Clovis Artur Almeida Silva1
1MD,
PhD. Head of Pediatric Rheumatology Unit
Department of Pediatrics
Instituto da Criança,
University of Sao Paulo
Sao Paulo, Brazil.
Correspondence:
Clovis
Artur Almeida Silva
Rua
Senador César Lacerda Vergueiro, 494/82
Vila
Madalena
CEP
05435-010
Sao
Paulo – SP - Brazil
clovisaas@icr.hcnet.usp.br
55
11 3069-8675
55 11 3069-8503
ABSTRACT
Patients with systemic
lupus erythematosus (SLE) have an increased frequency of disease flares during
pregnancy, compared to nonpregnant SLE patients.
Active renal disease and maternal hypertension are important predictors of
fetal loss. A case of active juvenile SLE and pregnancy is described in a
16-year-old white girl has had SLE for 9 years. She had delay in menarche,
early sexual activity and did not use any contraceptive methods. Her pregnancy was
complicated by hypertension and renal failure. The SLEDAI was 20 and SLICC/ACR
Damage Index was 4. Despite treatment with plasmapheresis, intravenous methylprednisolone
pulse therapy, prednisone and azathioprine, she had a spontaneous abortion as
well as renal failure requiring dialysis. Seven months later, she remains on
dialysis and is awaiting renal transplantation.
Keywords: Systemic
Lupus Erythematosus, Adolescent, Pregnancy.
With the improved survival of children and adolescents with SLE,
pediatric rheumatologists have to care for an ever increasing population of
adolescents with systemic lupus erythematosus (SLE). Rheumatologists and other
physicians must take into consideration the many
aspects of adolescence, particularly the presence of sexual activity and its possible
consequences, such as pregnancy.
A
study performed in the
A
16-year-old white adolescent girl was diagnosed with SLE at seven years of age.
Her diagnosis was based on the presence of malaise, alopecia, malar rash,
photosensitivity, pericarditis, leucopenia, hypertension, proteinuria,
hypocomplementemia, positive antinuclear and anti-dsDNA antibodies. The initial renal biopsy showed
membranous glomerulonephritis (World Health Organization Class V) with activity
index of 4 and chronicity index of 4. Her major clinical problems included
hypertension, persistent nephrotic syndrome, vasculitis and arthritis. SLE
activity for this period of follow-up was classified into relapsing-remitting
according Barr et al [5]. She was treated in this period with prednisone
(cumulative dose of 65.5g), intravenous cyclophosphamide (cumulative dose of
5.18g), azathioprine (cumulative dose of 82.66g), methotrexate (cumulative dose
of 0.55g), cyclosporine (cumulative dose of 3.9g) and chloroquine (cumulative
dose of 174.9g).
Her menarche was at age 15 years. After one year, her menses were
normal. The menstrual cycles were associated with dysmenorrhea. The first
sexual activity was at 15.8 years old with a frequency of intercourse four per
month. Despite extensive counseling on sexual health, pregnancy and
contraception, she did not use barrier contraceptive methods (male or female
condom), emergency contraception (levonorgestrel), an injectable contraceptive
(depo-medroxyprogesterone acetate), or other forms of contraception.
At the age of 16, she stopped her SLE treatment and follow-up, and her
disease appeared to be in remission. At the age of 16 years and 8 months, she
was admitted in our hospital in the first trimester of pregnancy with fatigue,
edema, hypertension, arthritis and renal insufficiency. The pregnancy was unplanned,
unwanted and she received no help from the baby’s father.
Laboratory testing revealed a hemoglobin of 9.8 g/dl, platelet count of
328,000/mm3 and white blood cell count of 10,,600/mm3
(76% neutrophils, 11% lymphocytes and 13% monocytes).
Antinuclear antibodies (HEp-2) and anti-dsDNA antibody (Crithidia
luciliae) were positive. The C3 and C4 were reduced.
Antiphospholipid antibodies, anticardiolipin
antibodies (ELISA) and lupus anticoagulant (kaolin clotting), were negative.
The urinalysis showed microscopic urine blood, casts and pyuria. The proteinuria was 0.45 g/day, urea nitrogen
143 mg/dl and plasma creatinine 5.2 mg/dl. The ultrasound showed a 5 week
pregnancy. The systemic lupus erythematosus disease activity index (SLEDAI) was
20.
She was treated with both plasmapheresis and intravenous pulse therapy
with methylprednisolone for 3 days plus prednisone 60 mg/day. However, despite
this treatment, one week later the hypertension, edema and renal insufficiency
worsened and azathioprine and hemodialysis were added to the treatment. Two weeks
later, it was decided that a therapeutic abortion was indicated but the
pregnancy ended in spontaneous abortion.
At the age of 19, a second renal biopsy demonstrated a proliferative
glomerulonephritis (World Health Organization Class IV) with activity index of
3 and chronicity index of 9. The Systemic Lupus International Collaborating
Clinics/ACR (SLICC/ACR) Damage Index was 4. By the age of 20, she was on
dialysis, waiting for kidney transplant and was then transitioned to the adult
rheumatology service of our
DISCUSSION
Patients with juvenile SLE often become sexually active during
adolescence like their peers and, despite their disease and medications, may
become pregnant. Our patient became
pregnant despite a delay in menarche, major disease activity and previous high
doses of immunosuppressive agents.
Britto et al [6] studied 178 adolescents with pediatric rheumatic
diseases (mean age of 18.1 years; 67% female; 69% with juvenile rheumatoid
arthritis and 8% with juvenile SLE). Of the 52 females undergoing screening at
follow-up, 31 (60%) were sexually active. Eleven (41%)
of 27 sexually active females were not using contraception other than condoms
(4 were not asked about contraception).
Studies show that women with SLE have a high abstention rate, a low
frequency of masturbation and genital petting, diminished vaginal lubrication,
poor general sexual adjustment, and a poor ability to adjust to psychosocial
stresses and increased depression [7,8]. Normal sex
drive, motivation, subjective arousal, orgasmic attainment and satisfaction
were not found to be different than controls [7]. Our patient reported normal
sex motivation, masturbation, and orgasm with four intercourses per month.
Our service has also previously
shown that the delay of menarche in patients with juvenile SLE [9]. The mean
age of menarche (13.5 ± 1.4 years) was greater than that found among 2578
healthy Brazilian adolescents (12.5 ± 1.3 years) (p=0.0002). The delay in
menarche correlated with an increase in the duration of the disease (p=0.0085)
and the cumulative dose of prednisone (p=0.0013) used until the appearance of
the menarche. The fertility of patients with juvenile SLE can be altered by the
activity of disease or medications in male [10] and female [9] adolescents. The
glucocorticoid therapy, especially in high doses [11] and immunosuppressive
agents [12], such as cyclophosphamide and chlorambucil, can lead to a pubertal
delay and gonadal dysfunction in both sexes. The alkylating agents most
frequently associated to infertility are chlorambucil and cyclophosphamide
[12]. Our group has also analyzed the
gonadal function of 23 adolescents and young females with juvenile SLE [9].
Sixteen female (70%) patients showed normal gonadal function and seven (30%) abnormal.
Gonadal function was not correlated with disease activity of juvenile SLE or
therapy with prednisone, cyclophosphamide, azathioprine and methotrexate. In
Studies published in the 1960s underlined the increased fetal and
maternal risk and recommended against pregnancy in lupus patients. The
prognosis for non-pregnant SLE active patients was also poor, making it
difficult to know whether pregnancy altered the prognosis of the disease.
Recent prospective studies indicate that the majority of lupus mothers can
sustain pregnancy without detrimental effects, providing that pregnancy is
planned during the inactive phase of the disease [13]. Pre-existing renal
involvement increases the risk for hypertension, but it does not contraindicate
pregnancy if it is adequately planned and monitored [14].
Rahman et
al [15] prospectively studied 141 SLE pregnancies to identify clinical
predictors of fetal outcome. Active renal disease was a statistically
significant predictor for fetal loss, with 13.4% patients with live births
having active renal disease compared to 33% with fetal losses. Hypertension was
a statistically significant predictor for pre-term delivery and intrauterine growth
restriction. Cervera et al [14] also studied 103 pregnancies in 76 SLE
patients. They showed that the frequency of lupus flare was approximately 23%.
The type of flare was cutaneous in 54%, thrombocytopenia in 33%, pericarditis
in 21%, arthritis in 21% and nephritis in 17%.
Petri et al [16] found an increase of disease flare in pregnancy
compared to after delivery and to nonpregnant patients. Flare of the disease
occurred in all trimesters: 18% in first trimester, 47% in second trimester,
15% in third trimester and 20% in postpartum. Pregnant lupus patients are
susceptible to pre-eclampsia, especially if they suffer from lupus nephritis, steroid-induced
hypertension, and hyperglycemia [17]. SLE pregnancy had also a significantly
increased incidence of urinary tract infection, diabetes and premature rupture
of membranes [16]. Fetuses are susceptible to placental insufficiency if
antiphospholipid antibody or other procoagulant states are present, and to
neonatal lupus if anti-Ro/La antibodies are present [17].
Because of the limitations on
medications that can be used safely during pregnancy, management of a lupus
flare can be problematic, as in our patient. Intravenous methylprednisolone
pulse, 1000 mg/day for 3 days can be used. Azathioprine can be added if the
patient has had a major renal, hematologic or neurologic system flare [16].
Plasmapheresis can be safely performed during pregnancy and has been used for
years in Rh-incompatible pregnancies. Four patients with lupus have been
treated during pregnancy [18]. Methotrexate, cyclophosphamide, mycophenolate,
and several other drugs should be avoided as they are teratogenic.
From our perspective, despite
knowledge and concern about the interaction of immunosuppressive therapy and
risk behaviors, few rheumatologists adequately screen the sexual behavior of
their adolescent and young adult patients with SLE. Time constraints,
organizational issues and physician beliefs remain barriers to widespread
screening [6]. Women who take cytotoxic drugs also should be informed of the
risks of impaired fertility and congenital malformations, and patients on these
drugs must use effective methods of contraception [19].
If a pregnancy is desired, the best
time to plan a pregnancy is during an inactive period of SLE, although there is
no guarantee that the disease will remain inactive. It should be emphasized
that the chance of a flare during pregnancy which occurs after 5 to 6 months of remission is 10%
or less [18].
In summary, pediatric and
adult rheumatologists have a crucial role in addressing these issues as they
are often the only health workers providing sexual counseling for these
patients [20]. Consequently, the pediatric rheumatologist and his/her staff
need to create space within the appointment times to approach and discuss
aspects of sexuality, offer guidance regarding contraceptive methods and warn
about the risks of sexually transmitted diseases (STD) and their prevention. Though
the risk of pregnancy to the mother and fetus in this situation has greatly
decreased in the last several decades, there still significant associated risk
for the mother and fetus and much care must be taken.
1. Badiani R, Quental I, Santos EM.
DST/AIDS e a pesquisa nacional sobre demografia e saúde: uma análise do nível
de conhecimento e comportamento de vulnerabilização. Rio de Janeiro,
BEMFAM/DHS, 1997.
2.
3. Petri M, Howard D, Repke J.
Frequency of lupus flare in pregnancy, the
4. Meng C, Lockshin M. Pregnancy in
lupus. Curr Opin
Rheumatol 1999; 11:348-351
5. Barr SG, Zonana-Nacach A, Magder LS,
Petri M. Patterns of disease activity in systemic lupus erythematosus. Arthritis
Rheum 1999; 42:2682-2688
6. Britto MT, Rosenthal SL, Taylor J,
Passo MH. Improving rheumatologists screening for alcohol use and sexual
activity. Arch Pediatr
Adolesc Med 2000; 154:478-483
7. Quaresma MR, Goldsmith CH, Lamont S,
8. Curry SL, Levine SB, Corty E, Jones
PK, Kurit DM. The impact of systemic lupus erythematosus on women’s sexual
functioning. J
Rheumatol 1994; 21:2254-2260
9. Silva CA, Leal MM,
Leone C, Simone VP, Takiuti AD, Saito MI, Kiss MH. Gonadal function in adolescents and
young women with juvenile systemic lupus erythematosus. Lupus 2002; 11:419-425.
10. Silva CA, Hallak
J, Pasqualoto FF, Barba MF, Saito MI, Kiss MH. Gonadal function in male adolescents and young males
with juvenile systemic lupus erythematosus. J Rheumatol 2002; 29:2000-2005
11. Gallant C, Kenny P. Oral
glucocorticoids and their complication. A review. J Am Acad Dermatol 1986; 14:161-177
12. Clements PJ, Davis J. Cytotoxic
drugs: their clinical application to the rheumatic diseases. Sem Arthritis Rheum 1996; 15: 2311-2354
13.
14. Cervera R, Font J, Carmona
F, Balasch J. Pregnancy outcome in systemic lupus erythematosus: good news for
the new millennium. Autoimmun Rev 2002; 1:354-359
li
15. Rahman P, Gladman D, Urowitz M.
Clinical predictors of fetal outcome in systemic lupus erythematosus. J Rheumatol 1998; 25:1526-1530
16.
17. Lockshin MD, Sammaritano
LR. Lupus pregnancy. Autoimmunity 2003; 36:33-40
18. Kitridou RC. The mother in systemic
lupus erythematosus. In: Wallace DJ, Hahn BH, Quasimorio Jr FP, Kilinberg JR,
editors. Dubois Lupus
Erythematosus. 5th ed. Baltimore: Williams & Williams: 1997, p.967-1002
19.
20. Schaller JG. Diagnosis
and management of rheumatic diseases in adolescence. Adolesc Med 1998; 9:1-10.