Drugs in Pregnancy and Lactation: Tenth Edition

ANAKINRA

Immunologic Agent (Immunomodulator)

PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk

BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible

PREGNANCY SUMMARY

One report has described the use of anakinra throughout pregnancy. The infant was severely growth-restricted, probably due to the mother’s disease. No other developmental toxicity was noted. The animal data do not suggest a risk of structural defects, but the agent prevented embryo implantation in one study. Although the near absence of data prevents an assessment of the risk for the human embryo–fetus, interleukin-1 receptor antagonist (IL-1ra) is a natural occurring cytokine that appears to have a role in the protection of the placenta/embryo–fetus from the maternal immune response mechanisms. Therefore, it is doubtful if recommended doses of recombinant IL-1ra will cause direct toxicity to the embryo or fetus. Until human pregnancy data are available, however, the safest course is to avoid anakinra during gestation. Planned or inadvertent pregnancy exposure appears to represent a low risk for the embryo and fetus. If anakinra 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.

FETAL RISK SUMMARY

Anakinra is a nonglycosylated form of the human cytokine IL-1ra produced by recombinant DNA technology. Anakinra (recombinant IL-1ra) is indicated for the reduction in signs and symptoms of moderate to severe rheumatoid arthritis. By binding to interleukin-1 receptors, IL-1ra competitively inhibits interleukin-1 activity, such as the stimulation of several inflammatory mediators. The terminal elimination half-life ranges from 4 to 6 hours (1).

Native IL-1ra is a normal constituent in the maternal, fetal, and amniotic fluid compartments (2,3). Endogenous IL-1ra has been measured in amniotic fluid and newborn urine. Fetal urine is a major source of the cytokine and is gender-dependent with the highest levels found in females. The investigators of one study concluded that the higher concentrations contributed to the better resistance of female fetuses against preterm birth and perinatal infections (3). Conversely, IL-1ra also has been shown to have partial agonist properties because it increases the prostaglandin E2 (PGE2) production of interleukin-1β in fetal membranes that is involved in the initiation of parturition at term (4).

Reproduction studies have been conducted in rats and rabbits. No evidence of impaired fertility or fetal harm was observed in either species at doses up to 100 times the human dose (assumed to be based on weight). Animal carcinogenic studies have not been conducted with anakinra, but it was not mutagenic with in vitro and in vivo tests (1).

In contrast to the above animal data, recombinant IL-1ra has been shown in mice to impair embryonic implantation by a direct inhibitory effect on transformation of the epithelial plasma membrane (5,6). Further, the embryos were morphologically normal and were viable when transferred to pseudopregnant mice (6).

In a 1992 mouse study, interleukin-1-induced preterm delivery was blocked by IL-1ra (7). However, IL-1ra did not prevent preterm delivery or prolong pregnancy in mice with endotoxin-induced preterm labor (8).

A 2001 Australian study found evidence that polymorphisms in the gene encoding for endogenous IL-1ra were associated with recurrent miscarriage (three or more consecutive pregnancy losses before 20 weeks’ gestation) (9). The study investigated 105 women with idiopathic recurrent miscarriage compared with 91 controls with a history of normal pregnancies and no pregnancy losses. Three alleles of IL-1ra polymorphisms were measured. Study subjects had a significantly higher level of polymorphic allele 2, suggesting that this was a genetic determinant of idiopathic recurrent miscarriage and that IL-1ra acted as a physiologic mediator. The study could not determine the degree of genetic IL-1ra deficiency that was associated with idiopathic recurrent miscarriage (9). In contrast, a 2003 Finnish study found that significantly higher levels of polymorphic allele 3 were associated with recurrent spontaneous abortion, suggesting that the allele frequencies varied considerably in different ethnic groups (10).

Anakinra crosses the rabbit placenta. The cervixes of pregnant rabbits were inoculated with Escherichia coli and then the rabbits were given a 5-hour infusion of anakinra (10 mg/kg) (11). Although the treatment did not affect clinical or microbiological outcomes or amniotic fluid levels of tumor necrosis factor-alpha or prostaglandins (PGE2), amniotic fluid concentrations of anakinra were markedly elevated compared with controls (14.8 ng/mL vs. none detected) (11).

An in vitro study was conducted using term human placentas obtained at cesarean section from uncomplicated pregnancies to determine if recombinant IL-1ra crossed the placenta (12). Both maternal-to-fetal and fetal-to-maternal directions were studied. Minimal transfer occurred in either direction. The findings appear to be consistent with the high molecular weight (17,300) of the 153-amino acid protein.

A 2009 case report described a 33-year-old woman with adult-onset Still disease who was treated with anakinra 100 mg/day throughout pregnancy (13). She gave birth at term to a severely growth-restricted (5th percentile), otherwise-normal 2700-g female infant with Apgar scores of 7, 8, and 9. Intrauterine growth restriction is a known complication of Still disease (see also Breastfeeding Summary) (13).

BREASTFEEDING SUMMARY

A 2009 report (see above) described the use of anakinra 100 mg/day during breastfeeding (13). The mother was treated throughout gestation and continued the therapy while breastfeeding. The small-for-gestational-age infant had appropriate growth (10th to 25th percentile) and normal psychomotor development (13).

Even though the molecular weight of the 153-amino acid cytokine is high (17,300), endogenous IL-1ra is excreted into colostrum and mature milk. In a 1996 study, concentrations of IL-1ra in colostrum were higher than those in milk (14). Both colostrum and milk had significantly higher concentrations than did maternal serum or plasma. The measurements of another 1996 study mirrored these findings of IL-1ra in colostrum, transitional milk, and mature milk (15). In the first study, the high milk concentrations persisted over a sequential collection period of 2–6 months (14). It was thought that the presence of natural IL-1ra contributed to the known anti-inflammatory properties of breast milk. Indeed, in a 2001 study, milk levels of IL-1ra in eight lactating women with acute mastitis were markedly increased (16). Because of the presence of native IL-1ra in milk, there appears to be no risk to a nursing infant from maternal administration of anakinra.

References

1.Product information. Kineret. Amgen, 2004.

2.Romero R, Gomez R, Galasso M, Mazor M, Berry SM, Quintero RA, Cotton DB. The natural interleukin-1 receptor antagonist in the fetal, maternal, and amniotic fluid compartments: the effect of gestational age, fetal gender, and intrauterine infection. Am J Obstet Gynecol 1994;171:912–21.

3.Bry K, Lappalainen U, Waffarn F, Teramo K, Hallman M. Influence of fetal gender on the concentration of interleukin-1 receptor antagonist in amniotic fluid and in newborn urine. Pediatr Res 1994;35:130–4.

4.Brown NL, Alvi SA, Elder MG, Bennett PR, Sullivan MHF. Regulation of prostaglandin production in intact fetal membranes by interleukin-1 and its receptor antagonist. J Endocrinol 1998;159:519–26.

5.Simon C, Frances A, Piquette GN, El Danasouri I, Zurawski G, Dang W, Polan LM. Embryonic implantation in mice is blocked by interleukin-1 receptor antagonist. Endocrinology 1994;134:521–8.

6.Simon C, Valbuena D, Krussel J, Bernal A, Murphy CR, Shaw T, Pellicer A, Polan LM. Interleukin-1 receptor antagonist prevents embryonic implantation by a direct effect on the endometrial epithelium. Fertil Steril 1998;70:896–906.

7.Romero R, Tartakovsky B. The natural interleukin-1 receptor antagonist prevents interleukin-1-induced preterm delivery in mice. Am J Obstet Gynecol 1992;167:1041–5.

8.Fidel PL Jr, Romero R, Cutright J, Wolf N, Gomez R, Araneda H, Ramirez M, Yoon BH. Treatment with interleukin-1 receptor antagonist and soluble tumor necrosis factor receptor Fc fusion protein does not prevent endotoxin-induced preterm parturition in mice. J Soc Gynecol Invest 1997;4:22–6.

9.Unfried G, Tempfer C, Schneeberger C, Widmar B, Nagele F, Huber JC. Interleukin 1 receptor antagonist polymorphism in women with idiopathic recurrent miscarriage. Fertil Steril 2001;75:683–7.

10.Karhukorpi J, Laitinen T, Kivela H, Tiilikainen A, Hurme M. IL-1 receptor antagonist gene polymorphism in recurrent spontaneous abortion. J Reprod Immunol 2003;58:61–7.

11.McDuffie RS Jr, Davies JK, Leslie KK, Lee S, Sherman MP, Gibbs RS. A randomized controlled trial of interleukin-1 receptor antagonist in a rabbit model of ascending infection in pregnancy. Infect Dis Obstet Gynecol 2001;9:233–7.

12.Zaretsky MV, Alexander JM, Byrd W, Bawdon RE. Transfer of inflammatory cytokines across the placenta. Obstet Gynecol 2004;103:546–50.

13.Berger CT, Recher M, Steiner U, Hauser TM. A patient’s wish: anakinra in pregnancy. Ann Rheum Dis 2009;68:1794–5.

14.Buescher ES, Malinowska I. Soluble receptors and cytokine antagonists in human milk. Pediatr Res 1996;40:839–44.

15.Srivastave MD, Srivastava A, Brouhard B, Saneto R, Groh-Wargo S, Kubit J. Cytokines in human milk. Res Commun Mol Pathol Pharmacol 1996;93:263–87.

16.Buescher ES, Hair PS. Human milk anti-inflammatory component contents during acute mastitis. Cell Immunol 2001;210:87–95.



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