Pregnancy in patients with SLE can be associated with many problems, including exacerbations, miscarriage, neonatal lupus, and breastfeeding.
Previous experience has shown that more than 50% of lupus patients experience exacerbations during pregnancy. The incidence is close in all three periods of pregnancy, but is high in the midterm period. However, the incidence of exacerbations during pregnancy and the postpartum period is decreasing progressively in the last 30 years, especially in patients with remission early in pregnancy, and is similar to the incidence of exacerbations in non-pregnant patients. This improvement may be due to more aggressive treatment (e.g., increased hormone dosage) and timely termination of pregnancy in patients with exacerbations.
Foreign studies have summarized the typical symptoms of lupus exacerbations most often as systemic symptoms, renal lesions or skin and joint involvement. The presence of hypertension, azotemia and active lupus lesions before pregnancy are risk factors for lupus exacerbations during pregnancy.
Patients who develop organ damage during pregnancy should be monitored more closely, as pregnancy increases the burden on otherwise dysfunctional organs, a condition that is particularly important in patients with nephritis. The frequency of exacerbations (or the development of persistent symptoms) in lupus varies at different stages of disease activity, ranging from 7 to 33% for patients with disease in remission for at least six months and from 61 to 67% for patients with active lesions at the time of pregnancy. Therefore, women with lupus nephritis should be encouraged to delay their pregnancy until the active lesions have stabilized for at least six months.
Miscarriage is another important problem encountered by patients with SLE. Nearly 20-30% of pregnancies in SLE patients will result in miscarriage, and the overall incidence may reach 50%, much higher than in the general population. In a retrospective comparative study of 481 pregnancies in 203 lupus patients, the incidence of spontaneous abortion, pregnancy failure or stillbirth was found to be higher in pregnant lupus patients (21%) than in their friends (14%) or relatives (8%). The risk of miscarriage was increased in women with hypertension, lupus nephritis, hypocomplementemia, and increased titers of anti-DNA antibodies or positive anti-cardiolipin antibodies.
Although the presence of antiphospholipid antibodies is not necessarily indicative of miscarriage, patients with SLE and positive antiphospholipid antibodies have a significantly increased risk of spontaneous miscarriage. One review reviewed 554 women with lupus from 10 studies and found that patients who were positive for antiphospholipid antibodies (38-59% versus 16-20% in patients without the antibodies), lupus anticoagulant (36% versus 13%), or anticardiolipid antibodies (39% versus 18%) had a significantly higher chance of miscarriage. Moreover, miscarriage occurs mainly in the middle of pregnancy. The risk of miscarriage in these patients can be reduced by appropriate preventive measures, therefore, all pregnant women with SLE should be tested for antiphospholipid antibodies.
Neonatal lupus is a major concern for lupus patients who are pregnant. It is a passively transmitted autoimmune disease with a prevalence of about 5% in the children of mothers with SLE. Once a child with neonatal lupus is born, the chance of that mother developing the disease in the next child increases to 15%.
The factors most associated with neonatal lupus are anti-SSA and SSB antibodies. In one study, sera were collected from four groups of mothers: 57 whose children had congenital heart block; 12 whose children had transient cutaneous manifestations of neonatal lupus, but no cardiac involvement was found; 152 whose children were healthy despite the presence of relevant antibodies; and 30 who had autoimmune diseases and had miscarriages, stillbirths or premature stillbirths with neonatal lupus during pregnancy. The following results were obtained: (1) Among the mothers who gave birth to children with heart block, transient neonatal lupus, healthy infants and stillbirths, the positive rates of anti-SSA antibodies were 100%, 91%, 47% and 43%, respectively, by ELISA, and the positive rates of anti-SSB antibodies in this group were 76%, 73%, 75% and 7%, respectively, by the same method. (2), The incidence of high titers of SSA antibodies was higher in mothers whose children had heart disease or transient neonatal lupus than in the other two groups. (3), By SDS immunoblotting, in 91% of the heart block group, the sera of SSA-positive but not SSB-positive mothers recognized at least one SSA antigen, significantly more than the anti-52KD component. In contrast, only 62% of the healthy group that was positive for anti-SSA antibodies and negative for anti-SSB antibodies recognized the 52KD and/or 60KD components. Based on the results of this study and other similar studies, it can be concluded that SSA antibodies are neonatal lupus-associated antibodies. Because SSA antibodies bind to antigens in the fetal heart and prevent the normal development of conduction fibers, they are important in the pathogenesis.
Studies have also shown that the majority of infants with neonatal lupus have mothers who are positive for SSA and SSB antibodies and positive for HLA A1, Cw7, B8, and DR3. The incidence of HLA DQA1*03 and DQB1*03 was significantly higher in affected infants, and the incidence of neonatal lupus children born to mothers with increased titers of SSA and SSB antibodies was increased. The IgG subtype of anti-SSB antibodies may not be associated with the development of congenital heart block in newborns. Anti-U1 RNP antibodies may be associated with the development of neonatal lupus in a small number of mothers who are negative for SSA or SSB antibodies. Anti-SSA antibodies isolated and purified from mothers of fetuses without congenital heart block can cause heart block in rabbits, suggesting that, possibly, multiple factors determine susceptibility to cardiac involvement.
Most fetuses with neonatal lupus present with a mild syndrome consisting of transient erythema, mainly on the scalp and periorbital areas, usually following UV exposure in the delivery room. Because the half-life of IgG antibodies is approximately 21-25 days, the syndrome is self-limiting and usually resolves within 3-6 months.
However, infants rarely develop symptoms as severe as congenital heart block. Congenital heart block can be diagnosed in the 18th-24th weeks of gestation when fetal bradycardia is detected. The fetus usually tolerates this condition well in the uterine environment, however, heart block is usually irreversible and there is a high incidence of stillbirth during the prenatal period. One review found that nearly 20% of affected children died early in life. Most survivors require a permanent pacemaker.
In addition to rash and congenital heart block, neonatal lupus has other manifestations: other cardiac abnormalities include right bundle branch block, second degree AV block, patent foramen ovale, aortic stenosis, tetralogy of Fallot, atrial septal defect, ventricular septal defect, mitral and tricuspid regurgitation, pericarditis and myocarditis.
Based on the potential cardiac manifestations of neonatal lupus and its associated morbidity and mortality, the following are recommended for women with SLE who are pregnant: (1), SSA antibody testing should be performed as early as possible in pregnancy, and if complete heart block occurs in the fetus, treatment with corticosteroids (betamethasone or dexamethasone) must be started at the 23rd week of pregnancy before birth and continued until the end of pregnancy. Although hormone therapy does not modify the heart block, hormones help to suppress the associated cardiac or pericardial effusion or myocarditis and improve the prognosis. (2), The development of heart block is followed by fetal electrocardiography and associated cardiac abnormalities are identified. (3), After delivery, the pediatrician should be prepared to implant a pacemaker. (4), If the mother is SSA antibody positive and the fetus is not bradycardic throughout most of the gestation, the likelihood of heart block is minimal, and the cutaneous symptoms of neonatal lupus are benign and transient, thus there is no cause for concern.
Most patients with SLE can be breastfed; however, some medications pass into breast milk, so immunosuppressants should be contraindicated, and antimalarials and long-acting NSAIDs are not appropriate. Short-acting NSAIDs and small doses of prednisone (<15 mg/d = appear to be safe.
Treatment should be considered in two ways: monitoring disease activity and treating patients with active disease. Maternity should be evaluated for disease activity at each trimester, and the frequency of monitoring should be increased if there are active lesions. Monitoring should include: (1), physical examination, including blood pressure measurement; (2), renal function – urinalysis, serum creatinine concentration, 24-hour urine protein test; (3), complete blood picture, anti-DNA antibody titer and complement level test; (4), pelvic ultrasound to monitor fetal development; (5), anti SSA, anti-SSB antibody and cardiolipin antibody tests (performed at the start of pregnancy).
Monitoring should be more intensified in pregnant women who have evidence of increased serum activity and remain asymptomatic. However, do not increase treatment because of a simple abnormal serology.
The following must be noted when treating patients: (1) Drugs used to treat SLE may pass through the placenta and cause fetal harm. Therefore, it is important to repeatedly weigh the pros and cons between the risks and benefits of treatment and the risk of SLE disease activity when giving treatment to pregnant women. (2), Nephrolithiasis during pregnancy requires special care because it may cause exacerbation and confusion with pre-eclampsia. (3), It is important to provide comprehensive treatment in mothers with antiphospholipid antibodies because of the risk of stillbirth and low birth weight fetuses.
Care should be taken in the selection of drugs: (1), drugs that can cause pregnancy failure such as cyclophosphamide and methotrexate should be avoided; (2), antimalarials have theoretical effects on the fetus, but they have not been reported in the literature. Therefore, hydroxychloroquine may be safe to use; (3), NSAIDs are safe but must be discontinued in the last weeks of pregnancy (to promote arterial duct closure); (4), prednisone is safe because no fetal defects have been reported, except for the rare occurrence of neonatal adrenal suppression. Adverse maternal effects of corticosteroids may be controlled by a low-salt diet (to prevent the occurrence of weight gain and hypertension), exercise (to prevent the appearance of bone loss and depression), and calcium supplementation (to prevent osteoporosis); (5), azathioprine may be used with caution.
Patients with significant lupus nephritis should be managed with high doses of prednisone and appropriate antihypertensives (e.g., hydrazidiazide, methyldopa, calcium channel blockers, but diuretics, angiotensin-converting enzyme inhibitors, or some ß-receptor blockers should be avoided). The cause of thrombocytopenia should be actively sought when present, including antiplatelet antibodies, toxemia, and antiphospholipid antibodies. Treatment includes high-dose prednisone and intravenous immunoglobulin.
The following principles should be followed in patients with positive antiphospholipid antibodies: (1), Patients with positive antiphospholipid antibodies must be treated with heparin (10,000 to 12,000 IU, bid, especially from week 12 to week 32) subcutaneously, plus a low dose of aspirin (81 mg/d). (2), If heparin and aspirin therapy do not prevent miscarriage, intravenous immunoglobulin (0.4 g/kg/d, 5 consecutive monthly doses) should be tried in the next pregnancy. (3), If intravenous immunoglobulin input does not work, then prednisone (20-40 mg/d) and low-dose aspirin can be tried in the next pregnancy. Patients with antiphospholipid antibody syndrome should be carefully monitored early in pregnancy by ultrasonography and, at 20 weeks, the fetal heart rate should be monitored. Women with a history of intravenous thrombosis should be treated with anticoagulation for several months until delivery