Immunologic Agent (Immunomodulator)
PREGNANCY RECOMMENDATION: Limited Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
The limited human pregnancy experience suggests that certolizumab pegol is low risk for embryo–fetal harm. In 2011, the World Congress of Gastroenterology stated, “Certolizumab pegol in pregnancy is considered to be low risk and compatible with use during conception and pregnancy in women” (1). Animal reproduction studies could not be conducted because the antibody is human specific. However, studies in rats with a rodent-specific antibody similar to certolizumab pegol found no evidence of fetal harm. There is some similarity between the action of immunomodulators with anti-TNFα activity and the human teratogen thalidomide, a drug that also decreases the activity of TNFα. (See Infliximab and Thalidomide.) However, decreased production of TNFα may not be a primary cause of the teratogenicity of thalidomide. Theoretically, TNFα antagonists could interfere with implantation and ovulation, but this has not been shown clinically (2).
FETAL RISK SUMMARY
Certolizumab pegol is a recombinant, humanized antibody Fab′ fragment that blocks human tumor necrosis factor alpha (TNFα). TNFα is a pro-inflammatory cytokine with a central role in inflammatory processes. Certolizumab is in the same subclass of immunomodulators (blockers of TNFα activity) as adalimumab, golimumab, and infliximab. It is conjugated with polyethylene glycol (PEG) to decrease the renal clearance and metabolism of the antibody. The agent is given by SC injection. Certolizumab pegol is indicated for reducing the signs and symptoms of Crohn’s disease and maintaining clinical response in adult patients with moderately to severely active disease that have had an inadequate response to conventional therapy. The terminal elimination half-life is about 14 days (3).
Reproduction studies in animals have not been conducted with certolizumab pegol because it does not cross-react with mouse or rat TNFα. However, studies were conducted in rats using a rodent anti-murine TNFα pegylated Fab′ fragment similar to certolizumab pegol. Doses up to 100 mg/kg revealed no evidence of impaired fertility or fetal harm (3). Although a comparison to the human dose was not specified, the maximum dose was about 17 times the human dose of 5.7 mg/kg from a 400-mg dose given to a 70-kg patient.
Long-term studies to evaluate the carcinogenic potential of certolizumab pegol have not been conducted, but the agent was not genotoxic in multiple assays. The rodent anti-murine TNFα pegylated Fab′ fragment had no effect on the fertility and reproductive performance of male or female rats (3).
Although the molecular weight is very high (about 91,000), certolizumab (but not PEG) crosses the human placenta to the fetus in late gestation (4). In 12 newborns (2 sets of twins) at a mean gestational age of 37.8 weeks (range 36–40 weeks), the median (range) of certolizumab concentrations in cord blood as a percentage of maternal concentration was 3.9% (1.5%–24%). The concentrations in cord blood and in the infant were all ≤1.65 mcg/mL and were undectable in four cord blood samples and three infants (lower limit of quantification <0.41 mcg/mL). PEG was not detected in any cord blood or infant. No birth defects or neonatal intensive care unit stays occurred in any infant (4).
BREASTFEEDING SUMMARY
Certolizumab was not detected in several milk samples from a mother who was breastfeeding her infant (4). The mother was receiving 400 mg every 4 weeks and had received a dose 1 week before delivery and 3 weeks after delivery. At birth, the levels in the cord blood level and infant were 0.94 mcg/mL and 1.02 mcg/mL, respectively. At 4 weeks post-birth, the levels in the mother and infant were 22.93 mcg/mL and 0.84 mcg/mL (3.7%), respectively. Breast milk samples were obtained at 1 and 2 weeks post-birth and at 4 hours, 3 days, and 6 days after the dose at 3 weeks. Concentrations in each of the five milk samples were undectable. PEG was not detected in the infant (4).
References
1.Mahadevan U, Cucchiara S, Hyams JS, Steinwurz F, Nuti F, Travis SPL, Sandborn WJ, Colombel IH. The London position statement of the World Congress of Gastroenterology on biological therapy for IBD with the European Crohn’s and Colitis Organization: pregnancy and pediatrics. Am J Gastroenterol 2011;106:214–23.
2.Khanna D, McMahon M, Furst DE. Safety of tumor necrosis factor-α antagonists. Drug Saf 2004;27:307–24.
3.Product information. Cimzia. UCB, 2008.
4.Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, Ullman T, Glover S, Valentine JF, Rubin DT, Miller J, Abreu MT. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11:286–92.