Author Information
Satia M*, Shilotri M**, Panchbudhe S***.
(* Professor, ** Third Year Resident, *** Assistant Professor, Department of Obstetrics and Gynecology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, India.)
Abstract
Systemic lupus erythematosus (SLE) is a chronic disease which causes inflammation of the connective tissues. Women are affected during their childbearing period. Pregnancy in patients with SLE was discouraged not only due to concern regarding the poor fetomaternal outcomes but also due to the increase in disease activity during pregnancy. Drugs like cyclophosphamide, methotrexate, steroids & mycophenolate are used for the treatment of SLE. Several of these are contraindicated in pregnancy due to their teratogenicity and they should be stopped at least three months prior to conception. We report a case of SLE who had received cyclophosphamide during the first trimester of pregnancy and hence underwent termination of pregnancy.
Introduction
Systemic lupus erythematosus (SLE) is a type of autoimmune and chronic inflammatory disorder affecting multiple organ systems and is characterized by exacerbation's and remissions. It is thought to be caused by polyclonal B-cell activation that leads to antinuclear antibody production against native tissue. These antibodies can cause direct damage to tissues. There is also widespread deposition of immune complexes in vascular beds with impairment of T- cell regulation causing a failure to remove these immune complexes.[1] This leads to activation of the complement system and inflammation. Thus, the mainstay of treatment of SLE is with immunosuppressive and anti-inflammatory drugs. The drug of choice depends on the disease activity and the patient’s response to therapy. A wide spectrum of anti-inflammatory and immunosuppressive drugs like non-steroidal anti-inflammatory drugs (NSAIDs), steroids, methotrexate, mycophenolate mofetil, cyclophosphamide, azathioprine and cyclosporine are used for the treatment of SLE. Most of these drugs cross the placenta and have teratogenic potential. Women with SLE should be seen in the pre-pregnancy period not only to ascertain the suitability of conception depending on the level of the disease activity but also to check whether they are on any anti-inflammatory or immunosuppressive drugs.
Case Report
A 26 year old gravida 3, para 1, living 1, abortion 1 with 7.6 weeks gestation was referred to our antenatal outpatient department by the rheumatologist for further management. She was a known case of beta thalassemia trait, systemic lupus erythematosus with antiphospholipid antibody syndrome, and autoimmune hemolytic anemia on pulse cyclophosphamide therapy. On examination, her general condition was fair, pulse and blood pressure were normal. She had no pallor, icterus, cyanosis or pedal edema. Cardiovascular and respiratory system examination were unremarkable. The abdomen was soft, there was no guarding, rigidity or tenderness and the Pfannenstiel scar of a previous lower segment cesarean section was seen. On per speculum examination the cervix and vagina were healthy. On per vaginal examination the uterus was 6-8 weeks in size, anteverted, os was closed and bilateral fornices were clear. She had received the last dose of pulse cyclophosphamide therapy around the time of conception; 2 weeks after her last menstrual period. She had also taken atorvastatin and telmisartan in the first trimester.
She was diagnosed to have systemic lupus erythematosus with autoimmune hemolytic anemia with beta thalassemia trait 1 year prior during the evaluation of severe anemia and jaundice. She had presented with hemoglobin of 2.2 gm % and bilirubin of 2.3 mg/ dl. Her anti-nuclear antibodies (ANA), lupus anticoagulant and antiphospholipid antibodies were all positive. Bone marrow aspiration and biopsy showed erythroid hyperplasia with hemolytic process. She was transfused with 8 units of packed red cells and started on pulse methylprednisolone therapy, pulse cyclophosphamide therapy, oral hydroxychloroquine, aspirin, atorvastatin and telmisartan. The DEXA scan was suggestive of osteoporosis and hence she was started on vitamin D and calcium supplements. Her hematological parameters improved gradually. She conceived despite her and her husband being counseled about the need to avoid pregnancy during the immunosuppressant therapy.
As per the rheumatologist’s advice, a complete evaluation was done to determine her disease activity. Complete blood count, liver and renal function tests, fasting, postprandial blood sugars, serum complement (C3, C4) levels, serum C-reactive protein (CRP) levels, serum lipids, thyroid function tests and 24 hour urine protein levels, were all in their respective normal ranges. A cardiology evaluation and an echocardiogram were done to rule out any cardiac lesions due to autoimmunity and cyclophosphamide therapy. The echocardiogram was normal. The couple was counseled regarding the risk of adverse effects on the fetus of the cyclophosphamide therapy received in the periconceptional period and the available modalities for screening of fetal anomalies. They opted for termination of pregnancy. First trimester medical termination of pregnancy was done by suction evacuation under total intravenous anesthesia. The procedure was uneventful. Post-procedure she was referred to the rheumatologist for further plan of action. The couple was counseled to avoid conception until the end of immunosuppressant therapy and they chose to use barrier contraception.
Discussion
Pregnancy in patients with SLE is a high risk condition. This condition is associated with an increased risk of maternal and perinatal morbidity and mortality. Active SLE in the early gestational period is associated with adverse pregnancy outcomes. The longer the woman is in remission, the better is the pregnancy outcome. Hence counseling prior to conception is mandatory so that pregnancies can be planned during periods of disease remission. Also, a detailed drug history is necessary in order to take a decision of continuation or changeover of the drugs depending on disease activity and teratogenicity of the drugs. There is a small to moderate risk of birth defects due to NSAIDs such as cleft lip/ palate, neural tube defect, eye defects, pulmonary valve stenosis and limb defects. However, there is no major risk for their use in early pregnancy.[2] Hydroxychloroquine is an antimalarial drug that has anti-inflammatory properties and helps maintain disease remission. It does not cause congenital malformations and its continuation through pregnancy is recommended.[3] Exposure to steroids should be limited to a minimum during pregnancy as higher doses are associated with an increased risk of diabetes, hypertension, pre-eclampsia and premature rupture of membranes. There are no major congenital malformations associated with steroids but risk of oral clefts and intrauterine growth restriction is increased.[4,5] The immunosuppressant drug azathioprine is one of the few agents that is safe during pregnancy and is used in the dose of 2 mg/kg/day, to avoid risk of fetal cytopenias and immune suppression.[6] The fetal liver does not have adequate levels of an enzyme inosinatopyrophosphorylase, which is required for the conversion of azathioprine to its active form, and therefore is protected from its harmful effects.[7] Other immunosuppressive drugs like the calcineurin inhibitors, tacrolimus and cyclosporine, are not reported to have any increase in fetal risk.
Cyclophosphamide is proven teratogenic and cyclophosphamide embryopathy includes ear and facial abnormalities, defects of the calvaria, absence of digits and hypoplastic limbs.[8] It also causes growth restriction and suppression of neonatal hematopoiesis. In some cases, mycophenolate is the only treatment that achieves disease stability and patients should be counseled regarding the fetal risks such as external auditory canal atresia with and without microtia, tracheo-esophageal atresia, severe hydronephrosis, atrial septal defect and myelomeningocele. Drugs such as cyclophosphamide, methotrexate and mycophenolate are contraindicated during pregnancy and should be stopped at least 3 months before conception.[6] The half-life of these drugs is very long and their effects may be seen up to a few weeks to months after discontinuation. Thus, women need to be counseled regarding the need for contraception during the period of immunosuppressant therapy and for 3 months thereafter. Barrier contraception and progesterone only pills or depot progestogens are safe in SLE. Low dose combined oral contraceptive pills (COCs) may be used with caution in selected cases of SLE.[9] In case a woman conceives while on teratogenic immunosuppressant drugs, she should be counseled regarding the measures that can be taken to antenatally detect any fetal anomalies. Ultrasound for nuchal translucency and nasal bone, detailed anomaly scan and fetal 2D echo, double, triple and quadruple markers, amniocentesis, chorionic villus sampling are the methods that can be used. However, she must be told that these measures are not foolproof. If the tests show that the fetal condition is untreatable or associated with significant handicap then termination of pregnancy may be suggested. Alternatively, the antenatal management, time, place and mode of delivery may be planned in order to ensure the optimal prognosis of the neonate.
Conclusion
Management of pregnancy with SLE requires a multidisciplinary approach involving the obstetrician and rheumatologist. Stress should be laid on pre-pregnancy counseling and history of use of drugs, especially during the first trimester of pregnancy. The need to use contraception must be emphasized while patients are taking teratogenic medications.
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Satia M, Shilotri M, Panchbudhe S. Use Of Immunosuppressive Drugs For Systemic Lupus Erythematosus In Pregnancy. JPGO 2017. Volume 4 No.4. Available from: http://www.jpgo.org/2017/04/use-of-immunosuppressive-drugs-for.html