Management of Rheumatologic Diseases in Pregnancy

Oier Ateka-Barrutia; Catherine Nelson-Piercy

Disclosures

Int J Clin Rheumatol. 2012;7(5):541-558. 

In This Article

Medications During Pregnancy & Breastfeeding

Most data regarding medication safety in pregnancy and lactation come from retrospective case series and isolated case reports. The pregnancy categories of the US FDA are of little help for the clinician dealing with women with chronic diseases during pregnancy and lactation. However, a recent expert consensus has described the safety in pregnancy and lactation of many of the drugs used in autoimmune and rheumatic diseases.[108] A summary of safety of these drugs is shown in Table 1.

Frequently Used medications

NSAIDs are generally safe drugs in pregnancy if they are used in short limited courses, but may be associated with renal and cardiac failure, hypertension and fluid overload in the mother, and oligohydramnios and renal impairment in the fetus if used for long periods. Their use should be withheld towards the end of pregnancy (>30–32 weeks) owing to increased risk of early closure of the baby's ductus arteriosus.[108] At present there are no reliable data on selective COX-2 inhibitors and they should therefore be avoided.

Treatment with LDA (75–100 mg/day) or dipyridamole is safe, whereas clopidogrel or ticlopidine are not recommended.[108] If indicated, aspirin should be continued throughout pregnancy. There is no evidence to suggest that aspirin needs to be discontinued before labor or due to planned epidural anesthesia in order to decrease hemorrhagic complications.

Antimalarials are one of the fundamental treatments in SLE because of their protective properties on activity, damage, long-term survival and thrombosis,[20] and are also used in other disorders such as RA or UCTD. HCQ is the preferred drug due to its low rate of side effects. Its safety profile for both the mother and the baby has been widely researched, with no reported fetal neurosensory toxicity or malformations.[109] By contrast, chloroquine has been associated with increased risk of retinopathy in the mother and fetal ototoxicity.[20] HCQ should be continued throughout and after pregnancy in lupus patients, and probably in patients with RA. Mepacrine, by contrast, should be avoided because of the lack of safety data.

Nonfluorinated corticosteroids (prednisone, methylprednisolone and hydrocortisone) are largely metabolized by placental 11β-hydroxysteroid dehydrogenase, and thus minimal amounts reach the fetal circulation (<10% of total dose).[108] Even so, the use of these drugs is related to several undesirable complications in the mother such as hypertension, preeclampsia, diabetes, infections and premature rupture of membranes,[33] hence minimum maintenance doses (prednisone <7.5 mg/day), combined with steroid sparing agents are recommended, rather than higher (prednisone >7.5 mg/day) sustained doses. Stress doses of hydrocortisone at delivery are recommended in patients on long-term therapy. Nonfluorinated corticosteroids are minimally excreted into breast milk (5–25%) and, therefore, compatible with breastfeeding. At high doses (>prednisone 40 mg/day) consider timing breastfeeding to 4 h after the dose.[108]

The majority of the immunosuppressive drugs are contraindicated during pregnancy and breastfeeding, with the exception of azathioprine, sulfasalazine, ciclosporin and tacrolimus.[108] With regards to the latter drugs, their use should be justified and the aim should be to keep them at the lowest effective dose. In women of child-bearing age taking pregnancy-contraindicated immunosuppressants such as mycophenolate mofetil, methotrexate, leflunomide or CYC, safe and effective contraception is necessary. If pregnancy is considered, these drugs should be switched to safer alternatives (e.g., azathioprine, sulfasalazine and tacrolimus) and conception should be delayed for at least 3 months, in order to monitor new flares or side effects from the change in drug regime.[108]

A recent meta-analysis showed that sulfasalazine is not related to teratogenic effects.[110] However, women should be advised to take high-dose folic acid (5 mg/day) from 3 months prior to conception until at least the end of the first trimester, in order to prevent neural tube defects. The same folic acid regime is recommended in women who were taking methotrexate. Because of the long half-life of the active metabolite of leflunomide, it may be detectable in plasma up to 2 years after withdrawal of the drug. The manufacturer recommends cholestyramine 8 mg tds to enhance elimination for 10–14 days or until plasma levels of leflunomide are undetectable.[108]

The use of immunosuppressive drugs during pregnancy does not generally hamper the correct development of the newborn's immune system or its response to scheduled vaccinations.[111]

Anti-TNF therapy is frequently used in RA, AS and other chronic arthritides. All women should have tuberculosis screening before starting these medications, and should undergo appropriate treatment if previous latent infection is detected. Likewise, live vaccinations are not recommended in patients receiving anti-TNF therapy.

Despite a dubious association between anti-TNF drugs and congenital malformations described by some authors,[112] several groups have demonstrated no increased risk of malformations in fetuses exposed to these drugs,[113,114] based on different registries and databases. Anti-TNF drugs are monoclonal IgG antibodies and, therefore, behave similarly to maternal IgG antibodies both in terms of active transplacental transfer and their persistence in neonatal circulation up to 6 months postpartum. As the transplacental transfer does not notably start until the end of the second trimester, the fetus is not exposed during the first trimester, and hence the risk for teratogenicity is very low. The current available data on infliximab-exposed pregnancies show that in women who remain on this treatment during the third trimester, cord blood levels are two- to three-fold higher than in the mother's circulation.[115] However, it seems that these children have no problems in developing appropriate immunologic responses to regular vaccinations,[116] although there are no specific data regarding live vaccinations. Anti-TNF agents are poorly excreted in breast milk, and hence breastfeeding is considered to be safe.[117–119]

Despite the few cases available in the literature, certolizumab (a pegylated anti-TNF), which does not cross the placenta is considered to be safe due to the low levels detected in both cord blood and breast milk. Wider experience is needed in order to corroborate these data.[120]

Rituximab is a chimeric anti-CD-20 monoclonal antibody used in several severe conditions such as SLE, RA or vasculitis. Two recent retrospective series identified 240 exposed pregnancies in women with different autoimmune and hematological diseases, including data from clinical trials and isolated reports of maternal exposure. Pregnancy outcomes were available for 162 exposures. Over 61% (n = 99) resulted in live births of which 26% delivered preterm, while the first trimester miscarriage rate was 20%. Eleven neonates had hematological abnormalities, but none presented infectious complications. Two cases of congenital malformations were described (clubfoot in a twin and cardiac malformations in a singleton). Given the maternal indications for its use and the heterogeneity of the reports, until more robust data are available women should be counseled against pregnancy for 6–12 months after rituximab exposure due to the risk of neonatal B-cell depletion.[114,121] Neonates who were exposed to this biologic during the second or third trimester should receive close white blood cell and infection surveillance.

Anakinra, a recombinant IL-1 receptor antagonist, is thought to be safe in pregnancy and breastfeeding (US FDA category B), although experience in human pregnancies is still scarce and it is unknown whether it is excreted in human breast milk.[122,123]

Current recommendations are to withhold abatacept (a selective costimulation modulator that inhibits T-cell activation) and tocilizumab (an IL-6 receptor inhibitor), because of the lack of data regarding their use in pregnancy and breastfeeding.

Belimumab is a human monoclonal antibody that inhibits B-cell activating factor, and the first biologic drug licensed for the treatment of SLE. Experience in pregnancy is scarce, hence the current recommendation is to withdraw it at least 4 months prior to conception.[124]

IVIG can be safely used in pregnancy and lactation, and is useful when there is a desire to withhold strong immunosuppressants especially in situations where infection and flare cannot be easily differentiated.[108]

Summary of Drug Treatment of Connective Tissue Disease in Pregnancy Mild flares during pregnancy can be treated with NSAIDs, HCQ and low-dose oral steroids. For moderate or severe disease, the use of methylprednisolone pulses or high-dose oral steroids followed by rapid reduction of oral steroids to low maintenance doses, combined with safe immunosuppressants, biologic agents and/or IVIG may be necessary. More severe cases may require a risk/benefit assessment and prioritization of the mother's welfare over fetal concerns, and therefore the use of stronger agents such as mycophenolate mofetil or CYC.

Drugs to Treat Pulmonary Hypertension

Endothelin receptor antagonists such as bosentan, sitaxsentan and ambrisentan are considered to be category X by the FDA. Their effect in human pregnancies is still unknown, but they are teratogenic in rodents and conception should be delayed for at least 3 months after stopping these agents.

Phosphodiesterase-5 inhibitors such as sildenafil and tadalafil are considered category B by the FDA. Their use in human pregnancy has not resulted in fetal side effects.[125]

Prostaglandin derivatives such as prostacyclin (epoprostenol) and iloprost are considered to be category B by the FDA and have been safely used in pregnancy and breastfeeding.[126]

Antihypertensive Therapy

The drugs of choice for managing hypertension in pregnancy are labetalol, methyldopa and nifedipine, and, less frequently, hydralazine, amlodipine and doxazosin.[201] ACEI and ARB may cause fetal renal impairment and oligohydramnios, and they are associated with an increased risk of miscarriage[127] and malformations.[128] Therefore, these drugs are generally contraindicated during pregnancy. More recent data suggest that exposure to ACEI and ARB in the first trimester may not relate to an increased risk of malformations in the fetus.[127,129] Postnatally, methyldopa should be avoided because of higher risk of depression, and ARBs avoided because of lack of data.[201]

Anticoagulants

Heparins (both unfractionated and LMWH) do not cross the placenta and are safe during pregnancy and breastfeeding. By contrast, warfarin and coumadin are teratogenic during organogenesis (6–10 weeks of gestation) and they should be avoided during this period. Their use is related to an increased risk of miscarriage, still birth and fetal bleeding.[108] Current recommendations include switching to LMWH as soon as pregnancy is confirmed.[202] This regime is generally continued throughout pregnancy, although switching back to warfarin during the second and third trimesters with close international normalized ratio monitoring is another option for special situations such as previous thromboembolic events on therapeutic dose of LMWH, some women with mechanical heart valves or in countries/settings where both the health system and the women cannot afford the expense of LMWH. Vitamin K antagonists are safe in lactation.[108]

Fondaparinux crosses the placenta (fetal levels ~10% of maternal ones) suggesting that, although less innocuous than heparin, it could be safely used with caution.[108]

Currently, little is known about the safety of the new anticoagulants (e.g., rivaroxaban and dabigatran) during pregnancy and lactation, and, therefore, their use is not recommended.[108]

Others

Although they are considered as class C by the FDA, the safety of bisphosphonates (BPs) in human pregnancies is unknown. A recent review of the literature[130] identified 78 cases of mothers exposed to bisphosphonates before conception or during pregnancy. In total, 69 resulted in live births (88.5%) and none of the infants had serious adverse events secondary to bisphosphonates. Due to insufficient robust data, pregnancy should be postponed for at least 6 months after withdrawal of bisphosphonates.[108]

The available data regarding the teratogenic risk of statins are contradictory, thus they are considered contraindicated in pregnancy. Their pleiotropic effects of vascular protection have been suggested to be of potential benefit in the management of preeclampsia. Statins have shown positive effects on serum markers involved in preeclampsia in murine models.[131] The ongoing StAmp trial in the UK will hopefully provide some insight into the role of statins during pregnancy and the possible effect on pregnancy outcomes.

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