| Anti-Rheumatic Drugs In Pregnancy Ann L. Parke, MD
Division of Rheumatology
University of Connecticut Health Center,
School of Medicine
Farmington, CT
Summary Points
Introduction
Pregnancy occurring in patients with rheumatic diseases
poses several problems for the health-care provider: 1) the effect of the pregnancy on
disease; 2) the effect of the disease on the pregnancy; and 3) how to manage the disease
during the pregnancy. This article focuses on the effects of commonly used medications to
treat rheumatic diseases on pregnancy.
Many of the drugs used to treat rheumatic diseases are
listed in Table 1.The coding listed next to the name of the drug is the FDA coding with
reference to their risk in pregnancy.
Guidelines for the use of these drugs in pregnancy are
given in Table 1.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
All NSAIDs are contraindicated in the third trimester
because they can promote premature closure of the ductus arteriosus, which will result in
pulmonary hypertension for the fetus. However, some studies have shown reversal of the
ductal constriction within 48 hours of the stopping the NSAID (1).
Reduction of the amount of amniotic fluid, an increased
risk of fetal hemorrhage, and postpartum bleeding have all been described with the use of
NSAIDs throughout pregnancy. Certain NSAIDs may be indicated for a variety of problems
associated with pregnancy, including premature labor.
A study by Monika and Harold Ostensen addressed NSAID use
in pregnancy and compared 2 groups of patients with rheumatic diseases during pregnancy.
Eighty-eight patients were enrolled in the study, and half were randomized to continue
NSAIDs throughout pregnancy. This study showed no difference between the 2 groups with
respect to pregnancy outcome, duration of labor, and neonatal health (2).
Some NSAIDs are approved for use during lactation, but,
because these drugs have a potential to displace bilirubin, there is the risk of
increasing jaundice and kernicterus in these neonates. Insufficient data are available on
the selective COX-2 inhibitors and breast-feeding.
Glucocorticoids
Patients with rheumatic diseases often require
glucocorticoids to control their disease, and this is important in patients with diseases
that may flare during pregnancy. Prednisone is the usual oral treatment of choice, and it
is safe to use in pregnancy as only very small amounts crosses the placenta. Even large
doses (ie, > 60 mg daily) can be given without too much concern for the fetus.
Hydrocortisone and cortisone cross the placenta, but a placental enzyme
11ß-ol-dehydrogenase converts the hydrocortisone to cortisone, which is a biologically
inactive steroid.
Steroids given to treat an ailing or premature fetus must
cross the placenta. Fluorinated steroids, betamethasone, or dexamethasone cross the
placenta.
Antimalarial Drugs
The use of the 4-amino quinoline drugs during pregnancy is
controversial. Concern has arisen because these drugs can cross the placenta and are
deposited in fetal-pigmented tissues (3). The tissue deposition of hydroxychloroquine is
approximately 2.5 times less than that of chloroquine, so hydroxychloroquine is the more
desirable if these agents are continued throughout pregnancy.
The argument for not stopping these drugs during pregnancy
is that they are very useful for treating SLE, and several studies have shown that
stopping them can result in flares of disease activity. For the lupus patient who becomes
pregnant unexpectedly, because the half life for these drugs is so long, the fetus will
still be exposed throughout organogenesis, even if the drug is stopped as soon as the
pregnancy is known. Our current recommendation for lupus patients who become pregnant
unexpectedly is that it is safer to continue antimalarial medication throughout pregnancy
than to discontinue it. Hydroxychloroquine is preferred, and the lowest possible dose
always should be used.
For the lupus patient who is planning a pregnancy, the
potential toxicity should be explained carefully. The patient must understand that
stopping the drug may precipitate a flare, and any flare of disease may delay conception.
A recent survey of antimalarial drug use during lupus
pregnancy and lactation revealed that the majority of lupus experts continue these drugs
throughout pregnancy and lactation (4). Motta, Tincani et al recently reported 35 infants
born to 34 women who took hydroxychloroquine throughout pregnancy and the postpartum
period as treatment for a rheumatic disease. Eight infants were breastfed and 16 of the 35
infants studied had an ophthalmologic assessment at birth and again at 1 year. No baby had
ocular symptoms or complications as a consequence of the maternal treatment with
hydroxychloroquine (5).
The current recommendation is that these agents can be used
during lactation but the data examining excretion in breast milk is very scant and
requires further study.
Methotrexate
Methotrexate is an antimetabolite and interferes with folic
acid metabolism and purine synthesis. Fifty percent of fetuses exposed to methotrexate may
be abnormal with multiple cranial abnormalities, particularly with exposure during the
first trimester. This drug is also an abortofactant and should not be used by women
attempting to become pregnant. Methotrexate is widely distributed throughout body tissues
with reports of persistence of this drug in the liver up to 116 days after exposure.
Because of concerns about the potential for abnormalities in ova and spermatoza, we
recommend that patients taking methotrexate discontinue this drug 4 months prior to
conception.
Methotrexate is contraindicated during lactation.
Leflunomide
Leflunomide inhibits pyrimidine synthesis and is an immune
modulator by inhibiting T cell proliferation and activation, as well as DNA synthesis.
Animal studies have shown that leflunomide is embryotoxic.
The current recommendations are that leflunomide should not be used in pregnancy, and any
patient taking this drug and wishing to become pregnant should be treated with
cholestyra-mine (8 grams three times daily for 11 days) or charcoal to reduce the blood
level to 0.03 mg/litre which is considered to be the safe human level. The current
recommendations are to treat with cholestyramine and then wait for three cycles before
attempting pregnancy. Patients who become pregnant unexpectedly need to understand that
even if cholestyramine is used as soon as the pregnancy is known, the fetus will be
exposed to leflunomide during organogenesis. The most dangerous time for neural
development is between 8 and 15 weeks of gestation.
The concern for men taking leflunomide during conception is
less because the drug is not mutogenic (6). Human experience with this drug is limited,
but it is recommended that men discontinue this medication prior to fertilization.
Leflunomide is considered to be incompatible with breast
feeding, but little is known about the pharmacokinetics of this drug in breast milk.
Sulfasalazine
Sulfasalazine (5-aminosalicyclic acid and sulfapyridine)
and some of its metabolites cross the placenta but this drug is considered safe in
pregnancy. Men planning to start a family should be advised that this drug is known to
affect spermatogenesis. It also interferes with folic acid metabolism. Sulfapyridine is
excreted in breast milk but current recommendations are that it can be used with caution
in lactating women.
Azathioprine
Even though this drug does cross the placenta, the fetal
liver lacks the enzyme inosinate pyrophosphorylase, which is necessary to convert
azathioprine and 6-mercaptopurine to active metabolites, thus protecting the fetus from
potential teratogenic effects. Previous reports of offspring born to mothers taking
azathioprine have documented intrauterine growth retardation, neonatal leukopenia,
lymphopenia, hypogammaglobinemia and immunosuppression (7).
Breast-feeding is contraindicated in patients taking
azathioprine.
Cyclosporin A
Cyclosporin A is a selective immunosuppressant that has an
ability to inhibit the activation of T cells, preventing the formation of IL-2.
Cyclosporin A is known to cross the placenta and is found in fetal blood.
DiPaolo et al evaluated immunological function in 6 infants
born to mothers taking cyclosporin A, and determined that T, B, and NK cell development
and maturation were impaired in these infants and continued to be impaired for up to 1
year after birth (8).
A recent study designed to determine the outcome of
pregnancy after exposure to cyclosporin A involved a meta-analysis of 15 studies and
assessed outcomes in terms of congenital malformations, premature delivery and low birth
weight. These authors concluded that the prevalence rate for congenital malformations in
these pregnancies was not statistically significantly different from that described in the
general population (2% to 3%), however, they comment that this lack of significance may in
fact be due to a paucity of data from human pregnancies. The odds ratio for pre-term
delivery and low birth weight were also not significantly different (9). Other studies
have reported a reduction in birth weight in up to 40% of these infants and an increased
risk for spontaneous abortions.
Cyclosporin A is not a teratogen, but it does cross the
placenta and exerts immune effects in the fetus and should therefore be avoided during
pregnancy.
Cyclosporin A is found in breast milk. A single case report
found a mean breast milk/maternal blood level of 84% of cyclosporin A, however,
undetectable levels were measured in the infant. This suggests that there was minimal
absorption of the drug by the infant who was observed to grow and develop normally (10).
Cyclophosphamide
Animal studies have revealed that this alkylating agent is
both teratogenic and embryotoxic. Results from human observation are less clear, and the
general recommendation is that cyclophosphamide should be avoided during pregnancy,
particularly during the first trimester. The estimated risk for congenital malformation in
these infants is about 20%, considerably higher than is normal.
Cyclophosphamide is also known to impair fertility, and the
age of the patient (> 31years) and the total dosage of the cyclophosphamide given are
additive factors that contribute to ovarian failure (11). Both male and female young
patients who are planning to have children in the future and who require cyclophosphamide
treatment should be informed of the potential infertility risks and advised of the various
options available to try to protect testicular and ovarian function. These include banking
spermatozoa for the male and suppressing ovulation or timing cyclophosphamide therapy with
menses for the female.
Cyclophosphamide is contraindicated in lactating women.
TNF Inhibitors (Etanercept and Infliximab)
Etanercept is a dimeric fusion protein and infliximab a
chimeric monoclonal antibody and both of these agents inhibit TNF-a, a pro-inflammatory
cytokine.
Because they are comparatively new, human experience with
etanercept and infliximab use during pregnancy is limited. Animal studies of etanercept,
given at dosages 60 to 100 times the usual human dose did not produce fetal toxicity. As
of the end of 2001 there were a total of 85 patients with known dates of infliximab
exposure associated with pregnancy, including 12 with exposure during the first trimester.
One case of Tetralogy of Fallot was reported in the offspring of these pregnancies, but
the incidence of live births, miscarriage and therapeutic terminations were the same in
these infliximab patients as in the normal population (12).
It is not known if etanercept is excreted in breast milk. A
single case report studying infliximab levels in breast milk suggests that infliximab is
not excreted in breast milk, as levels at 24 hours and 1 week after exposure were
undetectable (13).
Mycophenolate Mofetil
Mycophenolate mofetil is the prodrug of mycophenolic acid
(MPA), which is a purine synthesis inhibitor, exerting a greater cytostatic effect on
lymphocytes than on other cell types. MPA induces apoptosis of activated T lymphocytes,
suppresses glycosylation and expression of adhesion molecules and suppresses the
production of nitric oxide synthetase.
Reports on its use during pregnancy are limited, but to
date, no structural malformations have been noted in offspring exposed to this drug (14).
One recent case described an infant exposed to mycophenolate mofetil throughout pregnancy.
This infant was born premature, had hypoplastic nails, and short 5th fingers but is
growing and developing normally otherwise.
Animal studies have shown that this drug is excreted in
breast milk, but human studies are lacking. This drug is considered contraindicated in
pregnancy and lactation.
Conclusion
Many patients with rheumatic diseases are young women, some
of whom desire a family. Making the right therapeutic choices for these patients and
guiding them rationally through pregnancy is important.
There is data available showing that certain drugs, like
prednisone and sulfasalazine are safe when taken during pregnancy. Drugs such as
methotrexate, leflunomide and cyclophosphamide are toxic to the fetus. There is not
sufficient information available regarding the safety of the newer anti-TNF biologics
during pregnancy to advocate their use.
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