Rheumatoid Arthritis and Pregnancy
- Author: Katherine K Temprano, MD; Chief Editor: Christine Isaacs, MD more...
Effects of Pregnancy on Rheumatoid Arthritis
Pregnancy alters the immune state, possibly contributing to a change in the course of rheumatoid arthritis (RA).[1, 2] For decades, the ameliorating effects of pregnancy on the disease activity in women with RA have been observed.
In a prospective study from late pregnancy to 6 months postpartum in 140 women by Barrett et al, 63% of the patients reported improvement in disease activity at the third trimester, although only 16% were in remission.
In a 2008 study, de Man et al reported that disease activity decreased during pregnancy but increased after delivery. The investigators monitored 84 patients with RA for disease activity before conception; at each trimester of pregnancy, if possible; and at 6, 12, and 26 weeks postpartum. Among patients with at least moderate disease activity in the first trimester, at least 48% had a moderate response during pregnancy, whereas patients with low disease activity in the first trimester reported that their disease activity remained stable during pregnancy. Thirty-nine percent of patients had at least 1 moderate flare postpartum.
No specific guidelines address obstetric monitoring in patients with RA. Because few available data suggest a significantly increased risk for preterm birth, preeclampsia, or fetal growth restriction, no special obstetric monitoring is indicated beyond what is performed for usual obstetric care.
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Possible causes for the effects of pregnancy on rheumatoid arthritis
The reasons behind the ameliorating effect of pregnancy on RA activity remain unknown, but various theories have been proposed. Nonetheless, no single mechanism satisfactorily explains the observed improvement, and multiple factors are probably responsible for the decreased disease severity.
Some of the proposed theories are as follows:
The effect of pregnancy on cell-mediated immunity (eg, decreased cell-mediated immunity, predominance of helper T-cell 2 [TH2] cytokine profile) 
Elevated levels of anti-inflammatory cytokines, such as interleukin-1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor-alpha receptors (sTNFRs), as well as down-regulation of Th1 cytokines during pregnancy 
The effect of hormonal changes during pregnancy (eg, increased cortisol, estrogen, and progestin levels)
The effect of pregnancy on humoral immunity (eg, a proportional decrease in immunoglobulin G lacking terminal galactose units, an elevated serum alpha-2 pregnancy-associated globulin [PAG] level) [8, 9, 10, 11]
Altered neutrophil function during pregnancy (eg, decreased neutrophil respiratory burst) [12, 13]
The degree of HLA disparity between the mother and the fetus (the less genetically similar the mother and fetus, the more likely the RA will remit) 
Possible causes for flare-ups during the postpartum period include the following:
A decrease in the anti-inflammatory steroid levels
Elevated levels of prolactin (ie, proinflammatory hormone) 
Change in the neuroendocrine axis
Change from a TH2 to a helper T-cell 1 cytokine profile
It is important to counsel women of childbearing age about the teratogenicity and adverse effects of the medications used to treat RA before starting therapy. These patients may need a reminder about the importance of using contraception during therapy with disease-modifying antirheumatic drugs (DMARDs), especially methotrexate, leflunomide, and cyclophosphamide. Educate patients that because of a prolonged half-life, some of these medications may need to be discontinued several months before conception is planned. In addition to discontinuation, some patients who take DMARDs may require treatment with other medications to enhance their clearance.
Cesarean delivery does not appear to be performed more commonly in patients with rheumatoid arthritis (RA).
Diet and supplements
A low-fat, high-carbohydrate, high-fiber diet is recommended in pregnant patients with RA. Fish oils in moderate quantities can be taken during pregnancy. Over-the-counter (OTC) herbal remedies should probably be avoided. Routine oral calcium and vitamin D supplementation is recommended.
The physician providing obstetric care needs to work closely with the patient's rheumatologist, especially if the patient is taking disease-modifying antirheumatic drugs (DMARDs) or steroids. Patients on hydroxychloroquine (HCQ) may need an eye examination by an ophthalmologist to assess for drug toxicity.
None of the medications used in the treatment of rheumatoid arthritis (RA) is absolutely safe during pregnancy. Hence, the decision to use medications should be made after careful assessment of the risks and benefits in consultation with the patient. Pain control through nonpharmacologic management (eg, paraffin baths, decreased physical activity, splinting, cold packs) can be used as adjunctive care.
Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be stopped at the beginning of a menstrual cycle when conception is planned, because these agents have been shown in animal studies to interfere with blastocyst implantation. Most traditional NSAIDs are considered category B medications but should be used with caution in pregnancy.
Possible effects on the mother include prolonged gestation and labor, increased peripartum blood loss, and increased anemia. The potential adverse effects to the fetus include impaired fetal renal function with oligohydramnios and increased cutaneous and intracranial bleeding. Monitoring for oligohydramnios should be considered if the pregnant patient is on prolonged NSAID therapy.
NSAIDs are contraindicated in the third trimester, because they promote premature closure of the ductus arteriosus, leading to fetal pulmonary hypertension. Ductal constriction can occur at any gestational age; however, one study noted a dramatic increase in indomethacin-induced ductal constriction at 31 weeks’ gestation.
Stopping NSAID therapy before 31 weeks’ gestational age is prudent for potentially avoiding adverse effects to the fetus. Short-acting NSAIDs (eg, ibuprofen, indomethacin, diclofenac) are preferred over long-acting agents.
Cyclooxygenase-2 (COX-2) inhibitors are generally considered category C medications and potentially share the same adverse effects as traditional NSAIDs.
Corticosteroids are potent anti-inflammatory agents. They are considered relatively safe in pregnancy when used in low doses and are designated as category B medications. Nonetheless, corticosteroids may increase the maternal risk of hypertension, edema, gestational diabetes, osteoporosis, premature rupture of membranes, and small-for-gestational-age babies.
One meta-analysis found a 3.5-fold increase in the risk of cleft palate in fetuses with first-trimester exposure to corticosteroids.
The choice of glucocorticoid depends on whether the mother or the fetus needs to be treated. Hydrocortisone and cortisone cross the placenta, but 11 beta-dehydrogenase, a placental enzyme, converts hydrocortisone to cortisone, which is biologically inactive; thus, the fetus is exposed to only approximately 10% of the maternal dose. Therefore, if steroid treatment is desired for the mother, hydrocortisone, cortisone, or prednisone should be chosen.
The lowest possible steroid dose needed to control disease activity should be used in pregnancy. Stress doses of steroids should be used during labor and delivery if the mother received steroids (even low-dose) for more than 2-3 weeks during pregnancy, and the neonate should be monitored for evidence of adrenal insufficiency and infection.
Methotrexate, a folic acid antagonist, is contraindicated in pregnancy (category X), because it is an abortifacient and has teratogenic effects, such as causing the development of craniofacial abnormalities, limb defects, and such CNS defects as anencephaly, hydrocephaly, and meningo myelopathy, especially with first-trimester exposure. Because its active metabolites have a long half-life, methotrexate must be discontinued at least 3 months before conception; compensatory treatment with folic acid should be continued during that period and throughout pregnancy. Male partners should also discontinue methotrexate at least 3 months prior to attempting to conceive.
Leflunomide, a pyrimidine synthesis inhibitor, is also a category X medication; it is extremely teratogenic and is absolutely contraindicated in pregnancy. Its half-life is 14-15 days, but the active metabolite undergoes extensive enterohepatic circulation; thus, the drug takes up to 2 years to be undetectable in plasma. Consequently, discontinuation of the drug before conception is insufficient. The drug needs to be eliminated with administration of cholestyramine (8 g tid for 11 d). Plasma levels of less than 0.02 mg/L should be verified with 2 separate tests at least 2 weeks apart. If unacceptably high levels persist, additional cholestyramine may be given.
A study by Chambers et al of 64 women who became pregnant while taking leflunomide and underwent cholestyramine treatment found no significant increase in adverse pregnancy outcomes; these authors suggested that although the sample size was small, the findings can provide some reassurance to women in this situation.
Azathioprine (AZP), although a category D medication, can be used if the benefits outweigh the risks. Although fewer women who received this drug for renal transplantation completed their pregnancies, no increase in fetal anomalies was observed. AZP crosses the placenta, but the fetal liver lacks the enzyme inosinate pyrophosphorylase, which converts AZP to its active metabolite, 6-mercaptopurine; thus, the fetus is protected from the agent's teratogenic effects.
A retrospective cohort study of 155 patients found no statistical difference in conception failures, abortion secondary to a birth defect, major congenital malformations, neoplasia, or increased infections among patients taking 6-mercaptopurine compared with controls. A study of 101 pregnancies in women with inflammatory bowel disease on AZP at doses of 100 mg/d revealed no association with poor pregnancy outcomes.
HCQ, an antimalarial agent, is considered a category C medication. Previous reports of fetal toxicity with this agent were based on the effects of chloroquine, which has 2.5 times the amount of tissue deposition as HCQ. No fetal toxicity is associated with HCQ at the dosage used for RA and connective-tissue disease (6.5 mg/kg body weight). Several studies and case series have provided further evidence that no fetal toxicity is associated with HCQ therapy in mothers.[27, 28, 29]
Tumor necrosis factor–alpha antagonists
Medications in the anti–tumor necrosis factor (TNF)-alpha class (eg, etanercept, adalimumab, infliximab) are commonly used in the treatment of RA. These agents have been labeled as class B medications; animal studies have shown no harm to the fetus,[3, 30] but thus far, no randomized, blinded, placebo-controlled trials on potential teratogenicity in humans have been completed. Numerous case reports have shown positive outcomes with anti–TNF-alpha use in pregnancy, with an incidence of spontaneous abortion and birth defects similar to that in the general population.[4, 6, 7, 8, 31, 32, 33, 34, 35]
Compared with healthy controls, the risk of preterm delivery and poor growth of offspring in all patients with RA is increased, but this is believed to be more attributable to the underlying systemic disease than to use of TNF blockers.[9, 36, 37, 38, 39]
Rituximab (Rituxan), a monoclonal antibody that inhibits CD20 antigen on B lymphocytes, is currently a pregnancy category C medication. Rituximab is indicated for the treatment for moderate to severe RA. Case reports have also shown that rituximab therapy results in detectable levels of the drug in cord blood and results in B-cell depletion in the mother and the neonate.[40, 41, 42, 43, 44, 45]
Recovery of B-cell levels in the neonate has been reported to occur at age 3-4 months and does not appear to impair antibody formation in response to immunizations. The dosing of rituximab in case reports was 375 mg/m2 for 1-6 cycles. Although it is unknown whether rituximab is excreted in human milk, immunoglobulin G is present in human milk, and rituximab has been detected in the milk of monkeys.[40, 44, 45]
Anakinra (Kineret), an interleukin 1 receptor antagonist, is used to treat severe RA. No studies or case reports on the use of this medication during human pregnancy or lactation were found in the literature or reported in data provided by the drug manufacturer. Anakinra is a pregnancy category B medication. No adverse effects have been reported in rats and rabbits receiving up to 100 times the recommended human dose. No data are available to indicate whether anakinra is excreted in human milk.
Ostensen and Förger recommend in a 2011 report that because of the very limited experience with anakinra in pregnancy, its use cannot be recommended. They confirm again that no controlled studies have been published in 2009-2010 on the use of anakinra in pregnancy.
Abatacept (Orencia) is a selective costimulation modulator that binds to CD80 and CD86, thereby inhibiting activation of T lymphocytes and interactions with CD28. This drug is indicated for the treatment of moderate to severe RA.
No human studies have investigated the use of this medication during pregnancy or lactation. Similarly, there are no case reports of abatacept therapy in human pregnancy or lactation in the literature or in drug company records.
Abatacept is a pregnancy category C medication; it has been found to cross the placenta and is excreted in rat milk.
No teratogenic effects were reported in mice or rabbits treated with doses 29 times greater than those recommended for humans. Similarly, no adverse effects in rat offspring were reported when rats were treated with 3 times the human dose throughout the lactation period.
In a sample of 20 rats (10 male, 10 female) treated with 11 times the human dose of abatacept, 1 female offspring had an increased response of T-cell–dependent antibodies and experienced thyroid inflammation.
As with anakinra, Ostensen and Förger advised in a 2011 report that because of very limited experience with abatacept in pregnancy, its use also cannot be recommended. A 2014 review noted that data on anakinra, abatacept, and tocilizumab remained extremely limited.
Postpartum and Breastfeeding
Patients with rheumatoid arthritis (RA) must be monitored closely following delivery, because they have the potential to have arthritis flare-ups during the postpartum period. Hyperprolactinemia has been associated with worsening of RA. Thus, breastfeeding may increase the likelihood of arthritis flare-ups.
Nonsteroidal anti-inflammatory drugs
NSAIDs can be used with caution, provided newborns do not have jaundice, because NSAIDs can displace bilirubin and predispose patients to kernicterus. If NSAIDs must be used during breastfeeding, only NSAIDs with a known safety record should be used.
Data on COX-2 inhibitors and breastfeeding are insufficient.
Prednisone can be used safely during breastfeeding, because only small amounts (5% of the glucocorticoid dose) are secreted in breast milk. At doses higher than prednisone 20 mg once or twice daily, it is recommended that breast milk be pumped and discarded 4 hours following the steroid dose to minimize drug exposure to the infant.
HCQ is found in human breast milk, and the infant may be exposed to 2% of the maternal dose per kilogram per day. Although the elimination is slow and there is a potential risk for accumulation in the infant, most experts believe that the drug may be continued during breastfeeding. HCQ can potentially displace bilirubin and result in the development of kernicterus. The drug should be discontinued if the neonate has jaundice.
Methotrexate is excreted in breast milk in low concentrations and can accumulate in neonatal tissues; thus, it is contraindicated during breastfeeding.
Leflunomide is contraindicated during breastfeeding. Breastfeeding is contraindicated during azathioprine (AZP) therapy because the drug is transferred into maternal milk.
Only negligible amounts of SSZ were found to transfer into breast milk. SSZ is believed to be safe during nursing, although the American Academy of Pediatrics has cited a reported case of bloody diarrhea in an infant as a reason to use caution with this drug during nursing.
A prospective study in three nursing mothers treated with infliximab for Crohn disease found that infliximab was not detectable in their breast milk or in their infants' sera. These authors suggest that mothers who are taking infliximab should not be discouraged from breastfeeding. In case reports, however, small amounts of etanercept were found in the breast milk of lactating patients with RA; the risk this may pose is unknown.[56, 57]
Until more data are available on TNF-alpha antagonists and lactation, breastfeeding should probably be avoided during therapy with these agents. Because no data are available on the use of anakinra, abatacept, or rituximab in breastfeeding, lactation should be avoided during therapy with these agents.
Up to date information on medication safety in breastfeeding is available at the Drugs and Lactation Database (LactMed).
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