Immunologic Agent (Immunomodulator)
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
The maternal benefits from treatment with adalimumab appear to far outweigh the unknown embryo–fetal risks (1,2). No developmental toxicity attributable to adalimumab has been observed in a limited number of cases and the animal data suggest low risk. In 2011, the World Congress of Gastroenterology stated “Adalimumab in pregnancy is considered low risk and compatible with use during conception and pregnancy in at least the first two trimesters” (3). Theoretically, tumor necrosis factor-alpha (TNF-α) antagonists could interfere with implantation and ovulation, but this has not been shown clinically (4). Because of the long elimination half-life, use before conception may result in inadvertent exposure of an unplanned pregnancy. If adalimumab 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 Organization of Teratology Information Specialists (OTIS) Rheumatoid Arthritis study and pregnancy registry.
FETAL RISK SUMMARY
Adalimumab is a recombinant IgG1 monoclonal antibody that binds specifically to human TNF-α to block its action on cell surface TNF receptors. TNF-α is a pro-inflammatory cytokine with a central role in inflammatory processes. Adalimumab is in the same subclass of immunomodulators (blockers of TNF activity) as etanercept, certolizumab pegol, golimumab, and infliximab. It is indicated for reducing the signs and symptoms and inhibiting the progression of structural damage in adult patients with moderate to severe active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs. It has also been used in Crohn’s disease. The mean terminal elimination half-life is about 14 days (range 10–20 days) (5).
An animal reproduction study for perinatal development toxicity was conducted in pregnant cynomolgus monkeys. Doses up to 266 times the human AUC (SC 40 mg with methotrexate every week) or 373 times the human AUC (SC 40 mg without methotrexate) revealed no fetal harm (the timing of the exposure was not specified). No clastogenic or mutagenic effects were observed in various tests, but adalimumab has not been tested for carcinogenic or fertility effects (5).
Although the molecular weight is very high (about 148,000), adalimumab crosses the human placenta to the fetus in late gestation (6). As an IgG1 antibody, the drug would be transported actively across the placenta, especially in the 3rd trimester, but with minimal transfer in the 1st trimester. In 10 cases at a mean gestational age of 39 weeks (range 38–41 weeks), the median of infliximab concentrations in cord blood as a percentage of maternal concentration was 179% (range 98%–293%). The last dose was given a median of 5.5 weeks (range 0.14–8 weeks) before birth. Infant or cord blood concentrations were higher than maternal levels in every case. Moreover, infliximab was detected in the infants for at least 11 weeks. No birth defects, infections, or neonatal intensive care unit stays occurred in any infant (6).
A 2005 case report described a 34-year-old woman with long-standing Crohn’s disease who was treated throughout gestation with adalimumab and prednisone (7). The woman received 38 weekly SC doses of adalimumab (40 mg/dose). Normal fetal growth was documented during the uncomplicated pregnancy. An elective cesarean section at 38.5 weeks’ delivered a normal infant with Apgar scores of 8 and 9, presumably at 1 and 5 minutes, respectively. The infant was growing and developing normally at 6 months of age (7).
The preliminary results of an on-going prospective cohort study and pregnancy registry involving adalimumab that is being conducted by OTIS were reported at an October 2006 meeting (D. Johnson, personal communication, University of California, San Diego, 2006). Of the 95 women enrolled in the study or registry, 26 involved exposure in the 1st trimester. Thirteen outcomes were known, 12 of which resulted in healthy, full-term infants without birth defects. In the 13th case, a woman with twins, one fetus was aborted and the other was delivered prematurely without defects.
A 35-year-old woman with Crohn’s disease was treated with adalimumab (SC 40 mg every other week) throughout gestation (8). She delivered a normal infant (details not provided) that had normal growth and development at 6 months of age.
A 34-year-old woman with Crohn’s disease was treated with budesonide, then prednisone only from 6 to 20 weeks’ gestation (9). At that point, she was started on azathioprine 100 mg/day and adalimumab 80 mg (one dose), then 40 mg every other week. Prednisone was tapered and stopped by the 32nd week. Labor was induced at 38 weeks’ and she delivered a healthy, 2.89-kg, male infant who was well and developing normally at 1 year of age (9).
A 2006 communication from England described the pregnancy outcomes of 23 women directly exposed to TNF-α agents at the time of conception (17 etanercept, 3 adalimumab, and 3 infliximab) (10). Additional therapy included methotrexate in nine women and leflunomide in two. There also were nine patients (four etanercept, five infliximab) that discontinued therapy before conception. The outcomes for the 32 pregnancies were 7 spontaneous abortions (SABs), 3 elective abortions (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 (10).
A 2007 case report and literature review described the use of adalimumab in a 41-year-old woman with rheumatoid arthritis (11). The woman had received a single dose of 40 mg after conception when an unplanned pregnancy at 5 weeks’ was discovered. A healthy 2.6-kg infant was delivered at 32 weeks’ gestation. At 25 months of age, the child was growing and developing normally (11).
A 2008 report described a 22-year-old woman with Takayasu arteritis who conceived while taking adalimumab 40 mg SC every 4 weeks, leflunomide 10 mg/day, prednisolone 5 mg/day, and dalteparin 500 IU/day (12). Leflunomide was discontinued by the patient at 8 weeks’ gestation but the other agents were continued throughout. At 37 weeks’, a cesarean section was performed to deliver a healthy 2550-g male infant with Apgar scores of 9, 9, and 10 at 1, 5, and 10 minutes, respectively (12).
A woman with lupus nephritis took mycophenolate mofetil (1000 mg/day) and adalimumab (40 mg every other week) during the first 8 weeks of pregnancy (13). She underwent a cesarean section for transverse position at 32 weeks’ gestation to give birth to a 4422-g female infant with normal karyotype (46,XX). The infant had multiple birth defects including arched eyebrows, hypertelorism, epicanthic folds, micrognathia, thick everted lower lip, cleft palate, bilateral microtia with aural atresia, congenital tracheomalacia, and brachydactyly. Shortly after birth, a tracheostomy was done for respiratory distress and a G-tube was placed because of feeding difficulties. The cleft palate was repaired surgically. At 20 months of age, the infant had normal growth and slightly delayed motor development. The tracheostomy was still required as were G-tube feedings. She seemed to have some hearing, but had significant expressive speech delay. The defects were attributed to mycophenolate (13).
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) (14). 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. It was concluded that, although only 29 were treated throughout gestation, the malformation rate was similar to the general population (14).
A 32-year-old woman with Crohn’s disease was treated with adalimumab 40 mg every other week for a total of 18 doses (15). Therapy at that time was stopped when her pregnancy was diagnosed. She had received 40 mg doses at 2, 4, and 6 weeks’ gestation. She eventually delivered at term a healthy 3360-g female infant with Apgar scores of 10, 10, and 10. The child was doing well at 2 years of age (15).
In 2008, investigators reviewed >120,000 adverse events involving TNF-α agents that had been reported to the FDA in 1999–2005 (16). There were 61 congenital anomalies in 41 children born to mothers taking etanercept or infliximab. There were no cases of birth defects involving adalimumab (16).
In a 2010 case report, a 34-year-old woman was treated for psoriasis with adalimumab from 3 months before conception through 5 weeks of pregnancy (17). An elective cesarean section at 38.5 weeks gave birth to a low-birth-weight infant (weight and sex not specified). The child was developing normally at 12 months of age (17).
A 26-year-old woman with Crohn’s ileitis was treated with adalimumab before and during gestation up to week 30 of gestation (18). At that time the drug was discontinued, and she gave birth at 38 weeks’ to a healthy infant (weight and sex not specified).
In subfertile women with T helper 1/T helper 2 cytokine elevations undergoing in vitro fertilization, adalimumab and IV immunoglobulin significantly improved the rates of implantation, clinical pregnancies, and live births (19).
BREASTFEEDING SUMMARY
Adalimumab is excreted into breast milk. In a case described above, adalimumab therapy was discontinued at 30 weeks’ gestation and the woman gave birth to a healthy infant at term (18). The mother did not require therapy while breastfeeding her infant during the first 4 weeks after birth but, at that time, she experienced a flare-up of Crohn’s disease. Nursing was discontinued when a 40-mg SC dose was given. Immediately before the dose, maternal serum and breast milk concentrations of adalimumab were undectable. Postdose, the serum level peaked at 4300 ng/mL at 3 days, whereas the peak milk concentration of 31 ng/mL was reached on day 6 (18).
In another study described above, 9 of 10 mothers continued to take adalimumab after birth and 6 of 10 infants were breastfed (6). No other details were provided.
The very low adalimumab concentration in breast milk is consistent with its high molecular weight (about 148,000). The systemic bioavailability of the drug from milk and any effect of this exposure on a nursing infant are unknown. However, two mothers, described above, did continue adalimumab during breastfeeding and no adverse effects in their infants were mentioned (7,8).
References
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