Rheum Dis Clin N Am

33 (2007) 319–343

Rheumatoid Arthritis and Reproduction

Amit Golding, MD, PhD, Uzma J. Haque, MD,
Jon T. Giles, MD*
Division of Rheumatology, The Johns Hopkins University School of Medicine,
733 N. Broadway, Suite G49, Baltimore, MD 21224, USA

Because of the potential for rheumatoid arthritis (RA) to present during

the childbearing years, every practicing rheumatologist must be able to pre-
pare the RA patient who is newly or expectantly pregnant on how their
pregnancy may affect the signs and symptoms of RA and, perhaps most im-
portantly, how RA and its treatments will affect the hopes for an optimal
outcome. Even so, there remain many unanswered (and unasked) scientific
questions that often preclude the practitioner’s ability to provide the most
concrete and informed advice. Yet still, as important as providing the best
advice and care for the pregnant RA patient is, unraveling the mechanisms
underlying the changes in RA disease activity typical of pregnancy may help
better understand the pathogenesis and treatment of RA for all patients.
Since the earliest days of pharmacotherapy for RA, the observation of clin-
ical improvement during pregnancy has prompted attempts to harness the
disease-remittive properties of pregnancy [1]. Indeed, broadly compared,
the efficacy of pregnancy in inducing clinical remission in RA is superior
to any currently used pharmacotherapeutic agent or agents. Unfortunately,
the beneficial effects of pregnancy on disease activity are not observed in
every RA patient and tend to rapidly abate postpartum [2]. In contrast, it
has been suggested that certain aspects of pregnancy, such as parity and
breastfeeding, may be associated with an increase in the incidence and/or
severity of RA [3,4]. These observations suggest that the mechanisms
underlying RA disease outcomes in pregnancy are, like RA itself, complex
and heterogeneous.
To date, the bulk of scholarship in this area has been largely observa-
tional in nature and, particularly in older studies, derives from relatively

* Corresponding author. Johns Hopkins University, The Johns Hopkins Arthritis Center,
5501 Hopkins Bayview Circle, Suite 1B.1, Baltimore, MD 21224.
E-mail address: gilesjont@jhmi.edu (J.T. Giles).

0889-857X/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.rdc.2007.01.001 rheumatic.theclinics.com
320 GOLDING et al

small cohorts of subjects. A simple estimation of the annual number of preg-

nancies occurring in women with RA (detailed below) shows that pregnancy
in women with RA is relatively uncommon and distributed over a wide geo-
graphic region. Only recently has interest fueled the organization of multi-
center prospective cohorts of pregnant RA patients and the analysis of
nationally collected administrative claims datasets with adequate numbers
of patients to arrive at reliable conclusions about even the most basic aspects
of the natural history of the disease in relation to reproduction.
In the last decades, discoveries and advances in cytokine and hormone re-
search have permitted detailed investigation into the immunodynamics of
pregnancy. However, only a handful of investigations have delved into the
molecular basis of the disease-modifying properties of pregnancy in RA
[5–7]. The inherent complexity of studying the interplay of many immune,
inflammatory, and endocrine pathways, coupled with expense and the diffi-
culty in establishing the cohorts are also to blame for the current lack of
depth in the understanding of the mechanisms underlying the changes ob-
served in RA during pregnancy and in the postpartum period. Over these
same decades, aggressive management of RA disease activity has become
the norm in all RA patients, presenting unique challenges to practitioners
who care for RA patients of childbearing age. With the introduction of
new drugs and combination regimens to daily practice, particular attention
is required to understand the short- and long-term effects on reproduction.
Unfortunately, most of this information is not known before widespread use
and is difficult to systematically evaluate. The result is that some drugs may
be improperly used in the RA patient of childbearing potential, whereas
others that are withheld may be of benefit.
Within this context, this chapter reviews the current understanding of the
natural history of RA over the course of reproductive life, including how
pregnancy may affect RA disease outcomes and, in turn, how RA may affect
pregnancy outcomes. Building on these clinical observations, we explore
proposed mechanisms of immunomodulation during normal pregnancy
and pregnancy in the RA patient. Finally, a practical outline of the safety
profiles during pregnancy and lactation of commonly used RA pharmaco-
therapeutics is presented.

Rheumatoid arthritis and pregnancydclinical observations

Estimating the annual incidence of pregnancy in rheumatoid arthritis
In considering the interplay between pregnancy and RA, it is helpful to
know how often these two conditions co-exist. This not only frames the dis-
cussion, but can also give a reasonable prediction of the frequency with
which practitioners, either obstetricians or rheumatologists, are likely to en-
counter the unique challenge of managing both pregnancy and RA concur-
rently. However, vital statistics for the annual incidence of pregnancy in
 RHEUMATOID ARTHRITIS AND REPRODUCTION 321

women with RA are not readily available. For this review, we attempt to ar-
rive at an estimate of the yearly incidence of pregnancy in RA by combining
separately derived national epidemiologic data on the two conditions.
The estimated number of women with RA in United States is approxi-
mately 2 million, based on the most recent study of prevalence reporting
13.7 per 1,000 women and a total population of 150 million women in the
United States [8]. As discussed below, approximately 91% of women have
one child in their lifetime [9], yielding an expected number of total births
of 1,820,000. Of those who decide to have one child, the minority are diag-
nosed with RA before becoming pregnant (17% in Katz [9]), bringing the
number of newly pregnant women to 309,400. If we assume that the major-
ity of women becoming pregnant are between the ages of 20 and 40, the Cen-
ters for Disease Control cumulative number of pregnancies per 1,000
women in the year 2000 was 136 [10]. Therefore, the number of newly preg-
nant women age 20 to 40 years with a diagnosis of RA is approximately
42,000, which, divided by 20 years, is 2,100 pregnancies annually. This is
likely an overestimate, because the number of pregnancies per 1,000 women
with RA of childbearing age is likely less than the general population, for
example, because the majority of women with RA choose to have only
one child in their lifetime (see below).
In a study by Reed and colleagues [11] conducted in Washington State
(population of about 6 million, versus the US population of 300 million)
there were 243 live births to women with RA from 1987 to 2001 (15 years).
Therefore, the estimated annual number of live births for the United States
is 243 of 15 multiplied by 296 of 6, or approximately 800 annual live births
to mothers with RA (assuming equal geographic distribution over the
United States).
If the number of women with RA becoming pregnant each year is in the
range of approximately 800 to 2,100 in the United States, most American
rheumatologists will only see a few pregnant women with RA during 1
year of practice. This emphasizes the importance of large databases from
multiple clinical centers to achieve meaningful epidemiologic data as well
as a centralized system for gathering patient data. In a very recent national
survey of pregnancies in women with systemic lupus erythematosus (SLE)
and RA using the Nationwide Inpatient Sample of Healthcare Cost and Uti-
lization Project, the total number of pregnancies in women with RA was
1,425 in 2002 [12], a statistic consistent with the estimated range calculated
above.

The impact of pregnancy on rheumatoid arthritis

The impact of pregnancy on disease activity in rheumatoid arthritis
The observation that pregnancy ameliorates the symptoms of RA led in
part to the discovery of corticosteroids as a treatment for autoimmune dis-
ease, a discovery for which the 1950 Nobel Prize in medicine was awarded to
322 GOLDING et al

Drs. Edward Kendall and Phillip Hench of the Mayo Clinic and Dr. Tadeus
Reichstein of the University of Basel, Switzerland. The following is an ex-
cerpt from Dr. Hench’s [13] Nobel lecture in 1950:
As a result of observations on the effect of 34 pregnancies on 20 patients
with RA the pattern of the articular relief during pregnancy was described
in 1938. Regarding a possible relationship between the antirheumatic sub-
stance X of jaundice and that of pregnancy, the following tentative conclu-
sion was reached: ‘‘It does not seem illogical to suppose that the agents
responsible for both these phenomena are closely related, perhaps identical,
and if the agent is a chemical substance, it would appear that it is neither
bilirubin nor a strictly female sex hormone.’’

In the initial study by Hench [14] in 1938, 90% of women had relief of
arthritis during pregnancy. Subsequent studies have all found amelioration
in approximately three quarters of pregnancies [15–18].
There are, however, examples of RA symptom worsening in a minority of
patients during pregnancy. Klipple and Cecere [19] documented worsening
of symptoms in one quarter of pregnancies studied. Rarely, initial onset
of disease has occurred during pregnancy and even progression of erosive
disease has been documented [17,18].
Parallel to the observation of amelioration in the majority of women dur-
ing pregnancy, the opposite is frequently seen in the postpartum period,
with postpartum recurrence and flare symptoms commonly observed. For
example, in one study, 36% of women had a recurrence in the first postpar-
tum month, 69% by 2 months, 85% by 3 months, and 98% by the end of 4
months [16].
The largest prospective study to date is by Barrett and colleagues [2] pub-
lished in 1999, in which 140 women, of whom 95 (68%) satisfied complete
America College of Rheumatology (ACR) criteria for RA, were followed
up with through pregnancy and into the postpartum period (Table 1).
The median HAQ score (Health Assessment Questionnaire, a measure of
physical function) decreased from 1.1 to 0.9 (P ¼ .01) with a fairly wide dis-
tribution. Notably, one quarter of women became worse and had significant
disability during pregnancy with HAQ scores O1.4. Two thirds reported de-
creased swelling and pain; however, 16% of respondents reported worsening
of joint pain, and 19% reported increased joint swelling. Only 16% had
complete remission defined as no synovitis and not receiving antirheumatic
drugs. Postpartum observations were divergent between HAQ and pain/
swelling scores. The HAQ scores actually improved 1 and 6 months postpar-
tum compared with those in prepregnancy. Specific joint symptoms, how-
ever, were worse than those during pregnancy in the majority of women 1
and 6 months postpartum, with joint pain increasing from 54% to 66%, re-
spectively, and joint swelling increasing from 66% to 77%, respectively.
Stratification for rheumatoid factor (RF) positivity was only significant
for a higher rate of remission in the RF-positive subset of 28% compared
Table 1
Summary of publications investigating the impact of pregnancy on rheumatoid arthritis outcomes
Impact of pregnancy
Study Year Study design Sample size Risk for incident RA on RA activity
Hench [14] 1938 Case series 22 RA; 37 d 20 (91%) improved;
pregnancies 2 (9%) worse

RHEUMATOID ARTHRITIS AND REPRODUCTION

Oka [16] 1953 Retro. cohort 732 RA; 16 (19%) new-onset 70 (81%) improved; 77
86 pregnancies RA during pregnancy (90%) postpartum flare
Neely et al. [17] 1977 Retro. cohort 56 RA 4 (7%) new-onset 35 (63%) improved;
pregnancies RA during pregnancy 8 (14%) no change;
9 (16%) worse
Ostensen et al. [18] 1983 Pros. cohort 31 RA d 75% remission during
pregnancy; 62%
postpartum flare
Barrett et al. [2] 1999 Pros. cohort 95 RA d 66% with improved joint
pain/swelling; 16% worse
Spector et al. [33] 1990 Case-control 270 RA; 80% increase in odds d
245 control if nulliparous
Dugowson et al. [20] 1991 Case-control 85 RA; 2.2-fold increase in odds d
386 Control if nulliparous
Pope et al. [22] 1999 Case-control 34 RA; No significant association d
68 control with parity
Karlson et al. [23] 2004 Nested case-control 674 RA versus No significant association d
103,968 control with parity. Duration of
breast feeding protective
Abbreviations: Pros. cohort, prospective cohort study; Retro. cohort, retrospective cohort study.

323
324 GOLDING et al

with 10% in the RF-negative group but not significant for changes in HAQ
or pain and swelling. Complete or partial remission during pregnancy was
predictive of decreasing HAQ and less pain/swelling during pregnancy but
was not predictive of the postpartum course.
The impact of parity on disease outcomes in rheumatoid arthritis
If the state of being pregnant could ameliorate RA but then cause in-
creased post-partum activity, it was hypothesized that longer-term disease
activity might be influenced by parity (number of pregnancies). The ob-
served association between parity and incidence of RA has been variable.
One early study suggested that multiparity was associated with increased se-
verity of RA [3], whereas subsequent studies observed an increased risk of
RA in nulliparous women ([20] and reviewed in Silman [21] and Pope and
colleagues [22]). A recent cohort study of patients with newly diagnosed
RA compared 34 women with recent onset RA with 68 healthy controls
[22]. In this study, there were no significant differences in fertility, nullipar-
ity, or number of children. There was also no statistically significant differ-
ence in oral contraceptive use. Age at first pregnancy was younger in RA
patients (22.6 versus 35.5, P ! .008); however, unbalanced demographic
characteristics, such as higher average education level in the controls, could
possibly explain more delayed pregnancies in that group. In an analysis
of 674 women with RA who had participated in the longitudinal nurses’
health study, the risk of RA did not correlate with multiparity or nulliparity
after adjusting for breast feeding [23]. Based on the balance of available
data, there is no consistent effect of parity on risk or severity of RA
(Table 1).
The impact of lactation on disease outcomes in rheumatoid arthritis
An interesting corollary to the effect of pregnancy on disease activity is
the question of whether breast feeding might influence future risk of RA
or affect the likelihood of flaring in the postpartum period. Earlier case-con-
trol studies gave conflicting results [2,4,24]. A recent report from Karlson
and colleagues [23] analyzed data from 121,700 women enrolled in the lon-
gitudinal nurses’ health study. Six hundred seventy-four women with RA
were identified. Breast feeding was found to be protective against the devel-
opment of RA in parous women in a dose-dependent fashion; compared
with parous women who did not breast feed the relative risk (RR) was 1.0
for breast feeding (BF) !3 months total, but down to 0.5 for net BF
O24 months (95% confidence interval [CI], 0.3 to 0.8). Irregular menstrual
cycles and age of menarche earlier than 10 years tended to increase the risk
of RA. Evidence from this and other studies has suggested that multiple hor-
monal cycles related to menstruation, pregnancy, and breast feeding affect
the likelihood of the development of RA or affect the course of established
disease. A later section will include a discussion of the possible underlying
mechanisms by which sex hormones influence the inflammatory arthritis
of RA.
 RHEUMATOID ARTHRITIS AND REPRODUCTION 325

The impact of rheumatoid arthritis on reproduction

Fertility
A number of early population-based studies found that women with RA
had fewer offspring than controls [25,26]. More recent cross-sectional sur-
veys have argued that there is decreased fecundity (probability of concep-
tion) and fertility (ability to conceive a child) among women with RA
before and after disease onset [27,28]. However, at least one case-control
study with age-matched controls did not find a clear association between
RA and nulliparity or fertility [22].
Pregnancy rates are likely confounded by factors other than fertility.
Some studies indicate diminished sexual desire and lower frequencies of in-
tercourse in women with RA [29–31]. A recent publication recorded struc-
tured interviews of approximately 400 married women with RA [9].
Nearly one in five women reported that RA affected childbearing decisions,
especially in women with RA diagnosed at a younger age. The overall per-
centage of women deciding to have any children was 91% (not significantly
different from the general population); however, women with RA were
much more likely to decide to have only one child. It is possible, therefore,
that RA does not directly affect fecundity or fertility, but rather may be as-
sociated with lower pregnancy rates because of its psychosocial effects on
childbearing choices.

Obstetrical outcomes
There have been varying conclusions about the rate of miscarriage/spon-
taneous abortion in women with RA. Kaplan and Diamond [32] reported in
1965 on 96 women with RA compared with a control group with osteoar-
thritis and found a higher abortion rate (number of spontaneous abortions
per number of total pregnancies 25.1% versus 16.5%, respectively) (Table 2).
However, a more recent study by Spector and Silman [33] actually showed
a protective effect with lower risk of spontaneous abortion in 195 women
with RA compared with 462 age-matched controls, with an age adjusted
odds ratio of 0.6 (95% CI, 0.4 to 0.9). In a study in which 243 women
with RA with live births were surveyed for prior miscarriages compared
with 2,559 age-matched controls [11], no difference in the rate of spontaneous
abortion was observed (adjusted RR 1.09 [95% CI 0.78 to 1.50]).
Other concerns have been increased prematurity, low birth weight, and
increased rates of birth defects in children born to mothers with RA. Earlier
studies by Morris [15] in 1969 and Ostenson and colleagues [18] in 1983 did
not show an increased rate of ill effects on the fetus. However, later studies
have shown increased rates of fetal complications. Skomsvoll and colleagues
[34] in 1998 reported on patients with inflammatory arthritis (including RA,
juvenile RA, and ankylosing spondylitis) and showed an increased risk for
prematurity (odds ratio [OR] ¼ 1.28; 95% CI, 1.11 to 1.48) and low birth
weight (OR ¼ 1.30; 95% CI, 1.18 to 1.44). Bowden and colleagues [35] in
 326
Table 2
Summary of publications investigating the impact of rheumatoid arthritis on pregnancy outcomes
Miscarriage/ Preeclampsia/
spontaneous Prematurity/ hypertensive Birth by
Study Year Study design Sample size abortion low birth weight disorder cesarean section
Morris [15] 1969 Case series 17 RA; 34 2/34 (6%) 2/18 (11%) LBW d d
pregnancies
Kaplan et al. [32] 1965 Case-control 96 RA versus 25.1% RA versus d d d
141 control 16.5% non-RA
Spector et al. [33] 1990 Case-control 195 RA versus RA: Odds Y 60% d d d
462 control

GOLDING
Skomsvoll et al. [34] 1998 Retro. cohort 4,323 RA/JRA/AS d RA: Odds Pr [ RA: Odds [ 29% RA: Odds [
versus 1,541,170 28% RA: 51%
Hist. controls Odds LBW [ 30%
Bowden et al. [35] 2001 Pros. cohort 133RA versus 3.3 kg RA versus 3.5 kg d

et al
d d
103 controls non-RA (P ¼ .04)
Reed et al. [11] 2006 Case-control 243 RA versus No statistically RA: Odds Pr [ 78% No statistically RA: Odds [
2559 control significant no difference LBW significant 66%
difference difference
Chakravarty et al. [12] 2006 Cross-sectional 1425 RA d IUGR: 3.4% in RA 11.1% in RA 37.2% in
versus1.6% versus 7.8% RA versus
non-RA (P!.001) non-RA (P!.01). 26.5% non-RA
(P!.01)
de Man et al. [36] 2006 Pros. cohort 75 RA versus d No difference LBW d d
Pop. controls except subset with
severe RA
Abbreviations: LBW, low birth weight; PR, prematurity; Pros. cohort, prospective cohort study; Retro. cohort, retrospective cohort study.
 RHEUMATOID ARTHRITIS AND REPRODUCTION 327

2001 showed an average lower birth weight of 3.3 kg compared with 3.5 kg
in age-matched controls (P value, 0.04), although this weight range is still
O2.5 kg, it is commonly used as the cutoff for low birth weight. In the study
by Reed and colleagues [11] of 243 live births, there was an increased risk for
prematurity (adjusted RR ¼ 1.78; 95% CI, 1.21 to 2.60) but no increased
risk for low birth weight after adjusting for gestational age (ie, because of
prematurity). In a follow-up period from 7 days to 1 year after birth, this
study also found an increased risk for postpartum infant hospitalization
O3 days (adjusted RR ¼ 1.86; 95% CI, 1.32 to 2.60), but no increased
risk of prolonged ventilation or infant death nor increased risks of birth
defects.
In a very recent abstract presented at the 2006 ACR meeting, results were
reported from a cohort of 75 pregnant women with RA [36]. The average
birth weight in newborns of women with RA was not statistically different
from that of the general population (both were around 3.4 kg). However,
the subset of newborns of mothers with more severe RA, as indicated by
a DAS28 (disease activity score) of O3.9, had a birth weight on average
310 g lower than the subset with lower disease activity (P ¼ .02). Again,
it is not clear that these differences have any effect on the health or future
development of the newborn, because the average birth weight in the
more active RA group was O3.2 kg, well above the cutoff of 2.5 kg com-
monly used to define low birth weight. Although not directly linked to de-
creased birth weight because of limitations in the data set, the recent
national survey of birth complications in RA did show an increased rate
of intrauterine growth retardation in RA (3.4% versus 1.6% of control
pregnancies, P!.001) [12].
A role for RA in increasing risk to the mother also has been addressed.
Preeclampsia and cesarean delivery rates have been shown to be higher in
mothers with RA, with preeclampsia rates increased by 28% (95% CI,
1.05 to 1.56) and delivery by cesarean section increased by 51% (95% CI,
1.36 to 1.68) compared with age-matched controls [34]. Reed and colleagues
[11] showed a trend toward increased preeclampsia (adjusted RR ¼ 1.55;
95% CI, 0.97 to 2.50) and a significant increased risk for delivery by cesar-
ean section (adjusted RR ¼ 1.66; 95% CI, 1.22 to 2.26) in mothers with RA.
Similarly, in a national survey of pregnancies in women with SLE, RA, and
pregestational diabetes mellitus, the authors found a significant increase in
the rate of hypertensive disorder (11.1% versus 7.8%, respectively; P ! .01)
and cesarean delivery (37.2% versus 26.5%, respectively; P ! .001) in
pregnant women with RA compared with controls [12].

Potential mechanisms
As introduced above, the observation of ameliorated RA disease activity
during pregnancy was a major clue prompting Hench [14] to isolate and use
328 GOLDING et al

cortisone as a treatment for RA in the 1940’s. Hench considered cortisone

itself to be the ‘‘substance x’’ elaborated during pregnancy responsible for
improvements in disease activity. When cortisone was found to not be the
‘‘substance x,’’ valiant efforts were undertaken to identify the agent with
such potent abilities to induce remission. When no single agent could be
identified and synthesized, studies were even performed in which blood
products from pregnant women were infused into RA patients in an attempt
to gain the benefits of the elusive ‘‘substance x’’ [1].
More than a half century later, the identity of the ‘‘substance x’’ remains
elusive. Rather than a single agent, the effects of the ‘‘substance x’’ of preg-
nancy appear to be caused by a complex interplay of shifts in hormone and
cytokine pathways that in most, but not all, patients result in favorable im-
munomodulation during pregnancy, but can quickly lose their effectiveness
postpartum. The inherent complexity and prior elusiveness of the search
have attracted only a handful of investigators to the problem in the last de-
cades. However, as methods in cytokine and endocrine signaling research
have become more sophisticated and large multicenter prospective cohorts
with serial sampling are assembled, undoubtedly more progress will be
made in understanding the fascinating disease-modifying properties of an
entirely physiologic process. Normal pregnancy is associated with massive
changes in immune and endocrine signaling required to allow the developing
fetus and placenta to survive in the hostile environment of the maternal im-
mune system. Fetal, paternal, and placental antigens are continuously pre-
sented and recognized by the maternal immune system and, rather than
inducing rejection of the fetoplacental graft, are tolerated and supported
[37,38]. This process is coordinated through the concerted activities of ma-
ternal and placental-derived sex hormones and their associated effects on cy-
tokine signaling and cellular immunity.
Normal pregnancy is associated with maternal levels of estrogen and pro-
gesterone that are elevated many fold over normal physiologic concentra-
tions. These increases are associated with general shifts in circulating
cytokine patterning away from Th1 type cytokines (eg, interferon-gamma
[IFN-g], tumor necrosis factor-alpha [TNF-a], interleukin [IL-12]) and to-
ward Th2 cytokines (eg, IL-10, IL-4, IL-1 receptor antagonist) [39–41].
These observed shifts are dependent on the stage of pregnancy and occur
more as the result of a relative increase in the production of Th2-type cyto-
kines rather than a decrease in Th1-type cytokines [42,43]. Several investiga-
tions have noted TNF-a and IFN-g levels to be altered little by early
pregnancy, although elevated levels of soluble TNF receptors suggest that
effective TNF-a signaling is blunted during pregnancy [44,45]. However,
in late pregnancy, lipopolysac charide-induced peripheral blood monocyte
production of IL-12 and TNF-a is markedly diminished, corresponding to
third-trimester increases in cortisol, estradiol, progesterone, and catechol-
amines [46]. These relationships are reversed in the immediate postpartum
period [46]. In a simplified way, Th2 cytokines can be thought of as
 RHEUMATOID ARTHRITIS AND REPRODUCTION 329

promoting humoral (ie, antibody-mediated) immunity in contrast to the

action of the Th1 cytokines in promoting cellular immunity. Conceptually,
this shift is to the dual benefit of the fetoplacental unit, because diminished
cellular immunity protects the fetoplacental graft against host rejection,
whereas heightened humoral immunity provides added protection against
infectious microorganisms [47].
Estrogen and progesterone and their derivatives are not the only hor-
mones associated with the Th1 to Th2 cytokine shift in pregnancy. The an-
drogens dehydroepiandosterone (DHEA) and dehydroepiandosterone
sulfate (DHEAS) are increased during pregnancy and under experimental
conditions are independently associated with the down-regulation of Th1
cytokines [48]. In addition, increases in prolactin signaling in late pregnancy
may augment the expression of Th1 cytokines to the level required to sup-
port the developing fetoplacental unit at this critical stage [49].
Although the Th1 to Th2 cytokine shift is in many ways an oversim-
plification of a complex process, it is consistent with typical clinical find-
ings observed in patients with rheumatic disorders. Under the normal
pregnancy conditions outlined above, a shift away from Th1 cytokines
would be expected to benefit patients with RA, a disorder in which the
pathogenic processes are driven more by cellular rather than humoral
immunity. Although autoantibody production is a feature of RA, the
antibodies themselves are not likely to worsen disease activity during
the course of pregnancy. In contrast, disease activity in SLE is associated
with pathogenic autoantibodies, and flares of disease activity are typical
during pregnancy [50].
Does the shift toward Th2 cytokines observed in normal pregnancy differ
in RA? The relative paucity of investigations examining circulating cyto-
kines in pregnant RA patients presents apparently conflicting conclusions.
In a prospective investigation of 19 women with RA with serial sampling be-
fore, during, and after pregnancy, Ostensen and colleagues [5] observed
overall levels of circulating IL-10, IFN-g, IL-1Ra, and soluble TNF recep-
tors in pregnant women with RA consistent with those of pregnant women
without RA. Although levels of IL-10 were uniformly low at all stages of
pregnancy, circulating levels of soluble TNF receptors and IL-1Ra progres-
sively increased over the course of pregnancy with a precipitous decline in
the 8 postpartum weeks. In comparison, IL-1Ra and soluble TNF receptor
levels did not increase significantly over the course of pregnancy in non-RA
controls but were noted to decline in the immediate postpartum period.
RA subjects without clinical improvement during pregnancy had lower
IL-1Ra levels overall compared with subjects who improved. These data
would suggest that the shift toward anti-inflammatory pathways in RA
pregnancy is mechanistically similar, but not identical, to non-RA pregnan-
cies. Indeed, pregnant women with RA may have an even greater anti-
inflammatory potential, demonstrated by the greater ability to up-regulate
IL-1Ra and soluble TNF receptor expression, than women without RA.
330 GOLDING et al

This is in contrast to long-held observations that RA patients may lack the

ability to appropriately use physiologic anti-inflammatory mechanisms (ie,
up-regulation of cortisol) in the setting of intense systemic inflammation.
In another prospective investigation of four RA patients with samples
collected at each trimester of pregnancy and in the postpartum period,
Munoz-Valle and colleagues [6] noted lower peripheral blood mononuclear
cell TNF-a mRNA expression levels in RA patients at all stages of preg-
nancy compared with 13 non-RA controls. In contrast, IL-4 mRNA expres-
sion was markedly lower in RA patients at all stages of pregnancy compared
with controls. These findings would suggest that decreased Th1 cytokines
rather than increased Th2 cytokines were the predominant mechanism in
RA. However, IL-1Ra and soluble TNF receptors were not assayed in
this study, and the small numbers of patients involved make statistical com-
parisons difficult.
In a study of six pregnant RA patients compared with 14 pregnant non-
RA patients, Tchorzewski and colleagues [7] noted comparable third trimes-
ter and postpartum levels of the Th1 cytokines IL-12, IL-6, and IFN-g
between the two groups. The only difference in levels of the three cytokines
between RA and non-RA groups was a transient increase in IL-12 levels in
RA subjects two days postpartum. As in the studies noted above, making
definitive conclusions based on these comparisons is problematic because
of the small numbers of patients involved.
On the surface, these studies may appear to have conflicting results.
However, taken together, it would appear that an effective shift from
Th1 to Th2 profile is accomplished in RA patients by stability or decrease
in Th1 cytokines and an increase in the cytokine inhibitors IL-1Ra and
soluble TNF receptors rather than an increase in IL-10 or IL-4. Although
not identical to the cytokine shifts observed in normal pregnancy, the net
effect does not appear to differ dramatically in RA. Studies with greater
statistical power are required to support more definitive conclusions. In
particular, additional detailed investigation into cytokine profiles accord-
ing to clinical disease characteristics across the trajectory of pregnancy
would be particularly enlightening. Only the study by Ostensen and col-
leagues [5] included this type of comparison, although sample size issues
and the method of classifying disease activity raise questions about the
validity of comparisons in this study. The interrelationships between
cytokines, hormones, and other potential immunomodulatory factors
(eg, prolactin, hormone binding proteins, and others) have not been
studied in pregnant RA patients with the rigor required to yield confident
conclusions. In particular, prolactin is associated with up-regulation of
Th2 cytokines, but also is a potent upregulator of IFN-g [49]. Hyperpro-
lactinemia has been associated with disease activity in RA [51] and may
contribute to accelerated disease activity in the postpartum period and
the associations with new-onset and worsening RA reported with breast
feeding (see above).
 RHEUMATOID ARTHRITIS AND REPRODUCTION 331

Rheumatoid arthritis therapeutics and pregnancy

There is a real risk of inadvertent early fetal exposure to medications used
to treat RA. Thus, the rheumatologist plays a critical role in assessing the
risks and benefits of these medications during conception, pregnancy, and
lactation in their patients. Data regarding the safety of medications in preg-
nancy are inherently inadequate. For ethical reasons, pregnant women as
a group are excluded from all premarketing clinical trials and safety studies.
In postmarketing reporting, most data are anecdotal, presented as isolated
case reports or observational case series, such that true causal association
cannot be established. Animal reproductive studies often are used to fill in
these substantial gaps, despite the fact that knowledge resulting from animal
studies may not truly define the human risk. In the United States, the US
Food and Drug Administration (FDA) uses a category classification to de-
scribe risk and safety of individual medications during pregnancy (Table 3).
Although used as an important resource by physicians and patients, the
FDA category is almost exclusively based on animal reproductive data
and thus is limited in its ability to precisely predict the human risk [52].
Also, this category does not provide any detailed clinical management ad-
vice. With insufficient and often questionable safety data, pharmacologic
management of RA during pregnancy continues to be a difficult challenge
for physicians. Recent reviews have comprehensively evaluated the safety
profiles of many commonly used drugs in patients with rheumatic diseases

Table 3
US Food and Drug Administration safety classification of pharmacotherapies for use during
pregnancy
Category Description
A Adequate and well-controlled studies in pregnant women fail
to demonstrate a risk to the fetus in the first trimester and no
evidence of a risk later in pregnancy.
B Animal studies fail to demonstrate a risk to the fetus and no
adequate and well-controlled human data available.
C Animal studies have revealed no evidence of harm to the fetus; however,
there are no adequate and well-controlled studies in pregnant women.
or
Animal studies have shown an adverse effect, but adequate and
well-controlled studies in pregnant women have failed to
demonstrate a risk to the fetus.
D Animal studies have shown an adverse effect, and there are no
adequate and well-controlled studies in pregnant women.
or
No animal studies have been conducted, and there are no adequate and
well-controlled studies in pregnant women.
X Animal or human studies demonstrate fetal abnormalities, and there is
evidence of human fetal risk based on investigational/marketing experience
in humans/risks clearly outweigh any potential benefit.
332 GOLDING et al

in general [53]. Here, the authors present a brief summary for the practi-
tioner of commonly used drugs used in RA.

Hydroxychloroquine
Hydroxychloroquine (HCQ) is an antimalarial agent used to treat pa-
tients who have lupus and mild to moderate RA. Although its exact mech-
anism of action is unknown, it is thought to interfere with the presentation
and processing of antigens [54]. With a half-life of approximately 8 weeks, it
is eliminated very slowly and may persist in the body for months after dis-
continuing therapy.
HCQ crosses the placenta. Concerns regarding its fetal toxicity were
based on reports of retinal and ototoxicity in humans exposed to chloro-
quine, a related antimalarial agent [55,56]. In several small studies of preg-
nant lupus patients, however, no increased risk of birth defects with HCQ
exposure was observed. One controlled study prospectively followed 20
pregnant lupus patients randomly assigned to receive HCQ or placebo
[57]. Neonatal and 3-year follow-up of these children showed no congenital
malformations in the HCQ-exposed group compared with the placebo
group. In another large cohort of 133 HCQ-exposed pregnancies, there
was no evidence of visual or hearing abnormalities in the exposed children
after 9 years of follow-up [58]. Recent data form the Johns Hopkins Lupus
Cohort [59] showed no fetal or maternal risks associated with the continu-
ation of HCQ throughout pregnancy, whereas disease activity and use of
corticosteroids were increased in lupus patients who stopped taking HCQ.
Although available data do not suggest increased fetal risk with exposure,
HCQ is classified as a category C drug.
HCQ is secreted in the breast milk. Although there may be accumulation
of the drug in the infant, no adverse effects have been observed in the breast-
fed infants [60], and most experts believe that HCQ therapy can be contin-
ued during lactation.

Methotrexate
Methotrexate (MTX) is a dihydrofolate reductase inhibitor that inhibits
folic acid metabolism and purine synthesis [54]. It is prescribed extensively in
treatment of RA, both as monotherapy and in combination with other
disease-modifying antirheumatic drugs. Oral MTX has a half-life of 3 to
10 hours and can persist in the liver for several months [61].
MTX crosses the placenta. High-dose MTX exposure during pregnancy
is associated with a specific pattern of cranial, central nervous system, and
limb defects referred to as aminopterin/methotrexate syndrome [62]. Thus,
MTX is teratogenic and classified as a category X drug. While its teratoge-
nicity at high doses is well established, there are inadequate data to deter-
mine the outcomes of pregnancy exposed to low-dose MTX, as used in
treatment of RA. A review of 20 pregnancies exposed to MTX (20 mg or
 RHEUMATOID ARTHRITIS AND REPRODUCTION 333

less weekly) in the first trimester [63] found a high rate of spontaneous abor-
tions (20%); however, no congenital anomalies were seen. Another series of
MTX-exposed pregnancies was published by Lewden and colleagues [64].
The mean dose of MTX was 10 to 15 mg per week, and maximal exposure
was up to 11 weeks of pregnancy. Twenty-eight pregnancies resulted in four
spontaneous abortions, five elective abortions, and 19 live births. One child
was born with metatarsus varus and eyelid angioma, which were considered
minor congenital anomalies. Other publications, however, report cases of
major fetal anomalies with variable doses and duration of exposure to
MTX during pregnancy [65,66]. Thus, currently, the safety of low-dose
MTX use during pregnancy remains uncertain, and most experts recom-
mend discontinuing MTX use 3 to 4 months before conception to prevent
fetal exposure.
Methotrexate is excreted into the breast milk and is contraindicated dur-
ing lactation [67].

Sulfasalazine
Sulfasalazine is a folic acid antagonist and is used to treat patients with
RA and inflammatory bowel disease (IBD). Its half-life is between 5 and
10 hours. Both sulfasalazine and its metabolite, sulfapyridine, cross the pla-
centa, and equal concentrations of the drug are found in maternal serum
and cord serum [68].
Observational studies of more than 300 women with IBD exposed to sul-
fasalazine during pregnancy found no evidence of teratogenicity [69,70].
However, two recent case-control studies show a possible increased risk of
oral cleft, neural tube, and cardiovascular defects in pregnancies exposed
to folic acid antagonists including sulfasalazine [71,72]. A few published
cases also report congenital malformations such as oral cleft, cardiac and re-
nal defects with sulfasalazine exposure in utero [73,74]. These findings, how-
ever, could not be confirmed by a larger case-control study [75]. Thus,
available data, although conflicting, indicate that the potential risk of tera-
togenicity of sulfasalazine is low. Sulfasalazine is classified as a category B
drug.
A small amount of sulfasalazine is excreted into the breast milk [76]. Its
use during lactation should be advised with caution, given a published re-
port of bloody diarrhea in one breast-fed infant [60].

Leflunomide
Leflunomide is an inhibitor of dihydroorotate dehydrogenase and thus
inhibits pyrimide synthesis [77]. It is used to treat patients with moderate
to severe RA. It has been shown to be embryotoxic in animal studies [78]
and is labeled as a category X drug. Leflunomide has a half-life of 14
days but its active metabolite undergoes extensive enterohepatic circulation
and may persist in the body for up to 2 years [79]. Thus, to prevent fetal
334 GOLDING et al

exposure, the drug has to be discontinued and eliminated using cholestyr-

amine. After cholestyramine chelation therapy, women should wait at least
3 menstrual cycles before attempting pregnancy.
Although pregnancy is contraindicated during leflunomide therapy, there
are reports of inadvertent exposure to leflunomide during early pregnancy.
The largest reported number comes from a prospective cohort study of RA
medications in pregnancy. The published abstract shows no difference in
outcomes between 43 leflunomide-exposed pregnancies and 78 control RA
pregnancies [80]. Although such reports may not show a clear teratogenic
risk, there currently is lack of sufficient data on the safety of leflunomide
in human pregnancy.
It is unknown whether leflunomide is secreted into breast milk. Given the
potential risk of serious adverse effects to the infant, leflunomide is contra-
indicated during nursing.

Anti–tumor necrosis factor agents

Three anti-TNF agents, infliximab, etanercept, and adalimumab are
available on the market for use in moderate to severe RA. These biologic
agents inhibit TNF-a, a key player in pathogenesis of inflammation in
RA. In animal studies using analogous anti-TNF antibody, no evidence
of teratogenicity was seen [81]. Thus, these medications are classified as cat-
egory B drugs by the FDA.
Although anti-TNF agents cross the placenta in rodents, their placental
transmission in humans is unknown. In a retrospective survey, no fetal mal-
formations were reported in 14 patients who were exposed to etanercept
during pregnancy [82]. A prospective controlled study of RA medications
in pregnancy conducted by the North American Organization of Teratology
Information Specialists [83] reported 32 pregnancy outcomes after etaner-
cept exposure. Even though the numbers were small, no difference in birth
defects compared with nonexposed RA control group was seen.
The infliximab safety database has reported on 131 pregnancies exposed
to infliximab [84] with outcomes data available for 96 pregnancies. The ma-
jority of patients were treated with infliximab for Crohn’s disease. Twenty-
six percent of the patients received infliximab 3 months before conception,
29% before conception and during first trimester, and 28% during the first
trimester only. These pregnancies resulted in 66% live births, 14% miscar-
riages, and 19% therapeutic abortions, outcomes comparable with that ex-
pected in the general US pregnant population [85]. Congenital abnormalities
were reported in three newborns, including intestinal malrotation and Te-
trology of Fallot. However, the occurrence of these malformations was sim-
ilar to that expected in the general population.
There is one published case report of a patient treated with adalimumab
throughout pregnancy for Crohn’s disease, which resulted in a normal full-
term infant [86]. Similarly, an abstract summarizes the result of an online
 RHEUMATOID ARTHRITIS AND REPRODUCTION 335

survey of rheumatologists in which 84 pregnancies exposed to an anti-TNF

agent were identified (81% to etanercept, 12% to infliximab, and 9% to ada-
limumab) [87]. Outcomes, as established by rheumatologists, were similar to
those of the general population, although no normal control group existed.
Thus, although the safety of anti-TNF medications during pregnancy has
not been documented sufficiently, the available information is reassuring.
Excretion of anti-TNF agents into the breast milk has not been well stud-
ied. In one abstract, infliximab was not detected in the breast milk of a pa-
tient with Crohn’s disease [88]. In another report, etanercept was identified
in the breast milk of a nursing patient with RA [89]. Given the lack of stud-
ies and unknown safety of these medications during lactation, it is advisable
to avoid breast feeding while on anti-TNF therapy.

Anakinra
Anakinra is a recombinant IL-1 receptor antagonist approved for treat-
ment of moderate to severe RA. Its use in RA has been limited, given the
poor efficacy of anakinra in RA and availability of other superior medica-
tions. There are no available human pregnancy or lactation data on ana-
kinra. However, animal reproductive studies have not found any fetal
malformations, thus, anakinra is classified as a category B medication. Be-
cause there are no available data regarding safety of anakinra during lacta-
tion, it should be avoided during nursing.

Rituximab
Rituximab is a monoclonal antibody against the CD 20 antigen on
B-lymphocytes. Its main use has been in the treatment of non-Hodgkin’s
lymphoma, but it is now used in the treatment of patients with refractory
RA [90]. Currently, there are insufficient data regarding the safety of rituxi-
mab in animal or human pregnancy. Two case reports of successful outcomes
in women treated with rituximab for non-Hodgkin’s lymphoma during
pregnancy are reported in the literature [91,92]. For pregnant RA patients,
there are safer alternative medications available, thus, rituximab should be
avoided during pregnancy. The FDA classifies it as a category C drug.
Rituximab excretion and safety during breast feeding has not been
established.

Abatacept
Abatacept is an anti-CD 80/86 monoclonal antibody and selectively
blocks costimulation of T cells. It has been approved recently for the treat-
ment of severe and refractory RA [93].
Although results of animal studies reveal no teratogenicity, currently
there are no published data on outcomes of human pregnancy after expo-
sure to abatacept. Abatacept is classified as a category C drug.
336 GOLDING et al

The safety of abatacept during lactation is unknown, thus, it is advisable

to avoid nursing while on abatacept therapy.

Corticosteroids
Corticosteroids (CS) are potent anti-inflammatory medications and are
considered safe during pregnancy. Dexamethasone and betamethasone cross
the placenta and are often used to treat fetal conditions such as respiratory
distress syndrome. Other preparations such as hydrocortisone, cortisone,
and prednisone cross the placenta but are rendered biologically inactive
by a placental enzyme and thus often are chosen for treating maternal con-
ditions during pregnancy. Corticosteroids are classified as category B
medications.
Prolonged CS use during pregnancy is associated with an increased
risk of pregnancy-induced hypertension, pre-eclampsia, and gestational
diabetes [94,95]. One meta-analysis reports an increased risk of oral cleft
defects with first-trimester exposure to steroids [96]. However, most
studies do not reveal an increased risk of birth defects with CS use
[97,98]. Fetal adrenal suppression is rare [99]. Intrauterine growth retar-
dation with CS use during pregnancy has not been reported in several
studies [94,100] and in others may be a reflection of the underlying
maternal disease [101].
CS are secreted in the breast milk at low concentrations and are consid-
ered safe to use during breast feeding. At doses exceeding 20 mg daily, some
experts recommend an interval of 4 hours between nursing and the last dose
of CS to minimize exposure to the infant [102].

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin
synthesis by blocking cyclooxygenase enzymes. Prostaglandins are impor-
tant mediators of pain and inflammation. Thus, the analgesic and anti-
inflammatory properties of NSAIDs makes their use frequent in patients
with RA.
NSAIDs cross the placenta and enter the fetal circulation [103]. Most
traditional NSAIDs are considered category B medications. A few studies
have found possible increased risk of oral cleft, cardiac, and gastric de-
fects with NSAID use in early pregnancy [104,105], whereas others do
not confirm this finding [106,107]. Two population-based cohort studies
show an association between early NSAID use and miscarriages, but true
causal association could not be established [106,107]. Thus, currently,
available data document relative safety of these medications in early
pregnancy.
The association of NSAID use in late pregnancy with premature closure
of the ductus arteriosus is well documented [108]. Renal dysgenesis and
 RHEUMATOID ARTHRITIS AND REPRODUCTION 337

oligohydramnios have also been reported with use of traditional NSAIDs in

late pregnancy [109]. Fetal and postpartum hemorrhage may be increased
with use of NSAIDs late in pregnancy [110]. Thus, NSAIDs are contraindi-
cated beyond 32 weeks of gestation.
COX-2 selective inhibitors do not have adequate safety data in human
pregnancy and are classified as category C medications. Thus, it is advisable
to avoid these medications during pregnancy.
NSAIDs are considered safe during lactation, but there may be poten-
tial risk of displacement of bilirubin and jaundice in the infant. Currently,
there are insufficient data on the safety of COX-2 inhibitors during
lactation.
Given the general lack of qualitative and quantitative data regarding
the safety of medications during pregnancy, avoiding these medications
is probably the safest approach to management of pregnant patients
with RA. Indeed, signs and symptoms of RA may remit during
pregnancy, but the effect is not universal [2]. It is impossible for the
physician to predict the course of disease during pregnancy in individual
patients. Withdrawal of an agent before pregnancy may risk exacerbation
of disease activity, which can have a negative effect on maternal and fetal
outcomes. Thus, treatment decisions require careful consideration of the
risks and benefits to the mother and fetus and should be made together
with obstetrical consultation.
If possible, all disease-modifying therapy should be stopped in women
who are planning to conceive and in pregnant and lactating women, unless
severe or intractable disease activity during pregnancy is anticipated. Use of
methotrexate and leflunomide should be discontinued at least 3 months be-
fore conception in both men and women. Cholestyramine should be used to
enhance the elimination of leflunomide until its levels are undetectable in
plasma. If indicated, HCQ can be continued throughout pregnancy. Current
data suggest that sulfasalazine is unlikely to cause any fetal harm and may
be used during pregnancy with folate supplementation. With lack of suffi-
cient safety information on the biological agents, it is best to avoid these
medications during pregnancy.
Traditional NSAIDs can be used with caution during the first two trimes-
ters of pregnancy. As discussed above, all NSAIDs should be withdrawn at
32 weeks’ gestation to avoid risks associated with their use in the last trimes-
ter. COX-2–selective NSAIDs should be avoided during pregnancy. CS are
not teratogenic and can be used throughout pregnancy, either on a daily
dosing or in a tapering schedule to manage flares. However, to avoid preg-
nancy complications that may be associated with the use of CS, the cumu-
lative amount should be minimized to the smallest dose required to control
the symptoms.
While these may be general guidelines, it is important to carefully evalu-
ate each case and the potential risk and benefit of termination or continua-
tion of disease-modifying therapy.
338 GOLDING et al

Summary
Pregnancy is a normal, physiologic process consistently associated with
dramatic changes in RA disease activity. However, the exact nature of these
changes remains elusive, and the effects are not uniform throughout the
population. Women with RA tend to have comparable fertility, fecundity,
and pregnancy outcomes compared with women without RA, although cer-
tain subsets of patients may be at an increased risk for adverse outcomes
such as low birth weight, hypertensive disorders of pregnancy, and cesarean
delivery. Additional investigation into the molecular basis of pregnancy in
RA will help identify and risk stratify these subsets and perhaps shed addi-
tional light on the pathogenesis of RA itself. The care of the pregnant RA
patient is complex, because little direct information is available regarding
the safety of disease-modifying antirheumatic drugs and other commonly
used pharmacotherapies. However, disease improvement during pregnancy
often allows the safe discontinuation of potentially harmful agents. Addi-
tional research is needed to establish the safety of biologic agents in preg-
nancy and lactation. The practitioner should convey information
regarding the natural history of RA during pregnancy and safety issues re-
lated to pharmacotherapies to every woman of childbearing age with RA,
well before conception and pregnancy, to ensure optimal outcomes.

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