Arch Gynecol Obstet (2011) 283 (Suppl 1):S61–S65 DOI 10.1007/s00404-011-1859-0
M A T ER N O - F E T A L M E D I C I N E
Successful pregnancy after cyclophosphamide therapy for lupus nephritis Gabriela Lannes · Fernanda R. Elias · Bernardo Cunha · Nilson Jesus · Evandro M. Klumb · Elisa M. N. Albuquerque · Francinne M. Ribeiro
Received: 3 October 2010 / Accepted: 4 February 2011 / Published online: 18 February 2011 © Springer-Verlag 2011
Abstract Background Systemic lupus erythematosus (SLE) often requires administration of cyclophosphamide (CYC), especially for severe glomerulonephritis. As this disease usually aVects young women in reproductive age, pregnancy, though not recommended may occur. The teratogenic eVects of this drug make pregnancy prognosis and fetal survival indeterminate. Methods We reviewed retrospectively the medical records of Wve patients with SLE who received inadvertently CYC during pregnancy and analyzed fetal outcome. Results All patients were exposed at the Wrst trimester. Two patients suVered miscarriages, two went to full term and one presented premature labor. Conclusion In spite of potential successful pregnancies after CYC exposure, this drug has teratogenic eVects and prescription must be avoided during the pregnancy period. At the same time, the occurrence of these reported unplanned pregnancies strengthen the need of improving patients’ education on pregnancy risks during immunosuppressive treatment. Keywords Systemic lupus erythematosus · Pregnancy · Cyclophosphamide · Teratogenesis · Glomerulonephritis · Miscarriage G. Lannes · F. R. Elias · B. Cunha · E. M. Klumb · E. M. N. Albuquerque · F. M. Ribeiro (&) Division of Rheumatology, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rua Dois de Dezembro, 131/702 Flamengo, Rio de Janeiro, RJ 22220-040, Brazil e-mail:
[email protected] N. Jesus Division of Obstetrics, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
Introduction Cyclophosphamide (CYC) is an alkylating agent with a powerful immunosuppressive eVect widely used in the treatment of several kinds of neoplasms and autoimmune diseases. Among systemic lupus erythematosus (SLE) patients, CYC is the Wrst line therapy glomeronunephritis (GN) and central nervous system (CNS) involvement. CYC active metabolites, phosphoramide mustard and acrolein inhibit cellular replication and synthesis of new proteins, causing cellular apoptosis, which explain immunomodulatory action and clinical eYcacy. This drug has shown teratogenic eVects in many studies with animal models [1]. Teratogenicity in humans cannot be completely determined [2], although genetic anomalies have been described since 1960s [3]. CYC toxic eVects are unpredictable in human embryos since deformities do not necessarily occur after exposure in the Wrst trimester. Some studies have reported both normal and malformed newborns after CYC intrauterine exposure, and there is a general consensus that the drug should be avoided in this delicate period [4, 5]. As many SLE patients are at childbearing age, accidental pregnancy is occasionally observed. In this article we review pregnancy outcome of SLE patients who were exposed to CYC after conception.
Materials and methods A chart review of patients who had at least one pregnancy during CYC treatment for LN was done. All cases met at least four American College of Rheumatology (ACR) [6] criteria for SLE and were under regular outpatient followup at Hospital Universitário Pedro Ernesto’s lupus. Pregnancies were followed at the high-risk antenatal clinic at
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Arch Gynecol Obstet (2011) 283 (Suppl 1):S61–S65
Wrst trimester of pregnancy. Class IV (WHO or ISN/RPS 2003 [7]) nephritis was conWrmed by renal biopsy in all patients. The mean creatinine levels at the Wrst trimester and at postpartum were 97 § 44 mol/L and 150 § 80 mol/L, respectively. Two patients presented stage II chronic renal disease since the beginning of pregnancy. One patient presented negative cardiolipin and lupus anticoagulant autoantibodies although none met clinical Sydney criteria for antiphospholipid syndrome [8]. No patient presented positive serology for HIV, HBV, HCV, toxoplasmosis or syphilis. The antibody anti-Ro was negative in three patients and was not available to the others. None of the patients developed preeclampsia, gestational diabetes mellitus, or any signs of placental insuYciency. The pregnancy characteristics of SLE patients under CYC are shown in Table 2. Besides CYC, the concomitant medications administered were: hydroxychloroquine or chloroquine phosphate and prednisone (5 mg/day) for four patients, and prednisone (¸20 mg/day) and azathioprine for the other. Among the drugs used, antimalarials merit a special comment, with no ocular, auditory or neurological malformations detected.
the same unit. All women were submitted to clinical and laboratory evaluation (complete blood count, serum creatinine, glucose, alanine and aspartate aminotransferase, uric acid and lactic dehydrogenase, HIV, syphilis, toxoplasmosis and hepatitis antibodies, urinalysis and protein/creatinine ratio in a random spot). Periodic ultrasound scan looking for major fetal malformations, uterine Doppler velocimetry, and antenatal cardiotocography (CTG) were performed in all patients. Genetic analysis of amniotic Xuid was not available. All cases were followed within close antenatal outpatient consultations by rheumatologists and obstetricians.
Results Five patients were found to be pregnant during CYC administration for lupus nephritis treatment between August 1995 and December 2009. Their general characteristics are shown in Table 1. The mean age at SLE and pregnancy diagnosis was 23 § 7 and 26 § 7 years, respectively. All patients have been exposed to CYC at Table 1 General characteristics of SLE patients 1
2
3
4
5
Age at SLE diagnosis (years)
24
18
37
21
28
Age at beginning of pregnancy (years)
30
21
39
21
28 IV
WHO and ISN/RPS Class
IV
IV
IV
IV
CYC cumulative dose (g)
6.9
NA
18.0
8.0
6
T (w)a
