Keys to Managing Rheumatologic Diseases in Pregnancy

During pregnancy, rheumatologic diseases present particular challenges, and the clinician should be aware of these challenges. The most frequently encountered rheumatologic disorders in women during their childbearing years are systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), antiphospholipid syndrome (APS), Sjögrens syndrome, and scleroderma. SLE is one of the most common autoimmune disorders affecting women in their childbearing years. Image courtesy of Wikipedia Commons.

The most common symptoms of SLE during pregnancy include arthritis, rashes (such as the classic malar rash, shown), and fatigue. SLE activity during pregnancy remains stable or increases, although flares are usually mild. However, SLE increases the risk for spontaneous abortion, intrauterine fetal death, preeclampsia, intrauterine growth retardation, and preterm birth.^[1] Prognosis for both mother and child are best when SLE is quiescent for at least 6 months before conception and the mother's underlying renal function is stable and normal.^[2] The mother's health and fetal development should be monitored frequently during pregnancy by an obstetrician with experience in high-risk care.

Screening for SLE often begins with an antinuclear antibody (ANA) test, which is positive in more than 95% of cases. ANA testing is followed by confirmatory tests. The speckled ANA pattern shown here is frequently associated with SLE, as well as RA, Sjögren syndrome, scleroderma, and other disorders. Among the antibodies with this staining pattern are those that follow. Anti-Sm antibodies are more specific for SLE than other antibodies and are detectable in 10%-25% of cases. Anti-ribonucleoprotein antibodies are found in SLE and other rheumatic disorders. Anti-SSA and anti-SSB antibodies are associated with SLE, Sjögren syndrome, scleroderma, and other conditions. SSA antibodies are present in 25%-40% of patients with SLE, and SSB antibodies are present in 10%-15% of patients with SLE.

Neonatal lupus erythematosus syndrome (shown) occurs in 1%-2% of pregnancies of women with anti-SSA or anti-SSB antibodies. This infant with neonatal lupus presented with petechial lesions, hepatosplenomegaly, and thrombocytopenia. Other manifestations of neonatal lupus syndrome include congenital heart block, cardiomyopathy, hepatobiliary disease, and thrombocytopenia. The risk for congenital heart block is low, but fetal echocardiography should be performed in pregnant women with systemic autoimmune disease, particularly those with anti-SSA or anti-SSB antibodies, and in asymptomatic pregnant women with a prior pregnancy complicated by fetal heart block.

A 24-year-old woman has a 2-year history of SLE. Renal biopsy showed diffuse lupus nephritis with early crescent formation (shown). ANA titer was 1:1280 in a speckled pattern, anti-Sm and anti-SSA antibody tests were positive, and anti-RNP and anti-SSB antibody tests were negative. She received cyclophosphamide 6 monthly intravenous pulse doses followed by azathioprine 150 mg daily and hydroxychloroquine 200 mg daily, with no recurrence of renal disease. She is 2 months pregnant with persistent malar rash, 30 minutes of morning stiffness, and occasional polyarthralgias, but no other findings of active SLE.

Which of the following should be monitored during the patient's pregnancy?
A. Monthly complete blood count and platelet count
B. Glomerular filtration rate, urine protein/creatinine ratio, serum complement, and anti-dsDNA antibody at the end of each trimester
C. Fetal echocardiography
D. Ultrasonography
E. All of the above

Answer: E. All of the above

The patient's anti-dsDNA antibody titer was high, with low C3 and C4 levels. Elevated anti-dsDNA antibodies and low C3 and C4 levels are associated with active lupus nephritis, but levels tend to normalize with control of nephritis. It is important to monitor the patient throughout pregnancy. Lupus flares can mimic preeclampsia and may be associated with leukopenia, thrombocytopenia, inflammatory rashes, pleuritis, fever, hypertension, proteinuria, decreased complement, or increased anti-dsDNA. Echocardiography can help assess for congenital heart block and ultrasonography (shown) can estimate fetal gestational age, as patients are at risk for having growth restriction and preterm birth.

Repeat laboratory tests are ordered for the patient at her first rheumatology visit after confirmation of pregnancy. Results are shown. The patient's normal erythrocyte sedimentation rate and C- reactive protein level suggest no active inflammation. Her anti-dsDNA titer level never normalized with therapy, but remains low. A rising titer would have been worrisome at this point. Urinalysis contains no active sediment and serum creatinine is normal, but the urine protein/creatinine ratio is borderline.

Which of the following should be the next step(s) in this patient's management? Select all that are correct.
A. Order anticardiolipin antibody and lupus anticoagulant (LAC) studies
B. Refer the patient to an obstetrician who specializes in high-risk patients
C. Recommend pregnancy termination
D. Discontinue hydroxychloroquine
E. Discontinue azathioprine

Answer: A and B

LAC may cause infertility, fetal loss, and preterm delivery (shown). Order anticardiolipin antibody and LAC studies. The patient has no history of a thromboembolic event, previous pregnancy, or fetal loss, but antiphospholipid antibody status is unknown. The patient is at risk for a lupus flare, as well as for urinary tract infection, diabetes mellitus, hypertension, premature rupture of the membranes, preterm labor/delivery, preeclampsia/eclampsia, intrauterine growth restriction, and fetal demise, and she should be monitored in a clinic that specializes in high-risk obstetrics patients. The patient's LAC was positive and she required an emergency cesarean section at 26 weeks of gestation. Pathologic evaluation of the placenta revealed areas of infarction and intervillous fibrin deposition. Image courtesy of Wikipedia Commons.

RA is a chronic systemic inflammatory disease of unknown cause, with persistent symmetric polyarthritis that affects the hands (shown) and feet. Any joint with a synovial membrane may be involved. Extra-articular involvement of organs such as the skin, heart, lungs, and eyes can be significant. No test results are pathognomonic for RA, but the presence of both anti-cyclic citrullinated peptide antibodies and rheumatoid factor is highly specific. The disease activity of RA generally improves during pregnancy. However, RA may flare postpartum, especially if the woman is breastfeeding. This is thought to be associated with hyperprolactinemia. No specific guidelines exist for monitoring patients with RA. Close monitoring with fetal ultrasound can help detect early gestational problems that result from poorly controlled RA or medication complications.^[3]

A 28-year-old woman with RA wishes to start a family. Although severe joint deformities developed in the patient's mother (shown), the patient's joint examination is notable only for some limited range of motion in the wrists and reduced grip strength. Current medications are methotrexate 20 mg weekly, folic acid 1 mg daily, adalimumab 40 mg every 2 weeks, naproxen 500 mg as needed for pain, and an oral contraceptive. She reports minimal restrictions in her daily activities, with manageable fatigue. She has 4 swollen joints and 6 tender joints. Complete blood count with differential and hepatic function panel are normal. Erythrocyte sedimentation rate is 18 mm/hr, global health score is 15 mm, and disease activity score is high (4.16 on the DAS28). What advice would you give the patient regarding pregnancy? Would you make any changes to her medication regimen?

Advise the patient that conception is best when RA is in remission or well controlled. Methotrexate (FDA category X, shown), adalimumab, oral contraceptive, and naproxen should be removed from her medication regimen, and barrier contraception should be used for at least 1 ovulatory cycle.^[4,5] Little or no information is available for any of the biologic agents; thus, their use should be avoided during pregnancy.^[6] Prednisone and prednisolone are FDA category B, but may cause a slightly increased risk for cleft palate, premature rupture of membranes, small-for-gestational-age babies, and (in the mother) gestational diabetes, hypertension, osteonecrosis, and osteoporosis. Therefore, use the lowest prednisone/prednisolone dose to control disease activity, and use stress doses during labor/delivery. Add hydroxychloroquine (FDA category C) and/or sulfasalazine (FDA category B) if appropriate.^[7]

Patients with antiphospholipid syndrome (APS) may present with symptoms such as livedo reticularis (shown). It may be associated with, but is often separate from, SLE and other rheumatologic diseases. APS manifests clinically as recurrent venous or arterial thrombosis and/or fetal loss. LAC and anticardiolipin antibody tests are used to screen; most patients with APS have both LAC and anticardiolipin antibodies. In addition to fetal loss, APS is associated with pregnancy complications such as fetal growth restriction, preeclampsia, thrombosis, and autoimmune thrombocytopenia.^[8]

A 24-year-old white woman with a history of a child born prematurely with low birth weight but an otherwise normal birth and a second trimester miscarriage presents 2 months pregnant. Her medical history is significant only for thrombophlebitis at age 19 while taking birth control pills. Laboratory test results are shown.

Which of the following is true about this patient? Select all that are correct.
A. She is at increased risk for hemorrhage
B. She is at increased risk for fetal distress
C. She is at increased risk for hypertension during pregnancy
D. She has an 80% chance of a miscarriage of this pregnancy

Answer: B and C.

Preeclampsia, in which the smooth muscle of the maternal blood vessels is hypertrophic (shown), is associated with APS and LAC. Hypertension and preeclampsia are frequent complications of pregnancy in women with rheumatologic diseases, especially those with antiphospholipid antibodies or LAC. Close fetal monitoring under the direction of an obstetrician is essential for pregnant women who have preeclampsia. Placental insufficiency may lead to fetal distress, low birth weight, and premature delivery. The risk for repeat miscarriage has been estimated to be 20%. LAC promotes clotting and increases the risk for phlebitis, pulmonary emboli, and other clots. Image courtesy of Wikipedia Commons.

Sjögren syndrome is a systemic chronic inflammatory disorder characterized by lymphocytic infiltrates in exocrine organs (shown). A pregnant woman with Sjögren syndrome and antiRo/SS-A antibodies is at risk for fetal loss, complete heart block in the fetus, and neonatal lupus syndrome in the newborn. If congenital heart block develops in this child, the risk for congenital heart block during a subsequent pregnancy is 15%.

Scleroderma is characterized by fibrosis and vascular alterations. A patient with skin tightness and induration is shown. Pregnant women with systemic sclerosis have a higher risk for pregnancy loss and higher complication rates, but a diagnosis of systemic sclerosis is not an absolute contraindication for pregnancy. Pregnancy risk is greatest in those who have had the disease for less than 4 years and who also have diffuse cutaneous involvement. Some symptoms may increase during pregnancy (eg, edema, arthralgias, gastroesophageal reflux disease). Skin manifestations are not reported to worsen. Raynaud symptoms may improve during pregnancy, only to worsen after delivery. Medications including D-penicillamine, cytotoxic agents, and angiotensin-converting enzyme inhibitors should be discontinued prior to pregnancy.

Key take-home points for managing patients with rheumatologic disease in pregnancy are shown.

Conception advice for patients with rheumatologic disease includes the following:

• The disease should either be in remission or under good control during the period of conception;

• Limit or stop medications when appropriate and under a physician's advice;

• Treat symptoms, not the disease (or laboratory tests);

• Pay attention to available drug-specific information regarding fertility and lactation; and

• Any patient considering conception should consult with a rheumatologist, obstetrician, and primary care provider before conception.

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• Distinguishing Rheumatologic Diseases on Plain Radiography
• Fibromyalgia
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• Other Slideshows

For more information, see the following resources:

• Medscape Reference: Antiphospholipid Syndrome
• Medscape Reference: Evaluation of Gestation
• Medscape Reference: Lupus Nephritis
• Medscape Reference: Neonatal and Pediatric Lupus Erythematosus
• Medscape Reference: Rheumatoid Arthritis
• Medscape Reference: Scleroderma

For more information, see the following resources:

• Medscape Reference: Sjögren Syndrome
• Medscape Reference: Systemic Lupus Erythematosus and Pregnancy

Contributor Information

Author
Kristine M. Lohr, MD
Professor, Department of Internal Medicine
Center for the Advancement of Women's Health and Division of Rheumatology
Director, Rheumatology Training Program
University of Kentucky College of Medicine
Lexington, Kentucky

Disclosure: Kristine M. Lohr, MD, has disclosed no relevant financial relationships.

Editor
Lars Grimm, MD, MHS
House Staff
Department of Diagnostic Radiology
Duke University Medical Center
Durham, North Carolina

Disclosure: Lars Grimm, MD, MHS, has disclosed no relevant financial relationships.

Contributor Information

Reviewers
Serena Wu, MD
Assistant Professor
Department of Obstetrics & Gynecology
University of Nebraska Medical Center
Omaha, Nebraska

Disclosure: Serena Wu, MD, has disclosed no relevant financial relationships.

Herbert S. Diamond, MD
Adjunct Professor of Medicine
Division of Rheumatology
University of Pittsburgh School of Medicine
Chairman Emeritus
Department of Internal Medicine
Western Pennsylvania Hospital
Pittsburgh, Pennsylvania

Disclosure: Herbert S. Diamond, MD, has disclosed the following relevant financial relationships:
Owns stocks, stock options, or bonds from: GlaxoSmithKline; Merck & Co., Inc; Zimmer, Inc.