Immunologic Agent (Immunomodulator)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Etanercept was not toxic or teratogenic in animal reproduction tests at doses much higher than those used clinically. Although the human pregnancy experience is limited, there is no firm evidence of embryo–fetal harm. However, the human data are too limited for a full assessment of the risk. If etanercept is used in pregnancy for the treatment of rheumatoid arthritis, health care professionals are encouraged to call the toll free number (877-311-8972) for information about patient enrollment in the OTIS Rheumatoid Arthritis Study.
FETAL RISK SUMMARY
Etanercept is a dimeric fusion protein, produced by recombinant DNA technology, consisting of the extracellular ligand-binding portion of the human kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human immunoglobulin G1 (IgG1). The protein binds specifically to TNF, a cytokine involved in inflammatory and immune responses, to block its interaction with cell-surface TNFRs (1,2). Etanercept is in the same subclass of immunomodulators that inhibit TNF as adalimumab, certolizumab, golimumab, and infliximab. It is indicated for reducing the signs and symptoms and delaying structural damage in moderate to severe rheumatoid arthritis, including juvenile arthritis. The drug is administered by SC injection.
Reproduction studies in rats and rabbits at doses 60–100 times the human dose revealed no fetal harm (1,2). Animal fertility and carcinogenic studies have not been conducted with etanercept, but it was not mutagenic in in vitro and in vivo tests.
A 32-year-old woman with a 1-year history of rheumatoid arthritis and infertility was treated with SC etanercept (25 mg twice weekly), oral methotrexate (2.5 mg/week), and rofecoxib (25 mg/day) (3). Three months after stopping methotrexate and rofecoxib, and 4 weeks after the last dose of etanercept (total dose 3300 mg over 64 months), she underwent ovulation induction and intrauterine insemination. A successful pregnancy occurred and she delivered a healthy, 2659-g female infant at term. The baby was doing well at 3 months of age (3).
A 37-year-old woman with infertility secondary to antiphospholipid antibodies and elevated natural killer (NK) cells was treated with etanercept (25 mg SC twice weekly), low-dose aspirin (81 mg/day), and low-molecular-weight heparin (enoxaparin 30 mg SC daily) (4). The woman also had a history of chronic leukopenia that was attributed to Epstein-Barr virus. She became pregnant 1 month after the start of therapy. All three agents were discontinued at gestational week 32. At about 38 weeks’, she delivered a healthy male (about 2486-g) infant that was doing well at 21 months of age. Although it could not be proven, the authors speculated that etanercept might have played a role in the pregnancy by inhibiting TNF produced by the NK cells in the lining of the woman’s uterus (4).
Etanercept was used in a woman who had experienced implantation failure in five previous in vitro fertilization treatments (5). Etanercept 25 mg SC every 4 days was started 4 weeks before ovulation induction and then discontinued upon commencement of gonadotropins. The woman delivered male twins at 34.5 weeks (no additional information provided) (5).
A survey of 600 members of the American College of Rheumatology, partially conducted to determine the outcomes of pregnancies exposed to disease-modifying antirheumatic drugs (DMARD) (etanercept, infliximab, leflunomide, and methotrexate), was published in 2003 (6). From the 175 responders, the outcomes of 15 pregnancies exposed to etanercept were 6 full-term healthy infants, 1 spontaneous abortion (SAB) (also taking methotrexate), 1 elective abortion (EAB), 3 unknown outcomes, and 4 women still pregnant (6).
An early review recommended that pregnancy should be excluded before etanercept was administered to women of childbearing age and that effective contraception should be used during treatment (7). Another review speculated that etanercept could disrupt pregnancy because of its anticytokine activity (8). However, this theoretical concern has not been shown clinically (9).
The preliminary results of an ongoing prospective collaborative study of rheumatoid arthritis medicines in pregnancy conducted by the Organization of Teratology Information Specialists (OTIS) have been reported (10,11). The study covered the period 1999–2004. There were 33 women exposed in the 1st trimester to either etanercept (N = 29) or infliximab (N = 4). The outcomes of these pregnancies were compared with 77 prospectively ascertained disease-matched controls (did not use anti-TNFα agents) and 50 prospectively ascertained healthy controls. Three controls were lost to follow-up. There was no difference between the groups in the number of SABs and EABs. One malformation (1/33; 3.0%) was reported in the subject group (a chromosomal anomaly, trisomy 18; spontaneously aborted by a woman exposed to etanercept). Major malformations in the other groups were 4.0% (3/75) in disease-matched controls and 4.1% (2/49) in healthy controls. However, women exposed to etanercept or infliximab and disease-matched controls were significantly more likely to give birth to infants <37 weeks’ gestation and to have lower-birth-weight full-term infants than healthy controls. These results suggested that the disease itself was the causal factor (10,11).
A 2006 communication from England described the pregnancy outcomes of 23 women directly exposed to TNFα agents at the time of conception (17 etanercept, 3 adalimumab, and 3 infliximab) (12). Additional therapy included methotrexate in nine women and leflunomide in two. There also were nine patients (4 etanercept, 5 infliximab) that discontinued therapy before conception. The outcomes for the 32 pregnancies were 7 SABs, 3 EABs, and 22 live births. No major anomalies were observed in the live births, including one infant exposed to adalimumab and methotrexate early in gestation (12).
A 2007 case report and literature review described the use of etanercept in two pregnancies (13).
In the first pregnancy, the woman was started on etanercept 25 mg twice weekly before conception. Her pregnancy was diagnosed at about 2 months’ gestation. Although ultrasound revealed no abnormalities and normal growth, she elected to terminate the pregnancy. The second case involved a 21-year-old woman who was treated before conception with etanercept 25 mg twice weekly and prednisone 5 mg/ day. She became pregnant about 9 months later with her last dose of etanercept given at about 4 weeks’ gestation. At term, she gave birth to a healthy 3.520-kg male infant. During the neonatal period, the infant was treated for a urinary tract infection and jaundice. Adrenal congenital hyperplasia with 21-hydroylase deficiency, known in the father, was detected at 5 days of age and treated with prednisone. At 2 years of age, the child was developing normally (13).
A report using data from the FDA database described 61 congenital anomalies in 41 children born to mothers taking a TNF antagonist (22 etanercept and 19 infliximab) (14). The authors concluded that 24 of the children had one or more of the congenital anomalies that are part of VACTERL association (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal, renal, and limb abnormalities) and the rate was higher than historical controls (14). An accompanying editorial, however, concluded that the evidence for teratogenicity or with the VACTERL association was lacking (15). Many of the anomalies reported occur commonly, such as ventricular septal defects. In addition, such databases have selection bias (only cases with adverse outcomes are reported and emphasis is placed on exposures to new drugs) (15).
A 2009 study from France reported the outcomes of 15 women who took anti-TNF drugs during pregnancy (10 etanercept, 3 infliximab, and 2 adalimumab) (16). The drugs were given in the 1st, 2nd, and 3rd trimesters in 12, 3, and 2 cases, respectively. The outcomes were 2 SABs, 1 EAB, and 12 healthy babies without malformation or neonatal illness. They also reviewed the literature regarding the use of anti-TNF agents in pregnancy and found more than 300 cases. They concluded that, although only 29 were treated throughout gestation, the malformation rate was similar to the general population (16).
A woman with severe rheumatoid arthritis that was well controlled with etanercept was diagnosed with a pregnancy at 6 weeks’ gestation (17). Etanercept was discontinued but restarted at 20 weeks’ because of worsening arthritis. She was continued throughout the remainder of pregnancy. She gave birth at 39 weeks to 2.740-kg female infant with Apgar scores of 10 and 10. No malformations were observed in the newborn (17).
A 40-year-old woman was treated with SC etanercept 25 mg twice weekly and prednisolone 9 mg/day before and throughout pregnancy (18). Maternal blood concentrations of etanercept were measured in each trimester and at delivery. The concentrations decreased during pregnancy from 3849 ng/mL in the 1st trimester to 2239 ng/mL at delivery. She gave birth at 36 weeks’ to a 1.906-kg female infant with Apgar scores of 8 and 9. The cord serum concentration at delivery was 81 ng/ mL, about 4% of the mother’s concentration. No abnormalities were observed in the infant (18).
BREASTFEEDING SUMMARY
In the case described above (18), the mother exclusively breastfed her infant while continuing the same dose of etanercept. Maternal blood concentrations at postpartum weeks 1, 3, and 12 were relatively constant (2306–3512 ng/mL), whereas the infant’s serum concentrations, 81 ng/mL at birth, decreased from 21 ng/mL at 1 week to not detectable (detection level not stated) at 12 weeks. A breast milk concentration, measured at 12 weeks, was 3.5 ng/mL (18).
A woman 30 days after delivery was started on SC etanercept 25 mg twice weekly for an acute flare of arthritis (19). She did not breastfeed her infant. After the fifth dose, a blood sample (data not shown) was drawn and daily milk samples were obtained on postpartum days 44–49. The peak concentration in milk was 75 ng/mL, 1 day after the dose, and the concentration in the other samples declined from 50 to 25 mcg/mL. The estimated dose a nursing infant would have received was 50–90 mcg/day (19).
There is a marked difference in the milk concentrations in the two studies. The timing of the samples in relationship to the dose was only provided in the first case, and then only in approximate terms. Nevertheless, the milk concentrations are very low and there appeared to be no systemic absorption by the one infant that was breastfed. If confirmed, this would be evidence that the protein is digested in the infants’ gastrointestinal tract. Although additional data are required, the limited information suggests that breastfeeding is compatible with maternal use of etanercept.
References
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