinical criterion and the presence of at least one repeatedly positive aPL autoantibody, as defined by the international criteria ( Box 65.1 ). Because the clinical features of APS are relatively common and lack specificity, the final diagnosis of APS ultimately rests on the laboratory criteria: medium-to-high titers of IgG or IgM aCL or aβ2-GP-I antibodies or lupus anticoagulant (LA) present on two or more occasions at least 12 weeks apart.

The international guidelines emphasize several important points regarding aPL laboratory testing. The requirement for repeatedly positive results exists because other conditions—most commonly infections—can result in transiently positive aPL results. The performance characteristics of the aPL immunoassays, specifically for aCL and aβ2-GP-I antibodies, and the widely recognized interlaboratory variability in aPL results demand that reliable laboratories identify medium or high titer results for aCL and >99th percentile results for aβ2-GP-I antibodies. International calibration efforts using “units” for the aCL assay have established >40 IgG units (“GPL”) or IgM units (“MPL”) as being medium or high titer. Currently IgA aCL or anti-β2-GP-I antibodies are not recognized as diagnostic of APS.

There are several important caveats regarding the laboratory diagnosis of APS. First, LA is a better predictor of pregnancy morbidity or thrombosis than aCL or aβ2-GP-I antibodies. Second, the specificity of aCL and aβ2-GP-I antibodies for APS increases with higher titers and with IgG isotype. Finally, “triple” aPL positivity (LA, aCL, and aβ2-GPI) is of greater clinical significance than double or single aPL positivity. The development of aβ2-GP-I assays specific for domain 1 of β2-GP-I, particularly of the IgG isotype, shows promise as laboratory marker for both thrombotic and obstetric risk stratification. In a retrospective serum study of women previously diagnosed with APS or who had persistently positive aPL tests but not APS, the presence of anti–domain 1 antibodies was statistically associated with a history of thrombosis, fetal death, or preterm delivery for preeclampsia or placental insufficiency.

Clinical Features

APS may occur as a primary condition or in the setting of other autoimmune conditions, most commonly SLE (secondary APS). The condition is infrequent, with an estimated incidence and prevalence of 2 per 100,000 persons per year and 50 cases per 100,000 persons, respectively.

As detailed in Box 65.1 , the clinical features of APS are (a) venous or arterial thrombosis, including stroke, and/or (b) any of the following adverse pregnancy outcomes: (1) three or more otherwise unexplained recurrent early pregnancy losses (REPL) (preembryonic or embryonic losses <10 weeks’ gestation), (2) one or more otherwise unexplained fetal deaths (≥10 weeks’ gestation), or (3) one or more preterm births less than 34 weeks’ gestation secondary to severe preeclampsia or placental insufficiency.

Venous or Arterial Thrombosis

Deep venous thrombosis (DVT) of the lower extremity is the most common thrombotic presentation of APS. At least several percent, and perhaps as high as 15%, of DVTs are attributable to APS. , Stroke is the most common arterial thrombotic event, and positive aPLs are found in up to 20% of ischemic stroke patients <50 years of age. Small-vessel thrombosis may present as nephropathy. APS-related thrombosis may manifest in virtually any vascular bed, and APS should be considered in patients presenting with events as diverse as intracranial thrombosis, hepatic venous thrombosis, and intraabdominal thrombosis.

Recurrent Early Miscarriage

The proportion of women with REPL reported to be positive for aPL varies but may be as high as 15%. Though some have embraced the association of aPL with REPL, other experts have argued that most studies showing an association are flawed. Such flaws include poor standardization of assays, inclusion of women with other causes of recurrent miscarriage, inconsistent selection of controls, variability of aPLs or isotype tested, and varying definitions of aPL positivity and recurrent miscarriage (differing numbers and gestational ages of losses). Several experienced centers found no more than 3% to 4% of women with REPL and no other clinical features or autoimmune conditions have relevant aPL levels. These figures are similar to those found in otherwise healthy subjects. , Such findings support the view that APS as defined by international criteria as a “cause” of REPL is at best infrequent. Also, women with low levels of aPL who do not meet international laboratory criteria for APS have a very good pregnancy prognosis whether treated with low-dose aspirin (LDA) or other agents. That said, many obstetric specialists will encounter the patient who has been “diagnosed” with APS based on REPL and (1) low positive or equivocal aPL results or (2) seemingly positive laboratory results that have not been repeated. Failing to challenge the lack of a definitive diagnosis will contribute to the overdiagnosis and overtreatment of “APS” during pregnancy.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts