Topical
Medical Issues
Anti-Rheumatic Medications During
Pregnancy and Lactation (Part 2)
This article is a direct continuation of the article entitled “Anti-Rheumatic Medications During Pregnancy and
Lactation,” which was published in the Summer 2002 edition of this journal. The approach to the use of anti-rheumatic
medications during pregnancy and lactation was discussed in the previous article, and will not be reproduced here.
This article covers further anti-rheumatic medications, particularly disease-modifying anti-rheumatic drugs (DMARDs),
and their use in the treatment of pregnant and lactating patients. An extensive table covers those drugs not discussed in
the text, including biologics.
GOLD SALTS (SODIUM AUROTHIOMALATE)
(INTRAMUSCULAR INJECTION)
There are a very limited number of cases of gold
exposure during pregnancy to be found in the literature, and many of these reports are old—probably
reflecting the limited use of gold in the treatment of
rheumatic diseases in the world outside of Canada,
particularly with the increased use of methotrexate
(MTX) over the last two decades.
Gold salts cross the human placenta and deposit
within the placenta, fetal liver and kidney,1-3,5,6 but
the amount of the maternal dose that reaches the
fetus is variable (57% to equal maternal serum
concentrations and fetal-cord blood).1,2
There is no evidence of increased teratogenicity
or congenital malformations in fetuses that have
been exposed to gold during pregnancy.1-3,5,6
According to the Food and Drug Administration
(FDA), gold salts fall under “category C” (see bottom of Table on page 8). Almost all reports of fetal
exposure to gold have ended in uneventful deliveries of healthy infants. The relationship between the
few infants reported with abnormalities and the
exposure to gold during pregnancy is not clear.1,2,5
Overall, it seems unlikely that gold causes any
fetal abnormalities, however, more reports—
including long-term studies—of gold use during
pregnancy are needed to verify this statement.1-3,5,6
Gold is most commonly used to treat rheumatoid
arthritis (RA), although it is also used to treat other
rheumatic diseases, especially psoriatic arthritis. In
Stephanie Ensworth, BSc(Pharm), MD, FRCPC, FRCP(Rheum),
ABIM is Director of the Rheumatic Diseases in Pregnancy
Program at the Children’s and Women’s Health Centre of
British Columbia, Division of Rheumatology, University of
British Columbia, Vancouver, British Columbia.
4 / The Journal of the Canadian Rheumatology Association
70% to 75% of RA cases, the RA substantially improves or goes into remission during pregnancy, often
negating the need for medication during this period;
however, RA almost always flares post-partum.9,10
Thus, gold may not be needed during most RA pregnancies, but will be needed post-partum.
Management of RA during pregnancy must be
planned with the patient well in advance of her discontinuation of contraception, due to the long halflife of gold, and the finding in rats of gold in the
yolk sac. This finding suggests that if gold does
cause any teratogenicity, it may occur very early in
the pre-embryonic stage of pregnancy.11,12 It would
therefore appear pointless to discontinue gold at the
diagnosis of pregnancy, if the only reason is to protect the fetus from any potential risks due to gold
(although the risks appear very low). If the patient
and treating rheumatologist wish to avoid using gold
during the patient’s pregnancy, it is recommended
that it be discontinued three months prior to pregnancy. If gold is chosen to treat (or to help prevent)
post-partum RA flares (which can be very severe), it
should be restarted approximately one to three
months prior to delivery, due to the long onset of
action of gold (post-partum RA flares usually peak at
two to three months post-partum, but can begin as
early as two weeks post-partum). The use of gold in
the third trimester would be estimated to be associated with even lower risk than in the first trimester.
The American Academy of Pediatrics (AAP) considers gold salts to be compatible with breastfeeding,7 despite the fact that side effects have been
reported.8
METHOTREXATE (MTX)
Most of the data about the use of MTX prior to and
during pregnancy is derived from cancer literature,
where the dose of MTX used is much higher than in
the rheumatic diseases.1,3,5,14,22 MTX is stored in
maternal tissues and crosses the placenta to the
fetus.1 Maternal ingestion of MTX prior to pregnancy (three months prior in the rheumatic diseases,
but up to six to seven months prior in treatment of
cancers) and during pregnancy has significant
potential to cause spontaneous abortions, and is
embryotoxic, causing multiple fetal anomalies and
intrauterine growth retardation (IUGR).1-3,13-23 The
pattern of malformations that occur in infants
exposed to MTX or any other folic-acid antagonists,
particularly in the first trimester, is called the
Aminopterin Syndrome.3,18,19,22,23 Newborn myelosuppression has been reported with MTX, but could
also be due to other immunosuppressives coadministered.3,13 One case of a normal female karotype
infant was found to have chromosomal anomalies
(gaps and a ring chromosome) with a theoretically
increased risk for cancer and genetic damage in the
next generation.1
When being used to treat rheumatic disease,
MTX is contraindicated for both women and men
for three months prior to discontinuation of contraception. MTX is also contraindicated during pregnancy and breastfeeding.2-4,13-23 According to the
FDA, MTX falls under “category X.”
For men and women receiving MTX treatment
for rheumatic disease who wish to pursue pregnancy, months of pre-pregnancy planning is
required. The patient needs to be tapered off the
MTX (to avoid a post-MTX arthritis flare), and the
MTX should be switched to a DMARD that is safe
during pregnancy (discussed above and below and
also in Part 1 of this article). A change from MTX
to another DMARD therapy must be accomplished
at least three months prior to discontinuation of
contraception.3,13 In women with rheumatic
diseases such as connective-tissue disorders
(e.g., Systemic Lupus Erythematosus [SLE]) and the
rare patient with one of the serious vasculidities
(e.g., Polyarteritis Nodosa, Churg-Strauss or
Wegener’s Granulomatosis), the DMARD switch is
recommended six months prior to pursuing pregnancy, to ensure that the multisystem disease is
quiescent and stable on the new DMARD for six
months before pregnancy.24,25,29
When discontinuing MTX prior to pursuing pregnancy in either men or women it is recommended
that folic-acid supplementation be continued prepregnancy and throughout the pregnancy, as MTX is
a folic-acid antagonist and folic acid is extremely
important in preventing neural-tube defects in the
embryo.3,13,26
It is worthy of note that, in contrast to the above,
there are reported cases of normal, healthy infants
who were accidentally exposed to MTX in utero
(particularly, but not exclusively, if the MTX exposure was prior to six weeks gestation and in a low
dosage of 10 mg MTX per week).2,13,14,22,23,27
These scattered reports of normal infants, however,
are overwhelmed by the reports of severe teratogenicity and embryotoxicity, clearly indicating that
MTX is contraindicated three months prior to pregnancy, during pregnancy and during lactation.
These scattered reports of normal pregnancy
outcomes also do not change the recommendations
that men and women ingesting MTX must be using
a reliable form of contraception to avoid
pregnancy.2,3,13,14,27
When discontinuing MTX prior to pursuing
pregnancy in either men or women it is
recommended that folic-acid supplementation
be continued pre-pregnancy and throughout the
pregnancy, as MTX is a folic-acid antagonist
and folic acid is extremely important in
preventing neural-tube defects in the
embryo.3,13,26
AZATHIOPRINE (AZA)
AZA readily crosses the placenta, but the fetal liver
lacks the enzyme to convert AZA to its active
metabolite (6-mercaptopurine), which appears to
protect the fetus from teratogenic effects.2,3,5,13
Only trace amounts of 6-mercaptopurine (derived
from AZA in the maternal circulation) cross the
placenta.1,5,13
AZA has been used extensively in pregnancies in
patients who have undergone solid-organ
transplantation and in patients with inflammatorybowel disease, with no reports of any congenital
defects that have been definitely associated with
the AZA.1-3,5,13,16,21,30-34 AZA is now successfully
used in SLE pregnancies, and appears to be safer in
these pregnancies than in solid-organ-transplant
pregnancies.14 Various sporadic anomalies have
been reported, but these have not been felt to be
associated with AZA use during pregnancy.3,5,13,21
Spontaneous abortions,30,33 IUGR and prematurity
The Journal of the Canadian Rheumatology Association / 5
Table
ANTI-RHEUMATIC DRUGS DURING PREGNANCY AND LACTATION
Drug
FDA
Category*
Animal Studies
Human Experience
Breastfeeding
Leflunomide
(LF)
X
Animal data have shown an
increased rate of malformations & terogenicity as well
as fetal death in various
species.3,44
LF is a relatively new drug for treatNo information available and,
ment of RA, available in the USA
thus, considered contraindicated
since late 1998; thus, there is no induring breastfeeding.
formation about its use in pregnancy.
LF is currently contraindicated in
pregnancy & considered to have
teratogenic potential in humans (a
terogenicity registry is underway). Due
to LF’s long elimination half-life, it is
recommended that women & men
wishing a pregnancy should discontinue LF 2 yrs. prior to pursuing pregnancy or undergo a “drug-elimination”
procedure with either cholestyramine
(8 g po TID x 11 days) or activated
charcoal (50 g po QID x 11 days) followed by two blood tests, 14 days
apart, to verify LF plasma levels of
<0.02 mg/L, or repeat treatment.3,23,44-47
D-Penicillamine
(d-Pen)
D
Studies in pregnant rats, administered 6x the maximum
dose in humans, experienced
fetal resorptions & fetal
anomalies consisting of skeletal defects & cleft palates.1
Skin laxity in animals has
also been reported.3
Data on d-Pen use is sparse & conflicting & comes from the use of
d-Pen in patients with RA, Systemic
Sclerosis (SSc), Wilson’s disease &
cystinuria in pregnancy. D-Pen crosses the placenta, but there are reports
of normal infants who were exposed
to d-Pen for part or all of a pregnancy,
especially in Wilson’s disease. There
are also, however, reports of fetal anomalies. It is, thus, recommended that
d-Pen be used in pregnancy only
when absolutely necessary, such as in
Wilson’s disease, cystinuria or SSC,
in the lowest possible effective dose.
There are safer medications to treat
RA during pregnancy than d-Pen.
Thus, d-Pen should not be used to
treat RA in pregnancy & should be
stopped beforehand or immediately
at the beginning in the case of an
unplanned pregnancy.1,3,6,48
There are no reports of d-Pen in
lactation or on whether it is excreted in breast milk. D-Pen has
a short plasma half-life & is extensively protein-bound; thus,
one would theorize that only
small amounts should be present
in breast milk. Due to the lack
of information, breastfeeding
mothers ingesting d-Pen should
be advised against breastfeeding.1,49
* The Food and Drug Administration (FDA) in the United States has established categories of risk factors for most drugs in pregnancy, based on the
level of risk the drug poses to the fetus (risk factors A, B, C, D, and X):1,4
A - Controlled studies have revealed no risk to the fetus (virtually no drugs in this category)
B - No evidence of risk to the fetus has been reported in humans
C - Risk to the fetus cannot be ruled out, because either there is insufficient information available about the drug in animal or human pregnancies, or
there are animal studies that have revealed adverse effects but no studies or reports in humans
D - There is positive evidence of human fetal risk, but the benefit may outweigh the risk
X - Contraindicated; benefit does not outweigh the risks; there is evidence of fetal risk based on human experience
have been reported, but it is unclear whether these
are related to: 1) AZA; 2) other simultaneously ingested medications that most of these patients also
require; or 3) the underlying disease/condition for
which the patient required the AZA.1-3,5,14,30,32-34
8 / The Journal of the Canadian Rheumatology Association
Newborn immunosuppression of various severities (e.g., cytopenias and/or low immunoglobulin M,
A and/or G levels) have been reported1,2,5,13,14 with
in utero exposure to AZA. Most of these cases seem
to have resolved without incident, but one infant
Table (cont’d)
ANTI-RHEUMATIC DRUGS DURING PREGNANCY AND LACTATION (CONT’D)
Drug
FDA
Category*
Animal Studies
Human Experience
Breastfeeding
Tetracyclines
(Doxycycline;
minocycline)
D
Doxycycline administered
to pregnant rats resulted in
a delay in skeletal differentiation in the long
bones.50
Tetracyclines are generally contraindicated during pregnancy and should not
be used to treat rheumatic disease during pregnancy because tetracyclines are
associated with dental staining and interference with bone growth in exposed
fetuses in utero; thus, in treatment of
rheumatic diseases during pregnancy,
there are safer medications that can be
be used. When needed as an antibiotic,
there are conflicting reports regarding
association of tetracyclines with congenital anomalies.1,51-53
Tetracyclines are excreted into
breast milk in low concentrations
& serum levels of tetracyclines
in exposed infants have been
undetectable. There are theoretical concerns regarding dental
staining & inhibition of bone
growth that could occur in
breastfed infants of mothers ingesting tetracyclines. There is
also potential concern regarding
modification of bowel flora in
the breastfed infant, & interference with the interpretation of
culture results in the investigation of an exposed infant with a
fever. The AAP, however, considers tetracyclines to be compatible with breastfeeding.1,7
Cyclophosphamide (CTX), an
antineoplastic
alkylating agent
D
Clearly embryofetotoxic,
teratogenic & mutagenic in
animals.1,2,14 Teratogenicity
in mice, in one study,
was dose-related.14
Infants with and without congenital anomalies have been reported after exposure to CTX in utero.1,13 First-trimester
exposure to CTX appears to be teratogenic. Exposure in 2nd & 3rd trimesters
does not appear to be associated with
birth defects or neurologic abnormalities, but these infants are at risk for
bone-marrow suppression at birth &
low birth weight (but the latter could
also be due to the disease for which the
CTX is required as well as to other simultaneously administered meds). Longterm effects in humans from exposure
to CTX during pregnancy are unknown.
CTX should be considered teratogenic
& contraindicated during pregnancy
unless absolutely required to treat
maternal life-threatening rheumaticdisease flares in 2nd or 3rd trimesters
of pregnancy.2,3,13,14,48 CTX should be
discontinued three months prior to
discontinuing contraception.3
CTX is excreted into breast milk.
The AAP & others consider CTX
contraindicated during breastfeeding, with risks including
infant neutropenia & adverse
effects related to immune
suppression, growth & potential
carcinogenesis.1,3,7,13,14
AAP=American Academy of Pediatrics
was born with pancytopenia and severe combined
immune deficiency, and died of complications at
age 28 days.1,14 These reports of newborn immunosuppression seem to be related to the maternal dose
of AZA. One study revealed a significant correlation
between the maternal white-blood-cell count (WBC)
at 32 weeks’ gestation and the umbilical-cord WBC
at delivery. The investigators in this case halved the
maternal dose of AZA at 32 weeks’ gestation if the
maternal WBC count was at or below one standard
deviation for normal pregnancy; since commencing
this protocol, this institution has had no episodes of
newborn immunosuppression.1,3,5 There are two
reports of newborn cytomegalovirus infection.3,5,13
There has been one case report of a child with a
balanced translocation and partial deletion of
chromosome 7 following in utero exposure to AZA,
but it is unclear whether this was related to the AZA
therapy.3,14 There are also reports of other reversible
chromosomal aberrations.3,6
The Journal of the Canadian Rheumatology Association / 9
Table (cont’d)
ANTI-RHEUMATIC DRUGS DURING PREGNANCY AND LACTATION (CONT’D)
Drug
FDA
Category*
Animal Studies
Human Experience
Breastfeeding
Chlorambucil;
an antineoplastic
alkylating agent
D
In rats, chlorambucil has
shown to be 3x more potent as a teratogenic agent
(on a mg/kg basis) than
cyclophosphamide (CTX).14
Very similar to CTX during pregnancy
but less data available. Reports of
normal infants & infants with congenital anomalies exposed to chlorambucil
in utero. Two reports of left-kidney &
ureter agenesis following 1st-trimester
exposure1,13 & cardiovascular anomalies.3 Chlorambucil is contraindicated
during pregnancy.3,13,14,48
No reports of chlorambucil in
breastfeeding but because of its
potential for severe adverse
effects, breastfeeding is
considered contraindicated for
mothers ingesting
chlorambucil.1,3,13,14
Mycophenolate
mofetil (MMF)
C
Studies using MMF in subtherapeutic human dosages
in pregnant rats & rabbits
revealed fetal resorptions
& malformations.1
There are minimal data on the use of
MMF during human pregnancy, all of
which arise from use of MMF in pregnant solid-organ-transplant patients.
MMF is theorized to cross the placenta,
as MMF & its metabolite are of low
molecular weight and, also, presumed
to cross because of the results of animal studies.1 There is one case report
of a mother who had undergone renal
transplant who ingested MMF throughout the entire pregnancy (in addition to
tacrolimus & prednisone); a premature
(35 & 3/7 weeks gestation) but otherwise healthy female infant was delivered, & the only anomalies found were
hypoplastic nails & short 5th fingers.54
A report from one transplant registry
noted “no structural malformations”
among offspring exposed to MMF (five
mothers, 29 fathers);55 although the
same authors in another paper stated
that “there are concerns about the reproductive safety of MMF.”56 A European
transplant group does “not recommend”
MMF during pregnancy “based on current information available.”57 Due to
lack of sufficient data & results from
animal studies, there is concern re: the
safety of MMF during pregnancy, & the
manufacturer of MMF recommends
that patients ingesting MMF use contraception, and that pregnancy not be pursued until 6 weeks after stopping MMF.1
MMF is excreted into the breast
milk of rats but there are no
reports of the use of MMF in
human lactation. Due to lack of
available data & the potential for
risk to the infant if exposed to
MMF, breastfeeding should be
considered contraindicated for
mothers who are ingesting
MMF.1
* The Food and Drug Administration (FDA) in the United States has established categories of risk factors for most drugs in pregnancy, based on the
level of risk the drug poses to the fetus (risk factors A, B, C, D, and X):1,4
A - Controlled studies have revealed no risk to the fetus (virtually no drugs in this category)
B - No evidence of risk to the fetus has been reported in humans
C - Risk to the fetus cannot be ruled out, because either there is insufficient information available about the drug in animal or human pregnancies, or
there are animal studies that have revealed adverse effects but no studies or reports in humans
D - There is positive evidence of human fetal risk, but the benefit may outweigh the risk
X - Contraindicated; benefit does not outweigh the risks; there is evidence of fetal risk based on human experience
It is unclear whether these isolated reports of
immunoglobulin deficiency, chromosomal abnormalities and malformations in fetuses exposed to
AZA in utero are any more common than the rate
12 / The Journal of the Canadian Rheumatology Association
occurring in the normal healthy obstetrical population.14 There remain unanswered, potential, longterm affects on offspring exposed to AZA in utero,
such as the child’s future fertility and risk of carcin-
Table (cont’d)
ANTI-RHEUMATIC DRUGS DURING PREGNANCY AND LACTATION (CONT’D)
Drug
FDA
Category*
Etanercept (ET)
Infliximab (IN)
Animal Studies
Human Experience
Breastfeeding
B
Studies using ET in pregnant rats & rabbits, at
60-100x the human dose,
revealed no fetal
harm.1, Enbrel product monograph
The FDA has labeled ET as “class B” in
pregnancy based on short-term studies
in rats & rabbits;3 however, there is virtually no information on ET use in human pregnancy. A recent study reported
eight pregnancies in patients taking ET:
six resulted in full-term healthy infants
(two abortions—one spontaneous &
one therapeutic).23 The manufacturer of
ET recommends that “because animal
reproduction studies are not always
predictive of human response, this drug
should be used during pregnancy only
if clearly needed.”
No reports of ET during human
lactation. The effects of exposure
to ET on a breastfeeding infant
are unknown at this time. Thus,
breastfeeding not recommended
for mothers using ET. The manufacturer of ET states that “because
many drugs & immunoglobulins
are excreted in human milk, &
because of the potential for serious adverse reactions in nursing
infants from ET, a decision
should be made whether to discontinue nursing or to discontinue the drug.”
B
IN was administered to
pregnant mice as an “analogous antibody,” in doses
4-10x the human dose,
without any adverse fetal
effects.
Virtually no data on IN use during human pregnancy. In one recent study,
two patients became pregnant while
taking IN with delivery of one full-term
healthy infant (outcome of the other
pregnancy not stated).23 One abstract
reported pregnancy outcomes in 45
Crohn’s patients, four RA patients & one
JRA patient, with 16 having exposure to
IN in 1st trimester (the remainder had
exposure just prior to pregnancy); these
pregnancy outcomes were the same as
those of a national cohort of healthy
women.58 There is one report of a very
ill patient with Crohn’s disease on multiple medications, including AZA &
metronidazole, who received IN infusion
six weeks prior to conception & an
infusion at the time of conception; this
pregnancy ended with the premature
delivery of a 24-week, 681-g infant who
died at three days (it is unknown if IN
had any role in this outcome as there
were many confounding factors,, including severe maternal disease & multiple other meds).59 The manufacturer of
IN states that it “should be given to a
pregnant woman only if clearly needed.”
Exactly the same for IN as for ET
(above). The manufacturer states
in the product monograph that
“a decision should be made
whether to discontinue nursing
or to discontinue the drug, taking into account the importance
of the drug to the mother.”
AZA=azathioprine; RA=rheumatoid arthritis; JRA=juvenile rheumatoid arthritis
ogenesis.3,6,13,14,33-35 According to the FDA, AZA
falls under “category D.” At present, the greatest
known risk to infants exposed to AZA in utero is
IUGR and prematurity, and this risk is unlikely
related to AZA exposure alone.2,14,30,32-35
It should be noted that there are several reports
of renal-transplant patients ingesting AZA who
have conceived pregnancies with intrauterine contraceptive devices (IUDs) in situ. It is felt that AZA
may interfere with the contraceptive action of
IUDs; it is therefore recommended to advise
patients of this, and to advise them to consider
using either another form of contraception or an
additional form of contraception.1
Overall, it appears that AZA, in the lowest
effective dose, is relatively safe in pregnancy,
when the benefits of this medication outweigh the
possible risks to the fetus/newborn.2-5,13,21,30-34 If
The Journal of the Canadian Rheumatology Association / 13
AZA is necessary to control SLE disease activity
during pregnancy, its use has been associated with
improved pregnancy outcome compared to those
who were not treated.4,28 Of all the immunosuppressive agents, it would appear that AZA is the
safest to use during pregnancy, if an immunosuppressive agent is required.13
Motherisk, in Toronto, Canada, and others3,14
state that AZA is excreted into breast milk in low
concentrations. The AAP considers breastfeeding
not recommended when mothers are ingesting
AZA due to lack of information and data on longterm outcome.3,13,14
CYCLOSPORINE A (CSA)
The use and experience of CsA during pregnancy is
very similar to that of AZA and, in fact, these
immunosuppressive agents have frequently been
used together in the same patients, along with
prednisone (particularly in management of pregnant
patients who have undergone solid-organ trans-
Of all the immunosuppressive agents, it would
appear that AZA is the safest to use during
pregnancy, if an immunosuppressive agent is
required.13
plantation).2,14,30,32-35,37-39 CsA has been used to
treat a limited number of autoimmune patients with
severe RA, psoriasis, SLE and other connectivetissue disorders, inflammatory bowel disease and
chronic inflammatory demyelinating polyneuropathy during pregnancy.2,3,14,30-40 There are no
reports in humans of any fetal malformations
associated with the use of CsA during pregnancy.
Similar to AZA, there was a high rate of spontaneous abortions (approximately 35%), IUGR (average about 50%) and prematurity (54%).2,14,30,32-40
CsA has a lower bone-marrow toxicity and lower
carcinogenic potential compared to other immunosuppressive agents and, overall, complications in
newborns have been slightly lower than complications in newborns exposed to other immunosuppressive agents.2,14
Maternal morbidity was significant in those who
ingested CsA, including hypertension (56%),
14 / The Journal of the Canadian Rheumatology Association
pregnancy-induced hypertension (29%), preeclampsia and gestational diabetes. These maternal
morbidities were reported, however, in renaltransplant patients—patients who are already at
higher risk for development of these complications
than most patients with autoimmune diseases who
receive CsA during pregnancy.2,14,34
Two studies have followed offspring long-term,
who were exposed to CsA in utero (usually also with
prednisone and/or AZA), up to 11 years and 18 years
of age, respectively.35,39 No health problems developed in any of the offspring that were more than
those developed in the average population, except
possibly the development of “urinary-tract abnormalities on ultrasound” in four out of 40 (10%) in the
second study only.39 Both studies came to the same
conclusions that, despite the high incidence of preterm delivery and low birth weight, the offspring of
renal-transplant recipients were doing well.35,39
Long-term studies are still needed to determine
whether there will be any effects other than, possibly,
urinary-tract abnormalities.
CsA appears to be a safe immunosuppressive
agent to use in a pre-pregnant or pregnant
autoimmune-disease patient who requires such
therapy.2,14,30,32-40 According to the FDA, CsA falls
under “category C.”
The AAP considers CsA contraindicated in
breastfeeding due to the potential immune suppression, neutropenia, unknown effect on infant growth
and possible long-term risk of carcinogenesis.7
CONCLUSION
It is most important to avoid the use of any and all
medications during pregnancy, as the long-term
effects on the fetus/infant are often unknown. In any
pregnancy, there is a small chance (5%) of a
spontaneous congenital anomaly occurring, leaving
the physician(s) to wonder whether medication(s)
ingested by the mother played a role or not, and
usually always leaving the mother with strong
feelings of guilt (no matter how necessary the
medication was during the pregnancy). In the
rheumatic diseases in pregnancy, often, medications
cannot be avoided and are absolutely necessary for
the best pregnancy outcome for both mother and
infant. Medications often are required to control the
rheumatic disease through pregnancy, especially
when guiding mothers through a pregnancy with
SLE and other related connective-tissue disorders,
Behcet’s Syndrome, sarcoidosis or the vasculidities.
If the rheumatic disease becomes active or flares
through pregnancy, the pregnancy outcome can be
severely compromised, usually with premature
delivery of an IUGR infant who must spend time in
a special-care nursery, potentially developing
morbidities related to prematurity (or suffering an
intrauterine death); there is also significant maternal
morbidity and occasionally maternal death. Thus,
the risks of leaving some of these rheumatic
disorders untreated during pregnancy, for fear of
adverse drug effects, are far outweighed by the
benefits of careful use of medication during
pregnancy. Of course, with these particular
rheumatic disorders, pregnancy should never be
considered unless the disease is well controlled or,
most preferably, in remission, requiring minimal or
no medication use during pregnancy.
In other rheumatic diseases, where maternal
vital-organ involvement and appropriate fetal
development are not at risk directly due to the
rheumatic disorder (e.g., RA, psoriatic arthritis,
spondyloarthritis, juvenile idiopathic arthritis), the
potential risks of medications must be carefully
weighed against the progression of joint damage
through pregnancy, as well as maternal pain and
function.
References
1. Briggs GD, Freeman RK, Yaffe SJ: Drugs in pregnancy and lactation.
6th edition. Lippincott Williams & Wilkins, Philadelphia, 2001.
2. Esplin MS, Branch DW: Immunosuppressive drugs and pregnancy.
Obstet Gynecol Clin North Am 1997; 24(3):601-16.
3. Janssen NM, Genta MS: The effects of immunosuppressive and
anti-inflammatory medications on fertility, pregnancy, and lactation.
Arch Intern Med 2000; 160(5):610-9.
4. Ostensen M, Ramsey-Goldman R: Treatment of inflammatory
rheumatic disorders in pregnancy: what are the safest treatment
options? Drug Saf 1998; 19(5):389-410.
5. Ostensen M: Treatment with immunosuppressive and disease modifying drugs during pregnancy and lactation. Am J Reprod Immunol
1992; 28(3-4):148-52.
6. Needs CJ, Brooks PM: Antirheumatic medication in pregnancy. Br J
Rheumatol 1985; 24(3):291-7.
7. American Academy of Pediatrics Committee on Drugs: The transfer
of drugs and other chemicals into human milk. Pediatrics 1994;
93(1):137-50.
When counseling a breastfeeding mother, the
same risks versus benefits must be carefully balanced. It is sometimes necessary to advise the breastfeeding mother that the necessity for certain medications for her own health clearly outweighs the
benefits to the infant of being breastfed, and that
the decision to discontinue breastfeeding to allow
optimal treatment of the rheumatic disease is the
best decision for mother and infant. An ill, dysfunctional, depressed, breastfeeding mother who is unable to do anything else for that infant is of much
less benefit to the appropriate development of the
infant than is a much healthier, non-breastfeeding
mother.
Fortunately, as discussed in this article and in
Part 1 (see Summer 2002 issue of the CRAJ), there
are many medication choices that are now felt to
be safe during pregnancy (especially in the short
term or for part of a pregnancy) and lactation. The
use of these medications in these situations must
be clearly justified, with the benefits definitely
outweighing any potential risks. These medications
have allowed pregnancies in women with rheumatic diseases, when, only a decade ago, these
women were strongly advised against pregnancy.
Pre-pregnancy counseling and pregnancy planning
in the rheumatic diseases is imperative to a
successful pregnancy outcome.
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