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Update of the management of rheumatoid arthritis in pregnancy

Article  in  Expert Review of Obstetrics & Gynecology · December 2012

DOI: 10.1586/EOG.11.77

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Update of the management of

rheumatoid arthritis in
pregnancy
Expert Rev. Obstet. Gynecol. 7(1), 77–96 (2012)

May Ching Soh
and Catherine
Nelson-Piercy*
Guy’s & St Thomas’ NHS Trust, King’s
Health Partners, Women’s Health
Department, 10th Floor North Wing,
St Thomas’ Hospital, Westminister
Bridge Road, London, SE1 7EH, UK
*Author for correspondence:
Tel.: +44 207 188 7905
Fax: +44 207 188 6855
catherine.nelson-piercy@gstt.nhs.uk
As the maternal age increases, and with the emergence of more effective therapies, clinicians
are seeing more women with rheumatoid arthritis (RA) contemplating pregnancy. Newer
evidence shows that RA remains active in pregnancy; active RA correlates well with adverse
obstetric outcomes. Preeclampsia is common, as are operative and preterm deliveries in women
with RA. Women with active RA are also more likely to have babies of lower birthweight. This
article discusses the latest findings on population-based studies of women with RA and the
various drugs used to manage RA. Controversies regarding biological agents are addressed,
and guidance on prepregnancy counseling, antenatal care, delivery and breastfeeding based
on our experience are detailed here. With appropriate prepregnancy counseling and planning,
most women with RA can safely fall pregnant and continue to enjoy good disease control in
pregnancy and the postpartum interval.

Keywords : adverse obstetric outcomes • antenatal care • anti-TNF agents • biologic therapy • breastfeeding
• disease-modifying drugs • immunosuppressants • neonatal outcomes • pregnancy • rheumatoid arthritis

Clinicians caring for pregnant women are seeing
an influx of women with rheumatoid arthritis
(RA) falling pregnant as maternal age extends
into the 40s, and due to the advent of biologic
agents to control previously crippling RA. In
the past, women with RA seldom embarked
upon pregnancy due to a combination of inca-
pacitating polyarthritis, physical disability and
the fact that its first-line treatment – metho­
trexate (MTX) – is a teratogen. As the para-
digm shifts towards aggressive management
in early RA, fewer women suffer prolonged
inflammatory arthritis, and joint deformities
are now rarely encountered. Nowadays, young
women with RA remain relatively well and are
contemplating pregnancies.
Newer studies show that RA remains active
in pregnancy, resulting in poorer obstetric out-
comes. There is a pressing need for clinicians to
familiarize themselves with the disease-modifying
antirheumatic drugs (DMARDs) so that women
with RA can plan their pregnancies with appro-
priate prepregnancy counseling with ‘pregnancy-
friendly’ DMARDs; and so that when preg-
nant, appropriate therapy will not be withheld.
Treatment should be optimized so that women
are not debilitated from joint pain, nor will their
growing fetus be compromised from active RA.
RA is more common in older women [1] . The
prevalence of RA in women aged 18–44 years
in the UK is 1–2 per 1000 women per year
[2] . There is an estimated annual incidence of
approximately 800–2100 RA pregnancies in the
USA (population of 300 million) [3,4] . However,
as women delay pregnancy, clinicians caring for
pregnant women will see increasing numbers of
RA in their practice.
RA & fertility
Women with RA are less fertile [5] . Use of assisted
reproductive therapy (ART) in nulliparous
women with chronic inflammatory arthritis is
more frequent compared with the general popu-
lation [6] . Physical disability, joint stiffness and
diminished libido, which may be due to pain or
as a side effect of the medications, with resultant
reduced frequency of intercourse also result in a
lower birth rate [7,8] .
Fear of the potential teratogenic effects of
DMARDs may also lead women to avoid preg-
nancy, or at least to defer it [9] . Studies have
found that some women may have been coun-
seled against pregnancy for fear that it may
aggravate their disease process [10] .
NSAIDs inhibit the production of prostaglan-
dins leading to luteinized unruptured follicle

www.expert-reviews.com 10.1586/EOG.11.77 © 2012 Expert Reviews Ltd ISSN 1747-4108 77

 Review Soh & Nelson-Piercy
syndrome, which can cause infertility, which is reversible upon
discontinuation of the drug [11] . The exact incidence is not known.
Regular use of NSAIDs, especially in the week prior to concep-
tion, has been associated with an increased risk of miscarriage
(HR: 8.1; 95% CI: 2.8–23.4) [12] .
Estrogen-containing oral contraceptive pills contribute to
symptomatic improvement in R A. Reduced ovulatory func-
tion may further compound reduced fecundity of women with
RA [13] .
Some women with RA deliberately limit the number of preg-
nancies because of concerns about their physical ability to care for
their offspring [14] . However, researchers of the Norfolk Arthritis
Register have found that parous women with inflammatory poly-
arthritis had better functional outcomes over time compared with
nulliparous women [15] . Even with flares of disease, pregnant
women with RA have shown persistently stable mental health
scores (by the Short Form-36 Health Survey) [16] .
How does pregnancy affect RA?
The adage instilled in most of us that RA improves with preg-
nancy stems from Hench’s 1938 publication [17] . In pregnancy
there is a shift of Th1 dominance to Th2 dominance. Th2 cells
inhibit the production of interleukin and TNF. Progesterone also
inhibits interleukin activity and promotes Th2 activity [18,19] .
Hence, Th1-dominant autoimmune diseases such as RA and mul-
tiple sclerosis are more likely to be quiescent in pregnancy [20,21] .
These in vitro findings are supported by a subsequent study show-
ing undetectable IFN-g and IL-10, and increased IL-1 receptor
antagonist and soluble TNF-receptor levels in pregnant women
with inflammatory polyarthritides, coinciding with improved
symptomology [22] . Other factors that contribute include the
improved immune tolerance of the mother to the fetus, elevation
of a2-glycoprotein levels during pregnancy and increased IgG
glycosylation [23–26] .
Newer prospective multicenter studies have challenged the
belief that 75% of women with RA go into remission in preg-
nancy. The studies carried out in the UK and The Netherlands
indicate that only 40–66% of women experience an improvement
in pregnancy, and less than a quarter of women achieve remission
by the third trimester [27,28] .
What are the risk factors for active RA in pregnancy?
Due to limited numbers of women with RA undergoing pro-
spective follow-up, predictors for remission in pregnancy remain
obscure. Dutch investigators of the PARA study followed up
118 pregnant women between 2002 and 2006, in a prospective
study of pregnant women with RA, and found that levels of anti-
cyclic citrullinated peptide (anti-CCP), IgM-rheumatoid factor
(RF) and IgA-RF all declined in pregnancy. The women without
RF and anti-CCP were more likely to improve in pregnancy.
Postpartum, with the reintroduction of DMARDs, all autoanti-
body levels declined. However, lower autoantibody levels were not
necessarily associated with quiescent disease. Postpartum flares
of RA were comparable between women who were seropositive
and seronegative [29] .
78
Flares postpartum are common, with a third flaring within a
month postpartum and 98% flaring by the fourth month; this
occurs despite an increase of medications in the postpartum
period [28,30] .
How does RA affect pregnancy? Obstetric & neonatal
outcomes in women with RA
Due to the relatively small numbers of women with RA falling
pregnant, much of the recent data come from nationwide preg-
nancy outcome administrative databases (see A ppendix 1 for further
details on individual studies on pregnant women with RA). There
is only one small prospective study from the UK that followed
women from late pregnancy until 8 months postpartum [31] . Even
adjusting for maternal age and other confounding factors, all pub-
lished studies have indicated that women with RA are at greater
risk of adverse pregnancy outcomes.
Hypertensive disease and preeclampsia are more common.
Bowden’s study was the first to demonstrate a startlingly high
prevalence of hypertensive disease in pregnant R A women
(40%) [31] . Subsequent larger studies indicate that approximately
3.0–11.1% of women with RA will have a pregnancy compli-
cated by hypertension or preeclampsia (OR ranging from 0.6 to
2.22) (Table 1) [4,6,32–34] . Preeclampsia is a significant contributor
to preterm (<37 weeks gestation) births [35] .
Preterm deliveries are very common, affecting approximately
10–15% of pregnancies (OR: 1.15–1.91) [6,32] . After correcting
for the gestational age, women with RA are more likely to have
infants of lower birthweight (10% risk with OR: 1.47–1.96)
[6,34,36] . In a matched prospective case–control study carried
out from late pregnancy in which a 40-joint assessment of RA
activity was made on all pregnant women, researchers found
that women with definite RA had babies of lower mean birth-
weight (3.36 vs 3.52 kg in matched controls; p = 0.01). The
difference was even more marked when accounting for disease
activity. Women with active RA had much lighter babies – a
mean birthweight of 3.30 versus 3.74 kg in women with RA in
remission (p = 0.006). Of interest, none of the women in remis-
sion in this study were taking corticosteroids [31] . Approximately
6–16% of neonates of women with RA are more likely to be
small for gestational age (SGA) [6,33,34,36,37] , and are twice as
likely to have fetal growth retardation (FGR) [4] . Using ortho-
pedic procedures as a surrogate marker for severe disease in a
population-wide study in Denmark and Sweden, women with
severe RA were at greater risk of preterm birth (adjusted OR:
2.27; 90% CI: 1.35–3.81) and SGA infants (adjusted OR: 3.68;
95% CI: 2.27–5.98) [37] .
Rates of stillbirth (<1%) are low in women with R A, but
the risk is still two-times higher than the normal population
[37] . A higher perinatal mortality rate has been highlighted in
the Wallenius et al. study published in 2011. Risk of perinatal
mortality in the first birth was three-times higher (OR: 3.29;
95% CI: 1.05–10.35) than that of the women without RA [6] .
The reason for this is unclear, and given the wide confidence
intervals, these data, while worrisome, should be interpreted
with caution.
Expert Rev. Obstet. Gynecol. 7(1), (2012)
 Table 1. Obstetric outcomes in women with rheumatoid arthritis (or inflammatory polyarthritides).
Study Hypertension Preeclampsia Preterm LBW (%) SGA (%) IUGR (%) LSCS (%) Congenital Stillbirth Ref.
(year) (%) (%) deliveries OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) anomalies (%)
OR (95% CI) OR (95% CI) <37 weeks (%) (%) OR (95% CI)
OR (95% CI) OR (95% CI)

www.expert-reviews.com
Skomsvoll 1.15–1.46 1.30 1.21 1.05 [35]
et al. (0.80–1.81) (1.19–1.44) (1.03–1.41) (0.59–4.56)
(1999)†
Skomsvoll 1.01–1.29 1.37–2.64 [32]
et al. 2000† (0.61–1.69) (1.14–3.78)
Bowden 40.0 Nil 23 (emergency [31]
et al. (2001) LSCS in 50% from
failure to progress)
Wolfberg 5.6 6.9 15.2 8.0 3.2 3.2 0 [33]
et al. 1.8 (0.2–13.4)
(2004) ‡
Reed et al. 7.8 13.6 10.3 8.2 34.3 [36]
(2006)§ 1.55 1.78 (1.21–2.60) 1.57 1.57 (0.94–2.43) 1.66 (1.22–2.26) 1.08
(0.97–2.50) (0.97–2.52) (0.40–2.66)
Chakravarty 11.1 3.4 37.2 [4]
et al. (2006) 1.4 (0.9–1.9) 2.2 (1.2–4.1) 1.5 (1.2–1.9)
Nørgaard 5 1.4 5.9 26 4.3 0.9 [37]
et al. (2010) 1.59 (1.04–2.43) 1.60 (1.25–2.03) 1.42 2.14
(1.07–1.87) (1.18–3.88)
Lin et al. 2.7 8.5 8.1 17.3 42.0 [34]
(2010) 2.22 1.17 (0.98–1.40) 1.47 1.20 (1.05–1.38) 1.19 (1.07–1.31)
(1.59–3.11) (1.22–1.78)
Wallenius 3.1 12.5 9.4 16.4 22.7 3.1 [6]
et al. 0.60 1.91 (1.13–3.24) 1.96 1.59 (0.99–2.54) 1.71 (1.13–2.59) 1.03
(2011)¶ (0.22–1.62) (1.08–3.55) (0.38–2.79)
†
This 30-year population-based study was divided into various intervals accounting for the range in OR.
‡
Study includes various rheumatologic diseases inclusive of SLE; RA n = 29/114. The percentages expressed are for all rheumatologic diseases except for preeclampsia that is specifically for RA alone.
§
Study used adjusted relative risks instead of odds ratio.
¶
Study focused specifically on first birth.
For additional detail on each of the studies, refer to A ppendix 1 for a fuller description of each of the studies, its subjects studied and their controls.
IUGR: Intrauterine growth retardation; LBW: Low birthweight (<2500 g); LSCS: Lower section cesarean section; OR: Odds ratio; RA: Rheumatoid arthritis; SGA: Small for gestational age (<10th centile for USA
reference range or birthweight >2 standard deviations below the mean for neonates of similar gestational age); SLE: Systemic lupus erythematosus.
Update on the management of rheumatoid arthritis in pregnancy
Review

79
 Review Soh & Nelson-Piercy
Women with RA are more likely to deliver via cesarean sec-
tion (23–42%, with OR ranging from 1.50 to 1.71) [4,6,36,37] , of
which approximately half are emergency procedures from failure
to progress [31] . This can be partially accounted for by the high
rates of induction of labor in women with RA [32] . However,
many obstetricians may choose to electively perform cesarean
sections on women with RA (crude OR: 3.07; 95% CI: 1.70–5.57;
p < 0.001) [6] .
Congenital anomalies in neonates of women with RA
Rates of congenital malformations in women with RA differ in
various populations and study intervals. DMARD use is likely
to directly contribute to the risk. More recent studies have
shown only a very mildly elevated risk of OR of 1.03–1.08 [6,36] .
Longitudinal population-wide studies in Denmark, Sweden
and Norway that extend back to 1969 indicate a higher rate of
congenital malformations (OR: 1.21–1.42) [35,36] . Nørgaard’s
study from 1994 shows a 30% higher prevalence rate for con-
genital anomalies in neonates of women with RA compared
with the normal population. Congenital anomalies noted were
limb-reduction defects and cleft palate, but though there was no
increased risk of cardiac or urological system defects [37] . MTX
and high-dose corticosteroids potentially contribute to the con-
genital anomalies described here. It is possible that the reduction
of numbers of congenital anomalies in the more recent studies
is a result of improved methods for detection of fetal anomalies
(and subsequent termination). This only serves to emphasize
the need for careful preconception planning in women with
RA on DMARDs.
Drugs used in RA & pregnancy
With the exception of a few medications, most drugs will pass
through the placenta into the developing fetus. Most drugs are
not licenced for use in pregnancy. However, this does not pre-
clude appropriate prescribing in pregnancy and lactation. With
the accrued evidence that good maternal disease control leads to
improved obstetric and neonatal outcomes, it is vital that clini-
cians caring for pregnant women should familiarize themselves
with the best therapeutic options for the pregnant and lactating
patient (Table 2) [38] .
NSAIDs, COX-2 inhibitors & aspirin
These drugs are first-line medications for any person with inflam-
matory polyarthritis. Much of the NSAID data relate to indo-
methacin, as it was previously used as a tocolytic agent, but the
class effect prevails, and other NSAIDs appear to exert the same
effects on the fetal heart and kidneys. The effects of NSAIDs on
fertility and miscarriage have been discussed earlier.
Several large studies have confirmed a lack of teratogenicity for
NSAIDs [39] . In the third trimester, NSAIDs causes constriction
of the ductus arteriosus. Indomethacin-induced closure of the
ductus arteriosus increases from 0% from 0 to 27 weeks gestation
to 43% between 27 and 30 weeks to 61% during 31–34 weeks
[40] . Constriction of the ductus arteriosus reverses typically after
24–48 h of the discontinuation. Closure of the ductus arteriosus
80
is dose-related, leading to tricuspid regurgitation and pulmo-
nary hypertension in the neonate [41] . Expert opinion suggests
that NSAIDs, preferentially those with shorter half-lives and
at the lowest effective dose, may be continued until 32 weeks
­gestation [42] .
The effect of NSAIDs on the fetal kidney causing oligo-
hydramnios starts approximately 5 h after ingestion. The effect
is dose-dependent and reversible within a week of cessation [43] .
If a NSAID is administered within 24 h of delivery, transient
neonatal anuria may occur [44] .
Data on COX-2 inhibitors for pregnancy are limited. COX-2
inhibitors have also been implicated in delayed rupture of follicles
[45] . They are teratogenic in rats, causing delayed or asymmetrical
ossification in fetuses [46,47] . Human teratogenicity data are lack-
ing and it seems prudent to advise women planning pregnancy
to switch to a more traditional NSAID.
In a randomized trial comparing the COX-2 inhibitor celecoxib
to indomethacin, the researchers found the COX-2 resulted in a
slightly reduced risk of constriction of the ductus arteriosus; it
also decreased fetal urine output to a lesser degree compared with
indomethacin [48] . These findings need to be confirmed in larger
randomized controlled studies.
Large doses of aspirin at 3 g/day impair uterine contraction,
prolong labor and increase the risk of antepartum and postpartum
hemorrhage [49] . Low-dose aspirin (usually <325 mg/day) is more
commonly used in pregnancy, as meta-ana­lyses have proven that
it is modestly effective in reducing the risk of preeclampsia and
preterm delivery [50,51] . At low doses, Doppler studies show that
the fetal ductus arteriosus remains patent [52] . Low-dose aspirin is
safe with no adverse fetal effects; when continued until delivery,
the risk of bleeding is minimal, even with the use of regional
anaesthesia [53] .
Corticosteroids
Exogenous glucocorticoids are often used for active maternal RA
and fetal lung maturity. The fetus is relatively well protected from
excess free cortisol, as 11-b-ol-dehydrogenases produced by the
placenta converts active steroids to 11-keto-steroids. The fetus
also inactivates steroids by way of sulfate conjugation [54] . As a
result, the fetus receives <10% of the maternal dose of prednisone/
prednisolone. On the other hand, steroid formulations in the form
of dexamethasone and betamethasone readily cross the placenta;
they are frequently used in the obstetric setting to accelerate fetal
lung maturity when preterm delivery is considered likely.
A heavily criticized meta-ana­lysis found a 3.4-fold increased
risk of oral clefts with first trimester exposure to corticosteroids
after excluding the largest epidemiological study from its ana­lysis
[55] . Another population-based study has suggested environmental
syngergism with pesticide use as the cause of increased cleft pal-
ates [56] . Recently published, the largest population-based study
of over 800,000 births over a 12-year period in Denmark did
not show an increased risk of orofacial clefts with use of oral
corticosteroids [57] .
Use of prednisone >15 mg/day has been associated with preterm
delivery [58] . A major contributing factor is uterine infection from
Expert Rev. Obstet. Gynecol. 7(1), (2012)
 Table 2. Drugs used for rheumatoid arthritis and their recommendations in pregnancy.
Drug US FDA ADEC Half-life Effects on Effects on fetus/neonate Safety for Authors’ recommendations on its Ref.
organogenesis breastfeeding use in pregnancy
† [39–44]
NSAIDs B† C Depends None Constriction of ductus ü Likely a class effect for all NSAIDs. Use
on type of arteriosus after 27/40; if indicated at lowest dose possible

www.expert-reviews.com
NSAID oligohydramnios until 32 weeks gestation
Transient anuria and renal
failure if used before delivery
† [46–48]
COX-2 inhibitors C† B3–C Depends Teratogenic effects in Similar effects as NSAIDs on ü Safer to change to a NSAID in
on type of animals fetal heart and kidneys pregnancy until more information is
COX-2 available
† [57]
Prednisone C A Depends None Rarely has effect unless used ü Use lowest dose possible. When
on in very large doses – possible commencing steroids in pregnancy,
formulation cataracts, adrenal ensure there is a plan to taper the
of steroid insufficiency and infection dose. If disease persistently active,
then consider addition of
DMARD/biologic to ensure woman
does not remain on prolonged courses
of high-dose steroids
Hydroxychloroquine C D‡ 32–50 days None None ü Continue in pregnancy and [60–62]
breastfeeding
Sulfasalazine B A 5–10 h Likely no effect None ü (except in very Commence folic acid supplementation [63–65,118]
preterm 5 mg/day 3 months prior to
jaundiced pregnancy. In men with fertility
neonate) problems, it may need to be swapped
to another agent as it affects
spermatogenesis and motility
Methotrexate X D Up to Aminopterin If no congenital anomalies, û Reliable contraception advised. [66–71]
4 months in syndrome. High rate long term follow-up of Discontinue at least 3 months prior to
the liver of pregnancy loss and children exposed to MTX did pregnancy with daily high-dose folic
<15% rate of not reveal any problems acid supplementation. Exposed
congenital anomalies fetuses should be scanned as early as
if used in pregnancy possible (at 16/40 weeks) to
determine if there are any congenital
anomalies to facilitate elective
termination if the mother wishes
†
NSAIDS/COX-2 – risk category D from ≥30 weeks gestation.
‡
The reason for the D category in hydroxychloroquine in ADEC is because it was classified as chloroquine, which is used at much higher doses for the treatment of malaria.
§
Update on the management of rheumatoid arthritis in pregnancy

Azathioprine converts to active metabolite 6-thioguanine nucleotides in 15 min, but the half-life of the active metabolite in erythrocytes is weeks to months.
¶
Most oral bisphosphonates clear rapidly from plasma; however, it persists in bone, taking >10 years to clear.
ADEC: Australian Drug Evaluation Committee; DMARD: Disease-modifying antirheumatic drug; LBW: Low birthweight; TDS: Three-times daily.
Review

81
82
Table 2. Drugs used for rheumatoid arthritis and their recommendations in pregnancy (cont.).
Drug US FDA ADEC Half-life Effects on Effects on fetus/neonate Safety for Authors’ recommendations on its Ref.
organogenesis breastfeeding use in pregnancy
Review

Leflunomide X X 96 days In animal studies, If pregnancy continues, no û (no Reliable contraception advised. Wash [76–78]
malformations of the major structural anomalies information out with cholestyramine 8 g TDS
head, rump, vertebral noted especially after available) 11 days – repeat until drug levels
column and limb cholestyramine wash out as <0.03 µg/ml taken 2 weeks apart. If
defects. Increased suggested by manufacturer exposed in early pregnancy, offer
rate of miscarriages washout and reassure woman that
seen until date, birth outcomes of exposed
women not different from disease-
matched controls
Soh & Nelson-Piercy

Gold C 5 days None Can accumulate in fetal ü (but reports of Continue in pregnancy if already on it. [80–82]
– prolonged kidney and liver with no rash, nephritis Usual monitoring (checking for
with apparent untoward effect and hepatitis) nephritis, and so on) for gold therapy
multiple should be continued in pregnancy.
doses If other alternatives available, avoid
breastfeeding
Azathioprine D D 15 min§ None LBW and preterm delivery ü Continue in pregnancy and lactation [119–121]
– could be secondary to
maternal disease
Ciclosporin C C 15 h None Transient immune alterations ü Continue in pregnancy; probably safe [122]
in the neonate in breastfeeding, though wide range
of concentrations excreted in breast
milk
Cyclophosphamide D D 3–12 h Cyclophosphamide Transient cytopenias. No û Use only if there is life-threatening [123,124]
embryopathy with long-term effect on the maternal disease after the first
high rate of infant if survives pregnancy trimester. If maternal disease
miscarriages necessitates cyclophosphamide in first
trimester – discuss termination
Bisphosphonates C B3 ~1 h¶ Only in animal Reports if LBW and preterm No information Discontinue on confirmation of [111,125]
studies. None seen in delivery – likely related to pregnancy. Use shorter acting oral
case series in humans maternal disease bisphosphonates if the woman is
exposed planning a pregnancy
†
NSAIDS/COX-2 – risk category D from ≥30 weeks gestation.
‡
The reason for the D category in hydroxychloroquine in ADEC is because it was classified as chloroquine, which is used at much higher doses for the treatment of malaria.
§
Azathioprine converts to active metabolite 6-thioguanine nucleotides in 15 min, but the half-life of the active metabolite in erythrocytes is weeks to months.
¶
Most oral bisphosphonates clear rapidly from plasma; however, it persists in bone, taking >10 years to clear.
ADEC: Australian Drug Evaluation Committee; DMARD: Disease-modifying antirheumatic drug; LBW: Low birthweight; TDS: Three-times daily.

Expert Rev. Obstet. Gynecol. 7(1), (2012)

 Update on the management of rheumatoid arthritis in pregnancy
steroid immune suppression causing preterm rupture of mem-
branes. Studies linking dexamethasone and low birthweight are
likely to be biased. Dexamethasone is often used in preterm deliv-
eries to expedite fetal lung maturity; these neonates are likely to
be small for other obstetric reasons [59] .
Prednisone (or prednisolone) is the first-line agent to treat flares
of RA. The lowest possible doses should be used, and gradually
weaned. Women should be warned of the potential side effects of
steroid use, which are no different from the non-pregnant woman
(i.e., osteopenia, osteoporosis, increased risk of infections, espe-
cially urinary tract infections, hypertension, Cushingoid features,
and so on), with the additional risk of developing gestational dia-
betes and preterm labor. If a woman is on long-term prednisone
more than 7.5 mg/day for more than 2 weeks prior to delivery,
then supplemental intravenous hydrocortisone of 50–100 mg
every 6 h should be given once she is in established labor as there
is a risk of adrenal insufficiency from prolonged glucocorticoid
exposure. In some centers, increasing the daily prednisone dose
to 20 mg for the first 24–48 h after delivery is also practiced.
Supplemental calcium 1.25 g/day and vitamin D or a combined
supplement for bone protection should be considered in all
pregnant women taking steroids.
DMARDs
Hydroxychloroquine
Hydroxychloroquine (HCQ) is one of the best-studied DMARDs
in pregnancy because of its concurrent use for the management of
SLE. A meta-ana­lysis has not demonstrated an increase in congen-
ital malformations in the offspring [60] . Long-term follow-­­up of
the offspring have shown no growth or developmental problems,
nor problems with vision or hearing [57,61,62] . With its exceed-
ingly long half-life, discontinuing HCQ in early pregnancy does
not prevent fetal exposure and therefore should be continued in
pregnancy.
Sulfasalazine
Despite inhibiting gastrointestinal and cellular uptake of folate
and inhibition of dihydrofolate reductase, multiple studies and a
meta-ana­lysis of pregnant woman with inflammatory bowel dis-
ease (n = 642 women) receiving sulfasalazine (SSZ) did not find
any statistical differences in the rates of congenital malformations
[63] . An older well-conducted case–control study of dihydroflate
reductase inhibitors found that there was a two- to three-fold
increase in neural tube defects, oral cleft and cardiovascular
anomalies in neonates. However, the numbers exposed solely to
SSZ could not be analyzed [64] .
In males, sulfapyridine (the metabolite of SSZ) causes reversible
oligospermia and decreased sperm motility. A study comparing
the rates of congenital malformations in patients with inflamma-
tory bowel disease to the normal population found increased rates
of malformations in the offspring of men treated with SSZ [65] .
We would recommend the continuation of SSZ use in
pregnancy with the proviso of starting high-dose folic acid
(5 mg/day) 3 months prior to attempted conception, and this
should be continued for at least the first trimester. For men on
www.expert-reviews.com
Review
SSZ with fertility problems, SSZ could be discontinued for
3 months prior to conception. They should be made aware that
despite the issues with spermatogenesis, SSZ is not a means of
contraception.
Methotrexate
MTX is a folate analogue and folate antagonist, inhibiting dihy-
drofolate reductase. It causes ‘aminopterin syndrome,’ which
includes growth restriction, dysmorphic facies, multiple cranial
ossification abnormalities, limb skeletal abnormalities with par-
tial or absent ossification of bones, shortened limbs, syndactyly,
absent digits and clubfoot. Spina bifida and cardiac abnormali-
ties (dextrocardia) are less common [66] . The most vulnerable
period is between 5 and 11 weeks gestation, but teratogenesis can
occur at any time. There is no definite safe dosage threshold [67] .
A 2009 systematic review by Martínez Lopez looking specifi-
cally at MTX used at RA doses (≤25 mg/week) revealed that out
of 101 pregnancies, 23% (n = 19) resulted in miscarriages. Fifty-
five pregnancies (66%) resulted in live birth of which only five
children had congenital anomalies. Only one child had multiple
skeletal anomalies typical of aminopterin syndrome [68] . Long-
term follow-up of children exposed to MTX in utero did not reveal
any problems [69,70] .
The terminal half-life of MTX ranges between 3 and 10 h.
However, the median time for MTX polyglutamate concentra-
tions in red blood cells to become undetectable is 4–10 weeks
[71] . MTX is sequestered in the kidneys and liver for up to
4 months. When planning pregnancy a woman should wait for
at least 3 months after the cessation of MTX before attempting
to conceive. There should be concurrent folate supplementa-
tion of 5 mg/day from the time of cessation of MTX until at
least the second trimester of pregnancy. All women of child-
bearing age receiving MTX should be advised to use reliable
contraception. There are anecdotal reports of MTX causing
male factor infertility [66] . The case reports linking male MTX
use and congenital anomalies have been scarce and no defini-
tive links have been established in the published data between
paternal MTX exposure and congenital anomalies [72] . The
recently published largest case series of paternal MTX use of
42 males has not demonstrated any congenital anomalies in the
offspring [73] . However, the British Society of Rheumatology
guidelines published back in 2008 still advise a 3-month wash-
out period before conception – which is slightly longer than one
spermatogenic cycle [74] .
MTX is detected in breast milk at <10% that of the plasma dose
2 h after oral administration. However, the dose for the breastfed
infant would be equivalent to a full adult dose [75] . Breastfeeding
is not recommended in women on MTX, even at weekly doses
for RA.
Leflunomide
Leflunomide is a pyrimidine synthesis inhibitor that causes
craniofacial, axial skeleton, cardiac and great vessel malforma-
tion in offspring of exposed rats and rabbits [76] . A blood level
of <0.03 µg/ml 2 weeks apart has been determined as the ‘no
83
 Review Soh & Nelson-Piercy
effect level’ for embryotoxicity [77] . The half-life of leflunomide
is 96 days; it would take 2 years off the drug to naturally reach
no-effect levels. The manufacturer recommends the use of
choles­t yramine 8 g three-times daily for 10–11 days to reduce
leflunomide levels more quickly [201] .
The Organization of Teratology Information Specialists
(OTIS) Collaborative Research Group published outcomes of
64 women exposed to leflunomide in the first trimester, com-
pared with 108 women with RA without leflunomide (not on
MTX or cyclophosphamide) and 78 healthy pregnant women
[78] . Rates of congenital anomalies in the offspring – examined by
pediatric dys­morphologists – were no different in the leflunomide-
exposed group (5.4%) compared with 4.2% in the other two
groups (p = 0.13). Birth outcomes were similar across all three
groups. Gestational timing of the last leflunomide dose was on
average 3.1 weeks after conception, with latest exposure ending
at 8.6 weeks after conception. 95.3% of the women in the leflu-
nomide group underwent at least one course of cholestyramine
wash out.
This study provides some reassurance to women; while not
ideal, cholestyramine wash out can be undertaken in early preg-
nancy. All women on leflunomide should still use safe and reliable
contraception. There are little data on its effect on the fertility
of men [79] .
Gold
Sodium aurothiomalate or aurothiogluconate has been largely
superseded by other DMARDs. The results latest of the retro-
spective case series of 14 women with 20 pregnancies was from a
single clinic in Canada [80] and concurred with previous publica-
tions that gold therapy is an option for women with RA planning
pregnancy with no increased risk of major organ anomalies seen
in their offspring [81,82] . Gold passes readily into the fetus with
no apparent untoward outcome [83,84] .
Gold is excreted into breast milk and there are reports of neonatal
nephritis, hepatitis, rash and hematological problems although it
has been difficult to establish a causal relationship [49] . Even though
the American Academy of Pediatrics accepts gold as compatible
with breastfeeding, risk of accumulation in the neonatal tissue has
lead many clinicians to advise against breastfeeding [85,86] .
Ciclosporin, azathioprine & cyclophosphamide
Although these drugs are rarely specifically used to treat
RA they have been included in most reviews. A summary of
recommendations can be found in Table 2 .
Biologics: anti-TNF-a & B-cell-depleting agents
Use of biologics is currently the most contentious topic in the
management of RA in pregnancy. Since the controversial pub-
lication of the FDA database review by Carter et al. [87] , where
they attempted to link the constellation of malformations includ-
ing vertebral, anal, cardiac, tracheo-oesophageal, renal and limb
defect (VACTERL)-type deformities with anti-TNF-a use, clini-
cians have been exceedingly cautious about their advice to women
planning pregnancy. The mining of the FDA database – which
84
consists of voluntary post-marketing reporting of any adverse
event – revealed 41 children with a total of 61 congenital anoma-
lies were born to women who were taking either entanercept or
infliximab at some point during their pregnancy. There was only
one confirmed case of VACTERL-type deformity. This study
was heavily criticized as information on the total number of preg-
nancies exposed to anti-TNF, concurrent drug and alcohol use,
maternal disease activity and fetal chromosomal abnormalities
were lacking. Moreover, the authors’ attempt to ascribe commonly
occurring anomalies to ‘VACTERL associations’ has led to much
criticism in the published literature [88–91] .
Other databases on anti-TNF use in pregnancy – namely the
British Society for Rheumatology Biologics Register (n = 130
pregnancies) and the German biologics register (n = 37 pregnan-
cies) have not shown an increased rate of congenital anomalies
in the offspring of mothers exposed to anti-TNF agents [92–94] .
Anti-TNF-a agents are monoclonal IgG antibodies. In preg-
nancy, the fetus acquires its immunity by active transplacental
transfer of maternal IgG antibodies starting in the late second
trimester, continuing in a linear fashion until delivery onwards.
Hence, the fetus is probably well protected from anti-TNF-a
agents in the first trimester; the risk of teratogenesis is little if
nonexistent.
Most of the accumulated data is on infliximab, as it has been
widely used for inflammatory bowel disease. Nevertheless, we can
probably extrapolate its findings to most other anti-TNF agents.
With highly efficient transplacental transfer of IgG in the third
trimester and delayed clearance of the antibody from an immature
reticuloendothelial system, infliximab levels in the neonate at
birth and up to 6 weeks postpartum may be higher than maternal
levels if infliximab infusions are continued after the late second
trimester [95,96] . In a case series of four pregnancies in which inflix-
imab infusions were stopped at 21, 26, 26 and 30 weeks gestation,
respectively, with the exception of the first, infliximab levels were
two- to three-fold higher in cord blood compared with maternal
levels [97] . Infliximab can persist in the infant for up to 6 months
postpartum.
In spite of that, neonatal T- and B-cell development, IgA,
IgG and IgM levels are normal and there is a normal response
to vaccination with Hemophilius influenzae type B, Streptococcus
pneumoniae and tetanus in the offspring of a woman who was
receiving infliximab 10 mg/kg until 2 weeks prior to delivery
[98] . Four out of six infants of women who received infliximab
in the third trimester showed low IgM levels. At 7 months, all
except one had an appropriate response to vaccinations (tetanus
and H. influenzae). The authors concluded that infants exposed
to infliximab in utero were able to mount an appropriate response
to vaccination – none of them exhibited concerning immune
deficits [99] .
There is a case report of an infant who died aged 4.5 months
after receiving live vaccination with bacillus Calmette–Guérin
1.5 months prior [100] . The infant was born at 36 +3 weeks ges-
tation to a mother with Crohn’s disease managed with inflix-
imab at a dose of 10 mg/kg 8-weekly as monotherapy that was
continued throughout pregnancy. At post-mortem there was
Expert Rev. Obstet. Gynecol. 7(1), (2012)
 Update on the management of rheumatoid arthritis in pregnancy
disseminated granulomatous inflammation with multiple non-
caseating tuberculoid granulomas in the lungs, liver and dura.
Ziehl–Neelsen stain was negative for acid-fast bacilli and tuber-
culosis (TB) PCR was equivocal. Despite being born in a high-
prevalence area, all family members and contacts were free of TB.
The pathologist ruled that the death was an unusual reaction to
BCG vaccination known as disseminated TB. Infliximab levels
were not quantified.
Live vaccinations are not recommended in immunocompromised
individuals. If anti-TNF therapy is planned, patients are advised
to have their vaccination (particularly with live vaccines) per-
formed several months in anticipation of commencing therapy. To
date, there has been no advice about vaccination, particularly to
live vaccines for neonates whose mothers have received infliximab
therapy in the third trimester.
Certolizumab, a pegylated anti-TNF agent, has been touted as
one of the safer agents, as there is a no active transplacental trans-
port. This has been confirmed in a case series of ten patients with
inflammatory bowel disease who were treated with certolizumab
until up to 5 days prior to delivery [101] . Cord drug levels ranged
from undetectable to 1.66 µg/ml. In breast milk, drug levels were
below detection (<0.041 µg/ml).
Most other anti-TNF agents are excreted in small amounts in
breast milk. Being large proteinaceous molecules, they are readily
broken down by the infant’s gastrointestinal tract and have no
effect. Studies measuring the breastfed infants’ drug levels show
a continued decline in their drug levels despite being exclusively
breastfed by mothers who continued to receive their regular anti-
TNF agents. We would encourage breastfeeding for all women
on anti-TNF agents [95,102–105] .
Most women with RA are on a biological agent because of
refractory disease. As RA remains active in pregnancy and active
RA results in poor obstetric outcomes, we would advise a woman
who has active RA that is difficult to otherwise manage to con-
tinue her biologic agent in early pregnancy. The lack of long-
term outcome data on the use of biologics in pregnancy should
be discussed with the mother, and the decision to continue (or
discontinue) should be carefully balanced against the risk of
adverse pregnancy outcomes from active RA in pregnancy itself.
If her disease is quiescent and she is at the stage of planning
her pregnancy, a drug-free trial off her biological agent could be
tried while she is attempting to conceive. We would not advise
swapping one agent for another in pregnancy. If she were receiv-
ing an anti-TNF agent, we would endeavor to discontinue this
at 30 weeks gestation. However, if she has a flare of her RA that
requires large doses of prednisone to control (>20 mg prednisone
that we are unable to taper down), we would preferentially restart
her anti-TNF agents and taper down her corticosteroids to the
lowest possible dose. Her anti-TNF agents can be resumed in the
postpartum period.
We would encourage vaccination of the infant. However, spe-
cifically the use of live vaccines on infants whose mothers have
received a biologic (with the exception of anakinra – an IL-1
antagonist – and possibly pegylated anti-TNF) after the second
trimester should be discussed with the pediatrician, and possibly
www.expert-reviews.com
Review
deferred until 6 months of age. It seems injudicious to routinely
advise against vaccination of infants of mothers who have received
biologic therapy based on a single case report after thousands of
previously successful vaccinations.
Rituximab
Rituximab is a chimeric anti-CD-20 monoclonal B-cell depleting
antibody; it is used to treat SLE, hematologic malignancies and
anti-TNF-refractory RA. Much of the initial concern was sur-
rounding the risk of neonatal B-cell depletion [106,107] . As B-cell
depletion can last several months to years, manufacturers have
advised against pregnancy for at least 12 months postdose.
A case series of 253 pregnancies from the manufacturer’s global
drug safety database (which largely relies on voluntary self-report-
ing) was recently published [108] . Outcomes of 153 pregnancies
were known, of which there was a 60% live birth rate (n = 90)
with 21% first trimester miscarriages. There were only two cases
of congenital malformations. There were 11 cases of hematologi-
cal abnormalities, of which only three cases were associated with
rituximab use in the second trimester or later. In most cases
the cytopenias were transient and self-resolving. When tested,
rituximab detected in cord blood corresponded to neonatal B-cell
depletion following maternal rituximab administration within
12 weeks of delivery. There were no infectious complications
from neonatal cytopenias. The four cases of infections seen in
the infants were unlikely related to rituximab use.
Given the indications for rituximab use, active disease and con-
current drug/chemotherapeutic agent use would impact on obstet-
ric and neonatal outcomes; lack of this information and timing of
pregnancy/delivery in relation to last rituximab dose were major
shortfalls of this study. The unusually high rate of miscarriage may
also be explained by severe maternal disease for which rituximab
was indicated. These data are reassuring; while there appears to
be neonatal B-cell depletion in relation to maternal rituximab
use, there did not appear to be any adverse outcome or infections
related to it, although ongoing vigilance is advised.
At this time, all women on rituximab should be advised to
avoid pregnancy for at least 6 months following the last dose
administered to avoid any fetal exposure to the drug [109] . All
neonates who have been exposed to rituximab in the second tri-
mester or later should have a baseline full blood count checking
for cytopenia, and receive prompt treatment for any infection [108] .
Bisphosphonates
Once incorporated into bone matrix, they are potent inhibitors
of bone resorption. Animal studies have revealed accumulation
in fetal bone resulting in decreased bone growth and reduced
fetal weight in rats.
There are limited human data, but there were no congenital
malformations among the offspring in the 30 women (from two
case series) who were inadvertently exposed to bisphosphonates in
the first trimester [110,111] . Low birthweight, preterm delivery and
increased rate of miscarriages were attributed to maternal disease
in another case series [110] . There are no long-term follow-up data
on children exposed to bisphosphonates.
85
 Review Soh & Nelson-Piercy

it is stable as it may require more potent

immunosuppression to control. Women
with alveolitis related to MTX use or RA
itself should have formal lung function
testing, as well as exclusion of pulmo-
nary hypertension before embarking on
pregnancy.
Folic acid should be commenced at least
3  months before discontinuing contra-
ception. Low-dose aspirin (and calcium
supplementation in those with calcium-
deficient diets) for preeclampsia prevention
should be considered.
When pregnant, women with RA should
seek antenatal care early and be referred
for obstetrician-led care. Joint stiffness or
synovitis should be assessed and if there are
signs of active RA, NSAIDs or low-dose
corticosteroids should be prescribed with
the usual caveats and a planned review in
the near future by an obstetric physician or
Figure 1. Neonatal cutaneous lupus – a nonscarring rash in a photosensitive
the woman’s usual rheumatologist. If neces-
distribution that typically clears with the clearance of maternal anti-Ro (and/or
anti-La) antibodies by 6 months of age. sary, intra-articular steroid injections can
be undertaken in pregnant women for the
usual indications.
Discontinuation of bisphosphonates preferably prior to preg- A small subset of women may have overlap syndrome with
nancy or on confirmation of pregnancy is advised. To avoid theo- systemic lupus erythematosus or other autoimmune diseases.
retical risk of neonatal hypocalcemia, oral rather than intravenous These other disease processes should be separately assessed at
bisphosphonates are preferred for women planning pregnancy [42] . each visit. For these women, it is important to establish their
baseline extractable nuclear antigens as risk of congenital heart
Expert commentary block is 2–20% in mothers with anti-Ro (± anti-La) antibodies,
There are no guidelines on antenatal care specifically for women particularly in those with a previously affected child. Fetal car-
with RA. What is detailed below is our usual practice based on diac monitoring is advised from 16 to 28 weeks gestation, with a
experience in caring for these women. At all times, we endeavor detailed fetal cardiac scan – usually performed at 20 weeks gesta-
to normalize the woman’s pregnancy experience. tion. In the postpartum interval, there is a 5% risk of neonatal
Prepregnancy counseling remains of paramount importance. cutaneous lupus if the mother has anti-Ro or anti-La antibodies
Recognizing and overcoming the barriers to informing women – usually presenting within 6 weeks of delivery. It is a generalized
adequately about their teratogen risks is a responsibility of the cli- nonscarring erythematous rash that is very characteristic (Figure 1) ,
nician commencing the drug; contraception should be addressed occurring typically after sun exposure. This rash fades and does
concurrently. not cause scarring following the clearance of maternal ­antibodies
In women planning pregnancy, their DMARDs should be – usually in 6 months.
reviewed, and then they should be given appropriate reassur- As part of the overlap, quantification of antiphospholipid anti-
ance if the medications they are on are pregnancy-friendly. With bodies should be considered, as low-molecular-weight heparin for
increasing evidence that maternal disease control is important thromboprophylaxis should be considered if the woman is less
for good obstetric outcomes, we rarely advise withdrawal of non- mobile from active RA, and for at least a week postpartum when
teratogenic medications prepregnancy, especially in women who risk of venous thromboembolism is highest as recommended by
are rheumatoid factor and anti-CCP positive. We should be able the Royal College of Obstetricians & Gynaecologists (RCOG)
to reassure women that the use of DMARDs does not appear to Green Top Guidelines (No. 37a, published November 2009) [202] .
have any effect on the development of the neonatal immune sys- At 20–22 weeks, a detailed fetal anatomy scan should be under-
tem and their ability to cope with infections [112–114] . Longer-term taken. If there has been maternal exposure to MTX or leflunomide
studies on neurocognitive development ciclosporin use showed no in early pregnancy, we offer to perform an early anatomy scan at
difference in the offspring of mothers who had taken this drug 16 weeks in case termination is considered for fetal anomalies.
in pregnancy [115] . Serial growth scans should be performed for the usual obstet-
Extra-articular RA is rare nowadays. Any woman with extra- ric indications, unless there is a severe flare of maternal RA in
articular disease should be encouraged to defer pregnancy until pregnancy.

86 Expert Rev. Obstet. Gynecol. 7(1), (2012)

 Update on the management of rheumatoid arthritis in pregnancy Review

We routinely see our women with RA at least once every
4–6 weeks and more frequently if they have a flare necessitating an
adjustment of therapy. At each visit, women should have their dis-
ease activity and medications reviewed, symptoms of preeclampsia
enquired after, blood pressure quantified and urine dipped for
proteinuria and nitrites (for infection), in addition to their usual
obstetric review.
Women who are on corticosteroids should be additionally
screened for gestational diabetes. The physician should ensure
there is plan for reduction of steroid dose with improvement of
symptoms.
In women with cervical spine involvement, anesthetic review
is advised.
RA is not an indication for elective surgical delivery. Normal
vaginal delivery should be encouraged. Hip movement should
be assessed in early pregnancy and again closer to delivery. Hip
flexion to 90° (able to sit) and abduction to >30° should be con-
sidered adequate for a normal vaginal delivery. For women who
are unable to do so, delivery in the lateral position can be consid-
ered. In women with hip problems, use of regional anesthesia in
delivery may result in excessive abduction that may cause joint
injury and pain once the anesthesia wears off. Women who have
limitations in hip movement should be advised to discuss this
with their midwife and to be vigilant of the way their hips are
positioned in delivery to avoid this.
Postpartum, unless the woman is on MTX, leflunomide or
other therapies contraindicated in breastfeeding, women should
be encouraged to breastfeed. Wound infection is always a risk in
women on corticosteroids and other immunosuppressants. Pain
should be actively managed and women encouraged to mobilize
as this is the peak time for venous thromboembolism.
As postpartum flares are common, an early review (4–6 weeks
postpartum) with her usual rheumatologist is advised.
In women who have discontinued their medications in preg-
nancy and have successfully remained off all drugs until deliv-
ery, certain DMARDs could be safely resumed in the postpar-
tum interval even while breastfeeding. Biological agents are safe
in a lactating mother and could be resumed following delivery
once there is evidence of good wound healing and absence of
infection. NSAIDs and low-dose prednisone can be used to
treat flares of RA in the postpartum interval. Most DMARDs,
except for MTX, leflunomide and cyclophosphamide, are com-
patible with breastfeeding (Table 2) . If a woman has previously
been managed with MTX or leflunomide monotherapy and is
breastfeeding, we would advise waiting until there is a flare of
RA before resuming the DMARD. She will need to be made
aware of the risk of flares in the postpartum interval, particu-
larly so if she is off all DMARD therapy. Breastfeeding should
not interfere with how we screen prior to commencing a new
DMARD (the chosen DMARD should hopefully be compatible
with breastfeeding), or the subsequent monitoring laboratory
tests once established on the DMARD. Necessary immuniza-
tions of the mother can also be undertaken in the postpartum
interval.
In women who are already considering a subsequent preg-
nancy, they should be aware that if they have had an adverse
outcome in their first pregnancy, they have a statistically higher
chance of the same in the next pregnancy compared with women
without rheumatic disease. Recurrent PET is 25.9% compared
with 13.9% with OR of 2.22 (95% CI: 1.18–4.19). There is also
an increased risk of recurrence of low birthweight and preterm
delivery [116] .

Key issues
• Women with rheumatoid arthritis (RA) should plan their pregnancies. High-dose (5 mg/day) folic acid should be commenced and
teratogenic disease-modifying antirheumatic drugs (DMARDs, e.g., methotrexate and leflunomide) should be discontinued for at least
3 months prior to conception. Most other drugs can be safely continued in pregnancy and the woman should be given appropriate
reassurance.
• Active RA results in lower birthweight, small for gestational age infants and fetal growth restriction.
• Pregnant women with RA are also more likely to have hypertension, develop preeclampsia and have preterm deliveries.
• A normal vaginal delivery can be achieved in most. All women with cervical spine involvement should have an anesthetic
review.
• Flares of RA can be treated with NSAIDs until 32 weeks gestation; steroids (e.g., prednisolone) can be used throughout pregnancy.
Intra-muscular steroids and intra-articular steroids are preferred.
• If a flare necessitates the use of prednisolone 20 mg or more for more than 2 weeks, consideration should be given to restarting any
DMARDs (except methotrexate and leflunomide) that have been discontinued prepregnancy.
• A trial off her biologic agent for a woman with quiescent disease planning pregnancy is not unreasonable. Rates of congenital
anomalies in women on biologics are no different from the rest of the population.
• Ideally, biologics should be discontinued after 30 weeks of gestation, unless the woman is on a pegylated anti-TNF agent or IL-1
antagonist, or has very active disease necessitating ongoing use.
• Postpartum flares are common. Women who are off their DMARDs and biologics should restart their drugs once infection is excluded
and good wound healing is established. Most drugs and all biologics are compatible with breastfeeding.
• Vaccinations (with the exception of live vaccines, e.g., bacillus Calmette–Guérin) should be undertaken as normal in all infants, even
those exposed to anti-TNF agents.

www.expert-reviews.com 87
 Review Soh & Nelson-Piercy

Five-year view
With the shift in the management of RA towards early aggressive
management, which has taken place over the last decade or so,
rheumatologists may need to consider whether the management
of a young woman with RA should differ from that of her male
counterparts.
Few DMARDs have the same efficacy as MTX; it remains
the first-line DMARD, but it is also a teratogen. Should we now
consider commencing treatment of RA with a biological agent
in a young woman, hitting the disease hard early on to ensure
that disease damage does not take its toll, as we now know that
women with severe RA have worse obstetric outcomes? Should we
preferentially use a pegylated anti-TNF agent in a young woman
instead?
On the other hand, questions regarding congenital anoma-
lies and miscarriage in women on biologics remain. Until larger,
better-designed prospective studies of women with RA in preg-
nancy – which are notoriously hard to conduct – are undertaken,
we may not be able to fully reassure women. At present no one
yet knows the long-term outcomes of infants whose mothers have
been on biologics [117] .
As we continue to learn about RA in pregnancy, the identifica-
tion of risk factors for active RA will aid clinicians in deciding
which women will achieve remission in pregnancy and in whom
DMARDs could potentially be scaled back.
Meanwhile, the increasing knowledge base about RA in preg-
nancy should inspire clinicians to optimize control of RA with
appropriate and informed use of DMARDs, helping to normalize
the pregnancy experience for these women and their families.
Financial & competing interests disclosure
MC Soh was supported by the Rose-Hellaby Medical Scholarship from New
Zealand. The authors have no other relevant affiliations or financial involve-
ment with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of this
manuscript.

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 Appendix 1. Studies of women with rheumatoid arthritis and pregnancy.
Author, country, year Study Study design Cohort studied Women with RA (n) Other women/conditions Control
published and title interval included in study groups
Skomsvoll, Norway, 1999 1969–1995 Data from the All pregnant women in 3403 singleton Women with connective tissue 671,221 – all
Perinatal outcome in Medical birth Norway, after pregnancies in women diseases – SLE, Sjögren’s, systemic pregnancies in

www.expert-reviews.com
pregnancies of women with Registry of 16 weeks gestation with RA only sclerosis, polymyositis and Norway during
connective tissue disease Norway dermatomyositis – n = 333; the study
and inflammatory rheumatic specific arthritides – RA, JIA, AS interval
disease in Norway – n = 4323; nonspecific
inflammatory arthritis n = 499

Skomsvoll, Norway, 2000 1969–1995
Pregnancy complications ad
delivery practice in women
with connective tissue
diseases and inflammatory
rheumatic disease in Norway
Skomsvoll, Norway, 2002
The recurrence risk of
adverse outcome in second
pregnancy in women with
rheumatic disease
Bowden, UK, 2001
Women with inflammatory
Data from the All pregnant women in 3403 singleton Women with connective tissue 671,221 – all
Medical birth Norway, after pregnancies in women diseases – SLE, Sjögren’s, systemic pregnancies in
Registry of 16 weeks gestation with RA only sclerosis, polymyositis and Norway during
Norway dermatomyositis – n = 333; the study
specific arthritides – RA, JIA, AS interval
– n = 4323; nonspecific
inflammatory arthritis n = 499
1969–1995 Data from the All pregnant women in 918 women with Women with connective tissue 487,432
Medical birth Norway, after specific inflammatory diseases – SLE, Sjögren’s, systemic women
Registry of 16 weeks gestation arthritides. RD 1 – sclerosis, polymyositis and without the
Norway Excluded were women onset of rheumatic dermatomyositis – n = 333; diagnosis of a
with only one birth, disease before first specific arthritides – RA, JIA, AS rheumatic
multiple births, and pregnancy: n = 1065; – n = 4323; nonspecific disease
first births prior to RD 2 – onset of inflammatory arthritis n = 499
1967 rheumatic disease after
the first pregnancy but
before the second:
n = 919
Not Prospective Any pregnant women 133 women with RA or None Matched
specified Collected from a from late pregnancy undifferentiated controls (for
Appendix 1. Studies of women with rheumatoid arthritis & pregnancy

polyarthritis have babies of but UK-wide until 8 months inflammatory arthritis geographical
lower birthweight recruited campaign using postpartum only region and
from last media and social class) for
Update on the management of rheumatoid arthritis in pregnancy

trimester rheumatology n = 103 of the

until clinics subjects
6 months
postpartum
APS: Antiphospholipid syndrome; AS: Ankylosing spondylitis; JIA: Juvenile inflammatory arthritis; RA: Rheumatoid arthritis; RD: Rheumatoid drug; SLE: Systemic lupus erythematosus.
Review

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Appendix 1. Studies of women with rheumatoid arthritis and pregnancy (cont.).
Author, country, year Study Study design Cohort studied Women with RA (n) Other women/conditions included Control groups
published and title interval in study
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Wolfberg, USA, 2004 Dec Institutional All pregnant women 29 women with RA All rheumatic diseases: n = 114; SLE: 18,534 – all
Association of 1994–Aug database of with rheumatic only n = 37; other: n = 32; APS: n = 21 women without
rheumatologic disease with 1995, Brigham and diseases who delivered rheumatologic
preeclampsia 1998–2000 Women’s in the institution diseases
(total of Hospital during the study
33 months) Massachusetts interval
General Hospital
(MA, USA)
Reed, USA, 2006 1987–2001 Population-based All women who had 243 women with RA None 2559 controls
Soh & Nelson-Piercy

Pregnancy outcomes in retrospective singleton births in matched by the year

women with RA in cohort study Washington state of delivery randomly
Washington State utilizing between 1987 and selected without RA
Washington State 2001
birth records and
hospital
discharge data
Chakravarty, USA, 2006 2002 Nationwide All women with SLE, 360 women with RA Women with SLE: n = 943; APS: 976,527 obstetric
Obstetric hospitalization in inpatient sample RA and pregestational n = 719; pregestational diabetes hospitalizations
the USA for women with SLE of the Heathcare diabetes mellitus who mellitus: n = 8338
and RA Cost and delivered in USA in
Utilization Project 2002
Nøgaard, Denmark and 1994–2006 Population-based All female residents 1199 women with RA None 870,380 first-time
Sweden, 2010 heathcare with first-time singleton births in
RA and birth outcomes: databases. singleton live births or women without RA
a Danish and Swedish Medical birth stillbirths >27 weeks in
nationwide prevalence study registry of the study interval
Denmark and
Sweden and
national patient
registries
(includes data
from hospital
admissions and
outpatient
hospital visits)
APS: Antiphospholipid syndrome; AS: Ankylosing spondylitis; JIA: Juvenile inflammatory arthritis; RA: Rheumatoid arthritis; RD: Rheumatoid drug; SLE: Systemic lupus erythematosus.

Expert Rev. Obstet. Gynecol. 7(1), (2012)

 Appendix 1. Studies of women with rheumatoid arthritis and pregnancy (cont.).
Author, country, year Study Study design Cohort studied Women with RA (n) Other women/conditions included Control groups
published and title interval in study
Lin, Taiwan, 2010 2001–2003 Population-based All women with live 1912 women with RA None 9560 controls
Increased risk of adverse retrospective singleton births matched for age,

www.expert-reviews.com
pregnancy outcomes in study using 2001–2003. Excluded parity and year of
women with RA: a Taiwan National women with any delivery
nationwide population- Health Insurance chronic illness (e.g.,
based study Research Dataset hypertension, gout,
and national birth SLE, AS, sarcoidosis)
certificate registry
Wallenius, Norway, 2011 1967–2008 Medical Birth Women diagnosed 128 women with JIA, psoriatic arthritis, AS and Controls for
Pregnancy and delivery in Registry of with chronic chronic inflammatory undifferentiated inflammatory primiparous group:
women with chronic Norway (MBRN) inflammatory arthritides plus first polyarthritis n = 335,249; controls
inflammatory arthritides and from 2001 arthritides before age birth; 151 women with for subsequent births:
with a specific focus on first the Norwegian 45 years chronic inflammatory n = 464,751
birth DMARD Registry. arthritides plus
There were linked subsequent births
databases from
1970 to October
2007
APS: Antiphospholipid syndrome; AS: Ankylosing spondylitis; JIA: Juvenile inflammatory arthritis; RA: Rheumatoid arthritis; RD: Rheumatoid drug; SLE: Systemic lupus erythematosus.
Update on the management of rheumatoid arthritis in pregnancy
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Appendix 2. Risk categories in pregnancy by the US FDA and Australian Drug Evaluation Committee.
Category US FDA interpretation
A Controlled studies in pregnant women fail to demonstrate a risk
to the fetus in the first trimester with no evidence of risk in later
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trimesters. The possibility of fetal harm appears remote
B No evidence of human risk in controlled studies.
Either animal-reproduction studies have not demonstrated a fetal
risk but there are no controlled studies in pregnant women, or
animal-reproduction studies have shown an adverse effect (other
than a decrease in fertility) that was not confirmed in controlled
studies in women in the first trimester and there is no evidence of
a risk in later trimesters
C Risk cannot be ruled out
Either studies in animals have revealed adverse effects on the
fetus (teratogenic or embryocidal effects or other) and there are
no controlled studies in women, or studies in women and animals
are not available. Drugs should be given only if the potential
benefits justify the potential risk to the fetus
D There is positive evidence of human fetal risk, but the benefits
from use in pregnant women may be acceptable despite the risk
(e.g., if the drug is needed in a life-threatening situation or for a
serious disease for which safer drugs cannot be used or are
ineffective)
X Contraindicated in pregnancy
Studies in animals or human beings have demonstrated fetal
abnormalities or there is evidence of fetal risk based on human
experience, or both, and the risk of the use of the drug in
pregnant women clearly outweighs any possible benefit. The
drug is contraindicated in women who are or may become
pregnant
Expert Rev. Obstet. Gynecol. 7(1), (2012)
Australian Drug Evaluation Committee interpretation
Drugs which have been taken by a large number of pregnant women and
Review
women of childbearing age without any proven increase in the frequency of
malformations or other direct or indirect harmful effects on the fetus having
been observed
B1: Drugs which have been taken by only a limited number of pregnant
women and women of childbearing age, without an increase in the
frequency of malformation or other direct or indirect harmful effects on the
human fetus having been observed
Studies in animals have not shown evidence of an increased occurrence of
fetal damage
Soh & Nelson-Piercy
B2: Drugs which have been taken by only a limited number of pregnant
women and women of childbearing age, without an increase in the
frequency of malformation or other direct or indirect harmful effects on the
human fetus having been observed
Studies in animals are inadequate or may be lacking, but available data show
no evidence of an increased occurrence of fetal damage
B3: Drugs which have been taken by only a limited number of pregnant
women and women of childbearing age, without an increase in the
frequency of malformation or other direct or indirect harmful effects on the
human fetus having been observed
Studies in animals have shown evidence of an increased occurrence of fetal
damage, the significance of which is considered uncertain in humans
Drugs which, owing to their pharmacological effects, have caused or may be
suspected of causing, harmful effects on the human fetus or neonate
without causing malformations. These effects may be reversible
Accompanying texts should be consulted for further details
Drugs which have caused, are suspected to have caused or may be expected
to cause, an increased incidence of human fetal malformations or irreversible
damage. These drugs may also have adverse pharmacological effects
Accompanying texts should be consulted for further details
Drugs which have such a high risk of causing permanent damage to the
fetus that they should not be used in pregnancy or when there is a
possibility of pregnancy
Appendix 2. Risk categories in pregnancy by the US FDA and Australian Drug Evaluation Committee.