Systemic autoimmune diseases (SADs) are relatively common in women of childbearing age. Given the chronic relapsing nature of SADs, it is more likely that a woman with an established SAD will get pregnant than that a new SAD will be diagnosed in a previously healthy pregnant woman.
Pregnancy and disease outcomes during and after pregnancy of SAD patients have improved significantly in the past decades, as the result of a better understanding of the diseases and the creation of multidisciplinary teams-including rheumatologists, high-risk obstetricians, and neonatologists-experienced in autoimmune diseases.1 However, the overlapping features of physiologic and pathological changes during pregnancy, selected autoantibodies (eg, antiphospholipid [aPL] and anti-Ro/La antibodies), and the teratogenicity of commonly used immunosuppressive agents can complicate the management of patients with SADs during pregnancy.
The purpose of this review is to discuss the challenges health professionals may face while managing pregnant patients with established SADs, as well as optimal medication management, including counseling and safety.
PREGNANCY-RELATED PHYSIOLOGIC CHANGES
Pregnancy is an altered physiologic state characterized by particular signs, symptoms, and hormonal changes. Various changes can occur during a normal pregnancy and create a challenge in the management of pregnant patients with SADs2:
* Hemodynamic (intravascular volume increase, generalized edema)
* Renal (glomerular filtration rate and urine protein increase)
* Cutaneous (palmar and facial erythema)
* Musculoskeletal (arthralgia, back pain)
* Hematologic (anemia, thrombocytopenia, leukocytosis, erythrocyte sedimentation rate increase, prothrombotic profile)
* Immunologic (variation in the function of B cells, T cells, and monocytes; elevated complement [C]3 and C4 levels)
PREGNANCY-RELATED PATHOLOGIC CHANGES
Some pregnancy-related complications are more common in patients with SADs compared with the general population. Complications health professionals always should include in pregnancy-related discussions are:
* Preeclampsia (PEC): Blood pressure higher than 140/90 mm Hg after 20 weeks of gestation on at least 2 occasions and proteinuria more than 300 mg/d
* HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome
* Eclampsia: Seizures occurring in the setting of a PEC
* Preembryonic loss: Loss between conception through week 4 of gestation
* Embryonic loss: Loss between weeks 5 through 9
* Fetal loss: Loss between week 10 of gestation through delivery
* Intrauterine growth restriction (IUGR): Ultrasound-assessed fetal abdominal circumference < 5th percentile
* Preterm delivery: Delivery before week 37
PREGNANCY IN SELECTED SADs
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a wide spectrum of clinical manifestations and a variable course characterized by exacerbations and remissions. The disease can affect any organ system, including cutaneous, musculoskeletal, cardiovascular, renal, and neurological systems. It is characterized by specific autoantibodies, eg, anti-double-stranded DNA (dsDNA) and anti-Smith antibodies.
While pregnancy in SLE patients presents an additional risk to an already complex situation, the risk of a pregnancy-related complication in stable patients with no disease activity is relatively low. Many SLE patients can undergo successful pregnancies without significant deterioration in their clinical status and with good fetal outcome.
Case-control studies support little or no increased risk for disease flare during pregnancy3; however, SLE patients may flare any time during pregnancy, most often in the latter half, and in the postpartum period.4,5 Inactive disease for the 6 months preceding pregnancy is associated with a lower risk of disease flare6; the longer a patient is in remission, the better are her chances for completing a pregnancy without exacerbation. Hypertension and active kidney disease preceding pregnancy increase the risk of lupus renal flare and PEC7; renal insufficiency, in particular prepregnancy serum creatinine greater than 1.6 mg/dL, is an important risk factor for serious renal deterioration during pregnancy.8 Pregnancy is inadvisable in the setting of uncontrolled hypertension, progressive renal failure (serum creatinine > 2.5 mg/dL or glomerular filtration rate < 35 mL/min), severe neurologic and cardiopulmonary involvement (pulmonary hypertension or severe cardiomyopathy with ejection fraction < 30%-40% or severe restrictive lung disease with forced vital capacity < 50% of predicted), severe thrombocytopenia (< 30,000/mm3), and teratogenic medications.9
Proteinuria during pregnancy requires careful evaluation. The differential diagnosis includes new onset or worsening lupus nephritis, PEC, or both. Differentiating lupus flare from PEC can be challenging: rapid worsening of proteinuria over days; microscopic hematuria with erythrocyte casts; an increase in anti-dsDNA level, and extrarenal lupus activity, eg, lymphadenopathy, rash, inflammatory arthritis, fever, or leukopenia support lupus activity.10 Pregnancy-related rash may mimic a lupus rash as a result of palmar and facial erythema from increased blood flow to the skin. Bland joint effusion and diffuse arthralgias, common in pregnancy, may be confused with lupus arthritis.
The most common risks to the fetus in a lupus pregnancy are fetal loss, prematurity, or IUGR.11 Fetal outcome is related more to renal involvement, anti-Ro/La antibodies, and aPL, which is discussed below, than the occurrence of lupus flare. Proteinuria higher than 0.5 g per 24 hours is an independent predictor of poor fetal outcome: fetal loss occurs in almost 60% of patients with proteinuria as opposed to 10% of patients who do not have proteinuria.7 Hypertension and thrombocytopenia are additional risk factors for pregnancy loss in SLE patients.12
Anti-Ro (SS-A) and anti-La (SS-B) antibodies increase the risk of neonatal lupus erythematosus (NLE) consisting of photosensitive rash, thrombocytopenia, abnormal liver function tests, and rarely irreversible congenital heart block (CHB).13 With the exception of CHB, all manifestations disappear with the clearance of maternal antibodies at about 4 to 6 months. During pregnancy, maternal IgG anti-Ro/La are transferred through the placenta to the fetus, where they bind cross-reactive epitopes on calcium-regulating molecules in the fetal cardiac cells, such as ion channels, which lead to calcium overload and cellular apoptosis.14 Antibodies then may bind their antigen on the surface of apoptotic cells, inducing first-degree atrioventricular block. Depending on the fetal susceptibility, the local inflammation may be resolved or propagated, leading to permanent third-degree atrioventricular block. The first-time risk of NLE for the newborn of an anti-Ro positive woman is about 25%, and the risk of CHB is 1% to 2%.15 The CHB risk in mothers with a previous history of NLE of any type is approximately 20%.16,17
Antiphospholipid Syndrome
Antiphospholipid syndrome (APS) is defined as vascular thromboses and/or pregnancy morbidity occurring in patients with a clinically significant aPL profile (positive lupus-anticoagulant test, anticardiolipin [aCL] IgG/M > 40 GPL/MPL, and/or anti-[beta]2Glycoprotein I [a[beta]2GPI] IgG/M > 99th percentile on 2 or more occasions at least 12 weeks apart). Positive aPL without characteristic clinical complications does not indicate APS, and asymptomatic (no history of vascular or pregnancy events) aPL-positive patients exist. APS can occur in otherwise healthy individuals (primary APS) or in patients with other SADs, particularly SLE. Approximately 30% to 40% of SLE, 10% to 20% of rheumatoid arthritis (RA), and as many as 25% of systemic sclerosis patients are positive for aPL.18-20
Murine models demonstrate that aPL is a risk factor for pregnancy morbidities; purified IgG from women with aPL, when injected into pregnant mice, results in fetal loss and decidual necrosis.21
A positive LA test is the primary predictor of an adverse pregnancy outcome after 12 weeks of gestation in aPL-associated pregnancies.22 APS should be considered in clinically significantly aPL-positive patients with late fetal loss, which is more strongly associated with aPL, and with recurrent consecutive early embryonic losses.23 Other pregnancy morbidities associated with aPL include IUGR, premature delivery, early PEC, and HELLP syndrome.24 Other causes of pregnancy loss, such as anatomical, chromosomal, or hormonal abnormalities, always should be investigated in aPL-positive patients.
Although the risk of pregnancy morbidity is unknown in asymptomatic aPL-positive patients and in APS patients with only vascular events, untreated patients with high-titer aPL and a history of previous pregnancy loss have a 50% to 75% chance of subsequent fetal loss. With current therapy, discussed below, APS patients have almost an 80% rate of live births. However, 20% of pregnancies continue to experience pregnancy morbidities other than miscarriages, despite conventional treatment.
In the general population, the risk of venous thromboembolism increases during a physiologic pregnancy by a factor of 5, as a result of a prothrombotic state, eg, increased fibrinogen levels, venous stasis due to compression by the gravid uterus, and bed rest.25 Patients with aPL have an even higher risk of thrombotic events during pregnancy and the postpartum period.
Rheumatoid Arthritis
RA is a systemic, immune-mediated inflammatory disease, which results in chronic inflammation of the joints and symmetrical arthritis. Pregnancy usually has a positive effect on RA symptoms: as many as three-quarters of patients experience some degree of clinical remission during pregnancy, even in the absence of medications.26 The disease flare is common (40%) in the postpartum period.27 A slightly increased rate of fetal complications of prematurity and low birth weight, in particular in association with prednisone use and a higher disease activity during pregnancy, respectively, has been reported.28,29
Other SADs
The most relevant pregnancy-related issues associated with other selected SADs are summarized in Table 1.
MANAGEMENT OF SADs DURING PREGNANCY
Preconception Counseling
Preconception counseling to assess risks, strict follow-up during pregnancy to recognize complications early, and an experienced neonatal unit to assist newborns are essential for successful pregnancies in patients with SADs.9 Physicians should tell their patients about how pregnancy can affect their disease and how the disease could influence the gestational outcome. Patients should be reassured that a successful pregnancy is generally achieved, if conception occurs in a stable disease remission state and if teratogenic medications are managed properly. Patients must be informed about medications that must be withdrawn before conception-those that can be maintained, and those that could be added in the event of disease flare. The main message to patients should be to plan the pregnancy according to their doctors' advice.30 A close collaboration between the physician who follows the autoimmune disease and the obstetrician who will follow the pregnancy should begin as soon as possible.
Disease Assessment
Initial disease evaluation should include an assessment of the disease activity and organ damage, a review of medications, a laboratory evaluation, and a discussion of specific risks. The suggested initial laboratory tests for lupus patients who are planning pregnancy or who are already pregnant include a complete blood count, urinalysis, creatinine clearance, 24-hour urine protein (or protein-to-creatinine ratio), lupus anticoagulant test, aCL IgG-IgM, a[beta]2GPI IgG-IgM, anti-dsDNA, anti-Ro, and anti-La, C3, and C4.31 These recommendations could be followed with modifications for pregnant patients who have other SADs, eg, the assessment of baseline kidney function and aPL profiles. Further laboratory tests-depending on patient characteristics, the underlying SAD, and the laboratory profile-are recommended during each trimester or monthly, as needed.
Disease Management
Patients taking potentially teratogenic drugs should be removed from them or transitioned to safer ones. Conception should be delayed at least 3 months to monitor disease activity and adverse reactions.32
In general, the treatment of a disease flare in pregnant patients with an SAD does not differ from the treatment of patients who are not pregnant. Corticosteroids are the first-line choice, with the dose adjusted according to severity. Depending on the disease as well as the disease activity in steroid-resistant cases, certain immunosuppressive medications, plasma exchange, and/or intravenous (IV) immunoglobulin (IVIG) can be started after a disease flare during pregnancy.
Fetal echocardiography, generally at weeks 16 through 34, should be performed for the evaluation of fetal heart rhythm, pericardial effusion, or myocarditis in mothers positive for anti-Ro and anti-La antibodies.33 Treatment of incomplete CHB is betamethasone or dexamethasone, which easily crosses the placenta. Rarely, plasmapheresis may be helpful.34,35 Complete CHB in a newborn usually requires a permanent pacemaker. Fetal outcomes in anti-Ro/SS-A antibody-positive patients are significantly improved with screening fetal echocardiographies. A neonatal electrocardiogram to identify clinically silent first-degree block should be performed on all infants born to mothers with anti-Ro/La antibodies. A recent study suggested that hydroxychloroquine (HCQ) may lower the risk of CHB in mothers positive for anti-Ro/La antibodies.36 IVIG37,38 and plasmapheresis39 both failed to prevent CHB based on small-scale studies.
Although controversial because of a limited number of well-designed controlled studies, the current standard of care for pregnant aPL-positive patients during pregnancy includes low-dose aspirin (LDA) and prophylactic-dose heparin for patients meeting the APS classification criteria based on a history of pregnancy morbidity only; LDA and therapeutic-dose heparin for patients meeting the APS classification criteria based on a thrombotic vascular event, regardless of pregnancy history; and no treatment or LDA for asymptomatic (ie, no history of vascular or pregnancy events) medium- to high-titer aPL-positive patients.40
If patients fail the LDA and heparin combination, common next steps are increasing the heparin dose with antifactor Xa level monitoring with or without adding HCQ, corticosteroids, and/or IVIG, although a small placebo-controlled study showed no benefit.41 All patients with aPL require at least 8 to 12 weeks of anticoagulation postpartum (prophylactic-dose heparin) to prevent thrombotic events.42
Some obstetricians frequently use LDA to prevent PEC in women identified as being at high risk, usually because of preexisting hypertension, renal insufficiency, or a history of previous PEC. However, a recent meta-analysis concluded that early administration of LDA reduces the risk of preterm, but not term, PEC43 and of severe, but not mild, PEC.44 In high-risk pregnancies, uterine artery Doppler is recommended around 20 weeks of gestation, and if abnormal, it should be repeated around the 24th week. Abnormal waveforms are good predictors of PEC, while normal results are related to good obstetric outcomes.45
In patients with systemic sclerosis, careful monitoring of renal function and systemic arterial pressure is recommended during pregnancy. In general, angiotensin-converting enzyme inhibitors should be stopped because of the risk of fetal renal toxicity. However, they may be the only effective therapy for true scleroderma renal crisis-a life-threatening complication.46 A previous episode of renal crisis is not a strict contraindication for future pregnancy, but it is recommended that a woman should have good renal function and wait several years until her disease is stable before trying to conceive.
All pregnant patients should take folic acid during the first trimester to prevent fetal neural tube defects. Concomitant prophylactic calcium and vitamin D supplements should be prescribed to women who take corticosteroids and/or heparin, and/or are at high risk for osteoporosis.
Delivery
Patients with aPL who are receiving prophylactic-dose heparin should discontinue heparin once labor is established. Patients on a therapeutic dose should discontinue or decrease it to a prophylactic dose 24 hours before a planned delivery. Graduated elastic compression stockings should be recommended for thromboembolism prophylaxis in patients who are admitted for labor or delivery or who require prolonged bed rest.
Stress doses of hydrocortisone at delivery are recommended in patients on long-term corticosteroid therapy, especially more than 20 mg/d of prednisone or the equivalent for more than 3 weeks, to avoid hemodynamic instability.
Cervical spine arthritis with atlanto-axial instability dictates careful management of RA patients undergoing 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. Assessment for adequate hip range of motion should be carried out before vaginal delivery, especially if epidural anesthesia is planned.
In patients with significant Raynaud's phenomenon, measures that could prevent vasospasm during delivery-such as warming the delivery room and providing warm (IV) fluids, thermal socks, and warm external compresses-should be used routinely. Epidural anesthesia is preferred because it provides peripheral vasodilatation and increased skin perfusion of lower extremities. In systemic sclerosis, general anesthesia should be avoided because of the difficulty in intubation in patients with small mouths and concerns about aspiration.
MEDICATION SAFETY DURING PREGNANCY AND BREASTFEEDING
Knowledge of the drug pharmacology relevant to the SAD is essential to the management of pregnant patients. Most of the information regarding the safety of drugs during pregnancy is extracted from retrospective case series, case reports, and experts' consensus,32 which is summarized in Table 2.
Hydroxycloroquine can be safely continued during pregnancy and may even improve pregnancy outcomes in lupus patients.47 In RA patients receiving biologic therapies, manufacturers' guidelines recommend discontinuation of the medication before conception for different periods of time. Nevertheless, data from uncontrolled case reports show that exposure to anti-tumor necrosis factor-[alpha] (anti-TNF) therapies at the time of conception does not result in an increased risk of adverse pregnancy and fetal outcomes.48 Exposure to anti-TNF therapies in later pregnancy, particularly to monoclonal antibodies, is associated with high drug levels in the newborn. Live vaccines should be avoided for at least the first 6 months of life in children with in utero exposure to biologics. The long-term effects of this exposure remain unknown. In clinical practice, the goal is to continue the least possible number of medications during pregnancy. Thus, the current practice is to allow RA patients to conceive on these medications and to discontinue them when pregnancy is confirmed. If a pregnant patient has a severe flare of arthritis, restarting the anti-TNF therapy should be considered after a careful risk/benefit assessment.30 Pregnancy data for non-anti-TNF biologics are insufficient, and their use during pregnancy cannot be recommended.
CONCLUSIONS
Managing a pregnancy in patients with SADs still represents a challenge. The overlapping features of physiologic and pathological changes and selected autoantibodies, and the use of potentially teratogenic medications, can complicate the management of patients with SADs during pregnancy.
A planned pregnancy in a patient with disease remission or low disease activity control before conception has a better chance of success. Preconception counseling, expert monitoring by a multidisciplinary team with experience in the field, and neonatal intensive care units remain the best ways to manage these high-risk pregnancies and obtain favorable maternal and neonatal outcomes.
REFERENCES