Antirheumatic medications in pregnancy and breastfeeding
Mehret Birru Talabia and Megan E.B. Clowseb
INTRODUCTION
Rheumatic and musculoskeletal disorders (RMD) disproportionately affect women, many of whom are diagnosed while they are of reproductive age [1]. Advances in the treatment of RMDs have enabled women to live longer and healthier lives, and there- fore to consider the potential for pregnancy and childrearing [2]. Treatment decisions between patients and providers may thus require consider- ation of women’s plans for pregnancy, current preg- nancy, or desire to breastfeed. Fortunately, several sets of guidelines and recommendations have been published by national and international organiza- pregnancy have better pregnancy and perinatal out- comes than women with active rheumatic disease [7– 10]. Therefore, medical treatment, if safe and com- patible with pregnancy, may be necessary to facilitate healthy pregnancy and perinatal outcomes among some women with RMDs. Medication safety must also be considered in the context of breastfeeding. Eighty percentage of infants born in the United States are breastfed at least initially [11], with benefits that include bond- ing between mother and child; maternal protection against hypertension, diabetes, and cardiovascular disease; as well as reduction in their risk of obesity, tions that provide needed guidance for the use of medications to manage RMDs [3&& –6&&]. In this review, we summarize the current data and these guidelines to facilitated the safe use of medications during pregnancy and lactation. aDivision of Rheumatology and Clinical Immunology, University of Pitts- burgh School of Medicine, Pittsburgh, Pennsylvania and bDivision of Rheumatology and Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
Antirheumatic medications in pregnancy and breastfeeding Birru Talabi and Clowse increases steadily throughout the second and third trimesters of pregnancy. Thus, the fetus may be exposed to high concentrations of biologic DMARDs, immunosuppressing the fetus when it is born and theoretically increasing the risk for infec- tion. As a general principle, medications that are compatible with pregnancy are also compatible with breastfeeding [4&&]. As the concentrations of drugs found in breastmilk are generally 1% or less of the concentrations of drug found in maternal sera, most breastfeeding infants are exposed to exceptionally low levels of medications.SAFE DRUGS IN PREGNANCY AND LACTATION The following section reviews DMARDs and other drugs routinely used in rheumatology that are gen- erally considered compatible with pregnancy and breast-feeding. asthma, and sudden infant death syndrome [12]. Many women with RMD want to breastfeed: 80.5% of women with lupus initiated breastfeeding in Argentina and 87% in a US-based cohort; only 5% were taking a medication postpartum that was not compatible with breastfeeding [13,14]. Women with rheumatoid arthritis (RA) in a separately study were significantly less likely to breastfeed than were healthy controls [15]. Patients’ and providers’ con- cerns about the safety of medications while breast- feeding are one reason why women with RMDs are less likely than other women to breastfeed [16].
The placenta provides a complex and active barrier between the maternal and fetal circulation. The extent to which a drug may cross the placenta depends on placental biology and the drug’s phar- macokinetic properties. The timing of drug expo- sure to the fetus is critically important to our conceptualization of drug safety. Organogenesis, which is complete by around 12 weeks’ gestation, is the highest risk period for birth defects [17]. Some drugs diffuse across the placental barrier, whereas others, including the biologics, require active trans- port [18]. The Fc portion of IgG binds to a neonatal Fc receptor (FcRn) on the placenta, which facilitates its transfer across the synctiotrophoblast and into the fetal circulation. Biologic disease-modifying anti-rheumatic drugs (DMARDs) that are constructed with Fc portions may similarly enter the fetal circu- lation via the FcRn (e.g, adalimumab, golimumab, infliximab, rituximab, tocilizumab). The FcRn on the syncytiotrophoblast is nearly undetectable until 14 weeks’ gestation, but immunoglobulin transfer.
NSAIDs
While widely used, caution is warranted for NSAID use in the first trimester of pregnancy, as NSAIDs may potentially increase time to pregnancy among women who are trying to conceive [19], possibly by inhibiting ovulation [20]; and risk of miscarriage, as described inconclusively in studies of the general population [21,22]. At present, there is no contrain- dication to use of NSAIDs in the first or second trimesters of pregnancy. However, providers may consider discontinuation of NSAIDs among women who are trying unsuccessfully to conceive a preg- nancy. In the third trimester of pregnancy, NSAIDs should be avoided altogether, as they can cause premature closure of the fetal patent ductus arterio- sus, a risk that has been long-described in popula- tion-based studies [23]. Few studies have evaluated the safety of Cox-2 inhibitors in pregnancy, so clas- sic NSAIDs are preferred during pregnancy [24– 26]. Classic NSAIDs also appear to be compatible with breastfeeding based on consensus recommen- dations, with ibuprofen preferred due to limited cross-placental transfer and shorter half-life com- pared with other NSAIDs [27]. Given the absence of safety data for Cox-2 inhibitors, providers should consider switching patients to classic NSAIDs if possible [5&&].
Corticosteroids
Corticosteroids, particularly at relatively low doses (e.g., prednisone less than 10 mg or an equivalent dose), are considered compatible with pregnancy in oral, intraarticular, and/or intramuscular forms. Prednisone, prednisolone, and methylprednisolone are converted to inactive forms by the placental enzyme 11b-hydroxysteroid dehydrogenase [28]. Thus, activated prednisone and other nonfluori- nated steroids have more limited fetal exposure than fluorinated steroids [29,30], and therefore are pre- ferred during pregnancy. An exception is in congen- ital heart block, observed among some mothers with Ro antibodies, in which case fluorinated steroids may be used to try to reverse this rare fetal conduc- tion abnormality [31]. While corticosteroids are widely used in preg- nancies of women with RMDs, they also have been inconsistently associated with preterm birth and orofacial clefts in studies of RA, antiphospholipid antibody syndrome, and asthma, particularly at prednisone-equivalent doses greater than 20 mg daily [19,32– 35]. Corticosteroids may be necessary to control active disease during pregnancy, but it should be noted that some pregnancy-compatible DMARDs appear to have fewer fetal risks than mod- erate or high doses of corticosteroids. Corticosteroids are generally considered safe for breastfeeding. At prednisone-equivalent doses greater than 20 mg a day, breastmilk might be dis- carded or delayed 4 h after steroid administration to reduce infant exposure. Lower doses of steroids are considered compatible with breastfeeding without need for specific timing intervals.
Hydroxychloroquine
Hydroxychloroquine is an antimalarial medication with anti-inflammatory properties that is widely con- sidered compatible with pregnancy. Hydroxychlor- oquine does cross the placenta, which is why it can protect against adverse perinatal outcomes such as congenital heart block associated with maternal Ro antibodies [36,37]. When taken daily at doses of 400 mg or less, hydroxychloroquine is not associated with increased risk of adverse perinatal outcomes [38,39]. Hydroxychloroquine also improves mater- nal outcomes, and has been found to prevent disease flares among pregnant women with lupus [40,41]. As disease flares are associated with adverse perinatal outcomes, maternal hydroxychloroquine could potentially be protective toward fetal health as well. Hydroxychloroquine is safe to use while breast- feeding. Among 13 infants of mothers with systemic lupus erythematosus who were breastfed, all had normal development and visual function [42]. A review of 251 infants exposed to hydroxychloro- quine during pregnancy revealed that these children had no greater risk of visual function abnormalities than unexposed children [43].
Sulfasalazine
Sulfasalazine, a DMARD composed of a sulfa antibi- otic and salicylate, is compatible with pregnancy. Most safety data about sulfasalazine has been extrap- olated from pregnant women with inflammatory bowel diseases [24,44]. As sulfasalazine is a dihydro- folate reductase inhibitor, folic acid supplementa- tion may be considered for women who use sulfasalazine and who are considering pregnancy [4&&]. There are no guidelines that specify a dose of folic acid, although the standard dose in multi- vitamins and prenatal vitamins appears to be suffi- cient to reduce the risk for oral clefts, cardiovascular and urinary tract defects among pregnancy women who use sulfasalazine or other dihydrofolate reduc- tase inhibitors [45]. Sulfasalazine is compatible with breastfeeding. Sulfasalazine was found to cause bloody diarrhea in one infant whose mother used 3 g/day, and thus, women could be counseled to consider discontinu- ation of sulfasalazine if their infants develop intrac- table diarrhea [46].
TNF-a inhibitors
TNF-a inhibitors are biologic antirheumatic drugs composed of immunoglobulins or immunoglobulin fragments; this class of medications appears to be safe to use during pregnancy and lactation. TNF-a inhibitors are generally too large to cross the pla- centa by simple diffusion, and active cross-placental transport does not begin until approximately after 14 weeks’ gestation [47]. Multiple studies suggest that pregnancy and fetal outcomes do not differ between users and nonusers of TNF-a inhibitors [48– 51]. use during pregnancy is that they may immunosuppress the neonate, increasing the risk of infection. In a term delivery, the infant may have a circulating concen- tration of adalimumab or infliximab that is 60% higher than drug levels in the mother [47]. TNF-a inhibitor levels can be detected in the neonatal circulation up to 12 months postdelivery, particu- larly infliximab and adalimumab [47]. Despite this degree of transfer, maternal TNF-a inhibitor use does not appear to predict increased neonatal infec- tions [52]. Given concerns about immunosuppres- sion of the newborn, consensus recommendations generally recommend discontinuation of TNF-a inhibitors in the second or third trimesters. Only women with ongoing disease activity should con- tinue treatment through delivery.
However, certo- lizumab, a biologic TNF-a inhibitor, does not have an Fc portion, and therefore is not actively trans- ferred across the placenta during pregnancy [53]; this medication is therefore not expected to cause neonatal immunosuppression, even with dosing in the later third trimester. As a precaution, most consensus guidelines sug- gest that live virus vaccines are avoided among infants who were exposed to TNF-a inhibitors in the late second or third trimesters (i.e., rotavirus in the United States), but an otherwise normal vacci- nation schedule may otherwise be used [54&&]. One European study described a neonate who was exposed to infliximab in utero and developed dis- seminated tuberculosis in the setting of a bacille Calmette– Guerin (BCG) vaccine [55]; thus, BCG vaccines, which are not routinely administered to neonates in the United States, should be avoided by tumor necrosis factor-exposed children. The rotovi- rus vaccine is the primary live vaccine administered in the first months of life. Studies also suggest that there is minimal trans- fer of TNF-a inhibitors with lactation, and breast- feeding neonates have not been found to have increased risk of infections [5&&,56]. We recommend restarting TNF-a inhibitors within 1– 2 weeks after delivery to avoid the expected postpartum flare in women with inflammatory arthritis.
Azathioprine, tacrolimus, cyclosporine
Azathioprine, tacrolimus, and cyclosporine have been used for several decades in pregnant women with solid organ transplants and each has a solid basis of data demonstrating compatibility with preg- nancy [57– 59]. Azathioprine, an immunosuppressive antime- tabolite, is not associated with fetal defects or spon- taneous abortion. Among women with systemic lupus erythematosus, fetal and neonatal outcomes in one study were similar among women who did and did not use azathioprine [60]. While early animal studies reported fetal anomalies related to azathioprine exposure, the human fetal liver lacks the enzyme inosinate pyrophosphorylase, which converts azathioprine into active metabolites and may potentiate fetal anomalies; thus, the human fetus has limited exposure to active form of azathi- oprine [61]. Some studies suggest that preterm birth is more likely among women with renal transplants or systemic lupus erythematosus who use azathio- prine, but future studies are needed to assess if this is a reflection of maternal disease activity and/or disease burden [60,62,63].
Tacrolimus is a calcineurin inhibitor that is widely used among pregnant women with solid organ transplants.
Although it is not associated with birth defects, it has been associated with hyperka- lemia and renal insufficiency among exposed infants [64]. Thus, renal laboratory monitoring is suggested for exposed neonates. Cyclosporine reduces the expression of IL-II receptors and produc- tion of IL-II [65]. Cyclosporine is not associated with birth defects among women with solid organ transplants, although it is associated with maternal hypertension, gestational diabetes, and preeclamp- sia, and with low birthweight [66]. It is unclear if some of these effects are related to the underlying maternal disease. Azathioprine is compatible with breastfeeding due to its very minimal transfer into breastmilk [27,67]. In a small study of mothers with inflamma- tory bowel diseases who used azathioprine through- out pregnancy and lactation, offspring showed normal development and had similar rates of infec- tions and hospitalizations as children born to moth- ers did not use immunosuppression [68]. Relatively little is known about the safety profile of tacrolimus and cyclosporine during lactation. Maximum esti- mated absorption of tacrolimus from breastmilk was reported in one study to be 0.23% of the maternal dose, but the clinical significance of tacrolimus at that plasma level is unclear [69].
HIGH-RISK DRUGS IN PREGNANCY AND LACTATION
The following section reviews DMARDs and other drugs routinely used in rheumatology that contra- indicated during pregnancy and breast-feeding. The recently published guidelines are summarized for pregnancy (Table 1) and lactation (Table 2).
Methotrexate
Methotrexate is an antimetabolite that inhibits dihydrofolate reductase; its actions against folate, which is essential for neural tube development of the fetus, contribute to its teratogenicity. Exposure during pregnancy is associated with an incidence of birth defects between 6 and 10% and incidence of pregnancy loss of 40% [3&&,5&&,70]. Birth defects include the aminopterin syndrome, which classi- cally manifests as growth restriction, facial, skull, and limb dysmorphisms and defects, and neural tube defects [71]. Unintended exposure to metho- trexate during pregnancy is not uncommon. In our survey of young women with inflammatory arthri- tis, we found that 32% of methotrexate users who experienced pregnancy had conceived while using this drug [72]. Given the widespread usage of meth- otrexate in rheumatic disorders, it is critical that providers and patients understand the risks of pre- scribing this medication among reproductive-age women who do not use contraception.
Other biologics
Newer therapies, including B-cell activating factor inhibitors (i.e., belimumab), CTLA-4 inhibitors (e.g., abatacept), IL-6 blockers (e.g., tocilizumab), IL-17 blockers (e.g., secukinumab), IL-12/IL-23 (e.g., uste- kinumab), and IL-1 blockers (e.g., anakinra) have not been adequately studied to provide strong rec- ommendations toward or against their safety during pregnancy [54&&]. The large molecular size of these medications suggests that transmission into breast milk is low and is likely safe.
CONCLUSION
Studies suggest that 31– 62% of women with rheu- matic diseases stop refilling their medication pre- scriptions during pregnancy, including medications with low fetal risk [84– 86]. Because patients are required to receive regular laboratory testing, ocular exams, and other ‘toxicity monitoring’ measure- ments to ensure that their drugs are not harming them – it is therefore unsurprising that some women with RMDs are distrustful of the potential effects of these medications on their children’s health and development.
We encourage honest and accurate conversa- tions between rheumatologists and women with RMD to ensure appropriate pregnancy planning and management. Many women withhold preg- nancy plans due to fear of disapproval or being told not to conceive. Therefore, rheumatologists should inquire about pregnancy intentions in a nonjudg- mental and open-ended way to encourage the woman to be truthful and to facilitate a discussion that results in the woman making decisions that are in her best interest. For many women with RMD, this means continuing pregnancy-compatible med- ications through pregnancy. For others, it means delaying pregnancy until RMD is well controlled off
Acknowledgements
None.
Financial support and sponsorship
Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program (M.B.T.).
Conflicts of interest
M.B.T. has no conflicts of interest. M.E.B.C. is a consul- tant for UCB and has salary support from an indepen- dent medical education grant from GSK.
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