Immunomodulator
PREGNANCY RECOMMENDATION: Limited Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The animal reproduction data suggest that the risk of embryo–fetal harm is low. Moreover, an in vitro study with cultured human placental trophoblasts found that the systemic imiquimod concentrations obtained clinically should not alter normal placental function. The human pregnancy experience, however, is limited. Although the combined data suggest that the potential for human developmental toxicity is low, the data are too limited for a more complete assessment. Until such data are available, the safest course is to avoid imiquimod in pregnancy, but if exposure does occur, the risk to the embryo and/or fetus appears to be low.
FETAL RISK SUMMARY
The topical immune response modifier imiquimod is indicated for the treatment of: clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face and scalp of immunocompetent adults; biopsy-confirmed primary superficial basal cell carcinoma in immunocompetent adults; and external genital and perianal warts/condyloma acuminata in individuals 12 years of age or older. Small amounts of imiquimod are absorbed systemically and are eliminated slowly with a half-life of about 20 hours. An average dose of 4.6 mg, applied to the affected skin of patients with genital/perianal warts, produced a mean peak serum drug concentration of 0.4 ng/mL. In patients with actinic keratoses treated for 16 weeks, peak serum drug concentrations were 0.1–3.5 ng/mL. The amount absorbed systemically appears to be more related to the surface area treated than to the dose (1).
In vitro studies conducted with imiquimod have shown that it stimulates the production of the cytokines interferon-α, interleukin-1α, interleukin-1β, interleukin-6, and interleukin-8 (2). Because placental trophoblasts also express many of these same cytokines, an in vitro study was conducted to determine if imiquimod exposure during pregnancy could alter normal placental function. In 1st trimester trophoblasts cultured with imiquimod concentrations up to 5.0 mcg/mL, no increase in any of the above interleukins was detected. The results suggested that imiquimod would not induce the expression of inflammatory cytokines in placenta trophoblasts (2).
Reproduction studies have been conducted with oral and IV doses in rats and rabbits. In rats during organogenesis, oral doses 577 times the maximum recommended human dose (MRHD) based on AUC (MRHD-AUC) caused maternal and fetal toxicity. The fetal effects included increased resorptions, decreased body weight, delays in skeletal ossification, and bent limb bones. Two fetuses, among 1567, had exencephaly, protruding tongues, and low-set ears. The no-observed-effect-level for embryo–fetal developmental toxicity was 98 times the MRHD-AUC. In rabbits during organogenesis, no embryo or fetal developmental toxicity was observed with IV doses up to 1.5 times the MRHD based on BSA or with a dose that was 407 times the MRHD-AUC (1).
When imiquimod was given to male and female rats before and during mating, no effects on fertility or mating were noted with oral doses up to 87 times the MRHD-AUC. When these doses were continued throughout pregnancy, parturition, and lactation, no effects were observed on growth or postnatal development. However, bent limb bones in the fetuses were noted, as they were with exposure during organogenesis, in the absence of maternal toxicity. No treatment-related effects were noted at 41 times the MRHD-AUC. Multiple tests with imiquimod revealed no evidence of mutagenic or clastogenic potential (1).
It is not known if imiquimod crosses the human placenta. The low molecular weight (about 240) and long elimination half-life after systemic absorption (about 20 hours) suggest that the drug will reach the embryo and/or fetus. However, because the systemic concentrations are very low, the actual exposure appears to be clinically insignificant.
A 2004 case report described the use of topical imiquimod for the treatment of condylomata acuminata in a woman at 16 weeks’ gestation (3). The initial treatment was 3 nights a week for 4 weeks. Because there was very good clinical response, she was prescribed additional treatment, but the woman was lost to follow-up until she delivered vaginally at 41 weeks. The 3.74-kg normal female infant had Apgar scores of 6 and 10 at 1 and 10 minutes, respectively. Subsequent development was apparently normal (3).
A 2006 report described the outcomes of seven pregnancies exposed to topical imiquimod, all ending in live births with a mean birth weight of 3528 g (4). No major malformations or other adverse effects were noted in the infants. The drug had been used for genital warts in four cases and for warts of the hand, face, or foot in three. Doses of the 5% cream ranged from once daily to four times per week with durations ranging from 1 to 10 weeks (average 5 weeks). Two women used the drug in the 1st trimester, one in the 2nd trimester, two in the 2nd and 3rd trimesters, and two in the 3rd trimester only (4).
Two studies reported the use of imiquimod for the treatment of anogenital warts in a total of 21 pregnant women (5,6). No adverse pregnancy outcomes or fetal anomalies were observed.
BREASTFEEDING SUMMARY
No reports describing the use of imiquimod during lactation have been located. The relatively low molecular weight (about 240) and long elimination half-life (about 20 hours) suggest that the drug will be excreted into breast milk. However, the amount absorbed systemically and available for excretion into milk is very low and probably is clinically insignificant. Therefore, although the risk to a nursing infant is unknown, use of imiquimod by the mother appears to be compatible with breastfeeding.
References
1.Product information. Aldara. 3M Pharmaceuticals, 2006.
2.Manlove JM, Zaher FM, Tomai M, Gonik B, Svinarich DM. Effect of imiquimod on cytokine induction in first trimester trophoblasts. Infect Dis Obstet Gynecol 2000;8:105–11.
3.Maw RD. Treatment of external genital warts with 5% imiquimod cream during pregnancy: a case report. BJOG 2004;111:1475.
4.Einarson A, Costei A, Kalra S, Rouleau M, Koren G. The use of topical 5% imiquimod during pregnancy: a case series. Reprod Toxicol 2006;21:1–2.
5.Audisio T, Roca FC, Piatti C. Topical imiquimod therapy for external anogenital warts in pregnant women. Int J Gynaecol Obstet 2008;110:275–86.
6.Ciavattini A, Tsiroglou D, Vichi M, Di Giuseppe J, Cecchi S, Tranquilli AL. Topical imiquimod 5% cream therapy for external anogenital warts in pregnant women: report of four cases and review of the literature. J Matern Fetal Neonatal Med 2012;25:873–6.