Ciprofloxacin Use by Pregnant and Lactating Women

Ciprofloxacin is approved for prophylaxis following inhalational anthrax exposure¹. According to the Centers for Disease Control and Prevention (CDC), ciprofloxacin (500 mg, orally, two times a day for 60 days) is the antibiotic of choice for initial prophylactic therapy among asymptomatic pregnant women exposed to Bacillus anthracis. In instances where the specific B. anthracis strain has been shown to be penicillin-sensitive, prophylactic therapy with amoxicillin (500 mg, orally, three times a day for 60 days) may be considered². CDC guidelines for treatment of anthrax infection in pregnant women recommend either ciprofloxacin or doxycycline with one or two other antibiotics added for inhalational anthrax or systemic involvement³.

While there are no controlled studies of ciprofloxacin use in pregnant women to show safety, an expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data = fair), but the data are insufficient to state that there is no risk⁴. However, there are no human data available to assess the effects of long-term therapy in pregnant women such as that proposed for treatment of anthrax exposure. Ciprofloxacin is excreted into breast milk but is considered as "usually compatible with breastfeeding" by the American Academy of Pediatrics.⁵

Background: The association between fluoroquinolones and arthropathy, although observed in immature animals and rarely reported in humans, has resulted in the restricted use of fluoroquinolones during pregnancy. Young dogs given ciprofloxacin developed arthropathy with permanent cartilage erosion in weight-bearing joints. Similar arthropathies have been reported in neonatal mice⁶. Transient arthropathy has been reported in a small number of patients with cystic fibrosis⁷,⁸

Arthropathy as a Teratogenic Effect	· Animal reproduction studies have not shown arthropathy or other musculoskeletal problems in offspring exposed to ciprofloxacin in utero². · While no clinical studies have been conducted in pregnant women, controlled prospective observational data suggest that in utero exposure to fluoroquinolones is not associated with clinically significant major musculoskeletal dysfunctions⁹. · Seven women exposed to ciprofloxacin during second or third trimester delivered healthy normal babies. Motor, adaptive, social, and language milestones in each child were consistent with age, and no evidence of cartilage damage was found on regular clinical assessments up to five years of age¹⁰.
Other Teratogenic Effects and Outcomes	· Animal reproduction studies in mice, rats, and rabbits have revealed no evidence of teratogenicity in offspring exposed to ciprofloxacin in utero². Studies in pregnant monkeys did not produce detectable adverse effects on embryonic or fetal development¹¹. · Controlled prospective observational data on 200 fluoroquinolone-exposed human pregnancies (52.5% exposed to ciprofloxacin and 68% treated during the first trimester) showed the rate of major malformations among live-born children exposed during the first trimester was in the expected normal range of 1 - 5% as was the rate in controls. There were no differences in the rates of prematurity, spontaneous abortions, or birth weight⁹. · Non-controlled prospective observational data on 70 ciprofloxacin-exposed human pregnancies (60% exposed during the first trimester) showed the rate of congenital malformations in live-born children exposed during the first trimester was 4.7%. The frequencies of spontaneous abortion/fetal death, post-natal disorders, prematurity and intra-uterine growth retardation did not exceed background rates¹². · In a company-sponsored prospective registry of 116 human pregnancies, 54% were exposed during the 1st trimester and resulted in live births. Of these, six were malformed. There was no pattern of anomalies seen among the reported spectrum of minor and major malformations¹².
Other Teratogenic Effects and Outcomes (cont'd)	· An observational cohort study looking at human experience with five different antibiotics reported a total of 40 pregnancies with ciprofloxacin. Five of the nine women who received ciprofloxacin during the first trimester experienced normal births with no reported congenital abnormalities. The other four first trimester exposures were an ectopic pregnancy, a spontaneous abortion and two terminations¹³. · One publication described six pregnant women exposed to longer durations of ciprofloxacin therapy (3 weeks to 3 months) who delivered normal babies¹⁴. There has also been a case report of a pregnant woman exposed to three weeks of ciprofloxacin therapy during early third trimester who delivered a normal baby¹⁵.
Duration of Exposure	· The vast majority of reported experience with ciprofloxacin during human pregnancy (as described above) is short-term, 1st trimester exposure.

Prepared by the Pregnancy Team, Food and Drug Administration 10/30/01

1 Product information Cipro®, 2001
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2 Notice to readers: Updated recommendations for antimicrobial prophylaxis among asymptomatic pregnant women after exposure to Bacillus anthracis. MMWR 2001;50(43):960.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5043a5.htm
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3 Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR 2001;50(42);909-919 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm.
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4 Friedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press; 2000:149-195.
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5 Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108(3):776-789.
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6 Linseman DA, Hampton LA, and Branstetter DG. Quinolone-induced arthropathy in the neonatal mouse: Morphological analysis of articular lesions produced by pipemidic acid and ciprofloxacin. Fundam Appl Toxicol 1995;28:59-64.
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7 SamuelsonWM, Pleasants RA, and Whitaker MS. Arthopathy secondary to ciprofloxacin in an adult cystic fibrosis patient. Ann Pharmacother 1993;27:302-303.
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8 Jawad ASM. Cystic fibrosis and drug-induced arthropathy. Br J Rheumatol 1989;28(2):179-180.
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9 Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother 1998:42(6)
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10 Koul PA, Wani JI, Wahid A. Ciprofloxacin for multiresistant enteric fever in pregnancy. Lancet 1994;84:535-538.
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11 Schluter G. Ciprofloxacin: toxicological evaluation of additional safety data. Am J Med 1989;87:5A(37s)-5A(39s).
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12 Schaefer C, Amoura-Elefant E, Vial T, et al. 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;69:83-89.
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13 Wilton LV, Pearce GL, and Mann RD. A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies. Br J Clin Pharmacol 1996;41:277-284.
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14 Bomford JAL, Ledger JC, O'Keeffe BJ, and Reiter C. Ciprofloxacin use during pregnancy. Drugs 1993;45 (Suppl 3):461-462
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15 Ludlam H, Wreghitt TG, Thornton S, et al. Q Fever in pregnancy. J Infect 1997;34:75-78.
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