Subject: http://www.fda.gov/cder/drug/infopage/penG_doxy/doxypreg.htm
Doxycycline Use by Pregnant and Lactating Women
Doxycycline is approved for the treatment of anthrax. 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
considered. 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 involvement.
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 risk. 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 unknown.
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 pregnancy, 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 related.
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 discontinued.
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 doxycycline.
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 bias.
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 age.
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).
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 defects.
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 doxycycline.
Another study found no teratogenicity with doxycycline exposure in rats,
rabbits, or monkeys.
Maternal Liver Toxicity
While there are no published reports with doxycycline use, tetracycline use
has been associated with fatty liver of pregnancy,. This rare but often
fatal disorder has been reported to follow high dose intravenous
tetracycline use to treat pyelonephritis.
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
Forwarded by:
Frank J. Nice, DPA, CPHP
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