59 Drugs and pregnancy

Cianna Leatherwood • Bonnie L. Bermas

Key Points This chapter discusses the treatment of pregnant patients with rheumatic
■ Clinicians should outline a treatment plan and review the potential toxicities of
disorders with special emphasis on medication safety during pregnancy and
medications with patients before conception.
nursing. Medications reviewed in this chapter include aspirin and other
nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, antimalarials,
■ Patients with inflammatory arthritis and systemic rheumatic diseases should have
immunosuppressive agents, antimetabolites, cytotoxic agents, intravenous
their disease under good control before conception.
immunoglobulin (IVIG), and biologics (Table 59.1).Treatment recommen-
■ Patients who have preexisting renal disease, in the context of either systemic lupus
dations and approaches to patient care are described whenever possible.
erythematosus (SLE) or another autoimmune disease, should be transitioned to
medications compatible with pregnancy and be in remission for at least 6 months
before conception. PREGNANCY
■ Clinicians should not empirically treat diagnoses or a laboratory test result with For a pregnancy to be successful, the mother must tolerate the fetus, which
medications during pregnancy but rather reserve treatment for individuals with active is a hemiallograft. Some theories of what happens to the immune system
disease. during pregnancy to promote fetal survival include expression of nonclassical
■ Aspirin can be used throughout pregnancy, and other nonsteroidal antiinflammatory major histocompatibility complex class I by the trophoblast and the attenuation
drugs can be used judiciously from the time of implantation until the last trimester of natural killer cell activity.7 Recent murine data suggest that suppression
of pregnancy. of the maternal response to paternal alloantigens by extrathymic regulatory
■ Glucocorticoids at the lowest dose possible can be used during pregnancy for T cells also plays an important role in pregnancy immunology.8
disease flares with the understanding that there is an increased risk of small for
gestational aged infants and maternal glucose intolerance, hypertension, and
osteoporosis.
RHEUMATIC DISEASES AND PREGNANCY
■ Patients with SLE should be maintained on antimalarials during pregnancy. Changes in the immune system during pregnancy may modify the disease
■ Sulfasalazine, azathioprine, tacrolimus, and cyclosporine can be used during activity of different rheumatic diseases in disparate ways. Conventional wisdom
pregnancy. is that up to 70% of patients with rheumatoid arthritis (RA) experience
■ Cyclophosphamide, mycophenolate mofetil, methotrexate, and leflunomide should be remission when pregnant.9 However, more recent studies suggest that the
avoided during pregnancy. actual number of patients who improve during pregnancy may be closer to
■ Data on the use of anti–tumor necrosis factor therapy suggest that these medications 50%.10 Why this amelioration of symptoms occurs is unclear, but it may be
are compatible with pregnancy. In general, nonpegylated forms should be related to some of the alterations in inflammatory cytokine levels that are
discontinued in the third trimester. observed during pregnancy. For example, tumor necrosis factor-α (TNF-α)
■ There are limited data on other biologics and small molecules in pregnancy to
and other cytokines are downregulated during pregnancy,11 and this may
conclude whether they are compatible with pregnancy and lactation.
have a positive impact on disease activity in RA.12
In contrast to the data for RA, the data for systemic lupus erythematosus
(SLE) are unclear. Some studies suggest that SLE is not impacted by pregnancy,
but other studies suggest that SLE is exacerbated by pregnancy.13,14 There is
even more limited information regarding other rheumatologic disorders.
INTRODUCTION Therefore, clinicians may not be able to predict which patients with a rheumatic
condition are likely to experience flares during pregnancy.
Rheumatologic disorders occur commonly in women during their reproductive There are several guiding principles in managing patients with rheumatic
years. Thus, clinicians should be familiar with how to manage rheumatic diseases during pregnancy (Box 59.1). First, the patient should be in clinical
diseases during pregnancy. The impact of a pregnancy on the mother’s disease remission or have her disease under good control at the time of conception.
activity, coupled with the potential toxicity of many antirheumatic medications Specifically, in patients who have lupus nephritis or another rheumatologic
to both the mother and fetus, make treatment challenging. Data on the disorder with renal involvement, the kidney disease should be in remission
potential toxicity of a particular pharmacologic agent are often limited. for at least 6 months before conception. This approach should also be applied
Commonly, we rely on animal studies that use superpharmacologic dosing to patients who have other significant organ involvement as part of their
to evaluate a drug for teratogenicity. Alternatively, we refer to case reports rheumatologic disease. Second, patients should be following a therapeutic
of drug exposure in a handful of pregnancies. Neither of these approaches regimen that can be continued during pregnancy. For example, in patients
adequately reveals the true risk of a particular therapy during pregnancy. with active RA or SLE, it is prudent to continue only medications that are
The U.S. Food and Drug Administration (FDA) use-in-pregnancy ratings A, considered compatible with pregnancy. Third, the clinician should treat active
B, C, D, and X were deemed inadequate because they were overly simplistic, disease symptoms and signs and not a clinical diagnosis or a laboratory test
often based on limited information, and were inappropriately used as a result. Thus, there is no role for empirical immunosuppression in pregnant
grading system rather than a reflection of available data. The FDA has tried patients with rheumatologic disorders who are in clinically stable
to rectify these shortcomings by instituting the Pregnancy and Lactation condition.
Labeling rule (PLLR) on June 30, 2015.1 The intent of this labeling change
is to provide clinicians with as much available information—in particular ASPIRIN AND OTHER NONSTEROIDAL
human data—as possible to guide decision making. Medical governing
organizations, such as the American College of Rheumatology (ACR), have
ANTIINFLAMMATORY DRUGS
identified the unmet need for more consensus guidance regarding the manage- Aspirin and other NSAIDs, including the cyclooxygenase-2 (COX-2) selective
ment of women with rheumatologic disorders during pregnancy.2 In this inhibitors, are the cornerstones of treatment for the pain and joint inflammation
vein, the British Society of Rheumatology published guidelines on the treatment in arthritic conditions. In humans, exposure to high-dose aspirin in utero
of rheumatic disorders during pregnancy.3,4 Likewise, the European League during 5128 pregnancies did not result in an increased rate of fetal malforma-
Against Rheumatism (EULAR) presented a summary of this topic.5 These tion despite reports that high-dose aspirin exposure in animals can be tera-
updates provide a thorough review of the available data but similar to any togenic.15,16 Furthermore, low-dose aspirin is part of the treatment regimen
guidelines are limited by incomplete data and the lack of accounting for the for pregnant women with antiphospholipid syndrome and obstetric complica-
need for disease control and the impact of the underlying rheumatologic tions.17 The American Academy of Pediatrics (AAP) concludes that aspirin
disease on pregnancy outcomes.6 is compatible with breastfeeding.18

452
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 CHAPTER 59 Drugs and pregnancy 453

Table 59.1
Maternal, fetal, and breastfeeding effects of antirheumatic therapies
Humans
Drug Maternal Fetal Breastfeeding
Aspirin and NSAIDs Increased bleeding risk Premature closure of the ductus arteriosus; Compatible
during delivery discontinue by week 30
Glucocorticoids PROM SGA Crosses into breast milk at low
Hypertension Fluorinated forms promote lung maturity concentration; well tolerated
Glucose intolerance
Osteoporosis
Osteonecrosis
Antimalarials May improve SLE outcome Compatible Compatible
Sulfasalazine‡ — — Compatible in healthy full-term babies
Azathioprine — — Limited data but likely compatible
Cyclosporine A Renal insufficiency Spontaneous abortions Limited data but likely compatible
Mycophenolate mofetil ______— Shortened digits and hypoplastic nails Contraindicated
Auditory canal atresia
Cleft lip and palate
Micrognathia
Hypertelorism
Ocular coloboma
Methotrexate Can be used to induce Embryotoxic Contraindicated
abortion in ectopic Skeletal abnormalities
pregnancies Facial abnormalities
†
Leflunomide — Multiple congenital anomalies
Cyclophosphamide Decreased fertility in males SGA Contraindicated
and females Limb abnormalities
Coronary artery agenesis
Tumors in offspring*
†
Intravenous immunoglobulin — SGA
Autoantibodies
Etanercept, adalimumab, — Slightly increased rate of congenital anomalies no Large molecules thus very little gets
infliximab particular pattern seen transferred to breast milk; most
Certolizumab Pegylated form crosses the placenta at low likely compatible with nursing
concentration and may be preferable form
†
Rituximab — No increased risk of congenital anomaly
Hematologic anomalies reported
Neonatal infection reported
†
Abatacept — 8.1% rate of congenital anomaly; no particular pattern
†
Tocilizumab 4.5% rate of congenital anomaly; no particular pattern
†
Tofacitinib — Case of pulmonary stenosis
† †
Anakinra —
† †
Belimumab —

*Theoretical risk or case reports only.

BOX 59.1 TREATMENT PRINCIPLES FOR PATIENTS WITH age, diabetes, thyroid disease, hypercoagulable states, smoking status, inflam-
RHEUMATIC DISEASES DURING PREGNANCY matory conditions, history of recurrent miscarriage, in vitro fertilization,
and other factors.22
■ Disease should be in remission or under good control at the time of Data on the use of COX-2 selective inhibitors during pregnancy are limited.
conception. To date, there are no reports of fetal malformations after exposure to these
■ Medications should be minimized or discontinued as appropriate. drugs in utero; however, there are insufficient data in humans to evaluate
■ The disease symptoms, not the diagnosis, should be treated (e.g., a their safety during pregnancy. In animal studies, COX-2 selective inhibitors
patient with systemic lupus erythematosus does not need empirical steroid can interfere with both ovulation and implantation.23 Because nonselective
therapy during pregnancy unless the disease is active). NSAIDs have both COX-1 and COX-2 inhibitory effects, patients should
discontinue both nonselective NSAIDs and COX-2 inhibitors at the beginning
of the menstrual cycles in which they plan to try to conceive. Aspirin and
In animals, high doses of some NSAIDs are teratogenic.19 In humans, other NSAIDs can be used during the pregnancy. The NSAID should be
NSAIDs do not cause fetal malformations but can cause premature closure discontinued during the third trimester, and both NSAIDs and COX-2 selective
of the ductus arteriosus when used during the third trimester. 20 Some inhibitors should be held during a conception cycle. Aspirin should be
observational studies suggest there may be an increased risk of spontaneous continued if indicated. The AAP considers most NSAIDs to be compatible
abortion associated with NSAID use. A large case-control study from a Canadian with breastfeeding.18 No specific data are available on the safety of the COX-2
registry suggested that exposure to nonsalicylate, nonselective, and COX-2 inhibitors in breastfeeding mothers.
selective NSAIDs in the first 20 weeks of pregnancy may be associated with
an increased risk of miscarriage (odds ratio [OR], 2.4; 95% confidence interval,
2.1–2.8); however, the control group was not matched for maternal age (a
GLUCOCORTICOIDS
risk factor for spontaneous abortion), and the over-the-counter NSAID use Glucocorticoids are used to treat many rheumatologic disorders. Prednisone
and smoking status were unknown.21 Another study linked data from medica- and prednisolone, the forms most commonly used in rheumatology, are not
tion dispensing records to obstetric outcomes for more than 65,000 pregnancies readily metabolized by placentas and reach fetuses in low concentrations.
and found no significant increased risk for spontaneous abortion after In contrast, betamethasone and dexamethasone, the fluorinated glucocorticoids,
nonselective or COX-2 selective NSAID exposure after controlling for maternal reach fetuses at higher concentrations and can be used for treating fetal

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454 SECTION 5 Principles of Management
conditions such as lung immaturity.24 In animals, glucocorticoids have been we have a plethora of information on the use of these medications
shown to increase aggressive behavior in the mother and increase the incidence during pregnancy because of information gleaned from large transplant
of cleft palate formation.25,26 In humans, the data are more reassuring. In a registries. Azathioprine, cyclosporine, mycophenolate mofetil, and tac-
large series of patients with asthma who were treated with glucocorticoids rolimus are the major immunosuppressive agents used in the treatment of
(mean dose, 8 mg/day) during pregnancy, the rate of fetal anomalies was rheumatic diseases. Their safety for use in pregnancy is discussed in the
not above the background level.27 A large meta-analysis of the use of gluco- following section.
corticoids during pregnancy found a 3.4-fold increase in risk of cleft palate
formation in offspring who were exposed to glucocorticoids during pregnancy.28
However, a more recent study of 1449 Danish women exposed to either
AZATHIOPRINE
inhaled or oral corticosteroids from 30 days before conception through the The purine analog azathioprine has been used for the treatment of patients
first trimester showed an OR of 0.47 for the development of oral cleft.29 with SLE, RA, and the vasculitides. In pregnant rats treated with high doses
Similarly, a Danish cohort study of 51,973 first trimester corticosteroid of azathioprine (20 mg/kg/day), trophoblastic damage was observed.42 In
exposures found that the OR of cleft lip with or without cleft palate was humans, the placenta is unable to metabolize azathioprine into its metabolite
1.05.30 Glucocorticoids can contribute to premature rupture of the membranes 6-mercaptopurine, which suggests that little if any of the biologically active
and babies who are small for gestational age. Pregnant women who take form of this medication reaches the fetus.43 Although there have been case
glucocorticoids are at increased risk of the development of gestational diabetes, reports of infants born with pancytopenia, combined immunodeficiency,
hypertension, and osteoporosis. chromosomal abnormalities, and craniofacial malformations after in utero
Glucocorticoids can be used in pregnant patients for symptomatic relief exposure to azathioprine,44,45 several large case series have failed to demonstrate
or in those who require immunosuppression. Clinicians should use the an increased risk of congenital anomalies in exposed fetuses. In 142 transplant
lowest possible dose of glucocorticoids that controls clinical symptoms. In recipients who were given azathioprine during pregnancy, reported anomalies
patients who have been treated with glucocorticoids throughout pregnancy in infants included metatarsus adductus, kidney malformation, ventricular
and who have a prolonged labor or require a cesarean section, stress doses septal defect, patent ductus arteriosus, and a hearing deficit. Nonetheless,
of steroids (50–100 mg hydrocortisone sodium succinate intravenously every the number of observed anomalies was not above the background rate, and
8 hours) should be administered during labor and delivery. no particular pattern of malformation was reported.46 Moreover, patients
Five percent of the glucocorticoid dose is secreted in breast milk. This were concomitantly receiving other medications such as glucocorticoids and
is not an issue for lactating mothers who are taking less than 20 mg/day. cyclosporine, so attributing risk to any particular medication is difficult.
However, in patients who are taking more than 20 mg/day, the recommendation Lower birth weights have been described in infants whose mothers took
is to pump and discard breast milk produced during the 4 hours immediately azathioprine during pregnancy; however, whether this is due to premature
after the steroid dose.31 delivery or true small size for gestational age is a subject of debate.47,48 The
rate of premature delivery is likewise difficult to interpret given that patient
and physician preference for delivery time is often not discussed in these
ANTIMALARIALS studies.
The 4-aminoquinoloine antimalarial agents hydroxychloroquine and chlo- The existing data suggest that azathioprine does not increase the risk of
roquine are used to treat mild patients with RA and SLE. In animals, use of congenital anomalies above background rates. This medication is considered
these medications during pregnancy can cause chorioretinotoxicity in the a viable option for immunosuppression during pregnancy. Azathioprine is
fetus.32 In lower doses, the antimalarials have been safely used in pregnancy excreted in the breast milk in low concentrations.49 Therefore, the benefits
for malarial prophylaxis.33 In higher doses, these medications have been of breastfeeding must be weighed against the potential risk of adverse effects
given to pregnant patients with SLE with no increased reports of fetal in infants.
malformations. Khamashta and colleagues34 reported on 33 women who
safely took antimalarials during pregnancy, and Parke and Rothfield35 reported
on 16 patients with lupus who took antimalarials during pregnancy with
CYCLOSPORINE
no adverse effects. Furthermore, there is growing evidence that continuing In rodents, cyclosporine crosses the placenta in very low concentrations.50
hydroxychloroquine therapy in patients with SLE during pregnancy may Pregnant rodents administered high doses of cyclosporine (25 mg/kg/day)
improve maternal and fetal outcome.36 A survey of North American rheu- had increased fetal mortality and renal abnormalities in one study, although
matologists revealed that 69% of these physicians maintain patients on this other studies have not shown any impact on organogenesis.51,52 There are
medication during pregnancy, a result that supports the concept that differing opinions as to whether or not cyclosporine crosses the placenta in
hydroxychloroquine is compatible with pregnancy.37 Patients with RA or significant concentrations in humans.53,54 Regardless, there seems to be no
lupus should be encouraged to continue these medications during pregnancy increased risk of teratogenicity over background rates with in utero cyclo-
to ensure better outcomes. According to the AAP, this medication can be sporine exposure. In one study of 154 pregnancies in renal transplant patients
used in nursing mothers.18 in which the mothers were taking cyclosporine, there was no increase in
the incidence of malformations; however, the babies exposed to cyclosporine
were smaller and more often premature, and the mothers had an increased
SULFASALAZINE incidence of maternal diabetes and hypertension.55 In the U.S. National
Sulfasalazine was initially developed in the 1930s to treat RA. However, until Transplantation Pregnancy Registry, 500 pregnancies have been reported in
the past 2 decades, this drug has been used mainly to treat inflammatory which the fetuses were exposed to cyclosporine. There was no increase in
bowel disease. Sulfasalazine crosses the placenta with its metabolite sulfapy- congenital anomalies, although the live birth rate was lower in pregnant
ridine. The latter can displace bilirubin from albumin, but this is not thought patients who received cyclosporine. Importantly, sicker patients tend to be
to be clinically relevant.38 Although there have been case reports of fetal taking cyclosporine, which may help explain these observations.56 Finally,
malformations in humans after in utero exposure to sulfasalazine, a large a recent meta-analysis concluded that cyclosporine does not appear to be a
meta-analysis did not show a statistically significantly increased risk of major teratogen, although it may be associated with increased rates of
congenital anomalies after fetal exposure.39 Because sulfasalazine inhibits prematurity.57
the absorption of folic acid, pregnant women should take supplemental folic There is some concern that in utero exposure to cyclosporine may impair
acid beyond the dosages typically prescribed during pregnancy. This medication the development of T, B, and natural killer cells. Whether this will have
may be used during pregnancy and is a good option for women who have long-term impact and whether immunization schedules in these infants
active inflammatory arthritis. should be modified is unclear.58 The literature suggests that cyclosporine
Sulfasalazine interferes with both spermatogenesis and sperm motility. may be used for immunosuppression during pregnancy. There are limited
Therefore, men should discontinue this medication for 3 months before data on the transmission of this medication to breast milk; however, there
attempting conception.40 Because of a report of bloody diarrhea in a breastfed have not been reports of infant immunosuppression, suggesting that this
infant whose mother was ingesting sulfasalazine, the AAP warns against use medication is compatible with lactation.3
of this medication by nursing mothers; nonetheless, in certain circumstances,
it may be appropriate to continue this medication in lactating women.18,41
MYCOPHENOLATE MOFETIL
Mycophenolate mofetil is a purine synthesis inhibitor that has been used to
IMMUNOSUPPRESSIVE AGENTS prevent organ rejection. More recently, it has been used in the treatment of
Immunosuppressive agents are used in the treatment of rheumatic diseases lupus nephritis.59 In animals, this agent may cause premature meiotic matura-
to manage end-organ involvement and as steroid-sparing agents. Fortunately, tion.60 In a case series of 57 pregnancies in women taking mycophenolate

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 CHAPTER 59 Drugs and pregnancy 455

mofetil, a lower than expected rate of live births and a higher than expected CYCLOPHOSPHAMIDE
rate of congenital anomalies (6 per 29 live births) were reported.61 Given
the high rate of reported anomalies, this medication should be avoided Cyclophosphamide is a cytotoxic agent that is the backbone of many cancer
during pregnancy and nursing. chemotherapy regimens. In people with SLE and vasculitis, this medication
has greatly reduced the morbidity and mortality of renal disease and other
organ involvement.75 In pregnant mice, cyclophosphamide causes chromosomal
TACROLIMUS rearrangements and impairs blastocyst development in embryos.76 In humans,
Tacrolimus, a calcineurin inhibitor, is now being used to treat lupus cyclophosphamide exposure during pregnancy can lead to problems with
nephritis.62 digit development and limb formation, iris development, and coronary artery
There are limited data regarding tacrolimus exposure during pregnancies. abnormalities.77,78 Although there have been case reports of individuals being
One study of 100 pregnancies in 84 women treated with tacrolimus reported treated for granulomatosis with polyangiitis (at 17 weeks of gestation and
four babies with malformations, a finding not above the background rate. beyond) and Hodgkin lymphoma (in third trimester) with no adverse out-
Moreover, there was no consistent pattern of anatomic abnormality observed.63 comes, cyclophosphamide should be avoided during pregnancy.79,80 Patients
Very little tacrolimus is transported in breast milk; thus, this medication can who need to be treated with this medication during the first trimester and
be continued during lactation.64 early second trimester of pregnancy should be counseled about the high risk
of congenital anomalies in the fetus. Cyclophosphamide is transferred into
breast milk and should not be used by nursing mothers.
METHOTREXATE Prolonged use of cyclophosphamide can also induce infertility in women.
Methotrexate is a folate antagonist that has been used widely over the past 3 Risk factors for cyclophosphamide-induced infertility include maternal age
decades for the treatment of RA and other immune-mediated inflammatory older than 30 years, more than 15 pulses of therapy, and a cumulative dose
conditions. Current practice suggests that this medication should be the of more than 10 g. Concomitant use of leuprolide acetate or oral contraceptives
mainstay of therapy of RA.65 In pregnant rodents, this agent causes skeletal may offset this effect.81
abnormalities in the offspring and increased fetal resorption rate.66 In humans,
this medication is profoundly abortigenic and is commonly used for the
nonsurgical treatment of ectopic pregnancies.67 It can also cause severe
INTRAVENOUS IMMUNOGLOBULIN
teratogenicity, including craniofacial abnormalities and mental retardation.68 Intravenous immunoglobulin is used for the treatment of dermatomyositis
Most of the toxicity appears to occur during the sixth through eighth weeks and other rheumatic conditions. Data on the use of this medication during
of gestation and at dosages higher than 10 mg/wk.69 There have been a few pregnancy are limited. There have been several case reports about the safety
case reports of offspring in whom there was no teratogenicity when exposed of this medication during pregnancy. Moreover, this medication has also
to this medication before 6 weeks of gestation and at dosages lower than been used to manage the obstetric complications of antiphospholipid syndrome
10 mg/wk.70 Nonetheless, a recent review of this topic by Lloyd and col- without inducing congenital malformations.82 This medication is considered
leagues71 suggests that there is no safe window. In their series encompassing compatible with pregnancy.
42 pregnancies, there were 10 fetal abnormalities after in utero exposure to
methotrexate in the first trimester. They suggest that the washout period TUMOR NECROSIS FACTOR-α BLOCKADE
before conception in both men and women should be 6 months. Donnenfeld
and associates72 suggest that the medication should be discontinued 12
AND INHIBITORS
weeks before conception because of the high spontaneous abortion rate, Biologics that are directed against the TNF-α receptor or inhibit this cytokine
but the ACR recommends that women wait at least one ovulatory cycle are successful in treating RA.12 Although there was initial concern regarding
after stopping methotrexate before attempting conception. It is imperative TNF-α exposure during pregnancy based on the report to the FDA of potential
to counsel sexually active patients who have the potential to conceive about congenital anomalies consistent with VACTERL (vertebral defects, anal atresia,
consistently using reliable birth control while taking methotrexate and other cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormali-
teratogenic medications. Although the package insert recommends that men ties) syndrome,83 the significance of this finding has been questioned. A case
discontinue this medication 3 months before attempting conception, a study series of 118 pregnancies in which there was exposure to anti–TNF-α agents
of 113 pregnancies after paternal exposure did not show an increased rate either before conception or during pregnancy demonstrated a higher rate of
of fetal anomalies.73 Although very little methotrexate gets transferred into spontaneous miscarriage (several of the patients were taking methotrexate
breast milk, the current recommendations are to avoid this medication in and leflunomide as well) but no increased incidence of congenital anomalies.84
lactating women.3 Another recent study suggested a higher than background rate of congenital
Given the widespread use of methotrexate in rheumatic disorders, inadvert- anomalies after first trimester exposure to anti–TNF-α agents; nonetheless,
ent in utero exposure can and does occur. Thus, clinicians may be faced no disease control group was used in this study, and no particular pattern
with how best to counsel patients regarding whether to proceed with a of anomalies was appreciated.85
pregnancy or not. Reproductive choices are intensely personal and are based Animal data suggest that an anti–TNF-α pegylated Fab monoclonal antibody
on cultural, religious, and individual belief systems. The role of the clinician may not cross the placenta in significant concentration to accumulate in the
is to provide as much information as possible on reported fetal outcomes fetus.86 More recent human data for 339 pregnancies in women exposed to
after medication exposures so that patients can evaluate the potential risk certolizumab pegol, a pegylated anti–TNF-α agent, suggest no increased rate
to the fetus. In addition to providing this information, referring the patient of congenital abnormalities or pregnancy complications when this medication
for high-resolution fetal ultrasonography that can evaluate organ development is used during pregnancy.87 In cases of active disease in which patients have
can help the patient make an informed decision about how to proceed with previously not tolerated discontinuation of their TNF-α blockers, one should
the pregnancy. consider continuing these medications during pregnancy especially as disease
activity itself can result in pregnancy complications.88 Nonpegylated forms
of these medications should be discontinued by the third trimester, and
LEFLUNOMIDE infants exposed in utero to these medications should not be given live vaccines
Leflunomide is used to treat inflammatory arthritis, Behçet syndrome, and for the first 6 months of life.
other disorders. There are limited data regarding anti–TNF-α agents and lactation. These
One report on 45 pregnancies in which inadvertent exposure to leflunomide agents may be compatible with lactation because of the high molecular
occurred either just before conception or during gestation found that 2 of weights of the proteins and their likely digestion in the infant gut prior to
16 offspring exposed to leflunomide in utero had major malformations, and reaching the bloodstream.
an additional 3 had minor anomalies.74 Although the numbers suggest a
higher than background rate of congenital anomalies, the authors conclude RITUXIMAB, BIOLOGICS, AND
that leflunomide is not a major teratogen because no particular pattern of
malformations was found. Patients who are taking leflunomide should be
SMALL MOLECULES
carefully counseled regarding appropriate contraception. Because of its Data on the safety of rituximab and other depleting therapies during pregnancy
extremely long half-life, drug elimination with cholestyramine is recommended are limited. A recent review of data for 153 pregnancies involving fetal
for women who wish to become pregnant. The manufacturer recommends exposure to rituximab revealed 11 hematologic abnormalities, 4 neonatal
that cholestyramine be given at a dosage of 8 g three times a day for 11 days infections, and 2 congenital malformations in 90 live births.89 The authors
and that drug levels then be measured. Without cholestyramine, it can take concluded that rituximab should be avoided for 12 months before conception.
up to 2 years to eliminate this drug. Given that immunoglobulins do not cross the placenta until after the first

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456 SECTION 5 Principles of Management
trimester, this approach may be overly conservative, especially in patients Table 59.2
who are dependent on this medication for disease control. Although there
are limited data on the other biologics such as anakinra and belimumab, Treatment recommendations*
recent reports regarding some of the biologics and small molecules are Symptom or condition Treatment options
reassuring. One report of 161 pregnancies in which there was exposure to Mild arthralgias, arthritis, NSAIDs (after conception up until third
abatacept (151 maternal and 10 paternal) reported on outcomes. In the pleuritis, skin rashes trimester)
infants with maternal exposure that ended in live birth, there were 8.1% Low-dose glucocorticoids (5–10 mg/day of
congenital anomalies. Although this rate is higher than expected, no particular prednisone)
pattern of congenital anomalies was reported.90 In a study of 399 women Inflammatory arthritis Consider sulfasalazine in addition to above,
exposed to tocilizumab before or during pregnancy, 180 pregnancies were antimalarials, TNF-α blockade
followed prospectively. The rate of malformations was 4.5%, and no particular SLE or connective tissue Maintain antimalarials
pattern of anomalies was reported.91 In a small case series of 33 women disease
exposed to tofacitinib as monotherapy during pregnancy, 1 congenital case Moderate disease Glucocorticoids (higher doses), azathioprine,
of pulmonary stenosis and 4 spontaneous miscarriages were reported. Despite 6-mercaptopurine, cyclosporine, tacrolimus
these reassuring reports, current recommendations are to avoid these medica- Severe disease Pulse steroids, IVIG, azathioprine, cyclosporine,
tions during pregnancy and lactation until more data are available. tacrolimus
Life-threatening disease Cyclophosphamide
CONCLUSION *Methotrexate and leflunomide should be avoided.
Managing a pregnant patient with an underlying rheumatologic disorder is IVIG, Intravenous immunoglobulin; NSAIDs, nonsteroidal antiinflammatory drugs; SLE, systemic lupus
erythematosus; TNF-α, tumor necrosis factor-α.
challenging. Ensuring that the patient’s disorder is in remission or under
good control with medications compatible with pregnancy before conception
is crucial for good maternal and fetal outcomes. The potential toxicities of
medications to both the mother and the fetus must be weighed against the higher doses of glucocorticoids, azathioprine, cyclosporine, and tacrolimus
need for disease control in situations of disease flare. Often there is no ideal can be prescribed. In the case of severe disease activity, pulse steroid therapy,
therapy for a given situation. One approach (Table 59.2) is to treat mild IVIG, azathioprine, cyclosporine, and tacrolimus are all appropriate therapies.
symptoms with NSAIDs (after implantation and up until the third trimester), Cytotoxic agents should be reserved for life-threatening situations. Limited
low doses of glucocorticoids, or both. If inflammatory arthritis is the major data on biologics other than TNF-α and small molecules preclude their use
issue, hydroxychloroquine, sulfasalazine, and TNF-α blockers can be used. during pregnancy in most circumstances. In all cases, the treating clinician
Patients with SLE should continue to take their antimalarials during pregnancy. and the patient should discuss the potential hazard to the mother and the
For patients with moderate disease activity of their rheumatic condition, fetus of any therapy.

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