Small amounts of mesalamine are excreted into human milk. A 1990 report described the excretion of mesalamine and its metabolite, acetyl-5-aminosalicylic acid, into breast milk (21). The woman was receiving 500 mg 3 times daily for ulcerative colitis. In a single plasma and milk sample obtained 5.25 hours after a dose, milk and plasma levels of mesalamine were 0.11 and 0.41 mcg/mL, respectively, a milk:plasma ratio of 0.27. Milk and plasma levels of acetyl-5-aminosalicylic acid were 12.4 and 2.44 mcg/mL, respectively, a ratio of 5.1 (21). In another study, women treated prophylactically with 3 g/day of sulfasalazine had milk levels of mesalamine and acetyl-5-aminosalicylic acid of 0.02 and 1.13-3.44 mcg/mL, respectively (4). No adverse effects on the nursing infants were mentioned.

Low concentrations of mesalamine and its metabolite were also found in a woman taking 1 g 3 times daily (5). Maternal serum levels of the drug and metabolite, determined at 7 and 11 days postpartum, were 0.6 and 1.1 mcg/mL (day 7) and 1.1 and 1.8 mcg/mL (day 11), respectively. Milk concentrations of the drug and metabolite at these times were 0.1 and 18.1 mcg/mL (day 7) and 0.1 and 12.3 mcg/mL (day 11), respectively, representing milk:plasma ratios for mesalamine of 0.17 and 0.09 (days 7 and 11), respectively, and for the metabolite of 16.5 and 6.8 (days 7 and 11), respectively. The estimated daily intake by the infant of mesalamine and metabolite was 0.065 mg (0.015 mg/kg) and 10 mg (2.3 mg/kg), respectively, considered to be negligible amounts (5).

A study published in 1993 described the excretion of olsalazine, a prodrug that is partially (2.4%) absorbed into the systemic circulation before conversion of the remainder by colonic bacteria into two molecules of mesalamine (see Olsalazine), in the breast milk of a woman 4 months postpartum (22). Following a 500-mg oral dose, olsalazine, olsalazine sulfate, and mesalamine were undetectable in breast milk up to 48 hours (detection limits 0.5, 0.2, and 1.0 μmol/L, respectively). Acetyl-5-aminosalicylic concentrations at 10, 14, and 24 hours were 0.8, 0.86, and 1.24 μmol/L, respectively, but undetectable (detection limit 1.0 μmol/L) during the first 6 hours and after 24 hours. The quantities detected were considered clinically insignificant (22).

Diarrhea in a nursing infant, apparently because of the rectal administration of mesalamine to the mother, has been reported (23). The mother had relapsing ulcerative proctitis. Six weeks after childbirth, treatment was begun with 500-mg mesalamine suppositories twice daily. Her exclusively breastfed infant developed watery diarrhea 12 hours after the mother's first dose. After 2 days of therapy, the mother stopped the suppositories and the infant's diarrhea stopped 10 hours later. Therapy was reinstituted on four occasions with diarrhea developing each time in the infant 8-12 hours after the mother's first dose and stopping 8-12 hours after therapy was halted. Because of the severity of the mother's disease, breastfeeding was discontinued and no further episodes of diarrhea were observed in the infant (23).

Because of the adverse effect described above, a possible allergic reaction, nursing infants of women being treated with mesalamine or olsalazine should be closely observed for changes in stool consistency. In 2001, the American Academy of Pediatrics classified 5-aminosalicylic acid (i.e., mesalamine) as a drug that has produced adverse effects in a nursing infant and should be used with caution during breastfeeding (24).

Mesalamine is indicated for the maintenance or remission of ulcerative colitis in patients 18 years of age and older (1). The drug, also known as 5-aminosalicylic acid and 5-ASA, also results from metabolism in the large intestine of the oral preparations of sulfasalazine, which is split to mesalamine and sulfapyridine, and from oral formulations of balsalazide and olsalazine that are metabolized in the colon to mesalamine. Systemic absorption after oral administration is about 20%-43% and is variable. It has a major metabolite, N-acetyl-5-aminosalicylic acid (N-ac-5-ASA). Mesalamine and N-ac-5-ASA are about 43% and 78% bound to plasma proteins and have elimination half-lives of 9-10 and 12-14 hours, respectively (1).

Animal Data: Reproduction studies in rats and rabbits at oral doses of about 1.7 and 5.4 times the human dose based on body surface area, respectively, observed no fetal toxicity or teratogenicity (1).

Mesalamine was not carcinogenic. Multiple assays for mutagenicity were negative. No impairment of fertility was observed in rats (1).

Placental Transfer: Sulfasalazine and one of the metabolites, sulfapyridine, readily cross the placenta and could displace bilirubin from albumin if the concentrations were great enough. Mesalamine is bound to different sites on albumin than bilirubin and, thus, has no bilirubin-displacing ability (2). Moreover, only small amounts of mesalamine are absorbed from the cecum and colon into the systemic circulation, and most of this is rapidly excreted in the urine (3).

Human Data: A 1987 reference reported the concentrations of mesalamine and its metabolite, acetyl-5-aminosalicylic acid, in amniotic fluid at 16 weeks' gestation and in maternal and cord plasma at term in women treated prophylactically with sulfasalazine 3 g/day (4). The drug and metabolite levels (all in mcg/mL) and the number of patients were as follows: amniotic fluid (N = 4), 0.02-0.08 and 0.07-0.77, respectively; maternal plasma (N = 5), 0.08-0.29 and 0.31-1.27, respectively; and cord plasma (N = 5), <0.02-0.10 and 0.29-1.80, respectively. No effects on the fetus or newborn from the maternal drug therapy were mentioned (4). At delivery in a woman taking 1 g of mesalamine 3 times daily, the concentrations of the drug and its metabolite, 3.3 hours after the last dose, in the mother's serum were 1.2 and 2.8 mcg/mL, respectively, and in the umbilical cord serum 0.4 and 5.7 mcg/mL respectively (5). The cord:maternal serum ratios were 0.33 and 2.0, respectively.

A review of drug therapy for ulcerative colitis recommended that women taking mesalamine to maintain remission of the disease should continue the drug when trying to conceive or when pregnant (6). A study published in 1993 described the course of 19 pregnancies in 17 women (ulcerative colitis N = 10; Crohn's disease N = 7) who received mesalamine (mean dose 1.7 g/day; range 0.8-2.4 g/day) throughout gestation (7). Full-term deliveries occurred in 18; 1 patient, with a history of four previous miscarriages, suffered a spontaneous abortion. No congenital malformations were observed (7).

Only one report has described possible in utero mesalamine-induced toxicity that may have occurred during 2nd trimester exposure to the drug (8). The 24-year-old mother was treated, between the 13th and 24th weeks of gestation, for Crohn's disease with 4 g/day of mesalamine for 5 weeks, then tapered to 2 g/day for 6 weeks, and then stopped. A fetal ultrasound at 17 weeks' gestation was normal, but a second examination at 21 weeks showed bilateral renal hyperechogenicity. The term male infant had a serum creatinine at birth of 115 μmol/L (normal 18-35 μmol/L). Renal hyperechogenicity was confirmed at various times up to 6 months of age. At this age, the serum creatinine was 62 μmol/L with a creatinine clearance of 52 mL/min (normal 80-90 mL/min). A renal biopsy at 6 months of age showed focal tubulointerstitial lesions with interstitial fibrosis and tubular atrophy in the absence of cell infiltration. Because no other cause of the renal lesions could be found and there was some resemblance to lesions induced by the prostaglandin synthesis inhibitor, indomethacin, the authors attributed the defect to mesalamine (8). A letter published in response to this study, however, questioned the association between the drug and observed renal defect because of the lack of toxicity in an unpublished series of 60 exposed pregnancies and the lack of evidence that mesalamine causes renal prostaglandin synthesis inhibition in utero (9).

A 1997 report described the successful outcomes of 19 pregnancies followed prospectively in 16 women with proven distal colitis (10). The women received either 4-g mesalamine enemas 3 times weekly or a 500-mg mesalamine suppository every night throughout gestation. No fetal abnormalities were observed during pregnancy, and all of the full-term offspring were normal at birth and at a median follow-up of 2 years (range 2 months to 5 years) (10).

A 1998 prospective study reported the pregnancy outcomes of 165 women exposed to mesalamine (146 during the 1st trimester) who had contacted a teratogen information service (TIS) (11). The study patients were compared with 165 matched controls who had called the TIS concerning nonteratogenic exposures. There were no significant differences between the two groups in spontaneous abortions (6.7% vs. 8.5%), ectopic pregnancies (0.6% vs. 0%), or elective abortions (none were associated with malformed fetuses) (4.2% vs. 1.8%). There was one major defect (an extra right thumb) in the study group compared with five major anomalies in controls (ns). Eight subjects had minor malformations compared with five controls (ns). However, compared with controls, significantly more preterm deliveries occurred in subjects (13.0% vs. 4.7%), the mean birth weight was lower (3253 vs. 3461 g), and the mean maternal weight gain was lower (13.1 vs. 15.6 kg) (11).

A 2004 report described the pregnancy outcomes of 113 women who were being treated for inflammatory bowel disease (39 ulcerative colitis; 73 Crohn's disease; and 1 indeterminate colitis) (12). In the group, there were 207 pregnancies, 100 during treatment with a 5-ASA agent (mesalamine, sulfasalazine, balsalazide, or olsalazine) at sometime during pregnancy. Other agents used included 49 cases with prednisone, 101 with azathioprine or mercaptopurine, 27 with metronidazole, 18 with ciprofloxacin, and 2 with cyclosporine. The pregnancy outcomes of the first eligible pregnancy in the 113 women were 2 ectopic pregnancies, 2 elective abortions, 16 spontaneous abortions, 6 premature infants, 85 full-term infants (1 set of twins), and 3 major defects (2.7%). However, one of the “defects” was a case of immature lungs, which is not considered a congenital defect. The other two defects were imperforate anus and an unspecified heart defect. In addition, the two elective abortions were for unspecified fetal defects. The study concluded that there was no evidence that any of the drugs used either alone or in combination was associated with poor pregnancy outcomes (12).

A 2008 meta-analysis studied the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) following exposure to 5-ASA drugs (mesalazine, balsalazide, olsalazine, and sulfasalazine (13). In seven studies, 1158 received no medication and 642 received 5-ASA drugs. There was no statistically significant increase in birth defects, stillbirths, spontaneous abortion, preterm delivery, and low birth weight (13).

A 2012 case described a 27-year-old woman with ulcerative colitis who was treated throughout pregnancy with allopurinol 100 mg/day, mercaptopurine 25 mg/day, and mesalazine 4 g/day (14). Pregnancy was complicated by diarrhea and blood loss in the 2nd trimester. An elective cesarean section was performed at 39 weeks to give birth to a healthy 3550-g infant (sex not specified) with Apgar scores of 9, 10, and 10 at 1, 5, and 10 minutes, respectively. No anomalies were observed in the infant (14).

In contrast to sulfasalazine, mesalamine apparently has no adverse effect on spermatogenesis. Treatment of males with sulfasalazine may adversely affect spermatogenesis (15, 16, 17, 18, 19), but either stopping therapy or changing to mesalamine allows recovery of sperm production, usually within 3 months (16, 17, 18, 19). However, in a study of infertile males on mesalamine, sperm motility and total motile sperm significantly improved after mesalamine discontinuation (20).