Risk Factor: CM
Class: Anti-infectives / Quinolones

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Fetal Risk Summary

Ofloxacin is a synthetic, broad-spectrum antibacterial agent available in oral and parenteral formulations. As a fluoroquinolone, it is in the same class as ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, and sparfloxacin.

A study published in 1986 observed no ofloxacin-induced malformations with high doses in pregnant rats and rabbits (1). Similarly, no evidence of teratogenicity was observed in pregnant rats and rabbits at doses 11 times the recommended maximum human dose based on mg/m2 (RMHD) or 4 times the RMHD, respectively (2). These doses were fetotoxic, however, causing reduced birth weight, increased mortality, and, in rats only, minor skeletal variations. In rats dosed at 5 times the RMHD, no adverse effects were seen on late fetal development, labor, delivery, lactation, neonatal viability, or subsequent growth of the newborn (2).

In a study investigating the pharmacokinetics of ofloxacin, 20 pregnant women, between 19 and 25 weeks' gestation (mean 22.2 weeks), were scheduled for pregnancy termination because the fetuses were affected with b-thalassemia major (3). Two doses of ofloxacin, 400 mg IV every 12 hours, were given before abortion. Serum and amniotic fluid concentrations were determined concomitantly at 6, 10, and 12 hours after dosing. Mean maternal serum concentrations at these times were 0.68, 0.21, and 0.07 g/mL, respectively, compared with mean amniotic fluid levels of 0.25, 0.15, and 0.13 g/mL, respectively. The amniotic fluid:maternal serum ratios were 0.37, 0.71, and 1.86, respectively.

In a prospective follow-up study conducted by the European Network of Teratology Information Services (ENTIS), data on 549 pregnancies exposed to fluoroquinolones (93 to ofloxacin) were described in a 1996 Reference (4). Data on another 116 prospective and 25 retrospective pregnancy exposures to the antibacterials were also included. From the 549 follow-up cases, 509 were treated during the 1st trimester, 22 after the 1st trimester, and in 18 cases the exposure occurred at an unknown gestational time. The live-born infants were delivered at a mean gestational age of 39.4 1.5 weeks and had a mean birth weight of 3302 495 g, length of 50.3 2.3 cm, and head circumference of 34.9 1.5 cm. Of the 549 pregnancies, there were 415 live-born infants (390 exposed during the 1st trimester), 356 of which were normal term deliveries (including one set of twins), 15 were premature, 6 were small for gestational age (intrauterine growth retardation [IUGR], <10th percentile), 20 had congenital anomalies (19 from mothers exposed during the 1st trimester; 4.9%), and 18 had postnatal disorders unrelated to either prematurity, low birth weight, or malformations (4). Of the remaining 135 pregnancies, there were 56 spontaneous abortions or fetal deaths (none late) (1 malformed fetus), and 79 elective abortions (4 malformed fetuses). A total of 116 (all involving ciprofloxacin) prospective cases were obtained from the manufacturer's registry (4). Among these, there were 91 live-born infants, 6 of whom had malformations. Of the remaining 25 pregnancies, 15 were terminated (no malformations reported), and 10 aborted spontaneously (1 embryo with acardia, no data available on a possible twin). Thus, of the 666 cases with known outcome, 32 (4.8%) of the embryos, fetuses, or newborns had congenital malformations. From previous epidemiologic data, the authors concluded that the 4.8% frequency of malformations did not exceed the background rate (4). Finally, 25 retrospective reports of infants with anomalies, who had been exposed in utero to fluoroquinolones, were analyzed but no specific patterns of major congenital malformations were detected.

The defects observed in seven infants followed up prospectively (no ofloxacin-exposed cases among the retrospective reports), all exposed to ofloxacin during the 1st trimester, were as follows (4): Source: Prospective ENTIS Myelomeningocele, hydrocephaly Ureterostenosis Maldescensus testis Hypospadias Hernia inguinalis left side Bilateral hip dysplasia Small atrial septal defect The authors of the above study concluded that pregnancy exposure to quinolones was not an indication for termination, but that this class of antibacterials should still be considered contraindicated in pregnant women (4). Moreover, this study did not address the issue of cartilage damage from quinolone exposure, and the authors recognized the need for follow-up studies of this potential toxicity in children exposed in utero. Because of their own and previously published findings, they further recommended that the focus of future studies should be on malformations involving the abdominal wall and urogenital system, and on limb reduction defects.

A 1998 prospective multicenter study reported the pregnancy outcomes of 200 women exposed to fluoroquinolones compared to 200 matched controls (5). Subjects were pregnant women who had called one of four teratogen information services concerning their exposure to fluoroquinolones. The agents, number of subjects, and daily doses were ciprofloxacin, (N=105; 5001000 mg), norfloxacin (N=93; 400800 mg), and ofloxacin (N=2; 200400 mg). The most common infections involved the urinary tract (69.4%) or the respiratory tract (24%). The fewer live births in the fluoroquinolone group (173 vs. 188, p=0.02) was attributable to the greater number of spontaneous abortions (18 vs. 10, p=0.17) and induced abortions (9 vs. 2, p=0.06). There were no differences between the groups in terms of premature birth, fetal distress, method of delivery, low birth weight (<2500 g), or birth weight. Among the live born infants exposed during organogenesis, major malformations were observed in 3 infants of 133 subjects an 5 of 188 controls (p=0.54). The defects in subject infants were two cases of ventricular septal defect and one case of patent ductus arteriosus, whereas those in controls were two cases of ventricular septal defect, one case of atrial septal defect with pulmonic valve stenosis, one case of hypospadias, and one case of displaced hip. There were also no differences between the children of the groups in gross motor development milestone achievements (musculoskeletal functions: lifting, sitting, crawling, standing, or walking) as measured by the Denver Developmental Scale (5).

In summary, the use of ofloxacin during human gestation does not appear to be associated with an increased risk of major congenital malformations. Although a number of birth defects have occurred in the offspring of women who had taken this drug during pregnancy, the lack of a pattern among the anomalies is reassuring. However, a causal relationship with some of the birth defects cannot be excluded. Because of this and the available animal data, the use of ofloxacin during pregnancy, especially during the 1st trimester, should be approached with caution. A 1993 review on the safety of fluoroquinolones concluded that these antibacterials should be avoided during pregnancy because of the difficulty in extrapolating animal mutagenicity results to humans and because interpretation of this toxicity is still controversial (6). The authors of this review were not convinced that fluoroquinolone-induced fetal cartilage damage and subsequent arthropathies were a major concern, even though this effect had been demonstrated in several animal species after administration to both pregnant and immature animals and in occasional human case reports involving children (6). Others have also concluded that fluoroquinolones should be considered contraindicated in pregnancy, because safer alternatives are usually available (4).

Breast Feeding Summary

The administration of ofloxacin during breast feeding is not recommended because of the potential for arthropathy and other serious toxicity in the nursing infant (2). Phototoxicity has been observed with quinolones when exposure to excessive sunlight (i.e., ultraviolet [UV] light) has occurred (2). Well-differentiated squamous cell carcinomas of the skin has been produced in mice who were exposed chronically to some fluoroquinolones and periodic UV light (e.g., see Lomefloxacin), but studies to evaluate the carcinogenicity of ofloxacin in this manner have not been conducted.

Ofloxacin is excreted into breast milk in concentrations approximately equal to those in maternal serum (2,3). Ten lactating women were given three oral doses of ofloxacin, 400 mg each (3). Six simultaneous serum and milk samples were drawn between 2 and 24 hours after the third dose of the antibiotic. The mean peak serum level occurred at 2 hours (2.45 g/mL), then steadily fell to 0.03 g/mL at 24 hours. Milk concentrations exhibited a similar pattern, with a mean peak level measured at 2 hours (2.41 g/mL), and the lowest amount at 24 hours (0.05 g/mL). The mean milk:serum ratio varied from 0.98 to 1.66, with the highest ratio occurring 24 hours after the last dose. The manufacturer reports that, following a single 200-mg dose, milk and serum concentrations of ofloxacin were similar (2).

Because milk levels of the antibiotic are equivalent to those in maternal serum, the administration of ofloxacin during breast feeding is not recommended because of the potential for arthropathy and other toxicity in the nursing infant.


  1. Takayama S, Watanabe T, Akiyama Y, Ohura K, Harada S, Matsuhashi K, Mochida K, Yamashita N. Reproductive toxicity of ofloxacin. Arzneim Forsch 1986;36:12448. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:296.
  2. Product information. Floxin. Ortho-McNeil Pharmaceutical, 2000.
  3. Giamarellou H, Kolokythas E, Petrikkos G, Gazis J, Aravantinos D, Sfikakis P. Pharmacokinetics of three newer quinolones in pregnant and lactating women. Am J Med 1989;87(Suppl 5A):49S51S.
  4. Schaefer C, Amoura-Elefant E, Vial T, Ornoy A, Garbis H, Robert E, Rodriguez-Pinilla E, Pexieder T, Prapas N, Merlob P. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS). Eur J Obstet Gynecol Reprod Biol 1996;69:839.
  5. Loebstein R, Addis A, Ho E, Andreou R, Sage S, Donnenfeld AE, Schick B, Bonati M, Mortetti M, Lalkin A, Pastuszak A, Koren G. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Ag Chemother 1998;42:13369.
  6. Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones. Drugs 1993;45(Suppl 3):5964.

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