Preeclampsia in a Patient with SLE Case File

Preeclampsia in a Patient with SLE Case File

Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 37

A 27-year-old African American woman G1P0 is seen for prenatal care at 36 weeks’ gestation. She has a history of lupus with her most recent flare occurring over 6 months prior to conception. An antiphospholipid (aPL) syndrome workup is negative. Her renal evaluation prior to pregnancy revealed a serum creatinine of 0.8 mg/dL and 24-hour urine collection at 8 weeks gestation contained 120 mg of protein. At that time, her blood pressure was 110/70 mm Hg and liver function tests and platelet counts were normal. Today, she describes a persistent headache for the past 12 hours and you note her blood pressure is 145/95 mm Hg. Her weight has increased 3 lb since her last visit 1 week ago, and her urine dipstick protein is 3+. Her fundal height is 36 cm, and she notes normal fetal movement. Admission lab in the hospital reveals a platelet count of 225,000/μL, normal liver function tests, serum creatinine of 0.8 mg/dL, and normal complement levels. Her antinuclear antibody (ANA) test is positive.

➤ What is the most likely diagnosis?

➤ What is your next step?

➤ What are potential complications of the patient’s disorder?

ANSWERS TO CASE 37:

Preeclampsia in a Patient with SLE

Summary: This is a 27-year-old G1P0 patient at 36 weeks’ gestation with underlying systemic lupus erythematosus (SLE) who has developed hypertension, proteinuria, and excessive weight gain with neurologic symptoms. Her labs indicate normal LFTs, platelets, and complement levels. Fundal height indicates a normally grown fetus.

➤ Most likely diagnosis: Preeclampsia.

➤ Next step: Evaluate the patient for lupus flare and if workup negative, schedule for delivery.

➤ Potential complications: Placental dysfunction, abruptio placenta, worsening preeclampsia, HELLP syndrome, or eclampsia.

ANALYSIS

Objectives

1. Describe the preconception and antenatal evaluation of a patient with SLE.
2. Understand the importance of evaluating the patient with SLE for concomitant aPL syndrome.
3. List the laboratory evaluation that helps to distinguish preeclampsia from a lupus flare.
4. Discuss the evaluation and treatment of aPL syndrome during pregnancy.

Considerations

This patient has a clinical presentation that could either be preeclampsia or an exacerbation of her lupus. SLE can present with proteinuria, seizures, and hypertension. Since the treatment is dramatically different: magnesium sulfate and delivery for preeclampsia, and corticosteroids and expectant management in SLE, distinguishing the two diseases is critical. One reliable method of distinguishing the two processes is by assessing the serum complement levels. In SLE, the serum complement levels will be dramatically lower due to the immune complex processes, whereas in preeclampsia, the serum complement levels will be normal.

APPROACH TO

Preeclampsia in a Patient With SLE

The term lupus (Latin for wolf) is attributed to the 13th century physician Rogerius who used it to describe erosive facial lesions that were reminiscent of a wolf’s bite. In 1997 the American College of Rheumatology revised their 1982 criteria for the classification of systemic lupus erythematosus (SLE) to include 11 components (Table 37–1). For the diagnosis of lupus, the ACR recommends that a patient have at least 4 of the 11 criteria present in any order and over any time period. Patients who clinically have symptoms of lupus but who do not fulfill this 4/11 criteria are considered to have a “lupus-like” syndrome and may, in some cases, be treated as if they have the full syndrome. 

The female to male ratio of lupus is between 8:1 and 13:1 with a prevalence between 4 and 250:100,000 persons. In the United States, the highest incidence is in Asians in Hawaii, African Americans, and Native Americans. The risk of an African American female developing SLE is 1:250 compared to 1:700 if the woman is Caucasian. 

The etiology is unknown but is felt to have genetic, hormonal, immunologic, and environmental factors. 

There are a number of classical clinical features, each with its own frequency (Table 37–2). Arthralgias/myalgias, fatigue, arthritis, hematologic changes, fever, alopecia, weight loss, and photosensitivity are seen most frequently in patients with SLE. There are also a number of lupus-inducing drugs, many of which are used during pregnancy. These are listed in Table 37–3. The prognosis for 5-year survival of 50% in the 1950s has improved markedly to over 90% for a 10-year survival in 1994. The prognosis is worse with CNS involvement, hypertension, azotemia, and an early age at onset, and the major cause of death remains infection. 

Studies prior to 1985 suggested that pregnancy caused SLE exacerbations, but more recent publications find little or no increase in SLE flares during gestation. Older studies which indicated a worsening of the disease postpartum have been refuted by newer reports as well. Flares do occur during any trimester, and remission of SLE immediately before or at the time of conception probably do decrease the chances of an exacerbation during pregnancy and postpartum. Women with active lupus nephritis at the time of conception have a risk of flare during pregnancy that exceeds 50%. In a recent study of patients with lupus nephritis who became pregnant, 59% had no change in renal function, 30% had transient renal impairment, and 7% had permanent renal insufficiency after pregnancy. Patients with a serum creatinine greater than 1.5 mg/dL have significantly increased risk of deterioration of renal function during or after pregnancy. Preeclampsia occurs in over one-third of patients with lupus nephritis compared to less than 15% of patients without nephritis.

Table 37–1 CRITERIA FOR DIAGNOSIS OF SLE

1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds 2. Discoid rash 3. Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation 4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician 5. Arthritis Non-erosive arthritis involving two or more peripheral joints and characterized by tenderness, swelling, or effusion 6. Serositis Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion or Pericarditis—documented by electrocardiogram or rub or by evidence of pericardial effusion 7. Renal disorder Persistent proteinuria > 0.5 g/d or > 3+ if quantitation not performed or Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed 8. Neurologic disorder Seizures in the absence of offending drugs or known metabolic derangements, eg, uremia, ketoacidosis, or electrolyte imbalance or Psychosis in the absence of offending drugs or known metabolic derangements, eg, uremia, ketoacidosis, or electrolyte imbalance 9. Hematologic disorder Hemolytic anemia with reticulocytosis or Leukopenia < 4000/mm3 total on two or more occasions or Lymphopenia < 1500/mm3 on two or more occasions or Thrombocytopenia < 100,000/mm3 in the absence of offending drugs 10. Immunologic disorder Positive tests for antiphospholipid antibodies or Anti-DNA: antibody to native DNA in abnormal titer or Anti-Sm: presence of antibody to Sm nuclear antigen or False-positive serologic test for syphilis known to be positive for at least 6 mo and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test 11. Antinuclear antibodies An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point and in the absence of drugs known to be associated with “drug-induced lupus” syndrome

 

Table 37–2 CLINICAL MANIFESTATIONS OF SLE
FEATURE OF SLE	% FREQUENCY AT ANY TIME
Arthralgia/myalgia	95
Fatigue	90
Arthritis	90
Hematologic changes	90
Fever	80
Alopecia	71
Weight loss	60
Photosensitivity	58
Butterfly rash	50
Clinical lupus nephritis	50
Lymphadenopathy	50
Pleurisy	50+
Anemia	50+
aPL antibodies	25
Neuropsychiatric disorder	20

Table 37–3 LUPUS-INDUCING DRUGS
DEFINITE	POSSIBLE
Hydralazine	Phenytoin
	Aldomet
	Sulfonamides
	PTU
	Nitrofurantoin
	Atenolol
	Metoprolol
	Captopril

Other complications of pregnancy associated with SLE include intrauterine growth restriction (IUGR) (12%-32%), preterm birth (50%, typically due to preeclampsia, IUGR, or abnormal FHR testing), and neonatal lupus from autoantibodies that cross the placenta causing skin lesions, thrombocytopenia, anemia, and hepatitis. Women with anti-Ro and anti-La antibodies from Sjögren syndrome (anti-SSA and anti-SSB) also have a risk of congenital heart block in the fetus. 

Preconception counseling should include renal function evaluation with a 24-hour urine collection for total protein and creatinine clearance, serum creatinine, urinalysis, CBC and platelet count, liver function tests, complement levels, ds-DNA levels, and anti-SSA and SSB antibodies, and the patient should be tested for lupus anticoagulant and anticardiolipin antibodies (ACA). Patients considering pregnancy should be apprised of the risks to themselves and the fetus from SLE, and the need to discontinue NSAIDs and cytotoxic drugs such as methotrexate prior to pregnancy. It is also recommended that they delay conception until at least 6 months after remission of any SLE flare. 

Antenatal care should include visits every 2 weeks in the first and second trimesters and then weekly in the third to observe for hypertension, fundal height abnormalities, proteinuria, and symptoms of a lupus flare. Baseline labs should include a completion of their preconception labs if not recently obtained including 24-hour urine, CBC, and early dating ultrasound as well as a repeat of the lupus anticoagulant and anticardiolipin antibodies if previously negative. Serial ultrasounds for growth should be considered every 3 to 4 weeks after 20 weeks and biweekly non-stress tests (NSTs) or other fetal monitoring should commence by 32 weeks (earlier if IUGR is suspected). 

With the exception of methotrexate, most anti-lupus medications may be continued during pregnancy. Commonly used medications and potential side effects are listed in Table 37–4.

Table 37–4 MEDICATIONS FOR SLE

NSAIDs • Aspirin, NSAIDs should be discontinued. Antimalarials • Hydroxychloroquine (Plaquenil): stopping in pregnancy associated with lupus flare; may be first-line therapy. Immunosuppressive agents • Cyclosporine appears safe in humans. • Azathioprine (Imuran) appears safe in humans; associated with IUGR. • Cyclophosphamide (Cytoxan) should be avoided (cleft lip, skeletal abnormalities). • Methotrexate should be avoided (embryolethal, associated with multiple congenital anomalies). Glucocorticoids • Avoid fluorinated glucocorticoids (cross placenta). • Prednisone, prednisolone, methylprednisolone preferred.

 

If a lupus flare is suspected, it is critical to distinguish it from preeclampsia. Decreased levels of complement, the presence of urinary casts, and increased levels of ds-DNA antibodies may be present in lupus and are rarely seen in preeclampsia, which is more likely to evidence an increased level of uric acid. If the flare is mild-moderate (such as skin or joint pain), prednisone may be given at 15 to 20 mg/d or increase a prior dose to at least 20 to 30 mg/d. In severe flares without renal or CNS manifestation, a rheumatology consult as an outpatient is preferred. Glucocorticoids at 1.0 to 1.5 mg/kg per day should result in clinical improvement in 5 to 10 days. Steroids should be tapered when clinical improvement is noted; if symptoms recur during or after tapering, consider cyclosporine, hydroxychloroquine (Plaquenil), or azathioprine (Imuran) therapy. A severe flare with CNS or renal involvement requires hospitalization, a rheumatology consult, and IV glucocorticoids such as 10 to 30 mg/kg/d of methylprednisolone for 3 to 6 days. 

While most patients with lupus fare well during pregnancy, a subset has the additional risk of antiphospholipid syndrome (aPL syndrome) and its increasingly complicated course. The criteria for the aPL syndrome are listed in Table 37–5. It is advisable to test for both lupus anticoagulant and anticardiolipin antibodies (IgG and IgM), since a patient may have lupus anticoagulant or ACA alone or in combination. Clinically significant values include positive lupus anticoagulant, medium- or high-positive IgG, and probably isolated IgM positivity as well.

Table 37–5 CRITERIA FOR DIAGNOSIS OF aPL SYNDROMEa

Clinical Criteria • Pregnancy Loss • Recurrent spontaneous abortionb • Unexplained fetal death • Thrombosis • Venous thrombosis • Arterial thrombosis, stroke • Autoimmune thrombocytopenia • Other disorders • Autoimmune hemolytic anemia • Transient ischemic attacks • Amaurosis fugax • Chorea gravidarum • Livedo reticularis Laboratory Criteria • Lupus anticoagulant • Anticardiolipin antibodies > 15-20 IgG binding units

aAt least one clinical and one lab criteria required for diagnosis of aPL syndrome.

bThree or more spontaneous abortions with no more than one live birth.

Obstetric complications of aPL syndrome include pregnancy loss rates as high as 90% which may occur as second- or third-trimester IUFD. Recurrent spontaneous abortion is also associated with aPL syndrome as is early preeclampsia, IUGR and placental insufficiency, preterm birth, autoimmune thrombocytopenia, and venous or arterial thrombosis. The three goals of aPL treatment during pregnancy therefore include suppression of the immune system, prevention of thrombosis, and improvement of placental blood flow by decreasing the thromboxane-to-prostacyclin ratio. 

Early trials of aPL therapy in pregnancy reported successful pregnancies using high-dose (≥ 40 mg/d) prednisone and low-dose aspirin, but more recent reports demonstrate comparable efficacy and fewer complications with heparin and low-dose aspirin. Initiation of heparin therapy should begin as soon as pregnancy is confirmed using 10,000 to 20,000 U/d in two doses of unfractionated heparin (UFH) if no prior thrombosis (increasing to the higher dose in the third trimester), or full anticoagulation with UFH if prior thrombosis. Low-molecularweight heparin may be used instead of UFH, and low-dose aspirin should be included with any heparin therapy. IVIg has been used as an adjunct to heparin and aspirin with high cost and uncertain benefits. 

Surveillance of the patient with aPL syndrome in pregnancy is similar to other connective tissue diseases, and includes intensive monitoring for preeclampsia, IUGR, placental insufficiency, and thrombosis. Thromboprophylaxis or full anticoagulation should continue for 6 weeks postpartum and the patient should be counseled about the lifetime risk of thrombosis. Oral contraceptives are contraindicated with aPL syndrome in patients not on anticoagulation. 

The pregnant patient with SLE who enters pregnancy with no recent flare or nephritis has an excellent chance of a successful outcome. Recent flares, nephritis, an elevated serum creatinine, or concurrent aPL syndrome markedly increases risk to both mother and fetus and should trigger additional monitoring and usually consultation with maternal-fetal medicine and rheumatology specialists.

Comprehension Questions

37.1 A 29-year-old patient is seen for a preconceptional visit. She has a history of lupus. Which of the following characteristics place her health at greatest risk?

A. Current BP of 120/80 mm Hg.

B. Serum creatinine of 1.8 mg/dL.

C. Most recent lupus flare 8 months ago.

D. Current medications include prednisone and azathioprine.

37.2 For optimal pregnancy outcome, patients should be advised to wait at least 6 months before attempting conception with which of the following conditions?

A. Lupus nephritis

B. Positive antinuclear antibody titer

C. Discontinuing methotrexate

D. Resolution of rash of discoid lupus

37.3 A lupus flare may be distinguished from preeclampsia using which of the following?

A. Level of proteinuria

B. Presence of thrombocytopenia

C. Urinary casts

D. Severe hypertension

E. IUGR

37.4 A patient with lupus and aPL syndrome will have the best outcome with fewest complications when administered which of the following therapies?

A. Baby aspirin alone

B. Heparin plus baby aspirin

C. Prednisone plus baby aspirin

D. Prednisone alone

ANSWERS

37.1 B. Patients with lupus and a serum creatinine greater than 1.5 mg/dL who become pregnant have a high risk of renal deterioration during or after pregnancy.

37.2 A. Patients who conceive while experiencing lupus nephritis have a greater than 50% risk of lupus flare during pregnancy and a 7% chance of permanent renal insufficiency after pregnancy.

37.3 C. A lupus flare during pregnancy may be difficult to distinguish from superimposed preeclampsia. Measuring complement levels which are decreased and observing for the presence of urinary casts (which should not be seen in preeclampsia) may help determine the presence of a lupus flare.

37.4 B. When the aPL syndrome occurs with lupus, surveillance and therapy should be intensified for fetal and maternal complications. Therapy including prophylactic levels of heparin (with no history of thrombosis) or therapeutic anticoagulation (with a thrombosis history) plus low-dose aspirin offers the best efficacy with the lowest risk of side effects.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ Pregnancy should be postponed at least for 6 months after lupus nephritis (Level II-3).

➤ Patients with a serum creatinine greater than 1.5 mg/dL have an increased risk of deterioration of renal function during pregnancy (Level II-2).

➤ Other than methotrexate, most medications used to treat lupus are reasonable options during pregnancy (Level III).

➤ Antenatal evaluation of the lupus patient includes complement levels and renal function tests as well as determination of the presence of the lupus anticoagulant and anticardiolipin antibodies, if not previously detected (Level III).

➤ Pregnant women with lupus should undergo additional monitoring including serial sonograms for fetal growth and regular fetal monitoring until delivery (Level III).

➤ Patients with lupus and aPL syndrome are at additional maternal and fetal risk and should receive heparin and low-dose aspirin for optimal pregnancy outcome (Level I).

➤ Pregnant women with aPL syndrome should receive postpartum thromboprophylaxis (Level III).

REFERENCES

1. Burkett G. Lupus nephropathy and pregnancy. Clin Obstet Gynecol. 1985;28:310-323. 

2. Georgiou PE, Politi EN, Katsimbri P, Sakka V, Drosos AA. Outcome of lupus pregnancy: a controlled study. Rheumatology. 2000;39:1014-1019. 

3. Khamashta M. Systemic lupus erythematosus and pregnancy. Best Prac Res Clin Rheumatol. 2006;20:685-694. 

4. Lockshin M. Lupus pregnancies and neonatal lupus. Springer Semin Immunopathol. 1994;16:247-259. 

5. Molad Y. Systemic lupus erythematosus and pregnancy. Curr Opin Obstet Gynecol. 18:613-617. 

6. Petri M. Prospective study of systemic lupus erythematosus pregnancies. Lupus. 2004;13:688-689. 

7. Petri M, Magder L. Classification criteria for systemic lupus erythematosus: a review. Lupus. 2004:13;829-837. 

8. Tincani A, Bazzani C, Zingarelli S, Lojacono A. Lupus and the antiphospholipid syndrome in pregnancy and obstetrics: clinical characteristics, diagnosis, pathogenesis, and treatment. Semin Thromb Hemost. 2008;34:267-273. 

9. Warren JB, Silver RM. Autoimmune disease in pregnancy: systemic lupus erythematosus and antiphospholipid syndrome. Obstet Gynecol Clin N Am. 2004;31:345-372. This is an all encompassing review of SLE and aPL syndrome with an extensive review of etiology including genetics, epidemiology, and evaluation and management. 

10. Witter FR. Management of the high-risk lupus pregnant patient. Rheum Dis Clin N Am. 2007;33:253-265.

HomeHigh-Risk Obstetrics Case FilePreeclampsia in a Patient with SLE Case File