Pregnancy Management In Patients With Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is common in women of childbearing age, and pregnancy-related problems are extremely important for the mother’s disease progression and fetal development. With advances in the pathogenesis of lupus and advances in clinical management of pregnancy, pregnancy is now possible for most lupus patients, and maternal and fetuses can have good outcomes. This article will focus on the main issues and management strategies for different periods of SLE pregnancy in order to achieve optimal outcomes for both mother and fetus.

1.Before pregnancy

1.1 Planned pregnancy

Pre-pregnancy SLE disease activity is closely related to pregnancy outcome. SLE is safer in the control period and the pregnancy outcome is better. In the SLE active period, the fetus can have miscarriage, stillbirth, etc., resulting in a significant increase in fetal loss rate. A cohort of 267 patients with combined lupus and pregnancy found that women with high disease activity during early and mid-pregnancy had a three-fold chance of having a miscarriage and perinatal death in women with low disease activity. At the same time, studies have shown that in the case of combined renal damage, it often leads to pre-eclampsia, miscarriage, premature delivery, fetal growth restriction and fetal congenital heart disease. In addition, certain immunosuppressive agents such as mycophenolate mofetil, cyclophosphamide, methotrexate and leflunomide have significant teratogenic effects, and pregnancy must be avoided during the administration of these drugs. Therefore, planning a pregnancy is the most important measure necessary to ensure the health of mothers and babies.

1.2 Contraception

For SLE patients of childbearing age, it is important to use appropriate and effective methods of contraception. Effective contraceptives should be used especially during periods of lupus activity, high risk of thrombosis, and during the use of teratogenic drugs. The main contraceptive methods that patients can take include oral contraceptives, condom use, and intrauterine devices. Oral contraceptives containing estrogen and progesterone may induce lupus activity. Although clinical trials have produced inconsistent results in this regard, Ostensen et al. recommend that lupus patients avoid oral medications containing these two hormones, especially in lupus. During the period of activity. At the same time, the use of estrogen increases the risk of thrombosis in patients with antiphospholipid syndrome or nephrotic syndrome, and long-term use of progesterone increases the risk of osteoporosis. Condoms should also be used with caution as they increase the risk of secondary infection in SLE patients. However, intrauterine devices, especially copper-plated devices, can be used in all patients with lupus erythematosus and antiphospholipid syndrome without any gynaecological contraindications. Therefore, for most patients, copper-plated intrauterine devices are the best choice for contraception.

1.3 Pre-pregnancy assessment

1.3.1 Pre-pregnancy laboratory tests

In addition to routine pre-pregnancy laboratory tests, pre-pregnancy assessments should be performed on pre-pregnancy assessments: anti-phospholipid antibodies (aPL), lupus anticoagulants (LA), immunoglobulin G (IgG) and Immunoglobulin M (IgM) anti-cardiolipin antibody (aCL), and IgG and IgM type β2-glycoprotein 1 (β2GP1); anti-sjogren’s syndrome type A antibody (anti-Ro/SSA antibody) and Anti-Sjogren’s syndrome type B antibody (anti-La/SSB antibody); anti-double-stranded deoxyribonucleic acid antibody (anti-ds-DNA antibody); serum complement: total hemolytic complement (CH50) or complement 3 (C3) and complement 4 (C4) Kidney function (creatinine, urine analysis and urine sediment test, random urine protein/creatinine ratio), uric acid; complete blood count (CBC); liver function test.

1.3.2 Pre-pregnancy risk assessment

Pre-pregnancy risk assessment is an important measure to ensure a good pregnancy outcome. For specific assessments, please refer to the list of parameters for pre-pregnancy counseling and risk stratification of female patients with lupus published by the European Union of Rheumatology in 2017 [5]. The main list is as follows: 1 Whether it is in the period of lupus activity, that is, whether there is lupus disease activity in the past 6 to 12 months or during pregnancy. Lupus activity increases the risk of maternal severe activity during pregnancy and puerperium, increases the incidence of hypertension complications and fetal lupus, and increases the risk of preterm birth. 2 Whether there is or is there a lupus nephritis. Lupus nephritis is a powerful predictor of maternal preterm birth. 3 Whether there is serological activity, such as a decrease in C3/C4 complement and an increase in anti-ds-DNA antibody titer. Serological activity increases the risk of developing lupus disease during pregnancy. 4 Whether there is a bad pregnancy outcome in the past. In patients who have had an adverse pregnancy outcome, the likelihood of a worse pregnancy outcome in a second pregnancy will increase by 3.6% to 12.7%. 5aPL level. The presence of antiphos-pholipid syndrome (APS) is a powerful predictor of adverse outcomes in pregnant women and foetuses, especially in patients with persistent moderate to high titers of aPL, cerebral blood vessels during pregnancy. The risk of thrombosis will increase and the risk of preterm birth will increase. 6 anti-Ro/SSA and anti-La/SSB antibodies. If anti-Ro/SSA and anti-La/SSB antibodies are present, the chance of developing a new neonatal lupus will increase.

1.4 Lupus activity assessment

At present, the main parameters for the judgment of SLE activity in the world are: systemic lupus ery-thematosus disease activity index (SLEDAI), European consensus lupus activity measurement (ECLAM), Systemic lupus activity measure (SLAM), of which SLEDAI score is most commonly used [8]. SLEDAI scores for SLE condition: 0 to 4 are divided into basic activities, 5 to 9 are classified as mild activities, 10 to 14 are classified as moderate activities, and ≥ 15 are classified as severe activities.

1.5 Drug evaluation

Pre-pregnancy must be evaluated and adjusted to ensure that the disease is stable while using the safest possible drugs, while avoiding drugs that may have a negative impact on women’s fertility. Non-steroidal anti-inflammatory drugs (NSAIDs) may inhibit prostaglandin synthesis and interfere with ovulation, implantation and placental function. High doses of glucocorticoids may cause transient hypothalamic-pituitary-adrenal (HAP) axis inhibition. Cyclophosphamide can cause irreversible infertility by high dose cumulative effects of ovarian failure [9]. Therefore, the following drugs should be discontinued due to their negative effects on pregnancy: cyclophosphamide, methotrexate, angiotensin converting enzyme inhibitor, mycophenolate mofetil, angiotensin II receptor blocker.

1.6 Timing of pregnancy

Choosing the right timing for pregnancy is a necessary condition to ensure optimal outcomes in SLE patients and the fetus. Pregnancy can only be considered in patients with SLE who have completed the above assessments and meet the following criteria [5, 10-11]: 1 After standard treatment, the condition is stable for at least 6 months, preferably more than 1 year; 2 prednisone The maintenance dose is below 15 mg / d; 3 no pulmonary hypertension and refractory hypertension; 4 anti-ds-DNA antibody negative, C3, C4 normal; 5 no aPL positive or former positive need aPL negative for more than 3 months; 6 There are no SLE-related kidneys, heart, lung and other important organs and central nervous system diseases; 7 Stop cyclophosphamide, methotrexate, mycophenolate mofetil, tripterygium and other immunosuppressive agents for more than 6 months. 8 For patients taking leflunomide, oral cholestyramine (8 g/time, 3 times a day for 11 days) is required to accelerate the elimination of the drug and its metabolites, and can be determined by measuring the concentration of leflunomide. Whether it is eliminated or not, that is, two measurements are performed at a concentration of less than 0.02 mg/L, and two detection times are required to be separated by two weeks.

2.Pregnancy

Pregnancy between lupus erythematosus and pregnancy is an interaction. On the one hand, due to the influence of SLE disease itself, the risk of miscarriage, premature delivery, stillbirth, and fetal growth restriction during pregnancy is significantly increased. On the other hand, pregnancy may lead to SLE disease. Activity and recurrence. Therefore, for women with systemic lupus erythematosus, once the pregnancy is confirmed, it is necessary to work closely with rheumatologists and experienced obstetricians in high-risk pregnant women. Rheumatoid immunology and obstetric follow-up and regular prenatal care are needed to understand SLE condition and maternal fetal monitoring, if necessary, drug intervention and termination of pregnancy.

2.1 Assessing maternal lupus activity

The Department of Rheumatology evaluates the maternal disease activity once a month, and if there is already SLE activity, the assessment should be more frequent. The monitoring content includes: 1 detailed medical history and physical examination, including blood pressure. 2 Laboratory tests: blood routine, urine routine, renal function, random urine protein/creatinine ratio, liver function, anti-Ro/SSA and anti-La/SSB antibodies, anti-ds-DNA antibodies, complement (CH50 or C3 and C4). The interpretation and treatment of laboratory test indicators must be combined with the clinical context, as certain physiological changes in pregnancy may overlap with the characteristics of active SLE. Common physiological changes that need to be differentiated from the activity of lupus disease during pregnancy are: 1 mild anemia, which may be mild when compared to normal iron deficiency due to increased blood volume during normal pregnancy or increased iron demand. Anemia, but the degree of anemia is often mild, mostly with small cell hypochromic anemia; while SLE activity leads to anemia, often heavier, and follow-up blood changes, hemoglobin can be progressively reduced, mainly hemolytic anemia If necessary, the direct anti-human globulin test (Coombs test) can be improved, and a positive result can be seen. 2 mild thrombocytopenia, mild thrombocytopenia in some pregnant women during normal pregnancy, the specific mechanism is not clear, but generally no clinical bleeding; and SLE activity leads to thrombocytopenia, the degree is heavier, and generally have oral mucosa, Gingival hemorrhage, subcutaneous sputum, ecchymosis, and other immunological indicators can also be seen abnormal, such as decreased complement (CH50 or C3 and C4), increased anti-ds-DNA antibody titer. 3 The erythrocyte sedimentation rate is increased, and the erythrocyte sedimentation rate can be slightly increased during normal pregnancy, while the SLE disease activity is higher, and other immunological indicators are abnormal, such as anti-nuclear antibody and anti-dsDNA antibody titer. Increase. 4 proteinuria, proteinuria can occur during normal pregnancy, generally more common in morning urine, and mostly intermittent, urine protein qualitative examination is often low; and SLE disease activity caused by proteinuria, continuous, detection for 24 h A large amount of protein is generally seen in urine protein quantification. 5 Complement, during normal pregnancy, the level of complement may increase by 10% to 50%, while the complement of SLE disease activity decreases, the level of complement may remain normal after neutralization, so the trend of complement level is often more valuable than the actual value. At the same time, it can be combined with other immunological indicators and clinical manifestations to determine whether SLE is active.

2.2 Fetal monitoring

Because of the SLE disease itself and the use of the patient’s medication, it increases the risk of the fetus, so the perinatal period needs to strengthen fetal monitoring. In addition to routine prenatal testing, more fetal monitoring includes: 1 In the early pregnancy, an ultrasound assessment to determine the expected date of delivery, and an anatomical observation of the fetus at approximately 18 weeks of gestation. 2 In the second trimester, conventional ultrasound was used to assess placental function and fetal growth. The frequency of fetal growth monitoring depends on the health of the mother and the fetus, but is usually about once every 4 weeks. If the fetal growth restriction or placental dysfunction is suspected, or if the mother’s disease is active, more frequent monitoring is required. In this case, umbilical arterial blood flow velocity measurement is also recommended. 3 Most female lupus patients need to undergo a non-stress test and/or biophysical score for fetal examination during the last 4 to 6 weeks of pregnancy. The individual monitoring plan is based on the maternal fetal evaluation. 4 For patients with positive anti-Ro/SSA and/or anti-La/SSB antibodies, it is recommended to increase fetal cardiogram and echocardiography to detect possible fetal heart block early, and check once a week for 16 to 26 weeks. Check every 2 weeks from 26 weeks of gestation to delivery.

2.3 Medication during pregnancy

For medication during pregnancy, refer to the guidelines issued by the European Union Against Rheumatology in 2016 on the use of rheumatoid drugs during pregnancy and lactation [12]: 1 Before the planned pregnancy, family planning and adjustment of treatment plans should be carried out for women of childbearing age; 2 treatment of patients with rheumatic diseases during pregnancy and lactation should aim to prevent or inhibit the mother’s disease activities, while avoiding fetal damage; 3 should assess the risk of maternal and fetal use of drugs and no medication Risks involved; 4 drug treatment during pregnancy and lactation should be decided by a rheumatologist, obstetrician and patient. In addition, specific medications should also take into account clinical conditions and may be affected by pregnancy and other factors. Therefore, following the above principles and the practicality of comprehensive drug use, we will classify anti-inflammatory drugs and immunosuppressive drugs for the treatment of inflammatory diseases as follows: 1 fetal or maternal risk is minimal: hydroxychloroquine, sulfasalazine; 2 pregnancy Selective applications: NSAIDs (including aspirin), glucocorticoids, azathioprine and 6-oxime, cyclosporine, tacrolimus, tumor necrosis factor (TNF) inhibitors, intravenous immunoglobulins; Degree to high risk of fetal injury: methotrexate, leflunomide, late pregnancy application of NSAIDs (including aspirin), cyclophosphamide, mycophenolate mofetil; 4 risk is not clear: rituximab, tortoise Monoclonal antibody, selective cyclooxygenase-2 (COX-2) inhibitor, anakinra, abatacept (remarks: there is a difference in risk between different drugs of any class, and some drugs may Divided into multiple categories based on a variety of factors). In general, the types of drugs used during pregnancy are antimalarials, NSAIDs, glucocorticoids, immunosuppressants, and biological agents.

2.3.1 Hydroxychloroquine (HCQ)

Studies to date have shown that hydroxychloroquine has no teratogenic effects and is safe for use during pregnancy. In addition, some data indicate that HCQ also reduces the incidence of congenital heart block in high-risk fetuses in pregnant women who are resistant to Ro/SSA and anti-La/SSB antibodies. The discontinuation of hydroxychloroquine during pregnancy often leads to an exacerbation of SLE symptoms and an increase in the demand for glucocorticoids, so it is recommended to continue using hydroxychloroquine during pregnancy.

2.3.2 NSAIDs

For SLE patients, commonly used non-selective NSAIDs include acetaminophen and aspirin. These two drugs can cross the placenta and inhibit the synthesis of prostaglandins, leading to premature closure of the arterial catheter and fetal pulmonary hypertension. Therefore, the use of aspirin and acetaminophen should reduce the dose and avoid use in the last 3 months of pregnancy. . However, studies by Flint et al  have shown that aspirin can have a positive effect on mothers by preventing hypertension and pre-eclampsia, and many studies have shown that aspirin has no teratogenic effects, so it is recommended to take low doses throughout pregnancy. aspirin.

2.3.3 Glucocorticoid

Glucocorticoid is the main treatment for SLE pregnant women. After a rigorous pre-pregnancy assessment, SLE pregnancies have a lower disease activity. After the hard palate formation period, the lowest effective dose of glucocorticoid (prednisone 10 mg/d) is recommended to control the condition and closely monitor the condition. The pregnancy process may lead to severe disease activity. In the case of lupus crisis, glucocorticoid shock can be used to induce remission. The regimen is prednisone [1~1.5 mg/(kg·d)] or methylprednisolone (500~). 1 000 mg / d), 3d for a course of treatment. For pregnant women receiving glucocorticoid therapy, the risk of pre-eclampsia, gestational diabetes, hypertension and infection may be monitored regularly, and the HAP axis function should be suppressed, and prednisone should be changed during the delivery period. Hydrocortisone (100-200 mg/d) to prevent acute adrenal crisis during childbirth.

2.3.4 Immunosuppressive agents

Azathioprine is the only immunosuppressive agent allowed during pregnancy. Although thiazolium can pass through the placenta, it is converted to the inactive metabolite thiourea, which has a limited effect on the fetus. A study by Flint et al [16] showed no increase in spontaneous abortion in patients treated with azathioprine [

2.3.5 Biological agents

Belizumab (a humanized anti-B lymphocyte stimulator (BLyS) is currently the only biologic approved for SLE treatment. Experimental studies have shown that although it can cross the placenta and may result in a decrease in the number of fetal B lymphocytes, belizumab has no teratogenic effects and does not cause other adverse reactions. However, there are no experimental data on its use during pregnancy. Therefore, the current belibizumab is still a contraindication for pregnant women with lupus.

2.4 SLE pregnancy patients with antiphospholipid syndrome treatment

The best treatment for SLE pregnant women with APS is currently under investigation. Recently, glucocorticoids have been gradually replaced by anticoagulants or antiplatelet drugs. Current research is mainly about the use of aspirin and heparin, and low-dose aspirin can reduce the abortion rate in patients with APS. However, for those with a risk of thromboembolism or pre-eclampsia, it is not enough to take aspirin alone. In this case, it is recommended to use other anticoagulants, such as low molecular weight heparin. However, oral anticoagulants cannot be used because they affect the development of the fetus, especially during the 6 to 12 weeks of pregnancy. Therefore, women who receive oral anticoagulants before pregnancy must be given subcutaneous injections of heparin.

2.5 SLE patients when and how to terminate the pregnancy

The optimal timing and mode of termination of pregnancy for SLE pregnant patients should be selected based on SLE severity and obstetric indications. SLE patients with stable disease and no pregnancy complications can wait for natural childbirth, but must be closely monitored and guided by the Department of Rheumatology and Obstetrics. If you have a disease activity or pregnancy complications, you can refer to the Chinese Medical Rheumatology Association’s recommendations for termination of pregnancy: 1 There is a significant SLE activity during early pregnancy. 2 serious complications, such as lupus kidney crisis, lupus brain, blood system damage, cardiovascular disease, etc., have been improved without active treatment. 3 Abnormal immunological laboratory indicators, such as high titer anti-nuclear antibodies and low complement, deposit more immune complexes on the placental villi, resulting in thickening of the trophoblastic basement membrane and villus thrombosis, affecting the placenta Exchange function, resulting in intrauterine hypoxia, premature delivery, if the treatment has not improved, pregnancy > 34 weeks, then timely cesarean section, pregnancy

3.Lactation

Regarding breastfeeding, breastfeeding was thought to be a cause of SLE activity. However, recent data suggest that breastfeeding has nothing to do with increased disease activity in the absence of pregnancy-related complications and regular delivery. Most drugs are very concentrated in breast milk. The recommendations of the European Union Against Rheumatism on breastfeeding are as follows: 1 Drugs that can be considered for continued use during breastfeeding: hydroxychloroquine, prednisone, non-selective NSAIDs, sulfasalazine, azathioprine, cyclosporine, tac Moss. Breast milk contains only 5% to 20% of prednisone intake, which has no effect on infants. However, if prednisone dose exceeds 20 mg/(kg·d), the milk for the first 4 hours after administration should be discarded. 2 Avoid medications that are limited to breastfeeding: methotrexate, mycophenolate mofetil, cyclophosphamide, leflunomide, selective COX-2 inhibitor. 3 Use belizumab only if other treatments do not control SLE activity. 4 A comprehensive breastfeeding program should be developed based on factors such as disease activity, visceral damage, and treatment of each patient.