Pregnancy & Rheumatic Diseases: Introduction
Patients with rheumatic disease commonly have questions regarding conception, pregnancy, and breast-feeding, as well as using medication during all of these phases. In this chapter, these issues are discussed in the context of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), the antiphospholipid syndrome, scleroderma, and the systemic vasculitides Takayasu arteritis and antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. The use of individual medications is also discussed.
The classic teaching that RA improves during pregnancy and worsens in the postpartum period has been confirmed in several studies. For reasons that remain incompletely understood, pregnancy ameliorates RA activity in many women, even after the cessation of medications.
- Most pregnant patients with RA report improvement in joint pain and swelling during pregnancy.
- Clinical improvement is often more pronounced in patients with moderate-high disease activity compared to those with low disease activity.
- RA generally returns to its prior state of activity postpartum.
The mechanisms for improvement of disease in RA patients during pregnancy likely involve several mechanisms. HLA disparities, hormonal fluctuations, and changes in innate immunity have all been studied. Higher maternal-fetal incompatibility in HLA class II alloantigens has been associated with good pregnancy outcomes and improvement of clinical disease. Such findings suggest that greater recognition of the fetal allograft by the maternal immune system leads to more tolerance of maternal autoantigens.
Regulatory T Cells (Treg) are involved in the pathogenesis of RA. These cells promote tolerance both by suppressing the activity of effector T-cells and dendritic cells, and by producing anti-inflammatory cytokines such as interleukin (IL)-10 and tumor growth factor (TGF)-β. In nonpregnant RA patients, Treg activity is impaired, but during pregnancy, these Treg cells regain some activity, thus promoting an anti-inflammatory environment. Other alterations in immunity such as a down-regulation of Th1 cells and subsequent shift toward Th2 responses may also contribute to clinical improvement.
Up to three quarters of pregnant patients with RA report improvement in joint pain, joint swelling, and total number of joints involved. The average rate of remission in the third trimester nears 30%. Clinical improvement is more pronounced in patients with moderate-high disease activity than in patients with low disease activity. Disease response in previous pregnancies predicts clinical responses for subsequent pregnancies. RA often returns to its prior state of activity postpartum.
Although the data regarding pregnancy morbidity in the literature are mixed, consensus favors mildly increased rates of premature birth, preeclampsia or hypertensive disorders, and lower birth weights. Disease activity in the third trimester has been associated with lower birth weight. Prednisone use during pregnancy is associated with a higher likelihood of preterm delivery (before 37 weeks).
Systemic Lupus Erythematosus
SLE is a multisystem autoimmune disease with a predisposition for females of reproductive age. Fertility is not affected by the disease; however, treatment with immunosuppressive drugs, such as cyclophosphamide, may result in premature ovarian failure and reduced fertility rates. SLE itself is not a contraindication to pregnancy, with the exception of active severe lupus nephritis or pulmonary hypertension. Women with SLE have an increased risk of disease flare and adverse pregnancy outcomes. Pregnancy outcomes are affected by a number of factors, including disease status at the time of conception, presence of renal disease, and the presence of antiphospholipid antibodies, anti-Ro/SSA, and anti-La/SSB antibodies. In order to optimize pregnancy outcomes, medications should be altered to decrease the risk of teratogenicity but maintain disease quiescence, and pregnancy should be delayed until the disease has been well controlled for 6 months. Antenatal care should be provided in tandem with rheumatology and high-risk obstetrics. Regular rheumatology follow-up visits should be scheduled for every 4–6 weeks; the interval should be adjusted based on clinical status.
- Disease status at the time of conception strongly influences pregnancy outcomes.
- Lupus flares are usually mild and accompanied by skin and joint disease.
- Patients are at risk for thrombosis as well as infectious and hematologic complications.
Lupus flares are more common during pregnancy and in the puerperium. Flares are usually mild and accompanied by skin and joint disease. Serious flares, manifested by central nervous system dysfunction, nephritis, hematologic abnormalities, or vasculitis, occur in up to 20% of patients who experience disease exacerbations during or after pregnancy. Due to the natural disease course of SLE, rates of pregestational diabetes, hypertension, pulmonary hypertension, renal failure, and thrombophilia are higher in SLE patients compared with healthy women.
Pregnancy itself is a prothrombotic state and the risk of thrombosis is significantly increased in SLE patients, with a relative risk approximately 35 times higher than that of healthy women. Pregnant patients with SLE are also at higher risk for infectious complications (such as pneumonia and sepsis) and hematologic complications (including thrombocytopenia, anemia, hemorrhage, and increased transfusion requirements).
Disease status at the time of conception strongly influences pregnancy outcomes. In the Johns Hopkins lupus cohort, a prospective study divided women into two groups: low disease activity and high disease activity, based on the clinician’s estimate of activity. Results showed that having highly active SLE prior to conception led to a four-fold increase in pregnancy loss. Risk factors for poor pregnancy outcomes in lupus can be remembered by the PATH acronym: proteinuria, antiphospholipid syndrome, thrombocytopenia, and hypertension. The presence of any of these four risk factors during the first trimester of pregnancy is associated with at 30–40% risk of pregnancy loss.
Patients with both a history of lupus nephritis and currently active lupus nephritis have worse outcomes, often due to hypertension or worsening renal disease. Mild flares of renal disease are not uncommon; however, progression to irreversible renal damage may occur in a small percentage of patients. Lupus nephritis may be difficult to discern from preeclampsia or pregnancy-induced hypertension. Key elements in distinguishing between lupus nephritis and pregnancy-induced hypertension are the timing of the symptoms prior to the third trimester, the finding of an active urine sediment, and the presence of SLE activity in other organs. Compared with women who do not have active lupus nephritis at the time of conception, those with active renal disease are 4 times more likely to develop pregnancy-induced hypertension and more than 1.5 times likely to have adverse fetal outcomes.
Disease activity during pregnancy strongly influences obstetric outcomes. Rates of spontaneous abortion, preterm birth, stillbirth, intrauterine growth restriction (IUGR), bleeding complications, and neonatal morbidity are increased compared with healthy controls. The risk of preeclampsia is up to 22%, 3-fold higher than expected and eclampsia is 0.5%, 4-fold higher than expected.
Neonatal SLE is an autoimmune disease associated with the presence of anti-Ro/SSA and anti-La/SSB antibodies. All women should be screened for the presence of these antibodies early in pregnancy to identify patients at risk. The incidence of congenital heart block is about 2%, with a recurrence rate of around 10–20% in subsequent pregnancies. Heart block results from the deposition of antibodies into the cardiac conduction system, leading to local inflammation and irreversible damage to the atrioventricular node. This condition develops between 18 and 30 weeks gestation. Case reports support the reversal or halting of first and second degree block with dexamethasone 4 mg/d, but complete heart block is irreversible. Repeated fetal echocardiography can be performed to detect early cardiac block allowing a potential window for therapeutic intervention.
Annular polycyclic skin plaques are the most common manifestation of neonatal SLE, occurring in up to 15% of exposed infants. The lesions appear on the face and scalp after sun or UV exposure within the first 3–5 months of life. Disappearance of this rash coincides with disappearance of serum antibodies. The hematologic and hepatobiliary systems are less commonly affected and effects are generally transient.
- The inherently hypercoagulable state associated with pregnancy can be heightened in patients with the antiphospholipid syndrome, with potentially dire consequences for both the mother and fetus.
- The diagnosis of antiphospholipid syndrome is a strong contraindication to pregnancy.
Antiphospholipid antibodies (aPL) bind negatively charged phospholipids, leading to thrombosis and recurrent fetal loss. The antiphospholipid syndrome is defined by at least one clinical event, such as vascular thrombosis or pregnancy morbidity, in combination with the presence of one or more of the following antibodies: lupus anticoagulant, anti-β2-glycoprotein I (β2GPI), or anticardiolipin (aCL) antibodies. The antiphospholipid syndrome may be accompanied by thrombocytopenia.
β2GPI is a primary autoantigen in antiphospholipid syndrome that plays a role in anticoagulation by inhibiting platelet adhesion and activation of protein C and mediates binding to endothelial cells, monocytes, trophoblast, and neuronal cells. Inhibition of β2GPI results in thrombosis and fetal loss. Anti-β2GPI antibodies induce tissue factor release, which has negative effects on both the trophoblast and placenta and leads to thrombosis and fetal loss by affecting trophoblast differentiation and implantation.