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U.S. Department of Health and Human Services

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Doxycycline (Vibramycin, Monodox, Doryx, Doxy, Atridox, Periodox, Vibra-Tabs) Use by Pregnant and Lactating Women

Doxycycline is approved for the treatment of anthrax1. 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. Doxycycline should be used for prophylaxis only when there are contraindications to the use of other appropriate antibiotics. 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 doxycycline use in pregnant women to show safety, an expert review of published data on experiences with doxycycline 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 = limited to fair), but the data are insufficient to state that there is no risk4. The risk of cosmetic staining of the primary teeth by doxycycline is undetermined (quantity and quality of data = very limited)4. 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. Doxycycline is excreted into breast milk. Short-term use by lactating women is not necessarily contraindicated, however, the effects of prolonged exposure to doxycycline in breast milk are unknown5.

Background: The use of doxycycline during pregnancy has historically been discouraged unless other drugs are not likely to be effective or are contraindicated1. This is due to the knowledge that tetracyclines cause cosmetic staining of the primary dentition in fetuses exposed during the second or third trimester of pregnancy6,7 and manufacturer concerns about possible enamel hypoplasia and depression of fetal bone growth1.

 

Adverse Effects on Fetal Teeth and Bones

· There have been no published human data showing that fetal exposure to doxycycline causes cosmetic staining of the primary teeth, however this cannot be ruled out because of the tetracycline class effect. The concern about enamel hypoplasia and caries with in utero exposure to tetracycline has been shown to not be related8,9.

· While not reported with doxycycline or with in utero exposure, oral tetracycline given to premature infants has been associated with a decrease in fibular growth that was reversible when the drug was discontinued10.

· While there have been no reports in humans, an increased frequency of skeletal anomalies associated with maternal toxicity was seen among the offspring of pregnant mice, but not rabbits, treated with 17 times the maximum human dose of doxycycline11.

Other Teratogenic Effects and Outcomes

· A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. (Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline.) This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases. The authors thought the significant difference with total malformations could be attributed to recall bias12.

· A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age13.

 

Other Teratogenic Effects and Outcomes

(cont'd)

· A non-peer-reviewed surveillance study of Medicaid recipients involving 229,101 completed pregnancies reported that data on 1,795 doxycycline-exposed pregnancies did not support an association between doxycycline and any of the six specific malformations evaluated (i.e., cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) 14.

· Unpublished data from an ongoing case-control study reports 34 first trimester exposures to doxycycline among mothers of malformed infants, with no apparent clustering of categories or specific defects15.

· With the exception of skeletal anomalies (see above), the frequency of malformations was not increased with doxycycline exposure during pregnancy among the offspring of mice or rabbits, but at the highest dosage level decreased fetal weight (mice and rabbits), and increased fetal death (rabbits) were seen in association with maternal toxicity11.

· No teratogenic effects occurred among the offspring of pregnant mice, rats, or rabbits given about 100 times the usual human dose of doxycycline16. Another study found no teratogenicity with doxycycline exposure in rats, rabbits, or monkeys17.

Maternal Liver Toxicity

· While there are no published reports with doxycycline use, tetracycline use has been associated with fatty liver of pregnancy18,19. This rare but often fatal disorder has been reported to follow high dose intravenous tetracycline use to treat pyelonephritis20.

Duration of Exposure

· The vast majority of reported experience with doxycycline during human pregnancy (as described above) is short-term, first trimester exposure.

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


 1 Product information Vibramycin®, 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 Hale T. Medications and Mothers Milk. 9th edition. Amarillo, TX:Pharmasoft Publishing;2000:225-226. 
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 6 Toaff R, and Ravid R. Tetracyclines and the teeth. Lancet 1966;2:281-282. 
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 7 Cohlan SQ. Tetracycline staining of teeth. Teratology 1977;15:127-130. 
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 8 Genot MT, Golan HP, Porter PJ and Audra PH. Effect of administration of tetracycline in pregnancy on the primary dentition of the offspring. J Oral Med 1970;25:75-79.
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 9 Rebich T, Kumar J, Brustman B. Dental caries and tetracycline-stained dentition in an American Indian population. J Dent Res 1985;64(3):462-464.
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 10 Cohlan SQ, Bevelander G, and Tiamsic T. Growth inhibition of prematures receiving tetracycline. Am J Dis Child 1963;105:453-461.
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 11 Bastianini L and Felisati. [Studies on gravidic and fetal toxicity of alpha-6-deoxy-5-oxytetracycline (doxycycline) in mouse and rabbit.] Antibiotica 1970;8:161-178.
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 12 Czeizel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997;89:524-528.
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 13 Horne HW Jr,and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980;25:315-317.
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 14 Briggs GG, Freeman RK, and Yaffe SJ. Drugs in Pregnancy and Lactation. A reference guide to fetal and neonatal risk. 5th edition. Baltimore, MD:Williams & Wilkins; 1997: 1011-1013.
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 15 Personal communication - Allen Mitchell, MD, Slone Epidemiology Unit.
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 16 Cahen RL and Fave A. Absence of teratogenic effect of 6-alpha-deoxy-5 oxytetracycline. [Abstract] Fed Proc Fed Am Soc Exp Biol 1972;31:238.
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 17 Delahunt CS, Jacobs RT, Stebbins RB and Reiser N. Toxicology of vibramycin. [Abstract] Toxicol Appl Pharmacol 1967;10:402.
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 18 Kunelis CT, Peters JL, and Edmondson HA. Fatty liver of pregnancy and its relationship to tetracycline therapy. Am J Med 1965;38:359 - 377.
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 19 Wenk RE, Gebhardt FC, Bhagavan BS, Lustgarten JA, and McCarthy EF. Tetracycline-associated fatty liver of pregnancy, including possible pregnancy risk after chronic dermatologic use of tetracycline. J Reprod Med 1981;26:135-141.
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 20 Schultz JC, Adamson JS, Workman WW and Norman TD. Fatal liver disease after intravenous administration of tetracycline in high dosage. NEJM 1963;269(19):999-1004.
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