Management of the Patient with Rheumatic Disease During and After Pregnancy




INTRODUCTION


Rheumatic diseases disproportionately affect women and, in some patients, may be serious enough to preclude consideration of pregnancy; however, with advances in rheumatology therapies and sophisticated reproductive technologies, increasing numbers of patients with rheumatic disease have the option of pursuing pregnancy. Important considerations for every patient include the effect of pregnancy-related immune changes on underlying disease, the impact of rheumatic disease activity or damage on pregnancy outcome, the effect of maternal autoantibodies on fetal and neonatal health, and potential adverse fetal effects of medications.




NORMAL PREGNANCY


In order to monitor a patient with rheumatic disease through pregnancy, it is critical to have some understanding of normal pregnancy physiology. Immunologic changes in uncomplicated pregnancy are significant, although they are incompletely understood. Cell-mediated immunity is generally depressed with an increase in humoral and innate immune responses, and complement levels are elevated due to an increase in synthesis. Multiple mechanisms for fetal tolerance appear to protect the fetus from a maternal cytotoxic immune response.


Many physiologic adjustments of pregnancy are easily confused with active rheumatic disease, or may worsen existing rheumatic disease symptoms. One critical hemodynamic change is an increase in intravascular volume by 30% to 50%, providing additional stress for patients with renal or cardiac compromise (cardiac output similarly increases by 30%–50%). The glomerular filtration rate also increases by up to 50%, and, as a result, women with pre-existing proteinuria may be expected to have significant increases in urinary protein excretion, particularly during the second and third trimesters.


Hematologic changes are also significant: pregnancy generates a prothrombotic state, with increased plasma levels of fibrinogen, factor II, and other procoagulant proteins and decreased protein S levels and fibrinolytic system activity. This hypercoagulability, in conjunction with venous stasis, compression by the gravid uterus, and bed rest, increases the risk of venous thromboembolism in normal pregnancy by a factor of five. Pregnant women usually become anemic due to hemodilution in the third trimester, and although platelet production usually increases in a compensatory fashion, platelet turnover increases and mild thrombocytopenia (70–150 × 10 9 /L) occurs in about 8% of uncomplicated pregnancies. The white blood cell count rises progressively, with a relative increase in neutrophils; the erythrocyte sedimentation rate (ESR) also rises, making both these tests, which are otherwise useful in assessing vasculitis activity, unreliable indicators of inflammation.


Overall, a majority of organ systems experience some degree of change during pregnancy. Thirty to fifty percent of pregnant patients have significant gastroesophageal reflux disease, and patients with pre-existing gastrointestinal motility problems, especially those with scleroderma, are likely to experience an exacerbation of symptoms. Although saliva production is unchanged, gums may swell and bleed, exacerbating dental problems in patients with sicca symptoms. Facial erythema may mimic a lupus or other autoimmune disease rash, and mottled palmar erythema may be confused with cutaneous vasculits. Bland joint effusions and arthralgias due to ligamentous laxity may similarly be confused with mild inflammatory arthritis. Finally, both pregnancy and lactation cause reversible bone loss in healthy women; this loss is increased in women who breastfeed for longer intervals, an issue of potential concern for rheumatic disease patients on long-term corticosteroid therapy.




COMPLICATED PREGNANCY


Distinguishing common disorders of pregnancy from autoimmune disease activity may present a significant challenge. The pre-eclampsia syndrome includes complications that may mimic lupus nephritis, scleroderma renal crisis, or vasculitis: late pregnancy hypertension (blood pressure greater than 140/90 after 20 weeks’ gestation), proteinuria (greater than 300 mg/24 hours), edema, and hyperuricemia. When seizures occur, the syndrome is defined as eclampsia. The hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is a severe variant of pre-eclampsia, and presents with prominent hepatic enzyme abnormalities, abdominal pain, fever, thrombocytopenia, and encephalopathy. Pre-eclampsia, intrauterine growth restriction (IUGR) (infants weighing less than 10% of weight for age), preterm delivery (< 37 weeks’ gestation) and pregnancy loss are complications that are more common in a number of rheumatic diseases. Pregnancy loss may occur in any of four major developmental periods: pre-embryonic loss (conception through week 4 of gestation); embryonic loss (weeks 5 through 9); fetal loss (week 10 until delivery); and neonatal loss.


Interactions of pregnancy and specific rheumatic diseases are described later, with particular focus on maternal complications, neonatal outcome, and management recommendations. A detailed summary of medications and their safety in pregnancy follows.


Systemic Lupus Erythematosus


Systemic lupus erythematosus (SLE) is most common during the reproductive years, and patients require thorough evaluation both before and during pregnancy. With appropriate planning, monitoring, and medical therapy, most patients with SLE can undergo successful pregnancies with good fetal outcome.




A 27-year-old woman with long-standing SLE comes in to discuss plans for pregnancy. She presented with diffuse proliferative glomerulonephritis at age 18 and was treated with cyclophosphamamide for 6 months, followed by 2 years of azathioprine therapy. She is currently on hydroxychloroquine 400 mg/day, enalopril 5 mg/day, and prednisone 7.5 mg/day. Serum creatinine is 1.1 and creatinine clearance is 70 mL/hour, with mild baseline proteinuria of 350 mg/24 hours. Serologies include positive anti-SSA/Ro and anti-SSB/La antibodies, with negative antiphospholipid antibodies (aPLs). Anti-ds DNA antibody is negative, and complement levels (C3, C4) are normal. How does one advise this patient?


CASE STUDY 1


Maternal Considerations


Pregnancy in a patient with SLE represents an added risk to an already complex clinical situation. Large-scale epidemiologic studies confirm that despite improvements in overall pregnancy outcome over recent years, maternal morbidity is still high for patients with SLE: hypertensive complications, renal disease, preterm delivery, cesarean section, postpartum hemorrhage and thrombosis, fetal growth restriction, and neonatal death are all more common in SLE pregnancies. One national study found maternal mortality to be 20-fold higher among women with SLE; in addition, roughly one third of patients with SLE have cesarean sections, one third deliver prematurely, and one fourth develop pre-eclampsia. Fortunately, identification of particular risk factors can help predict likelihood of complications and aid in risk counseling. Important risk factors include presence of lupus disease activity, renal involvement, aPLs and anti-SSA/Ro and SSB/La antibodies. Pre-pregnancy evaluation involves assessment of level of disease activity, presence of disease damage, review of current medications, and laboratory tests, especially autoantibody status. The algorithm in Figure 31-1 illustrates a general approach to evaluation of rheumatic disease patients before pregnancy.




Figure 31-1


Pre-pregnancy evaluation of the rheumatic disease patient.


Medication Assessment


Review of medications before conception allows adjustment with careful follow-up to ensure maintenance of disease control. Detailed recommendations appear below. In brief, however, prednisone, methylprednisolone, hydroxychloroquine, azathioprine, cyclosporine, and intravenous immunoglobulin may be continued through pregnancy; in most circumstances, other immunosuppressive medications should be discontinued or replaced. Continuation of hydroxychloroquine is encouraged, because recent data support fetal safety and a lowered risk of maternal disease flare.


Disease Activity


The importance of quiescent disease at the time of conception cannot be overemphasized. Risk of flare during pregnancy is significantly higher if lupus was active before conception, and pregnancies with high levels of disease activity (but not mild disease) result in increased risk of premature birth and a decrease in live births. Cortes-Hernandez and colleagues found that risk of flare in pregnancy was associated with discontinuation of maintenance therapy before pregnancy and a history of 3 or more severe flares before pregnancy. In general, it is prudent to have quiescent disease for at least 6 months before attempting to conceive.


Evidence of any serious organ damage due to SLE—even in the absence of current disease activity—may represent a contraindication to pregnancy. This includes not only moderate to severe renal insufficiency but also seriously impaired cardiac or pulmonary function, uncontrolled hypertension, or presence of pulmonary hypertension.


Risk of Flare During Pregnancy


Relative risk of flare during SLE pregnancy remains controversial, with estimates ranging from 13% to 60%. Discordant findings likely reflect differences between patient populations and in the definition of lupus flare. For example, in Lockshin’s series of SLE pregnancies, thrombocytopenia, proteinuria, and hypocomplementemia were the most common abnormalities. If interpreted as SLE-related symptoms, the flare rate was 25%; if interpreted as due to pregnancy, pre-eclampsia, or aPLs, rate of flare dropped to 13%. More recently, Ruiz-Irastorza and associates demonstrated higher flare rates in pregnant lupus patients compared with both nonpregnant controls and with the patients themselves after pregnancy, but Georgiou and coworkers found no significant increase in flare during pregnancy, and an overall flare rate of only 13% in their cohort of patients. Existing instruments to measure disease activity have recently been modified and validated to differentiate pregnancy-related physiologic changes from lupus activity, and will allow greater comparability between future studies. Pregnancy-specific disease activity indices include the SLE-Pregnancy Disease Activity Index and the Lupus Activity Index Pregnancy Scale.


Despite the varied estimates of precise risk of flare during lupus pregnancy, it is reasonable to counsel patients regarding a small to moderate increased risk of disease exacerbation, even with long-term quiescent disease, which may occur during any trimester or the postpartum period. Prophylactic steroid therapy is not recommended to prevent flare.


Impact of Lupus Nephritis


Renal insufficiency is an important risk factor for poor fetal outcome and for serious renal deterioration during pregnancy. Precise renal histology is less important than the presence of clinical renal dysfunction. Although exacerbation of renal disease may occur in up to 40% of cases, severe or permanent renal deterioration develops in less than 10%. The physiologic stress of pregnancy, even in patients with quiescent nephritis, may accelerate deterioration, especially in those with initial serum creatinine greater than 1.6 mg/dL. Onset of worsening renal function usually occurs in the latter half of pregnancy. In addition to the risk of moderate renal insufficiency, baseline proteinuria presents an independent risk: Moroni and associates demonstrated that proteinuria greater than 500 mg/24 hours is an independent predictor of poor fetal outcome. Fetal loss occurred in 57% of patients with proteinuria versus 10% of those without. Recent active nephritis also increased risk of renal deterioration during pregnancy: risk of renal flare was 5% in those with quiescent nephritis, and 39% in those with recently active nephritis.


Patients with SLE with renal transplants usually have successful pregnancies. McGrory and colleagues compared pregnancy outcomes in renal transplant recipients with (60 pregnancies) and without (374 pregnancies) SLE. Significant hypertension and cesarean sections were less common in patients with SLE, and other maternal conditions and pregnancy outcomes were comparable in both groups.


Differentiation of Systemic Lupus Erythematosus Flare from Pregnancy-Related Complications


In the SLE population, the differential diagnosis for new-onset proteinuria in the second half of pregnancy includes lupus nephritis, pre-eclampsia, or both. Two thirds of patients with SLE entering pregnancy with pre-existing renal disease develop pre-eclampsia, compared with 14% of patients with lupus without kidney disease. It is often not possible to differentiate between SLE nephritis and pre-eclampsia during pregnancy, and frequently, therapy is directed toward both. Clinical signs of active SLE such as inflammatory arthritis or rash, fever, lymphadenopathy, hematuria, leukopenia, erythrocyte casts, and rising anti-DNA antibody favor the diagnosis of lupus glomerulonephritis. Thrombocytopenia, hypertension, and hyperuricemia occur in both SLE and pre-eclampsia ( Table 31-1 ). ESR, increased in normal pregnancy, becomes an unreliable measure of lupus activity during pregnancy. Normal serum complement favors a diagnosis of pre-eclampsia. Measures of alternative pathway complement activation (Ba and Bb), are reported to be abnormal in active lupus nephritis and normal in lupus pregnancies with proteinuria not due to active SLE. Seizures may occur due to eclampsia or to neuropsychiatric lupus.



Table 31-1

Clinical Laboratory Measures/Physical Findings in Preeclampsia Versus Systemic Lupus Erythematosus (SLE) Nephritis




















































Clinical Measure Pre-eclampsia SLE Nephritis
Complement Usually normal Usually low
Urine red cell casts Rare Frequent
Liver function tests May be elevated Usually normal
Proteinuria onset Abrupt Gradual/Abrupt
24-hour protein Does not differentiate (2–25 g) Does not differentiate (2–25 g)
Thrombocytopenia Does not differentiate Does not differentiate
Hyperuricemia Does not differentiate Does not differentiate
Hypertension Does not differentiate Does not differentiate
Arthritis Not present May occur
Inflammatory rash Not present May occur
Fever Not present May occur


Thrombocytopenia during SLE pregnancy varies in presentation, and may be due to flare, aPLs, HELLP syndrome, or even normal pregnancy itself. Active SLE-related moderate thrombocytopenia (50–120 × 10 9 /L) may be difficult to distinguish from benign (mild) thrombocytopenia of late pregnancy, unrelated to SLE. Although rare, severe lupus-related thrombocytopenia may occur, with counts less than 10 × 10 9 /L.


Pregnancy Outcome


Neonatal Lupus Erythematosus


SLE may influence neonatal outcome by direct or indirect effects on the fetus. Neonatal lupus erythematosus (NLE) reflects a direct effect of transplacental autoantibodies to the SS-A/Ro and SS-B/La antigens, leading to fetal inflammation. Clinical manifestations include photosensitive rash, thrombocytopenia, liver function abnormalities, and rarely, irreversible congenital heart block (CHB). With the exception of CHB, manifestations disappear with clearance of maternal antibody at 6 months. The mortality rate associated with CHB is 20%, and most surviving patients require permanent pacing. The risk of any manifestation of NLE for the neonate of an anti-SSA/Ro positive woman is 20%, and the risk of CHB less than 3%. Although anti-SSA/Ro antibodies are responsible for NLE, they do not affect other pregnancy outcomes, and the risk of NLE is determined by the presence of the antibody, not the underlying maternal diagnosis. The risk of CHB in offspring of women with a previously affected child is higher, approximately 20%.


Immunoblot patterns of anti-SSA/Ro and SSB/La antibodies are related to the risk of CHB: 75% to 100% of mothers whose children develop CHB show reactivity with recombinant 52-kD SSA/Ro antigen. Because the anti-SSA/Ro 52-kD test is not generally available in clinical laboratories, however, management decisions are usually based on enzyme-linked immunosorbent assay (ELISA) results. Current recommendations suggest fetal echocardiography be done weekly from 16 to 26 weeks for high-risk patients (previous child with any manifestation of NLE) and every 2 weeks from 26 to 34 weeks. Anti-SSA/Ro and/or anti-SSB/La–positive patients without a history of a child affected by NLE are usually followed by fetal echocardiography at more variable intervals of every 2 to 3 weeks: although it is reported that third degree heart block can appear within a period as short as 1 week, no evidence-based guidelines exist. If significantly prolonged PR interval, advanced degree block, or evidence of pericardial or myocardial inflammation is detected, fluorinated corticosteroid treatment is generally instituted, although efficacy is unproven: reversal of complete heart block has not been reported in any pregnancy treated with fluorinated corticosteroid. Steroid therapy is most effective in resolution of pleural effusion, ascites, and hydrops fetalis. Intravenous immunoglobulin (IVIG) and even plasmapheresis have been suggested as potential future therapies.


Prematurity, Intrauterine Growth Restriction, and Other Fetal Complications


IUGR and prematurity are the most common fetal complications of lupus pregnancy. Maternal risk factors for threatened fetal growth and development are active SLE, impaired renal function, and presence of aPL. A retrospective review of 72 SLE pregnancies found that preterm deliveries, observed in 39% of their patients, were associated with aPL and higher prednisone dose. Other authors have similarly identified aPL and corticosteroid use, as well as hypertension, hypocomplementemia, and thrombocytopenia, as predictive of preterm delivery or pre-eclampsia.


Other complications may be seen. Unexplained elevation of maternal alpha-fetoprotein may occur in patients with SLE in the absence of neural tube defects and is associated with increased risk of fetal death. Elevation correlates with preterm delivery, high prednisone dosage, and presence of aPL. Presumably, abnormalities in the fetoplacental barrier lead to increased transport of alpha-fetoprotein from fetus to mother.


Maternal immunoglobulin G (IgG)–mediated thrombocytopenia may occasionally be transmitted to the fetus, but most infants born of thrombocytopenic mothers with SLE have normal platelet counts. IgG Coombs’ hemolytic antibody may cause hemolysis in the fetus and newborn.


Short-term follow-up of offspring of women with SLE suggest children develop normally compared with children of similar prematurity. Long-term follow-up of SLE offspring compared with matched controls found intelligence to be normal but identified a high frequency of learning disabilities, particularly in boys.


Management and Therapy


Treatment of the pregnant patient with SLE does not usually differ from that of the nonpregnant patient. Careful follow-up and monitoring with both the rheumatologist and obstetrician are essential ( Table 31-2 ). Hydroxychloroquine should be continued to prevent disease flare. Clinical flares of skin, joints, blood, kidneys, and nervous system require therapy with (unfluorinated) corticosteroids. Use of immunosuppressive therapies other than corticosteroid is generally limited to azathioprine or cyclosporine (see details later). Corticosteroid should be prescribed for thrombocytopenia if the platelet count drops significantly; life-threatening thrombocytopenia (< 30 × 10 9 /L) or imminent delivery requires platelet transfusion, intravenous IgG, or both.



Table 31-2

Monitoring of the Pregnant Systemic Lupus Erythematosus Patient






















Schedule Monitoring Test
First visit


  • Complete blood count with platelets



  • Comprehensive metabolic panel



  • Urinalysis, creatinine clearance, 24-hour urine protein or spot protein/creatinine ratio



  • Anticardiolipin antibody, lupus anticoagulant, anti-β2-Glycoprotein I antibody



  • Anti-ds DNA, anti-SSA/Ro and SSB/La antibodies



  • Complement levels (C3, C4)

Every 4–6 weeks


  • Platelet count * ; anti-ds DNA antibody;



  • complement levels; urinalysis *

Each trimester Creatinine clearance with 24-hour protein or protein/creatinine ratio *
Weekly (third trimester) If aPL positive: Antenatal fetal heart rate testing (nonstress test) or fetal umbilical artery Doppler velocimetry
Weeks 16–34


  • If anti-SSA/Ro and/or anti-SSB/La positive:



  • Weekly fetal echocardiograms weeks 16–26, biweekly weeks 26–34 if high risk (previous child with neonatal lupus erythematosus)



  • Every 2–3 weeks fetal echocardiograms if not high risk


* More frequently if abnormal.



The risk of pre-eclampsia is significantly increased in lupus pregnancy. Although low-dose aspirin is used to prevent pre-eclampsia in high-risk women with pre-existing hypertension, renal insufficiency, or history of previous pre-eclampsia, there is as yet no systematic study of the use of aspirin to prevent pre-eclampsia in patients with SLE (with or without aPL), although it is frequently prescribed.


There is general agreement on several key observations regarding risk and outcome of lupus pregnancy: first, inactive disease at the time of conception (and for the 6 months preceding pregnancy) is associated with a lower likelihood of disease exacerbation and better fetal outcome. Second, although precise risk of exacerbation is difficult to quantitate, SLE may flare anytime during pregnancy, including the postpartum period. Third, renal insufficiency and hypertension may worsen during pregnancy, and active renal disease is associated with both unfavorable maternal and fetal outcome. Finally, fetal outcome is related to presence of aPL, renal involvement, and high levels of lupus disease activity.


Antiphospholipid Syndrome





A 32-year-old woman presents with a recent fetal loss at 18 weeks after several weeks of poor fetal growth during her first pregnancy; past medical history is otherwise unremarkable. Routine laboratories are normal, ANA and anti-ds DNA antibodies are negative, IgG anticardiolipin is greater than 80 GPL units, and lupus anticoagulant is positive. The patient is anxious to conceive again and asks what therapy is advised for a next pregnancy, and what to expect for likelihood of successful pregnancy next time.


CASE STUDY 2


Maternal Considerations


Obstetric manifestations of antiphospholipid syndrome (APS) are not restricted to fetal loss. Current APS criteria include pregnancy loss or early delivery due to pre-eclampsia, IUGR, or fetal distress in the presence of persistent moderate to high titer anticardiolipin antibody (aCL), anti-β2-Glycoprotein I antibody (anti-β2GPI), or lupus anticoagulant. Fetal loss (>10 weeks of gestation) is more strongly associated with aPL than are earlier pregnancy losses. Midtrimester loss is considered characteristic; however, up to one half of losses may be in the first trimester. Since pre-embryonic and embryonic losses (< 10 weeks of gestation) are common in the general population, the diagnosis of APS should be made only with three or more consecutive losses in the absence of other identifiable etiologies. The two greatest risk factors for fetal loss are high titer IgG aCL and a history of previous fetal loss: these patients have up to 80% risk of current pregnancy loss if untreated. Although aCL and LA are closely linked to pregnancy loss, the predictive value of anti-β2GPI for pregnancy loss is less well studied. Concordance between types of aPLs are incomplete, so all should be tested if APS is suspected. Antibodies directed against other phospholipids, such as antiphosphatidylserine or antiphosphatidylethanolamine, do not generally identify additional patients and are not usually tested.


Even in the presence of positive aPL antibody, exclusion of confounding conditions is important in patients with pregnancy morbidity, because more than one factor may be present. Gynecologic conditions may include uterine abnormalities, hormonal imbalance (e.g., luteal phase defect), maternal and paternal karyotype abnormalities, or fetal genetic abnormalities.


Other Maternal Complications


In addition to pregnancy loss, associated maternal obstetric complications include pre-eclampsia, eclampsia and HELLP syndrome. Rates of gestational hypertension and pre-eclampsia range from 30% to 50%. Arterial or venous thrombosis and aPL manifestations such as severe thrombocytopenia may occur. A report of cerebral infarction postpartum with discontinuation of aspirin therapy emphasizes the importance of postpartum thromboprophylaxis. Finally, fifteen cases of catastrophic APS developing during pregnancy have been reported, many associated with concomitant HELLP syndrome.


Pregnancy Outcome


Neonatal complications include prematurity and IUGR ; in one large series, the rate of preterm delivery was 43% and that of IUGR was 31%. Preterm delivery is the strongest risk factor for adverse neonatal outcome and reflects the greatest concern for patients with APS.


IgG aCL can traverse the placenta. Although most large studies of aPL pregnancies do not find fetal or neonatal thrombosis, rare cases of intrauterine thromboembolic stroke, arterial or venous thrombosis, and neonatal seizures have been reported.


Although at least one large study suggests no long-term developmental abnormalities in offspring, the rate of learning disability was increased in a single small series of 17 children of mothers with APS.


Management and Therapy


Low-dose aspirin plus subcutaneous low-dose heparin is the standard prophylactic therapy during pregnancy for patients who have had prior pregnancy events. Untreated patients with high-titer aPL and a history of previous pregnancy loss have a high chance of subsequent fetal loss; with low-dose aspirin and heparin therapy, the likelihood of a full-term delivery rises to 70% to 80%. A recent meta-analysis of randomized controlled trials of therapy for aPL-positive patients with pregnancy loss found that low-dose aspirin and low-dose heparin significantly reduced risk of pregnancy loss compared with aspirin alone (relative risk [RR], 0.46). Aspirin alone did not show a significant reduction in rate of pregnancy loss (RR, 1.05). Prednisone and aspirin treatment increased risk of prematurity (RR, 4.83) but did not significantly decrease the risk of pregnancy loss (RR, 0.85). Although initial studies used unfractionated heparin, most clinicians prefer low-molecular-weight heparin (LMWH) owing to convenience and lower risk of side effects including osteoporosis; recent small studies suggest at least equal efficacy. LMWH dosing is not uniform, but pregnancy-related pharmacokinetic changes suggest LMWH might best be given twice daily, even for pregnancy prophylaxis therapy. LMWH is generally converted to unfractionated heparin several weeks before the expected due date due to the latter’s shorter half-life.


There are no clear guidelines in the management of patients in a first pregnancy, or those who have no, one, or two embryonic or pre-embryonic losses; however, low-dose aspirin treatment is often given to these patients because of its low-risk profile. Low-dose aspirin and heparin in therapeutic doses with midinterval partial thromboplastin time (aPTT) or anti-factor-Xa level monitoring must be used in patients with APS with a history of vascular thrombosis. IVIG has been used in addition to aspirin and heparin for those in whom standard therapy has failed, although a small placebo-controlled study showed no benefit. Suggested guidelines for therapy of aPL pregnancies are shown in Table 31-3 .



Table 31-3

Suggested Treatment of aPL Antibody in Pregnancy








































Patient/Serology Obstetric History Treatment
Low titer aCL/aβ2GPI First pregnancy and/or no history of loss None
Low titer aCL/aβ2GPI 1–2 early losses Ld aspirin
Mod-high titer aCL/aβ2GPI or positive LA 0–2 early losses Ld aspirin
HTN or abnormal renal function plus any aPL First pregnancy and/or no history of loss Ld aspirin (preeclampsia prophylaxis)
Positive aPL


  • ≥ 3 early losses or



  • ≥ 1 fetal loss

Ld aspirin and prophylactic * heparin/LMWH
Positive aPL


  • Previous IUGR/



  • Preeclampsia/



  • Placental infarction/



  • Other prothrombotic risk/



  • Special circumstances (e.g., AMA and IVF)

Ld aspirin and prophylactic * heparin/LMWH
Positive aPL and previous thrombosis Any Ld aspirin and therapeutic * heparin/LMWH (heparin while trying to conceive)
Positive aPL and Ld aspirin and heparin failure


  • ≥ 3 early losses or



  • ≥ 1 fetal loss

Consider addition of IVIG to low dose aspirin/heparin

aβ2GPI, anti-β2-glycoprotein I antibody; aCL, anticardiolipin antibody; AMA, advanced maternal age; IUGR: intrauterine growth restriction; IVF: in vitro fertilization; IVIG: intravenous immunoglobulin G; LA, lupus anticoagulant; Ld aspirin, low dose aspirin; LMWH, low-molecular-weight heparin.

Early loss: < 10 weeks

Fetal loss: ≥10 weeks

* See text for dose recommendations:



All patients require at least 6 weeks of anticoagulation postpartum, whether with aspirin alone, heparin, or warfarin. The importance of fetal monitoring during pregnancy should also be emphasized. Nonstress tests, biophysical profiles, or fetal umbilical artery Doppler velocimetry starting at 26 to 28 weeks may provide early indications of fetal distress requiring intervention.


During long-term follow-up, long-term low-dose aspirin appears to be protective against development of vascular thrombosis in patients with APS with a history of pregnancy morbidity alone and is generally recommended.


Rheumatoid Arthritis





A 24-year-old woman with rheumatoid arthritis (RA) presents for evaluation. She just determined that she is 4 weeks pregnant. Her symptoms have been well controlled on etanercept 50 mg weekly and naproxen 500 mg bid. How do you advise her regarding medications and what to expect in terms of disease activity and pregnancy outcome?


CASE STUDY 3


Maternal Considerations


The effect of pregnancy on RA is usually positive: up to 73% of patients experience some degree of clinical remission of symptoms during pregnancy, even in the absence of usual medications. In one series of 308 pregnancies, amelioration in symptoms was detected in about 50% of patients in the first trimester, in an additional 14% in the second trimester, and in a further 6% in the third trimester. Improvement persisted throughout the course of the pregnancy. A prospective study of 140 women with RA during pregnancy demonstrated significant variability in degree of response, however, with about one quarter of patients doing worse, two thirds partially improved and only 16% of patients attaining complete remission.


Regardless of the degree of improvement experienced during gestation, most patients relapse following delivery, many of these within the first 6 weeks, and almost all by 4 months. Although this suggests that pregnancy-related hormones might influence remission, breastfeeding does not appear to change the timing of relapse. Recent work suggests that persistence of active disease during pregnancy may relate to a similarity between maternal and fetal HLA (HLA-DQ system).


The effect of pregnancy on the development of RA is controversial. Pregnancy as well as use of oral contraceptives has been suggested to reduce the risk of disease onset, and an increased risk of disease onset is noted in the postpartum period. A recent study, however, suggests no protective effect of parity but does demonstrate a protective effect of breastfeeding against development of RA.


Pregnancy Outcome


Fertility is not clearly decreased in patients with RA, and no increase in fetal loss has been demonstrated. A slightly increased rate of fetal complications of prematurity and low birth weight has been reported, however, and rates of pre-eclampsia and cesarean section are higher than in the general population. A case of marked fetal growth retardation has been described in severe RA with associated vasculitis.


Management and Therapy


Few of the common medications for treatment of RA are considered safe during pregnancy; fortunately, owing to high likelihood of at least partial remission, many patients discontinue medication entirely or can be managed with low doses of corticosteroid.


As with all rheumatic disease patients, the patient with RA should be counseled before attempting pregnancy. The preconception visit should include discussion of the likelihood (but not certainty) of some degree of remission, recommendations for discontinuation of medications as necessary, and the potential adverse effects of any medications that will be continued. Note that testing for presence of anti-SSA/Ro and anti-SSB/La antibodies should be done, and patients with positive results should be counseled and monitored as described earlier in the section on NLE.


Potential fetal effects of medications are discussed in detail at the end of the chapter. In general, NSAIDs are avoided, plaquinil and sulfasalazine may be continued, and methotrexate must be discontinued at least 3 months before conceiving. Leflunomide must be discontinued and “washed out” with a course of cholestyramine. Tumor necrosis factor (TNF) inhibitors have not been proven safe during pregnancy, but reports of immediate pre-pregnancy or early first-trimester use are reassuring, and if required, the fetal risk of continuing these until the diagnosis of pregnancy appears to be quite low. This is especially important for patients with fertility issues: although pregnancy may bring about remission, it may take many months to conceive for some patients. If even young RA patients experience delay in conceiving, aggressive pursuit of fertility therapy may minimize the amount of time their joints are not optimally protected. Low-dose prednisone (with calcium and vitamin D supplementation) is used as necessary throughout pregnancy.


Although uncommon, cervical spine arthritis with atlantoaxial instability requires careful management of the patient under general anesthesia since manipulation of the unstable spine may produce spinal cord compression. Severe cricoarytenoid involvement may also be a relative contraindication to intubation with general anesthesia. Hip range of motion should be assessed for adequacy before anticipated vaginal delivery. Stress dose steroid should be administered if the patient has been on long-term steroid therapy, and prophylactic antibiotics are recommended for patients with prosthetic joints.


A particular concern for the RA patient is the near-certainty of postpartum flare. For patients with severe erosive disease, it may be wise to recommend avoiding breastfeeding and restarting combination therapy immediately postpartum. Patients with mild disease often elect to breastfeed until they flare, then wean and restart medications.


Other Inflammatory Arthritides


Although little in the literature has focused on other types of inflammatory arthritis during pregnancy, juvenile RA patients appear to have similar positive effects on disease activity. Psoriatic arthritis also tends to improve during pregnancy, unlike ankylosing spondylitis, in which the majority of patients have unchanged or worsened symptoms.


Systemic Sclerosis


Because systemic sclerosis (SSc) often affects women in later reproductive years, pregnancy during established disease is less common than with SLE or RA.




A 30-year-old woman was diagnosed with diffuse scleroderma several months ago. Her symptoms of puffy hands, difficulty swallowing, and mild shortness of breath have been present for 1 year. Her blood pressure is 138/94, and renal function is normal. High-resolution chest computed tomography shows changes consistent with interstitial lung involvement. She would like to conceive as soon as possible. How would you advise her?


CASE STUDY 4


Maternal Considerations


Early reports of maternal morbidity in scleroderma pregnancy were negative: in a combined analysis of early studies, about one third of patients reported pregnancy-related aggravation of their disease. Ten percent died of pregnancy-related complications, primarily hypertension, renal failure, and cardiovascular complications. Importantly, however, these series included a number of cases described before advances in management.


In contrast, a retrospective case-control study found no difference in the rates of accelerated hypertension or renal failure in parous versus nulliparous scleroderma patients, suggesting that pregnancy may not adversely affect disease course. Incidence of hypertension, pre-eclampsia, or proteinuria was no different in pregnancies after diagnosis as compared with pregnancies before diagnosis of disease. In Steen’s prospective studies of 91 pregnancies in 59 patients with systemic sclerosis, maternal outcome was generally good, with worsening of disease during pregnancy in about 20% of patients. Raynaud’s phenomenon improved during pregnancy, whereas esophageal reflux became worse. There were three cases of renal crisis during pregnancy, all in women with early diffuse disease.


Pregnancy Outcome


Scleroderma patients were initially reported to have both decreased fertility and decreased parity when compared with control populations. Early case-control studies showed twice the rate of spontaneous abortion and three times the rate of infertility compared with controls as well as a significant incidence of IUGR and preterm births that occurred with equal frequency before and after the diagnosis of systemic sclerosis. More recent prospective data, however, show no consistent decrease in fertility or increase in frequency of miscarriage except in the subgroup of patients with long-standing diffuse scleroderma, in which miscarriage rates are as high as 45%. Preterm births occurred in 29% of pregnancies, but neonatal survival was good. Of note, four women in this series had five healthy infants while taking angiotensin-converting enzyme (ACE) inhibitors.


Management and Therapy


Preconception evaluation of disease status and organ function is critical in advising patients with systemic sclerosis about pregnancy. Patients with early diffuse disease are advised to delay pregnancy if possible until disease stabilizes, to reduce the risk of renal crisis during pregnancy. ACE inhibitors should be stopped due to risk of fetal toxicity, and other antihypertensives should be substituted. It is prudent to make this change before pregnancy and to observe for a minimum of several months to be confident that blood pressure is adequately controlled. Once pregnant, blood pressure and renal function should be monitored carefully, and include use of home blood pressure monitoring. For true scleroderma renal crisis during pregnancy, a life-threatening complication, ACE inhibitors are the only effective therapy and must be used to protect maternal health.


Skin thickening may be a concern for intravenous access or cesarean section, but wound healing is generally normal. In patients with severe Raynaud’s phenomenon, warming the patient throughout labor and delivery with use of blankets, socks, and increased room temperature may minimize symptoms.


Women with severe cardiac, renal, or pulmonary disease for whom pregnancy is contraindicated may consider in vitro fertilization and surrogate pregnancy with a gestational carrier.


Sjögren’s Syndrome


Sjögren’s syndrome is often secondary to RA and other autoimmune diseases, and relatively little is known about the interaction of pregnancy with the primary syndrome other than the obvious concern of NLE from fetal exposure to anti-SSA/Ro and anti-SSB/La antibodies.




A 28-year-old woman with primary Sjögren’s syndrome wishes to conceive. She has high-titer anti-SS-A/Ro antibody, and mild eye and mouth dryness with occasional arthalgias. She is on no medications other than topical cyclosporine eye-drops. How do you advise her?

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May 19, 2019 | Posted by in RHEUMATOLOGY | Comments Off on Management of the Patient with Rheumatic Disease During and After Pregnancy
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