Table 2.
Systemic immunomodulators
| Pregnancy | Lactation | Fertility (male) | Fertility (female) | |
|---|---|---|---|---|
| Systemic corticosteroids | Lowest effective steroid dose (Murase et al., 2014) and avoidance during first trimester when hard palate of the fetus is forming recommended. Recent studies have not shown increased risk of cleft deformities (Bandoli et al., 2017). Exposure during pregnancy may increase risk of premature rupture of membrane, placental insufficiency, low birth weight, and intrauterine growth restriction in babies.⁎ | Systemic corticosteroids are excreted into breast milk. Use of corticosteroids during lactation is deemed “usually compatible” by AAP if justified by potential benefit to the mother (Butler et al., 2014). Nursing delay recommended for 3-4 hours after high doses to minimize infant exposure. | Possible theoretical reversible decrease in sperm production and motility; however, discontinuation not necessary in male patients trying to conceive (Semet et al., 2017). | Limited data on women; however, oral corticosteroids are used as part of in vitro fertilization and infertility treatments for women. |
| Azathioprine | Conflicting results from transplant and inflammatory bowel disease studies. Use if benefit of immunosuppression appears to outweigh risks. | May be compatible with breastfeeding. Recommendation to wait 4 hours after ingesting medication and monitor infant full blood count.† | No recommendation to discontinue for male patients while trying to conceive. Case series on 18 patients did not show decrease in sperm quality (Dejaco et al., 2001). | Limited data. |
| Acitretin | U.S. boxed warning: Contraindicated, known teratogen. Two forms of contraception advised, with avoidance of pregnancy 3 years after discontinuation. | Excreted in breast milk. Avoid due to potential cumulative toxicity.† | No reported infertility cases; no alterations in sperm counts/motility (Millsop et al., 2013). | Limited data available. |
| Cyclophosphamide | Risk of teratogenicity in humans high, especially if used during first trimester (Briggs et al., 2014). Causes cyclophosphamide embryopathy (growth restriction, ear and facial abnormalities, absence of digits, hypoplastic limbs, and developmental delay). | Excreted in breast milk. Avoid. | High risk of permanent azoospermia. Cryopreservation of sperm necessary before treatment (Silva et al., 2010). | Risk of infertility related to cumulative dose and age (Janssen and Genta, 2000). |
| Cyclosporine | No increased rate of fetal major malformations compared with the general population.‡ Animal data suggest low risks. Associated with low birth weight and prematurity in babies of patients with complicated health status. If used, minimum dose should be administered with close monitoring of maternal blood pressure and renal function. | Enters breast milk, not recommended by AAP. | No recommendation to discontinue for male patients while trying to conceive.‡ Study showed normal semen parameters and testicular function (Haberman et al., 1991). | Limited data available. |
| Hydroxychloroquine | Can be continued during pregnancy and lactation to prevent disease flares. | Deemed compatible by AAP. | Limited data available, not well studied. | Limited data available. |
| Hydroxyurea | Contraindicated. Teratogenicity and embryotoxicity in animals. No adequate human studies. | Excreted in breast milk. Avoid. | Small retrospective study in male patients showed potentially irreversible decreased sperm motility and spermatogenesis (Grigg, 2007). | Limited data on female fertility. |
| Intravenous immunoglobulin | Compatible in pregnancy.⁎ Limited studies have shown intravenous immunoglobulin to be a safe therapy in pemphigus and pemphigoid gestationis (Ahmed and Gurcan, 2011). | Excreted in breast milk. Probably compatible.† | No impact on male fertility.‡ | Improves fertility rates in in vitro fertility studies. |
| Leflunomide | U.S. boxed warning: Leflunomide is contraindicated in pregnant women because of potential for fetal harm. Following treatment, pregnancy should be avoided until undetectable serum concentrations (< 0.02 mg/L) are verified. May use cholestyramine for enhanced drug elimination. | Unknown if excreted in breast milk. Avoid.‡ | Limited data. Preclinical animal studies demonstrate toxicity on animal reproductive organs; manufacturer recommends contraception and washout prior to conception.† | No influence on fertility; perform washout before planning pregnancy. |
| Methotrexate | U.S. boxed warning: May cause fetal death and/or congenital abnormalities. Stays in the liver for up to 116 days after exposure, so recommendation for discontinuation at least 3 months before attempts to conceive. | Excreted in breast milk. Contraindicated.† | Possibility of reversible impairment of spermatogenesis. Discontinue at least 3 months before planning pregnancy. ‡ | Discontinue 3 months before planning pregnancy. |
| Mycophenolate mofetil | Contraindicated. Teratogenic effects; associated with miscarriages and congenital anomalies. | Excreted in breast milk. Avoid. | No effect on male fertility or spermatogenesis, but male patients advised to discontinue medication for 3 months before attempting to conceive due to teratogenicity (Uptodate, 2019). | Limited data. |
| Sulphasalazine | Mixed findings. Case reports of cleft lip and palate, hydrocephalus, coarctation of aorta. Based on other data, increase in fetal malformations has not been observed after maternal use of sulfasalazine to treat inflammatory bowel disease or ulcerative colitis. Folic supplementation recommended. | Enters breast milk. Use with caution; bloody stools or diarrhea have been reported in nursing infants. May cause kernicterus in newborns. | Reversible oligospermia, asthenozoospermia, and teratozoospermia in male patients (Toovey et al., 1981). Recommendation to discontinue treatment for 3 months before planning pregnancy with male patients. | Limited data. |
| Thalidomide | U.S. boxed warning: May cause severe birth defects or embryo-fetal death. Avoid pregnancy 4 weeks prior, during, and ≥ 4 weeks after therapy is discontinued. | Unknown if excreted in breast milk. Avoid. | Limited data. Animal studies report testicular degeneration in rabbits.‡ | Limited data. Animal studies report no adverse effect on male and female fertility. |
| Tofacitinib | Indicated for psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. Limited data. Manufacturer suggests avoiding use in pregnant women. | Unknown if tofacitinib is present in breast milk. Manufacturer does not recommend breastfeeding during treatment and for at least 18 hours after last dose of immediate-release tofacitinib or 36 hours after last dose of tofacitinib extended release. Some guidelines recommend avoiding breastfeeding. | Limited data. | Limited data. Preclinical animal studies from manufacturer data suggest reduced fertility in women of reproductive potential. Unknown if effect is reversible. |
| Apremilast (Otezla package insert, 2017) | Adequate and well-controlled studies with apremilast have not been conducted in pregnant women. In animal studies, the administration of apremilast to cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures of 2.1 × MRHD, and no adverse effect at an exposure of 1.4 × MRHD. In mice, no apremilast-induced malformations were observed at exposures up to 4.0 × MRHD. Incidences of malformation and pregnancy loss in human pregnancies have not been established for apremilast. | Unknown whether apremilst or its metabolites are present in human milk; however, apremilast was detected in milk of lactating mice. | In fertility study of male mice, apremilast at oral doses up to approximately 3 × MRHD produced no effects on male fertility. | In fertility study of female mice, apremilast was administered at oral doses of 10, 20, 40, or 80 mg/kg/day. At doses ≥ 1.8 × MRHD, estrous cycles were prolonged due to lengthening of diestrus, resulting in longer intervals until mating. Mice that became pregnant at doses of ≥ 20 mg/kg/day also had increased incidences of early postimplantation losses. No effect of apremilast approximately 1.0 × MRHD |
AAP, American Academy of Pediatrics; MRHD, maximum recommended human therapeutic dose.