Version October 2023
INTRODUCTION — Inflammatory disorders such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) often occur in women of childbearing age; thus, the treatment of such disorders in women during pregnancy is an important aspect of their management.
When considering treatment options, a major tenet of treating women during pregnancy is to keep disease under good control while minimizing or avoiding medications that may increase maternal or fetal risk. The relative benefits and risks to the mother and fetus of using a particular medication to maintain disease control or to treat active disease during pregnancy depend upon the specific clinical context and may be influenced by gestational age and other factors. Importantly, untreated disease carries its own risks to both the mother and the developing fetus.
The risks in pregnancy and during lactation of antiinflammatory, immunosuppressive, and biologic medications used for the treatment of rheumatic diseases will be reviewed here. Additional information regarding each medication is provided in the drug information topic for each agent. Approaches to the therapy of individual conditions are presented separately within the appropriate topic reviews on the treatment of given disorders, and for some conditions, in separate topic reviews. (See "Rheumatoid arthritis and pregnancy" and "Pregnancy in women with systemic lupus erythematosus".)
Strategies for the preservation of fertility in patients undergoing cytotoxic therapy; cryopreservation of sperm, oocytes, and embryos; and the effects of antiinflammatory and immunosuppressive medications on male fertility are discussed in detail separately. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery" and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases".)
RISK CATEGORIES AND TREATMENT CONTEXT — The US Food and Drug Administration (FDA) has changed the format for labeling medications for safety of use during pregnancy and lactation. The previous letter categories inaccurately implied increased risk as one went from category A to B to C to D to X; in actuality, these categories reflected the quantity and type of data available. The system that began implementation in mid-2015 provides a discussion of the available data regarding a particular drug's safety in pregnancy and lactation, as well as information regarding the risk of untreated disease [1].
There is limited information regarding the toxicities and teratogenic potential of many antiinflammatory and immunosuppressive medications in pregnant women because there are ethical issues involved in testing such drugs in the setting of pregnancy. For some medications, the available evidence is limited to or primarily from animal research.
For practical purposes, we divide the medications used to treat rheumatic diseases into four categories of risk for use during pregnancy. We recognize that some drugs may fall into more than one category depending upon various factors. These categories are:
●Minimal fetal or maternal risk
●Selective use allowed during pregnancy
●Moderate to high risk of fetal harm
●Limited information
Information related to the toxicity and teratogenicity of rheumatic disease medications in pregnant women must be interpreted in light of the background risk of adverse pregnancy outcomes in all women. Major congenital anomalies are defined as events of medical, surgical, or cosmetic significance. It is estimated that the prevalence of major congenital anomalies is 2 to 4 percent among liveborn infants. This prevalence does not vary among ethnic groups (table 1). Evaluation of lactation risk often involves calculation of the relative infant dose (RID), which is the dose administered to the infant through breast milk in mg/kg/day divided by the maternal dose in mg/kg/day. Estimates of less than 10 percent of the maternal dose are generally considered safe.
MINIMAL FETAL OR MATERNAL RISK — The following medications are viewed as relatively safe in pregnancy:
●Hydroxychloroquine (HCQ) (see 'Hydroxychloroquine' below)
●Sulfasalazine (SSZ) (see 'Sulfasalazine' below)
●Low-dose aspirin (see 'Aspirin (low dose)' below)
●Azathioprine (AZA) and 6-mercaptopurine (6-MP) (see 'Azathioprine and 6-mercaptopurine' below)
●Colchicine (see 'Colchicine' below)
Hydroxychloroquine
●Pregnancy – HCQ can be continued during pregnancy. For most patients with rheumatic disease, the benefits of HCQ during pregnancy outweigh the potential risks.
●Lactation – HCQ use is compatible with breastfeeding.
HCQ is an antimalarial agent that is effective in the treatment of several rheumatic diseases. Specific details regarding the use and monitoring of this medication are presented separately. (See "Antimalarial drugs in the treatment of rheumatic disease" and "Pregnancy in women with systemic lupus erythematosus" and "Rheumatoid arthritis and pregnancy".)
HCQ is stored in tissues, particularly the liver, and has a half-life of approximately eight weeks. Thus, fetal exposure cannot be avoided by discontinuing the medication at the time the pregnancy is discovered.
HCQ crosses the placenta, but most studies have not described fetal toxicity with HCQ doses used for the treatment of systemic lupus erythematosus (SLE) or other rheumatic diseases [2-4]. However, one large population-based cohort study of rheumatic disease patients used claims data and compared 2045 HCQ-exposed pregnancies and 21,679 matched pregnancies not exposed to HCQ. HCQ use during the first trimester was associated with a small increased risk of major congenital malformations (adjusted relative risk 1.26, 95% CI 1.04-1.54) [5]. The absolute risk for exposed infants was slightly higher than in unexposed infants of autoimmune rheumatic disease patients (5.48 versus 4.32 percent). However, no particular pattern of malformations was identified. Moreover, this study did not account for variables not included in the data set, such as use of alcohol, tobacco, folic acid, other drugs, and over-the-counter medications, as well as unidentified confounders [6]. In a subsequent cohort study of pregnant individuals enrolled in the MotherToBaby/Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Study who were receiving HCQ, 279 persons exposed to HCQ were compared with 279 unexposed pregnant persons. There was no increased risk of structural congenital anomalies among infants exposed to HCQ in utero [7].
Several studies have suggested that continuation of HCQ may improve pregnancy outcome in women with SLE; these studies have not raised any safety concerns. As an example, in a retrospective series of 257 pregnancies from the Johns Hopkins Lupus Cohort, the pregnancies were divided into three groups: mothers with no HCQ exposure during pregnancy (n = 163), those in whom HCQ was used continuously (n = 56), and those in whom HCQ was stopped during the first trimester or within three months of conception (n = 38) [8]. The following observations were made:
●There were no differences among the three groups in miscarriages, stillbirths, pregnancy losses, and congenital abnormalities.
●SLE flares were more common, and the mean prednisone doses were higher, among the women who stopped taking HCQ during pregnancy. However, serious complications of SLE were not more common in that group.
●There are inconclusive data on whether HCQ reduces the risk of preeclampsia in SLE pregnancies. One retrospective cohort study of 119 SLE pregnancies that used propensity score matching demonstrated the safety of HCQ treatment but no reduction in preeclampsia [9].
●Another retrospective cohort study showed a trend toward less preeclampsia in SLE patients treated with HCQ during pregnancy [10].
The safety of HCQ in SLE pregnancy was further corroborated by two other studies [3,11]:
●In a series of 36 pregnancies in women with SLE exposed to HCQ during pregnancy, the percentage of women with successful pregnancies (ie, lack of teratogenicity and good obstetric outcome) was not different from that of 53 control women [3].
●During a mean of 26 months' follow-up of the children resulting from 133 HCQ-exposed pregnancies, there was no difference in the rate of growth, and there was no evidence of visual or developmental abnormalities [11].
HCQ is transferred to human breast milk: breastfed infants are exposed to approximately 2 percent of the maternal dose, which is well within levels considered to be safe [12]. The American Academy of Pediatrics (AAP) considers use of HCQ compatible with breastfeeding.
Sulfasalazine
●Pregnancy – For women with active inflammatory disease who require treatment during pregnancy, SSZ is an acceptable therapy with relatively low risk. Concomitant folate supplementation is advised because this drug is a dihydropteroate synthase inhibitor that can lead to folate deficiency. SSZ does not appear to increase the risk of adverse fetal outcome if the mother is taking a multivitamin with at least 0.4 mg of folic acid.
●Lactation – SSZ is transferred in low concentration into breast milk and is considered compatible with breastfeeding in healthy, full-term infants. However, women taking SSZ should avoid breastfeeding premature infants or those with hyperbilirubinemia or glucose-6-phosphate dehydrogenase (G6PD) deficiency.
SSZ possesses both antiinflammatory properties mediated by its 5-aminosalicylic acid moiety and antibacterial characteristics associated with its sulfapyridine moiety. Specific details regarding the use and monitoring of this medication are presented separately. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease" and "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis".)
SSZ has been used since its development in the 1940s as an agent for the treatment of inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Most of the information regarding the use of this medication during pregnancy is gleaned from its effects on patients with IBD.
SSZ and its metabolite sulfapyridine cross the placenta [13]. However, neither SSZ nor sulfapyridine causes significant displacement of bilirubin from albumin [14]. Thus, SSZ use by pregnant women does not appear to increase the risk of kernicterus.
Larger case series of patients have shown no increased incidence of adverse pregnancy outcomes in pregnancies in which the mother is taking SSZ [15,16]. One study reported 247 IBD patients who had a total of 240 births [15]. There was no increased risk of fetal anomalies in offspring of mothers treated with SSZ alone or with the combination of glucocorticoids and SSZ. In addition, none of the 107 mothers who received SSZ during pregnancy had babies with jaundice.
The amount of SSZ found in the breast milk and in the serum of nursing babies is low [17,18]. Sulfapyridine concentrations in the serum of nursing babies is 40 percent that of the level of the metabolite in mothers. Diarrhea in a nursing child whose mother was taking SSZ has been reported [19]; thus, in infants having diarrhea, consider discontinuation of SSZ in the lactating mother.
Aspirin (low dose)
●Pregnancy – Salicylate use in low doses (eg, aspirin, 81 to 160 mg a day) is considered compatible with pregnancy.
●Lactation – Salicylates in low doses (eg, aspirin, 81 mg daily as an antiplatelet agent) are compatible with nursing [20,21].
High-dose aspirin should generally be avoided during pregnancy and lactation, as discussed elsewhere. (See 'Aspirin (moderate to high dose)' below.)
Aspirin has been used as an analgesic and antiinflammatory agent in the management of rheumatic disease. Low-dose aspirin (81 mg a day) is used as part of the management of antiphospholipid syndrome and for prevention of preeclampsia as well. Aspirin, an acetylated salicylate (acetylsalicylic acid), is classified among the nonsteroidal antiinflammatory drugs (NSAIDs). The safety of moderate- to high-dose aspirin is described separately together with the non-salicylate NSAIDs (see 'NSAIDs' below). The mechanism of action, major toxicities, and use of aspirin in rheumatic diseases are described separately. (See "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases".)
Data regarding the safety of aspirin during pregnancy have limitations, as the outcomes associated with different dose ranges are often not presented.
●In a 2002 meta-analysis of 22 studies of aspirin exposure during pregnancy, the overall risk of congenital anomalies was not statistically significantly elevated (odds ratio [OR] 1.33, 95% CI 0.94-1.89), suggesting that aspirin did not expose an increased teratogenic risk. This same meta-analysis did report a significantly increased risk of the rare finding of gastroschisis (OR 2.37, 95% CI 1.44-3.88) [22]. However, information on aspirin dose, trimester of exposure, and duration of therapy were not available.
●An older observational study of Australian women attending an antenatal clinic reported that 6.6 percent of women were taking salicylates (dose not reported) [23]. Among the women who were constant takers, defined as daily use (dose unknown), there was a higher incidence of anemia and postpartum hemorrhage, prolonged gestation, and perinatal mortality. However, salicylate dose, indications for aspirin use, and confounders were not discussed.
●In another study of 50,282 pregnancies, 9736 had intermediate exposure to salicylates, and 5128 had heavy exposure during the first four months of gestation (defined as >8 days during a month period, dose not specified) [24]. No increase in congenital anomalies were reported.
Low-dose aspirin has been used to prevent preeclampsia, providing further evidence of its relative safety. Individual patient data from over 32,000 women and their babies showed that low-dose aspirin had no significant effect on the risk of bleeding events in either the women or their babies [25]. Low doses of aspirin have also been used during pregnancy in selected patients with antiphospholipid syndrome; it has also been used in patients undergoing in vitro fertilization/intracytoplasmic sperm injection [26]. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy" and "Preeclampsia: Prevention".)
Azathioprine and 6-mercaptopurine
●Pregnancy – When immunosuppression is necessary (eg, in renal transplant recipients, recently active lupus, or IBD), AZA or 6-MP can be used during pregnancy. While these medications do not appear to increase the risk of teratogenicity, higher rates of other pregnancy complications (low birth weight, prematurity, and jaundice) have been reported. AZA, the medication more commonly used in rheumatologic disorders, may be safer than 6-MP, and there is a general consensus that AZA may be safer than many other immunosuppressive agents during pregnancy [27].
●Lactation – AZA is considered compatible with breastfeeding. Available evidence suggests that excretion of AZA in breast milk is very low in most women [28,29].
AZA is a purine metabolism antagonist and is metabolized to 6-MP in vivo. Thus, these two medications should theoretically have the same effects during pregnancy. Specific details regarding the use and monitoring of these medications are presented separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease".)
Radioactive labeling studies in humans have shown that 64 to 93 percent of AZA administered to mothers appears in fetal blood as inactive metabolites [30]. This is because the placenta metabolizes AZA to thiouric acid, which is inactive, rather than 6-MP [30]. After birth, AZA is metabolized to 6-MP.
Data on the use of AZA in pregnant women come primarily from studies of patients who have undergone organ transplantation and patients who have Crohn disease [27,31-33].
Among transplant recipients, one report evaluated 146 renal allograft recipients who received AZA and prednisone (90 percent), AZA alone (2 percent), or glucocorticoids alone (8 percent) [34]. Low birth weights, prematurity, jaundice, respiratory distress syndrome, and aspiration all occurred significantly more frequently among the offspring of mothers in the two AZA groups. In addition, there were isolated cases of immunoglobulin deficiency, chromosomal abnormalities, and malformations, but the frequency of these events was not higher than that expected in a healthy obstetrical population [27].
In Crohn disease, a nationwide cohort study in Denmark included 900 children born to women with that disease between 1996 and 2004 [31]. Twenty mothers in that study were exposed to AZA or 6-MP during pregnancy. The following findings were observed:
●Women exposed to AZA or 6-MP alone or in combination with other Crohn disease medications had higher risks of preterm births (25 percent) compared with patients who received the combination of glucocorticoids and SSZ (13 percent), SSZ alone (4 percent), or no medications for Crohn disease during pregnancy (7 percent). Compared with the reference group of patients who received no medications, the relative risk (RR) of preterm birth was 4.2 in the AZA or 6-MP group (95% CI 1.4-12.5). It is possible that patients using these medications were sicker, which may have also affected the risk of preterm birth.
●Congenital abnormalities occurred in 15 percent of the AZA or 6-MP group, compared with 4, 6, and 6 percent in women treated with glucocorticoid and SSZ, with SSZ alone, and with no medications, respectively. Compared with the reference group of patients who received no medications, the AZA or 6-MP group had nearly three times the risk of congenital abnormalities (RR 2.9, 95% CI 0.9-8.9).
This study was limited by the small number of patients treated with AZA or 6-MP and by the fact that the investigators were not able to adjust their analysis for disease severity. In addition, results were not separately analyzed for each individual drug but were combined.
Other data on the use of AZA or 6-MP by women who are pregnant are more encouraging with regard to the risk of adverse birth outcomes.
●A retrospective cohort study of 155 IBD patients reported no statistical difference in fertility, congenital anomalies, infections, and maternal malignancies among the group treated with 6-MP [32].
●A retrospective study of 101 pregnancies in women with IBD on AZA also revealed no association with poor pregnancy outcomes [33].
Breastfeeding during AZA treatment of the mother has been discouraged in the past, including in a recommendation of the World Health Organization (WHO) that was formulated in 1988 [35,36]. While the manufacturers' inserts for AZA and 6-MP say that they are excreted in breast milk and should not be used in women who are breastfeeding, data suggest that excretion in breast milk is very low in most women [28,29]. One study of four women being treated with AZA found no detectable 6-MP in their breast milk [29]. The theoretical absolute infant dose was less than 0.09 percent of the mother's weight-adjusted dose, well within safety limits. Another study, involving 10 nursing women who provided a total of 31 breast milk samples, reported the following [28]:
●Twenty-nine of the 31 samples contained no detectable 6-MP.
●Two samples from one woman contained low concentrations of 6-MP (1.2 and 7.6 ng/mL, compared with a plasma concentration of 50 ng/mL that is normally considered therapeutic).
The AZA metabolites 6-MP and 6-thioguanine were not detectable in neonatal blood, and there were no clinical or hematologic signs of immunosuppression in any of the 10 neonates. Two smaller studies of women following renal transplantation reported similar findings [37,38]. Recommendations from professional organizations such as the British Society of Rheumatologists and the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) consider AZA compatible with nursing [39,40].
Colchicine
●Pregnancy – Colchicine is compatible with pregnancy [41].
●Lactation– Colchicine can be continued in nursing mothers [42-44].
Colchicine is used to treat familial Mediterranean fever (FMF), autoinflammatory conditions, and crystal-induced arthritis. While colchicine blocks mitotic cells in metaphase, it does not appear to cause human fetal anomalies [45]. A meta-analysis that included 554 pregnancies in women with FMF who continued colchicine during pregnancy found no congenital anomalies [41].
The use and side effects of colchicine are discussed in the drug information topic on this agent and in the treatment sections for the various disorders in which it is employed. Colchicine has drug interactions and altered metabolism in certain patient populations, which are also discussed separately.
While colchicine is transmitted into breast milk, the levels of drug found in the breast milk of women who are lactating and taking this medication are considered safe [42]. Case reports of breastfed infants whose mothers are taking this medication have not reported any safety concerns [43], and the AAP considers colchicine to be compatible with breastfeeding [44].
SELECTIVE USE ALLOWED DURING PREGNANCY
NSAIDs — The relative safety and the nature of the risks during pregnancy and lactation of nonsteroidal antiinflammatory drugs (NSAIDs) are generally dependent upon the timing of use during pregnancy, the dose, and the specific class of medication. These drugs are widely used for their analgesic, antiinflammatory, and antiplatelet properties. The use of nonselective NSAIDs (eg, ibuprofen) during pregnancy and lactation are discussed in the sections that follow. The use of high-dose aspirin or cyclooxygenase 2 (COX-2) inhibitors is generally avoided. (See 'Aspirin (moderate to high dose)' below and 'COX-2 inhibitors' below.)
Specific details regarding the use and monitoring of these medications are presented separately. (See "NSAIDs: Therapeutic use and variability of response in adults" and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs" and "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases".)
Fertility — Women who are having difficulty with conceiving may wish to avoid use of NSAIDs if disease control would not be compromised. Case reports and some small series have shown transient infertility in some women treated with NSAIDs, which appears to be mediated by inhibition of the rupture of the luteinized follicle [46-48].
Pregnancy up to 20 weeks — NSAID use during the first 20 weeks of pregnancy is appropriate when needed. Risk from NSAID use during the first trimester appears low overall. There does not appear to be an increased risk of spontaneous abortion.
Major risks of NSAID use during early pregnancy have not been clearly identified. Among three studies involving greater than 200,000 pregnancies overall and over 11,000 NSAID-exposed pregnancies (including a 2002 meta-analysis and two subsequent population-based studies), there was no significant increase compared with unexposed infants in the frequency of musculoskeletal or cardiac malformations, nor was there an effect upon infant survival [22,49,50].
However, some studies have suggested small risks of certain adverse birth outcomes. In a nationwide, population-based cohort study representing 1.8 million pregnancies in South Korea, exposure to NSAIDs during the first trimester was associated with a slight increased risk for neonatal outcomes of major congenital malformations (propensity score adjusted relative risk [RR] 1.14, 95% CI 1.10-11.18), low birth weight (adjusted RR 1.29, 95% CI 1.25-1.33), and oligohydramnios (adjusted RR 1.09, 95% CI 1.01-1.19) [51]. However, no particular pattern of congenital anomaly was identified, nor could the authors rule out confounding by indication. In another population-based study, there was a borderline association of ibuprofen use during the first trimester with structural heart defects detected during the first 18 months of life (odds ratio [OR] 1.2, 95% CI 1.0-1.6) [50].
NSAID use is not clearly associated with an increased rate of spontaneous abortion [52,53]. Several observation studies have suggested that NSAID use may be associated with an increased risk of spontaneous abortion [54-57]; however, these studies were limited by a lack of adjustment for the disorder for which NSAIDs were taken, and the effects of other comorbidities and medications, as well as dosing regimens, were not fully analyzed. As examples:
●A study of 1097 women showed that the risk of spontaneous abortion was increased in those women who used NSAIDs during early pregnancy compared with unexposed controls and with women who used acetaminophen [57]. After adjusting for multiple confounders, including maternal age, previous spontaneous abortion, and smoking, the effect remained, but only for women who used NSAIDs around conception (adjusted hazard ratio [HR] 1.9, 95% CI 1.3-2.7). Results for unexposed controls were similar to those for acetaminophen users. NSAID use for more than 14 days was associated with a higher risk of miscarriage compared with use for ≤14 days, and a lower body mass index (BMI <25) was associated with elevated risk, while a higher BMI was not. These findings are consistent with the hypothesis that impaired embryo implantation due to inhibition of prostaglandin production may increase risk of miscarriage.
●A large, nested, case-control study using data from a Canadian registry suggested that exposure to (non-salicylate) nonselective and COX-2 selective NSAIDs in the first 20 weeks of pregnancy may be associated with an increased risk of miscarriage (OR 2.4, 95% CI 2.1-2.8) [54]. These findings should be interpreted with great caution. The control group was not matched for maternal age, which is an important risk factor for spontaneous abortion, and smoking status and use of over-the-counter NSAIDs were not known.
●A large cohort study that linked data from medication dispensing records to information on obstetric outcomes for 65,457 pregnancies, including 6508 pregnant women with spontaneous abortions and 4495 pregnant women exposed to NSAIDs, found no significant increase in the risk of spontaneous abortion following NSAID exposure after controlling for maternal age, diabetes, thyroid disease, hypercoagulation disorders, smoking status, inflammatory conditions, history of recurrent miscarriage, in vitro fertilization, and other factors [53]. This was true both for nonselective NSAIDs (HR 1.10, 95% CI 0.99-1.22) and COX-2 selective NSAIDs (HR 1.43, 95% CI 0.79-2.59). The results for the subset of patients exposed to COX-2 selective NSAIDs were imprecise, given the low number of exposed patients (71) and events (11), and further study of the safety of these medications is needed. An increased risk observed specifically with indomethacin was likely to be related to its therapeutic use for preterm labor.
Pregnancy after 20 weeks — We generally avoid NSAIDs after 20 weeks gestation because of a small increased risk of oligohydramnios. In selected patients who have no alternative therapy, these medications may be used from 20 to 30 weeks with the caveat that amniotic fluid levels should be monitored by ultrasonography. From 30 weeks onward, we suggest avoiding the use of NSAIDs altogether because of the risk of premature closure of the ductus arteriosus. (See 'Third-trimester use of NSAIDs' below.)
In 2020, the US Food and Drug Administration (FDA) issued a warning that use of NSAIDs around 20 weeks gestation or later in pregnancy may rarely cause fetal kidney dysfunction leading to oligohydramnios and, in some cases, neonatal kidney impairment [58]. These outcomes could be seen within 48 hours of NSAID use but typically occurred after days to weeks of treatment. Oligohydramnios was often, but not always, reversible with discontinuation of the NSAIDs, but persistent oligohydramnios could potentially cause further complications. The FDA suggested that, if NSAID treatment was necessary between 20 to 30 weeks of pregnancy, it be at the lowest effective dose and shortest duration possible, monitoring by ultrasound be considered for those treated for more than 48 hours, and the drug be discontinued if oligohydramnios occurs. (See "Oligohydramnios: Etiology, diagnosis, and management in singleton gestations".)
Lactation — There is limited information on the safety of most NSAIDs in breastfeeding women. Ibuprofen is the preferred NSAID in breastfeeding individuals but only because it is secreted into breast milk in very small amounts, and there is the most information on its safety.
Ibuprofen levels were undetectable in the breast milk of individuals taking 1600 mg of ibuprofen a day [59].
Glucocorticoids
●Pregnancy – We use the lowest effective glucocorticoid dose during pregnancy. Whether stress-dose glucocorticoids are indicated in women who have been on glucocorticoids during pregnancy and undergo cesarean delivery is controversial. However, a 2016 review suggests that the recommendation for stress-dose glucocorticoids in this setting is based upon limited data [60]. Moreover, the 2017 American College of Rheumatology guideline for the perioperative management of antirheumatic medication for patients undergoing joint replacement does not recommend stress-dose glucocorticoids during joint replacement [61].
●Lactation – Glucocorticoids are considered compatible with breastfeeding. They are excreted in breastmilk in low concentration. We advise discarding breast milk for the first four hours following ingestion of a dose of prednisone ≥20 mg, as the peak concentration in breast milk is achieved two hours after maternal ingestion.
Glucocorticoids have a variety of side effects when given systemically or by inhalation. Specific details regarding the use and monitoring of these drugs, including the use of inhaled agents during pregnancy and prenatal use to promote fetal lung maturity in women at risk of premature birth, are presented separately. (See "Pharmacologic use of glucocorticoids" and "Major side effects of systemic glucocorticoids" and "Major side effects of inhaled glucocorticoids" and "Management of asthma during pregnancy", section on 'Inhaled glucocorticoids' and "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)
The most commonly used short-acting glucocorticoids are prednisone, prednisolone, and methylprednisolone. The most common long-acting agents are dexamethasone and betamethasone. Prednisone and prednisolone cross the placenta but appear in only small amounts in cord blood [62]. By contrast, dexamethasone and betamethasone reach higher concentrations in the fetus because they are metabolized less efficiently by the placenta.
Early evidence suggested that glucocorticoid exposure increases the risk of cleft palate formation in fetuses exposed in the first trimester. As an example, a cohort study and meta-analysis from year 2000 of epidemiologic studies of women who used glucocorticoids during pregnancy did report an increased risk of bearing a child with cleft palate (OR 3.4, 95% CI 1.97-5.69) [63]. Additionally, the administration of glucocorticoids to pregnant rodents can result in cleft palates in the offspring [64].
However, in contrast to these observations, no increase in orofacial clefts was identified among 51,973 infants exposed to glucocorticoids during the first trimester of pregnancy compared with unexposed infants in a 2011 nationwide cohort study of patients in Denmark involving 832,636 live births, among whom a total of 1232 isolated orofacial clefts were identified [65]. Orofacial clefts (cleft lip and/or palate) occur in approximately 1.7 in 1000 live births in the general population [66].
Glucocorticoid therapy during pregnancy may increase the risk of premature rupture of the membranes (PROM) and intrauterine growth restriction [67,68] and, in the mother, may increase the risk of pregnancy-induced hypertension, gestational diabetes, osteoporosis, and infection [27]. To avoid these risks, we recommend using the lowest dose of glucocorticoid possible during pregnancy to control disease activity. Use of high-dose glucocorticoids should be limited to women who have organ-threatening disease when the benefits are likely to outweigh the risks. A detailed discussion with the pregnant woman regarding the potential risks and benefits of high-dose glucocorticoids during pregnancy should take place.
The approach to addressing the potential need for stress dose glucocorticoids during labor and delivery is similar to that for patients undergoing surgery, which is discussed in detail separately (see "The management of the surgical patient taking glucocorticoids"). Significant suppression of the hypothalamic-pituitary adrenal axis in the newborn is infrequent and typically transient [69].
Glucocorticoids are excreted into the breast milk [70], but their use during lactation is deemed compatible by the American Academy of Pediatrics (AAP) and the British Society of Rheumatologists. We advise discarding breast milk for the first four hours following ingestion of a dose of prednisone ≥20 mg, as the peak concentration in breast milk is achieved two hours after ingestion of this medication by the lactating mother.
Tumor necrosis factor inhibitors
●Pregnancy – Tumor necrosis factor (TNF)-alpha blockers may be used in women who require these medications for the maintenance or establishment of control of active inflammatory disease during pregnancy. Some expert guidance suggests these medications should be discontinued in the late second or early third trimester [71]. However, use of these drugs can be extended, if necessary, to a later gestational age if benefits outweigh potential risks for an individual patient. Certolizumab is compatible for use throughout pregnancy. Only very limited information is available regarding golimumab.
Infants exposed to TNF-alpha blockade in utero should avoid live vaccines (table 2) during the first six months of life but otherwise can follow a standard vaccination schedule for inactive vaccines. Among the live vaccines that should be avoided during this period are rotavirus and Bacillus Calmette-Guérin (BCG). Rotavirus vaccine is the live vaccine generally recommended for administration before six months of age in the United States, and BCG is administered prior to six months in some other countries, although not the United States [39,40,72].
●Lactation – TNF blockers are considered compatible with breastfeeding. The large size of these molecules results in little of the drug being transported during lactation.
Observational studies and case reports of women exposed to TNF inhibitors during pregnancy suggest that their pregnancy outcomes, including rates of preterm birth, spontaneous miscarriage, and congenital anomalies, are similar to those in women with rheumatoid arthritis (RA) or inflammatory bowel disease (IBD) who have not received these medications [27,73-83]. These data are limited by the small number of studies exploring this issue but are supported by animal studies that have not raised any significant concerns [84,85]. Specific details regarding the use and monitoring of these medications are presented separately. (See "Overview of biologic agents in the rheumatic diseases", section on 'TNF inhibition' and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
More data are required to better assess the safety of these medications in pregnancy. Observations regarding safety during pregnancy have been made about the following TNF inhibitors to varying degrees:
●Etanercept (a soluble fusion protein)
●Infliximab (a chimeric monoclonal antibody)
●Adalimumab (a humanized monoclonal antibody)
●Certolizumab pegol (CZP; a pegylated human monoclonal antibody Fab' fragment)
●Golimumab (a human monoclonal antibody)
A prospective multicenter cohort study that included 495 TNF-alpha inhibitor-exposed infants suggested that the risk of major congenital anomalies was increased in exposed (5 percent) versus non-exposed infants (1.5 percent; OR 2.2, 95% CI 1.0-4.8) [86]. However, this study was limited by the lack of a non-exposed population with rheumatologic disease or IBD, and no particular pattern of malformations were identified, making it difficult to attribute causality to the TNF inhibitors.
CZP lacks the antibody Fc- region that is responsible for placental transfer of immunoglobulins. In humans, only minimal, if any, placental transfer occurs [87]. Updated results from the manufacturer's pharmacovigilance database, including 1137 prospectively documented maternal CZP exposures, identified 538 known outcomes (of 301 women with rheumatic diseases, 195 with Crohn disease, and 43 others) through March 6, 2017 [83]. Eighty-one percent of pregnancies had exposures in the first trimester, the major period for organogenesis. There was no increase in teratogenicity or fetal death in CZP-exposed pregnancies compared with the general population. Among the outcomes were 459 live births (85 percent), 47 miscarriages (9 percent), 27 elective abortions (5 percent), and 5 stillbirths (1 percent). There were 8 major congenital malformations (1.7 percent) among the 459 live births; this level is comparable to the background rate of congenital anomalies.
There are only very limited data available regarding the safety of golimumab during pregnancy. In one study of TNF inhibitors that included three pregnancies with exposure to golimumab, none of the congenital anomalies occurred in the golimumab group [86]. Animal studies also suggest that risk of golimumab during pregnancy is low [88].
Serious infections do not appear to be increased in offspring exposed to TNF inhibitors during pregnancy [89,90]. In one study of 380 children of RA mothers who were exposed to TNF inhibitors during pregnancy, the frequency of serious infections in the year following birth was similar to that in offspring of RA patients not exposed to TNF inhibitors and to non-RA offspring [89].
TNF inhibitors are large molecules and, as such, little of these drugs are transferred to breast milk. The concentration of etanercept in breast milk has been measured in a single patient who was lactating (but not nursing her newborn) and was approximately 4 percent of the maternal serum concentration, well below medication levels that are considered incompatible with nursing [91]. Similarly, in a patient who was receiving infliximab for the treatment of Crohn disease, levels of the medication were undetectable in the patient's breast milk [92]. Given that little drug is transferred into breast milk and the drug is likely digested in the infant's gut and therefore not absorbed by the infant, current guidelines consider these medications compatible with lactation [39,40].
Intravenous immune globulin
●Pregnancy – Intravenous immune globulin (IVIG; sometimes abbreviated by industry and regulatory agencies as "IGIV") is considered compatible with pregnancy [93]. It is used for a range of indications, including in primary or secondary antibody immunodeficiencies, dermatomyositis, and antiphospholipid syndrome. (See "Overview of intravenous immune globulin (IVIG) therapy" and "Causes of cholestasis in neonates and young infants", section on 'Gestational alloimmune liver disease (neonatal hemochromatosis)'.)
●Lactation – IVIG is compatible with breastfeeding.
IVIG is a modulator of inflammatory processes hypothesized to operate through anti-idiotype mechanisms. Specific details regarding the use and monitoring of this medication are presented separately. (See "Overview of intravenous immune globulin (IVIG) therapy".)
Immune globulin given by the subcutaneous route has been used safely in pregnancy. (See "Subcutaneous and intramuscular immune globulin therapy".)
There is little information regarding the teratogenicity of IVIG in animals. One report showed that IVIG was tolerated well in a mouse model of antiphospholipid syndrome in the setting of pregnancy [94].
In humans, IVIG appears to cross the placenta in significant amounts after 30 to 32 weeks of gestation, even after modification that alters the Fc binding sites [95]. There have been no reports of fetal malformations in humans. However, hemolytic disease of the newborn and (prior to 1994) transmission of hepatitis C have been reported in selected cases [96,97]. IVIG crosses the placenta beginning in the second trimester, but the highest transport is in the third trimester.
Available data suggest that IVIG is compatible with nursing, although there has been one case report of a transient rash in a breastfeeding infant of a mother receiving IVIG [98].
Cyclosporine
●Pregnancy – When the administration of cyclosporine A (CSA) is necessary during pregnancy, the minimum dose should be used, and the maternal blood pressure and renal function should be monitored closely.
●Lactation – Most evidence suggests that CSA can be taken by lactating women.
CSA is a calcineurin inhibitor. Specific details regarding the use and monitoring of this medication are presented separately. (See "Pharmacology of cyclosporine and tacrolimus" and "Cyclosporine and tacrolimus nephrotoxicity".)
There is little or no transplacental passage of CSA in rodents [99]. Studies in pregnant rats have generally shown no effect of CSA on organogenesis, although some renal proximal tubular cell damage can occur [100,101]. There are conflicting reports on the transfer of CSA across the human placenta; some reports have found little or no transfer, while others have found CSA levels in the placenta that were equivalent to those in maternal blood [102-104].
Other studies have reported the passage of cyclosporine to the fetus late in the third trimester, at birth, and with breastfeeding [105-114]. The cord blood to maternal plasma ratios ranged from 0.35 to 0.63.
Teratogenicity data in humans are derived primarily from organ transplant recipients. The risk of teratogenicity among the offspring of women treated with CSA appears to be low, but premature labor and infants who are small for gestational age have been reported [27,115]. Such findings may be related to the underlying medical condition rather than the drug and could also be related to both the medical condition and the drug. The following studies indicate the range of findings:
●A 2001 meta-analysis of 15 studies of women who received CSA during pregnancy reported major malformations in 4.1 percent of offspring, a rate similar to that of the general population [116].
●A second study compared the pregnancy outcomes of 115 renal transplant recipients (154 total pregnancies) treated with CSA with those of patients whose transplant immunosuppression regimen consisted only of azathioprine (AZA) and prednisone [34]. The overall complication rate among newborns in the CSA group was slightly lower, and no congenital malformations were seen. However, CSA was associated with lower birth weights and a higher incidence of maternal diabetes, hypertension, and renal allograft rejection. These may be related to the patients' medical conditions rather than to CSA itself.
CSA is excreted in breast milk, and therapeutic levels have been reported in some breastfed infants [84,114,117-119]. While the AAP has expressed concern regarding the potential toxicity of this agent in nursing infants [44], other professional organizations have suggested that CSA is compatible with nursing. Taken together, the evidence suggests that CSA can be taken by lactating women [39,40,120].
Tacrolimus
●Pregnancy – Tacrolimus use is compatible with pregnancy.
●Lactation – Tacrolimus is compatible with breastfeeding.
Tacrolimus is a calcineurin inhibitor. Specific details regarding the use and monitoring of this medication are presented separately. (See "Pharmacology of cyclosporine and tacrolimus" and "Cyclosporine and tacrolimus nephrotoxicity".)
Tacrolimus has been used as an alternative to more aggressive immunosuppressive agents for patients requiring therapy during pregnancy, although there are relatively few data concerning the effect of tacrolimus on pregnancy, and the long-term immunomodulatory effects of tacrolimus on the offspring of women who receive this medication are not known [121]. Among 100 pregnancies in 84 women treated with tacrolimus, 68 pregnancies progressed to live births. Sixty percent of these live births were premature [122]. There were four babies with malformations, but there was no consistent pattern of anatomic abnormality. Three other studies in which infants were exposed to tacrolimus in utero, representing a total of 66 pregnancies, showed no increased risk of fetal anomalies [123-125].
Two case reports found that the maximal dose infants received from nursing mothers was 0.02 to 0.5 percent of the mother's weight-adjusted dose, supporting this medication's use in breastfeeding women [126,127].
MODERATE TO HIGH RISK OF FETAL HARM — Some medications that are used to treat rheumatic diseases and have known potential for causing teratogenic effects may be used in pregnancy if the mother's health is directly threatened by an inflammatory illness. Such medications can be used with apparent safety but are always employed with reluctance because of their possible adverse impact on the pregnancy.
Cyclophosphamide
●Pregnancy – We do not use cyclophosphamide (CYC) during pregnancy, except in life-threatening medical conditions in which no alternative therapy is available. The risk of teratogenicity from CYC is highest when the medication is used during the first trimester.
●Lactation – CYC is excreted in breast milk and is contraindicated during breastfeeding.
CYC is an alkylating agent. Specific details regarding the use and monitoring of this medication are presented separately. (See "General toxicity of cyclophosphamide in rheumatic diseases".)
The administration of CYC to pregnant animals produces congenital anomalies such as exophthalmos, cleft palate, skeletal abnormalities, fetal resorption, and growth retardation. The risk of teratogenicity with CYC exposure in humans is high, and the medication should be avoided in all circumstances except the development of disease complications that pose grave health threats to the mother.
Most of the data in humans related to CYC exposure during pregnancy come from isolated case reports. Normal offspring have been born to mothers who received CYC during pregnancy [128]. The syndrome of "cyclophosphamide embryopathy" is discussed in more detail separately. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Teratogenicity'.)
The likelihood of embryotoxicity resulting from CYC administration during pregnancy varies according to the stage of pregnancy at which exposure to the drug occurs:
●The risk of teratogenicity from CYC is highest when the medication is used during the first trimester [27].
●Better outcomes are possible if exposure occurs during the second or third trimester. At least 36 women have been treated with CYC as part of chemotherapeutic regimens for breast cancer during the late second or third trimester without adverse pregnancy or neonatal events being described [129,130].
●Limited data suggest that the pregnancies of patients with systemic lupus erythematosus (SLE) fare poorly when severe disease flares occur during pregnancy, regardless of when CYC is used [131].
In organ- or life-threatening disease, administration of CYC to pregnant women is an option after a detailed discussion of the potential risks and benefits of such treatment.
CYC is excreted in breast milk; it should be avoided during lactation [132].
Methotrexate
●Pregnancy – We strongly advise against using methotrexate (MTX) during pregnancy. We also strongly advise contraceptive use in patients taking MTX. Women on MTX should discontinue this medication and should allow one to three full menstrual cycles to pass before attempting to conceive.
●Lactation – While MTX is excreted into breast milk in low concentrations, it is considered contraindicated during breastfeeding [133].
MTX is a folate antagonist. Specific details regarding the use and monitoring of this medication are presented separately. (See "Major side effects of low-dose methotrexate" and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease" and "Use of methotrexate in the treatment of rheumatoid arthritis".)
Animal studies have shown that MTX is embryotoxic in early pregnancy and causes skeletal abnormalities and cleft palate later in pregnancy [134].
In humans, MTX is teratogenic and an abortifacient. MTX exposure during pregnancy can induce multiple congenital deformities such as cleft palate, hydrocephalus, anencephaly, meningoencephalocele, congenital stenosis of tubular long bones, abnormal facial features (low-set ears, micrognathia), and delayed ossification [135,136].
Most of the data on adverse events related to MTX use in pregnancy are from patients undergoing cancer therapy [137-140]. The rate of congenital malformations has been estimated to be 9 to 17 percent [27,139]. In a 2006 review of the published literature, among 63 pregnancies in which the fetus was exposed to MTX during the first trimester, 19 were terminated electively [27]. Among the remaining 44 pregnancies, the following outcomes were observed:
●Healthy infants – 29 (66 percent)
●Miscarriages – 11 (25 percent)
●Congenital anomalies – 4 (9 percent)
In women with exposure very early during pregnancy, the risk of congenital anomalies may be lower than 9 percent.
MTX is widely distributed in maternal tissues and can persist in the liver for up to four months after exposure. However, in one study, 136 women exposed to MTX preconception (within three months) did not have a higher risk of congenital anomalies than expected compared with the general population, while the 188 women exposed postconception did have an increased rate, as expected [141]. Nevertheless, while somewhat reassuring for certain unplanned pregnancies, we continue to recommend that MTX be discontinued one to three months prior to conception. Folic acid supplementation should be continued during this time and throughout the pregnancy. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)
MTX is excreted in low concentrations in breast milk; data suggest that a breastfeeding infant would receive less than 1 percent of the mother's dose [142]. Despite this, expert guidelines suggest avoiding MTX in breastfeeding mothers [39,40,72].
Mycophenolate mofetil
●Pregnancy – We avoid the use of this medication during pregnancy and use mycophenolate mofetil (MMF) only in patients who employ reliable means of contraception. MMF use can decrease the effectiveness of oral contraceptives. This medication should be discontinued six weeks prior to conception.
●Lactation – There are no data on the transmission of MMF into breast milk; therefore, this medication should be avoided in lactating women.
MMF is an inhibitor of purine biosynthesis. Specific details regarding the use and monitoring of this medication are presented separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
A 2006 review of data from the manufacturer identified 119 human pregnancies with maternal or fetal exposure to MMF [27]. The outcomes, known for only 76 of the pregnancies, included the following:
●Healthy live births – 22 (29 percent)
●Pregnancy terminations – 13 (17 percent)
●Miscarriages – 20 (26 percent)
●Congenital anomalies – 10 (13 percent)
Similar findings have been noted in kidney transplant recipients [143]. Problems reported with MMF include increases both in first-trimester pregnancy loss and in congenital malformations, such as cleft lip and palate, anomalies of the distal limbs, heart, esophagus, and kidneys, and others [144-147]. A possibly characteristic phenotype including cleft lip and palate, microtia, and atresia of external auditory canals has been reported in six cases [148]. This medication should be discontinued six weeks prior to pregnancy. (See "Sexual and reproductive health after kidney transplantation", section on 'Management of immunosuppression'.)
Leflunomide
●Pregnancy – We strongly advise against using leflunomide (LEF) during pregnancy. We also strongly advise contraceptive use in patients taking LEF. In women treated with LEF within 24 months of planning pregnancy, demonstration of undetectable blood levels or using a cholestyramine wash-out with subsequent demonstration of undetectable levels is needed. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis", section on 'Treatment to accelerate drug elimination'.)
●Lactation – LEF is contraindicated during lactation.
Limited data are available on the outcomes of pregnancies occurring in women taking LEF, an antimetabolite that inhibits dihydroorotate dehydrogenase, the enzyme that catalyzes the rate-limiting step in pyrimidine biosynthesis [139,149-154]. Although the half-life of LEF is only approximately 15 days, its major metabolite (teriflunomide) undergoes extensive enterohepatic circulation and remains detectable in serum for up to two years. Thus, discontinuation of LEF immediately before conception is insufficient for drug elimination. However, elimination of the drug and its metabolites can be accelerated through the administration of cholestyramine (8 g orally three times daily for 11 days) and can be confirmed by measurement of drug levels less than 0.02 mg/L on two tests performed two weeks apart. Additional cholestyramine treatment is indicated if plasma levels remain greater than 0.02 mg/L [27].
Specific details regarding the use and monitoring of this medication are presented separately. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".)
Concerns regarding its safety during pregnancy derive both from animal studies, which have demonstrated embryotoxicity and marked teratogenicity [149,155], and from the persistence of drug metabolites for many months following discontinuation of therapy. Several case reports have also raised concerns, although good pregnancy outcomes have been observed as well [151-153].
The largest reported series of women exposed to LEF during conception and during the first few weeks of pregnancy compared 64 women with rheumatoid arthritis (RA) who became pregnant while taking LEF with 108 pregnant women with RA not on LEF and 78 healthy pregnant women [153]. LEF was discontinued in all exposed patients, with the last dose at a mean of 3.1 weeks postconception (range 0 to 8.6 weeks). Most women (95 percent) were treated with cholestyramine, resulting in undetectable levels at a mean of 10.7 weeks postconception. There were no significant differences in the rate of major structural defects in the exposed patients compared with either control group (5.4, 4.2, and 4.2 percent, respectively). No specific pattern of major or minor anomalies was seen, nor was there an increase in rates of pregnancy loss.
Third-trimester use of NSAIDs — Nonsteroidal antiinflammatory drugs (NSAIDs) should not be used during the third trimester because of the risk of premature closure of the ductus arteriosus. The inhibition of prostaglandin synthesis by NSAIDs or high-dose aspirin therapy in the third trimester has the potential for causing premature closure of the ductus arteriosus; indomethacin and ibuprofen appear to have strong ductal effects [156,157].
Aspirin (moderate to high dose) — We avoid the use of moderate- to high-dose salicylates in pregnant women and during lactation, although there is much less evidence available regarding the safety of higher-dose aspirin in such patients, compared with the available information regarding other NSAIDs and low-dose aspirin regimens. In particular, high-dose aspirin should be avoided during the third trimester because of the risk of premature closure of the ductus arteriosus.
Salicylates can cross the placenta and enter fetal circulation. Moderate or high doses of aspirin have been reported to be associated with fetal mortality, intrauterine growth retardation, salicylate intoxication, abnormal bleeding, and neonatal metabolic acidosis [27,158,159]. As an example, there has been a case report of metabolic acidosis in an infant whose mother was taking 2.4 g of aspirin a day [160]. High-dose aspirin near delivery may also increase the risk of fetal or neonatal bleeding or bruising, although data are inconsistent [20,156,161,162].
Reported maternal adverse effects include anemia, abnormal bleeding, and prolongation of gestation and of labor.
The safety of low-dose aspirin is described separately. (See 'Aspirin (low dose)' above.)
LIMITED INFORMATION
Overview of drugs with limited information — There is only limited information on which to base conclusions regarding the safety of the following medications in human pregnancy. However, for the biologic agents composed of an immunoglobulin (Ig) G1 component, placental transfer would be negligible during the first trimester. Thus, continuing these medications through conception is reasonable. There are insufficient data to make recommendations regarding the use during pregnancy of the small molecules.
Drugs for which there are limited data include:
●Biologics with limited data:
●Small molecules with limited data:
There is generally insufficient evidence related to the risks associated with the use of certain biologic agents and small molecules in pregnancy. Drugs for which the risk is unknown include:
●Biologic agents with unknown risk:
●Small molecules with unknown risk:
Biologics with limited data
Abatacept
●Pregnancy – Abatacept can be used up through conception.
●Lactation – Abatacept is a large molecule, and it is unlikely that significant amounts of this medication will be transferred to breast milk. While there are limited data on its compatibility with breastfeeding, given its large size, very little of this drug is likely to be transferred into breast milk.
Abatacept (cytotoxic T-lymphocyte-associated protein 4-Ig [CTLA4-Ig]) is an inhibitor of T-cell costimulation. Specific details regarding the use and monitoring of this medication are presented separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus abatacept' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)
Abatacept interferes with T-cell activation by binding to accessory molecules (CD80 and CD86) and by blocking interaction with CD28 (CTLA4) [163]. Abatacept is not teratogenic in animals, but there are no adequate studies of its effects on human pregnancy to allow an assessment of its risk.
Anakinra
●Pregnancy – Anakinra can be used through conception.
●Lactation – Anakinra is a large molecule, and it is unlikely that significant amounts of this medication will be transferred to breast milk. While there are limited data on its compatibility with breastfeeding, given its large size, very little of this drug is likely to be transferred into breast milk.
Anakinra is a recombinant human interleukin 1 receptor antagonist (IL-1RA). Specific details regarding the use and monitoring of this medication are presented separately. (See "Overview of biologic agents in the rheumatic diseases", section on 'IL-1 inhibition'.)
Studies on rats and rabbits using anakinra at doses up to 100-fold higher than those employed in humans did not indicate problems relating either to infertility or fetal harm [164]. There have been no adequate studies of these issues in humans, although several case reports of women with adult-onset Still's disease treated through pregnancy resulted in healthy neonates [165,166]. A systematic review reported that IL-1 inhibition during 88 pregnancies was not associated with an increased risk of perinatal outcomes [167].
Anakinra (recombinant IL-1RA) is a nonglycosylated form of the human cytokine IL-1RA. The native form is present in breast milk and is thought to contribute to the known antiinflammatory properties of milk. Thus, there appears to be no risk to a nursing infant from administration of anakinra.
Belimumab — Belimumab is a human monoclonal antibody that inhibits the soluble form of a B-cell survival factor (known as BlyS or BAFF). Specific details regarding the use and monitoring of this medication are presented separately. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Approach to drug therapy'.)
●Pregnancy – Across 18 clinical trials, birth defects were more common among belimumab-exposed pregnancies compared with placebo-exposed pregnancies (5.6 versus 0 percent) [168]. However, no consistent pattern of birth defects was found suggesting that there is not an increased rate of congenital malformations with early in utero exposure to belimumab. The American College of Rheumatology 2020 Reproductive Health Guidelines suggest that this medication can be continued up until conception [169].
●Lactation – No data are available to assess safety of belimumab in breastfeeding mothers.
Ixekizumab — Ixekizumab is a monoclonal antibody that selectively targets IL-17A. It is used for the treatment of plaque psoriasis.
●Pregnancy – One study of 99 pregnancies in which mothers were exposed to ixekizumab showed no safety signals [170].
●Lactation – Ixekizumab is a large molecule and will have low transfer into breast milk.
Rituximab
●Pregnancy – Rituximab can be used through conception. In life-threatening conditions, this medication can be used during pregnancy.
●Lactation – Transmission of rituximab in breast milk is low [171,172]. Women receiving this medication can breastfeed their infants.
Rituximab is a chimeric monoclonal antibody that leads to peripheral B-cell depletion through targeting the CD20 antigen present on B lymphocytes, the precursors of plasma cells. Specific details regarding the use and monitoring of rituximab are presented separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)
While the manufacturer recommends discontinuing this medication for one year prior to conception, little if any rituximab is likely to be transferred through the placenta before 12 weeks of gestation. Therefore, if medically indicated, this medication can be used through conception. In life-threatening conditions, it can be used throughout pregnancy after a detailed discussion of the potential risks and benefits of such therapy
Rituximab has been detected in high concentrations in umbilical cord blood. Case reports in humans provide information about the use of rituximab in the setting of pregnancy. The range of data is summarized by the following points:
●Rituximab caused complete but transient B cell depletion in the child of a mother with Burkitt lymphoma who received rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy during pregnancy [173]. The infant demonstrated B-cell count recovery, a normal immunophenotype, and normal responses to vaccinations.
●A patient under treatment for Hodgkin lymphoma inadvertently received rituximab during the first trimester of pregnancy [174]. The course of pregnancy remained normal, and a healthy, full-term baby was delivered.
●A patient with non-Hodgkin lymphoma was treated in the second trimester with rituximab [175]. A healthy baby was delivered at 35 weeks. Peripheral B-cell counts measured when the infant was four weeks old were normal.
●Fetal and neonatal outcomes have been reported for a series of pregnancies with rituximab exposure (for malignancy or autoimmune illness), either preconception or during pregnancy [176]. Of 153 pregnancies with known outcomes, 90 resulted in live births. Twenty-two infants were born prematurely, with one neonatal death at six weeks. Eleven neonates had hematologic abnormalities; none had corresponding infections. Four neonatal infections were reported (fever, bronchiolitis, cytomegalovirus hepatitis, and chorioamnionitis). Two congenital malformations were identified: clubfoot in one twin and cardiac malformation in a singleton birth, both in association with maternal exposure prior to conception. Of 21 pregnancies in which rituximab exposure occurred in pregnant women, only 2 patients received medication during the first trimester, and 6 out of 21 patients were exposed to multiagent chemotherapy. Seven neonates had cytopenias, but no congenital anomalies were reported.
Secukinumab
●Pregnancy – Data from the Novartis global safety database that includes 292 pregnancies did not show any safety signals [177].
●Lactation – Secukinumab is a large molecule, and it is unlikely that significant amounts of this medication will be transferred to breast milk. While there are limited data on its compatibility with breastfeeding, given its large size, very little of this drug is likely to be transferred into breast milk.
Secukinumab is a human IgG1K monoclonal antibody that binds to IL-17A and is used to treat psoriasis, ankylosing spondylitis, and psoriatic arthritis.
Tocilizumab
●Pregnancy – Tocilizumab can be used through conception.
●Lactation – Tocilizumab is a large molecule and it is unlikely that significant amounts of this medication will be transferred to breast milk. While there are limited data on its compatibility with breastfeeding, given its large size, very little of this drug is likely to be transferred into breast milk.
Tocilizumab is an IL-6 receptor inhibitor. Specific details regarding the use and monitoring of this medication are presented separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab'.)
Based upon animal data, tocilizumab may cause fetal harm, but there are no adequate studies of its effects on human pregnancy to allow an assessment of its risk [178].
Pregnancy outcomes have been reported for 32 pregnancies, which were associated with 13 elective abortions, 7 spontaneous abortions (5 also exposed to methotrexate [MTX]), 1 newborn infant death due to respiratory distress after fetomaternal hemorrhage due to placenta previa, and 10 healthy newborns [179]. No teratogenic effects were observed.
In another case series of 50 pregnancies exposed to tocilizumab with known outcomes, 36 resulted in live births. While there were 5 low-birthweight infants born and 1 case of neonatal asphyxia, there were no reports of congenital anomalies [180].
In an additional 16 cases of maternal exposure during pregnancies, there were 4 spontaneous abortions, 1 of which was in a case with fetal hydrops of unclear etiology, and 1 pregnancy termination. Of the 11 live births, there were no congenital anomalies [181].
Ustekinumab
●Pregnancy – Very limited data have not revealed adverse pregnancy outcomes after ustekinumab exposure; this medication can be used through conception [182].
●Lactation – Ustekinumab is a large molecule and it is unlikely that significant amounts of this medication will be transferred to breast milk. While there are limited data on its compatibility with breastfeeding, given its large size, very little of this drug is likely to be transferred into breast milk.
Ustekinumab is a monoclonal antibody that is directed against IL-12 and IL-23 and is predominantly used to treat psoriasis and inflammatory bowel disease (IBD).
Two case series, one of three pregnancies, the other of one pregnancy, have not shown increased risk of adverse pregnancy outcome [183,184]. Registry data have not shown an increase in the rate of spontaneous abortions or congenital malformations.
Small molecules with limited data
Tofacitinib
●Pregnancy – We avoid tofacitinib during pregnancy as there is insufficient data to conclude its safety; based upon European Alliance of Associations for Rheumatology (EULAR) recommendations, discontinue this medication two months prior to conception.
●Lactation – We avoid tofacitinib during lactation in women who are breastfeeding. There are insufficient data to address the issue of safety for breastfed infants, but given that it is a small molecule, it is likely to be transferred into breast milk at high concentrations.
Tofacitinib is an oral Janus kinase inhibitor used in the management of rheumatoid arthritis (RA) and other conditions. There are insufficient data regarding effects of this agent during pregnancy and lactation. In animals, the medication is teratogenic. While there is limited information regarding safety in human pregnancy, one report described outcomes in 47 pregnancies following tofacitinib exposure [185]. Thirteen of these women were also receiving MTX, and, in one, the exposure was blinded. There were seven spontaneous miscarriages, eight medical terminations, and one congenital anomaly (malformation of the pulmonic valve). In 25 births, there were no anomalies; six were lost to follow-up.
COX-2 inhibitors — There are insufficient data on the safety of cyclooxygenase 2 (COX-2) inhibitors during pregnancy; therefore, these drugs should be avoided.
OTHER RESOURCES — The LactMed database, produced by the National Library of Medicine in the United States, is a free, authoritative reference for lactation compatibility for prescription and over-the-counter drugs. This resource provides the most current available data on drug levels in human milk and infant serum, potential adverse effects on breastfeeding infants and lactation, and recommendations for alternative drugs. A free app is also available.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs" and "Society guideline links: Breastfeeding and infant nutrition".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Rheumatoid arthritis and pregnancy (Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)" and "Patient education: Inflammatory bowel disease and pregnancy (Beyond the Basics)" and "Patient education: Systemic lupus erythematosus and pregnancy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Hydroxychloroquine (HCQ), sulfasalazine (SSZ), azathioprine (AZA), and 6-mercaptopurine (6-MP) are considered compatible with pregnancy. (See 'Minimal fetal or maternal risk' above.)
●Low-dose glucocorticoid (eg, 5 to 15 mg of prednisone per day) is compatible with pregnancy, although higher doses and use later in pregnancy increases the risk of gestational diabetes and pregnancy-induced hypertension. (See 'Glucocorticoids' above.)
●In women with a history of delayed conception, discontinuing nonsteroidal antiinflammatory drugs (NSAIDs) may be reasonable. Risk of NSAID use during the first trimester cannot be excluded but appears low. NSAIDs should not be used beyond week 20 of gestation. Use of NSAIDs after the start of the third trimester carries the additional risk of premature closure of the ductus arteriosus. (See 'NSAIDs' above.)
●Tumor necrosis factor (TNF)-alpha inhibitors, cyclosporine, tacrolimus, and intravenous immune globulin (IVIG) are compatible with use during pregnancy. Some experts discontinue TNF-alpha blockers during the third trimester, although use of these drugs can be extended, if necessary, to a later gestational age if benefits outweigh potential risks for an individual patient. Certolizumab is compatible with use throughout pregnancy. (See 'Minimal fetal or maternal risk' above and 'Selective use allowed during pregnancy' above.)
●Infants exposed to TNF inhibitors in utero should avoid live vaccines during the first six months of life. (See 'Tumor necrosis factor inhibitors' above.)
●Abatacept, anakinra, belimumab, ixekizumab, rituximab, secukinumab, and tocilizumab may be used up until conception. While there are limited or no data on other biologics, one can consider continuing these medications through conception. Tofacitinib and the other small molecules should be avoided in pregnant and lactating women. (See 'Limited information' above.)
●In pregnant women, we limit the use of high-dose glucocorticoids, cyclophosphamide (CYC), and rituximab only to women with life-threatening rheumatologic autoimmune disease in whom the benefits of these agents is felt by the patient and clinician to outweigh the risks. (See 'Glucocorticoids' above and 'Cyclophosphamide' above and 'Rituximab' above.)
●Leflunomide (LEF), methotrexate (MTX), and mycophenolate mofetil (MMF) should be avoided in pregnant women with autoimmune disease, and counseling should be offered in the setting of inadvertent exposure. (See 'Methotrexate' above and 'Leflunomide' above and 'Mycophenolate mofetil' above.)
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