Anti-infective Drug Use in Obstetrics – Part III
Author: Gerald G. Briggs, B.Pharm.
Objectives: Upon the completion of this CNE article, the reader will be able to:
- Describe the potential concerns of using certain anti-helminthic drugs and anti-fungal agents during pregnancy or lactation.
- Discuss the potential concerns of using pentamidine during pregnancy or lactation.
- Describe the potential concerns of using the various anti-tuberculosis drugs during pregnancy or lactation.
This article is a continuation of Parts I & II. Again, for each drug that is discussed, the pregnancy risk factor category (as defined by the Food and Drug Administration) is shown in parentheses. To allow for easy reference as these drugs are discussed the categories are as follows:
Category A: Controlled studies in women fail to demonstrate a risk to the fetus and animal studies (if performed) also show no risk and thus, the possibility of fetal harm appears to be remote.
Category B: Either – No controlled studies in women have been done, but animal studies show no harm OR animal studies suggest a potential for harm, but controlled studies in women do not show harm.
Category C: Either – studies in animals suggest a potential for harm, and controlled studies in women have not been done OR no animal studies or human studies have been done – The potential benefit from use should exceed the potential for risk.
Category D: There is positive evidence that human fetal risk exists; however, the benefits of use may still outweigh the risk (for example, some anti-convulsive drugs).
Category X: There is positive evidence that human fetal risk exists and this risk clearly outweighs any potential benefit from using the drug. Thus the drug is contraindicated.
As stated in Parts I and II, the majority of drugs are classified as category C because
of the overall lack of studies in pregnant women.
V. Anti-helminthic Drugs
A. Albendazole (C)
This broad-spectrum anti-infective is a member of the benzimidazole class of anti-helminthic drugs. Albendazole is embryo and fetal toxic and teratogenic in rats and rabbits, but not mice, at doses less than the recommended human dose based on body surface area. Studies have not been conducted on placental transfer, but the low molecular of the drug suggests that it will cross the placenta. In humans, however, the oral bioavailability is only 1%, compared to 20% to 30% in rats. Only 61 cases, 10 in the first trimester, of human pregnancy exposure have been reported. Normal outcomes were observed in all of these pregnancies. However, because of the limb reduction defects observed with all doses in one animal study, and the potential for much greater oral bioavailability of the metabolite if consumed with a fatty meal, the use of albendazole during human pregnancy should be avoided if possible, especially during the first trimester. The use of this anti-helminthic drug has not been reported in breast-feeding women. The potential effects of exposure on a nursing infant are unknown.
B. Ivermectin (C)
Ivermectin is teratogenic in mice, rats, and rabbits at doses below or slightly above the recommended human dose on a body surface area basis. These doses, however, would be maternal toxic so the agent does not appear to be selectively fetal toxic. It is not known if ivermectin crosses the human placenta. Inadvertent use of ivermectin in pregnant women (207 cases with 97 in early gestation) during a mass treatment campaign for onchocerciasis was not associated with an increase in abortion or birth defects. Because of the high risk for blindness from onchocerciasis (a nematode or roundworm), one review concluded that the agent could be given after the first trimester. Low levels of ivermectin are excreted into human breast milk, but the four women tested were not breast-feeding. The effects on a nursing infant from exposure to this agent are unknown.
C. Mebendazole (C)
Mebendazole is a broad-spectrum anti-helminthic drug that is used for treating pinworms, roundworms and hookworms. It was found to be teratogenic in rats after a single oral dose that was approximately equal to the human dose based on body surface area. Teratogenicity, however, was not observed in multiple other animal species. In addition, the drug has very poor human systemic bioavailability, and this would limit placental transfer. More than 5,000 cases of human pregnancy exposure have been described in the literature. No association with abortion or birth defects has been reported. In fact, in one large study the use of mebendazole during the second trimester for hookworm infections lowered the incidence of stillbirths and perinatal deaths compared to controls (1.9% vs. 3.3%, p = 0.0004) and low birthweights compared to controls (1.1% vs. 2.3%, p = 0.0003). Due to the poor oral absorption (only 2% to 10%) of mebendazole, the agent is not excreted into breast milk in detectable amounts. Consequently, adverse effects in the nursing infant would not be expected.
D. Praziquantel (B)
Reproduction studies in mice, rats, and rabbits with praziquantel revealed no evidence of impaired fertility or teratogenicity, but an increase in the abortion rate in rats was observed at a dose about 3 times the human dose. The drug is rapidly and nearly completely absorbed following oral administration, but placental transfer studies have not been conducted. Although praziquantel has been rated a B, only one report of human exposure during pregnancy has been published. Therefore, it is not possible to assess the fetal risk from this agent. Moreover, because of the potential for mutagenic and carcinogenic effects in humans, praziquantel should be reserved for those cases in which cestodes (tapeworms) or trematodes (flukes) are causing clinical illness or public health problems. Breast milk levels of praziquantel are about 25% of the maternal serum level. No reports describing the use of this agent during lactation have been published. The manufacturer recommends holding breast-feeding on the day of treatment and for 72 hours after a dose because of the potential for toxicity in the nursing infant.
E. Pyrantel Pamoate(C)
Pyrantel pamoate is an anti-helminthic drug that can be used for treating pinworms, roundworms and hookworms. The drug was not found to be teratogenic in rats and rabbits, but no reports describing its use in human pregnancy have been published. The oral form of the drug is poorly absorbed from the gastrointestinal tract, similar to mebendazole. Because of this, the effect on a nursing infant whose mother is using the drug would probably be minimal, however, this drug has not been studied during lactation.
F. Thiabendazole (C)
Thiabendazole was not teratogenic in mice, rats, and rabbits at doses near the human dose. However, when the drug was suspended in olive oil, cleft palate and skeletal defects were observed in offspring of mice. It is not known if thiabendazole crosses the human placenta. Human pregnancy experience is very limited; none have occurred during the first trimester, and no reports of teratogenicity have been published. It is not known if thiabendazole is excreted into breast milk.
VI. Anti-Fungal Agents
A. Amphotericin B (B)
Amphotericin B was not associated with fetal harm in pregnant rats and rabbits, and a substantial body of reports indicates that there is no evidence of adverse fetal effects in human pregnancy. The agent, however, readily crosses the human placenta. There are no reports of its use during breast-feeding.
B. Caspofungin (C)
The use of this anti-fungal drug has not been reported during human pregnancy. Animal reproduction studies have shown it to be embryo toxic in rats and rabbits at systemic exposures equivalent to those used in humans. Caspofungin crossed the placentas of both animals, but human studies have not been published. Due to the lack of data, the use of caspofungin is not recommended, especially in the first trimester.
C. Fluconazole (C)
This synthetic triazole anti-fungal agent causes teratogenicity and toxicity in the embryos of pregnant rats. The effects were thought to be consistent with inhibition of estrogen synthesis. It is not known if fluconazole crosses the human placenta, but its low molecular weight suggests that transfer should be expected. One case report of use during human pregnancy suggested that fluconazole might be a human teratogen at doses of 400 mg/day or more. The anomalies reported in the infant involved the head, face, skeleton, and the heart. The malformations resembled those observed in the Antley-Bixler syndrome, which is an autosomal recessive genetic disorder. However, because some of the anomalies were similar to those seen in the fetal rats, a causal relationship could not be excluded. Lower doses have not been associated with adverse fetal outcomes.
Fluconazole is excreted in low amounts into human breast milk. No adverse effects in exposed nursing infants have been reported. Moreover, much higher doses, than those obtained from breast milk, have been given to newborns without causing toxicity.
D. Flucytosine (C)
Flucytosine is metabolized by fungus to 5-fluorouracil, an anti-neoplastic drug that is a possible human teratogen. The agent is teratogenic in mice and rats, but not in rabbits. Placental transfer in humans has not been studied. Human pregnancy experience is limited to three case reports, all after the first trimester. Although no adverse effects were reported, the data are too limited to make an assessment of the human fetal risk. However, the agent should probably be avoided in the first trimester, if at all possible. Breast-feeding is not recommended because of the potential for serious adverse effects from exposure to the metabolite, 5-fluorouracil.
E. Griseofulvin (C)
The anti-fungal antibiotic, griseofulvin, is embryo toxic and teratogenic in mice and rats. The agent crosses the human placenta at term. There was an initial report that griseofulvin might promote the development of conjoined twins. However, several reports since that time have not confirmed this finding. The safest course, however, is to avoid griseofulvin during pregnancy because its use is seldom essential. Due to a lack of reports on the use of griseofulvin during lactation and the potential for toxicity, the agent should be avoided if the mother is breast-feeding.
F. Itraconazole (C)
Itraconazole is a triazole anti-fungal drug in the same class as fluconazole. It causes dose-related embryo toxicity and teratogenicity in mice and rats. Human placental transfer has not been studied, but some degree of fetal exposure should be expected. Although the data are limited, no reports attributing human malformations to itraconazole have been published. However, because of the possibility for teratogenicity with high-dose fluconazole, the use of itraconazole during organogenesis (the first trimester) is not recommended. Itraconazole is excreted into human breast milk and widespread tissue accumulation in a nursing infant may occur with continuous daily dosing. The potential infant toxicity of this exposure has not been studied, but women taking this anti-fungal drug should probably not breast-feed.
G. Ketoconazole (C)
Ketoconazole inhibits the production of certain steroid compounds in fungal cells. It is embryo toxic and teratogenic (syndactyly and oligodactyly) in rats. It is not known if ketoconazole crosses the human placenta, but fetal exposure should be expected. In humans, use during the first trimester for vaginal candidiasis has not been associated with adverse fetal outcomes. Ketoconazole has also been used in high doses (600 mg/day for 5 weeks) for the treatment of hypercortisolism in one case in the third trimester. A normal infant was delivered. The agent is probably excreted into breast milk, but no reports of its use during this period have been located.
H. Nystatin (C)
Nystatin is poorly absorbed after oral administration. It has not undergone animal reproductive testing. Human data, limited to two large surveillance studies, have found no support for an association with congenital malformations or other adverse outcomes.
I. Terbinafine (B)
No reports describing the use of terbinafine during human pregnancy have been published. Placental transfer has not been studied. In animal reproduction studies, no evidence of impaired fertility or fetal harm was found in pregnant rats and rabbits. Thus, the manufacturer classified it as a pregnancy risk category B drug. However, there is a lack of human pregnancy experience, which prevents an assessment of the fetal risk for this anti-fungal agent.
VII. Anti-Protozoal Drugs
A. Atovaquone (C)
(see Anti-Malarial Drugs in Part II)
B. Pentamidine (C)
Pentamidine is used for the treatment of pneumonia caused by Pneumocystis Carinii, a protozoa commonly seen in patients infected with HIV. In rat reproduction studies with doses close to those used in humans, pentamidine was not teratogenic, but was embryo toxic. Small amounts of the agent cross the human placenta. Limited human pregnancy experience (that involved both the aerosolized and intravenous forms of the drug) has been reported in all stages of gestation. In some of these cases, adverse effects occurred in the newborn (including growth retardation, albinism, and congenital cytomegalovirus infection), but these problems were probably related to the medical disorder that the mother was being treated for and thus, the relationship to the drug is unknown. The CDC and some manufacturers, however, have advised against using the drug in pregnancy because of the overall lack of information in human pregnancy. Reports describing the use of pentamidine during lactation have not been published.
VIII. Anti-Tuberculosis Agents
A. para-Aminosalicylic Acid (C)
No reports in animals or in humans have associated the use of this anti-tuberculosis agent with fetal harm. The drug is bacteriostatic and is usually used in combination with other agents for the treatment of multi-drug resistant tuberculosis. Although not studied, the low molecular weight of the agent suggests that it will cross the human placenta. Small amounts are excreted into human breast milk.
B. Capreomycin (C)
This injectable polypeptide antibiotic is a mixture of four active components. The oral absorption is very poor (<1%). The injectable form of capreomycin was found to be embryo toxic and did produce "wavy ribs" in rats at a dose 3.5 times the human dose. No reports of human pregnancy experience have been published. Several reviewers state that the drug should be avoided in pregnancy because of a risk for ototoxicity and deafness. Although excretion into human breast milk has not been studied, the very poor oral absorption suggests that the potential for toxicity in a nursing infant would be remote.
C. Cycloserine (C)
Cycloserine is a broad-spectrum antibiotic. It was not teratogenic in pregnant rats. Cycloserine has been shown to cross the placenta to the fetus. Reported human pregnancy experience is very limited (three cases). Because of this, it is not recommended for use in human pregnancy. Very small amounts are excreted into human breast milk. No adverse effects in infants have been reported. The American Academy of Pediatrics (AAP) classifies the drug as compatible with breast-feeding.
D. Ethambutol (B)
Ethambutol appears to be safe to use during pregnancy. The agent crosses the placenta resulting in therapeutic concentrations in the fetus and amniotic fluid. Most reviewers consider ethambutol, isoniazid, and rifampin to be the safest anti-tuberculosis agents for use in pregnancy. Reproduction studies in animals, however, have not been conducted. Ethambutol is excreted into human breast milk. The AAP considers the agent to be compatible with breast-feeding.
E. Ethionamide (C)
Ethionamide is teratogenic in mice, rats, and rabbits. The relatively low molecular weight suggests that it would cross the placenta to the fetus, but this has not been studied to date. There is limited human pregnancy experience, but one report found an increased incidence of birth defects. In that report, however, two of the seven cases of defects were Down Syndrome, a known chromosomal abnormality, and therefore not caused by the drug. The other reports found no association with congenital malformations. Although a causal relationship to birth defects seems unlikely, the data are too limited to fully assess the risk. No studies have reported the use of ethionamide in human breast milk and the risk to a nursing infant is unknown.
F. Isoniazid (C)
Isoniazid is frequently used during human pregnancy for the prevention and treatment of pulmonary tuberculosis. The drug does have a metabolite that is hepatotoxic in some individuals. Isoniazid was not found to be teratogenic in mice, rats, and rabbits, but was embryo toxic in the latter two species. Isoniazid crosses the human placenta resulting in fetal concentrations similar to maternal serum concentrations. From extensive human pregnancy experience, however, isoniazid appears to be safe and effective. It is considered the drug of choice for tuberculosis infection in a pregnant woman. Moreover, the American Thoracic Society states that untreated tuberculosis is a much greater risk to the fetus than the treatment of the disease. Both isoniazid and its hepatotoxic metabolite are excreted into breast milk. No reports of adverse effects in the nursing infant have been published, but a potential for interference with nucleic acid function and for hepatotoxicity exists. The AAP classifies isoniazid as compatible with breast-feeding.
G. Pyrazinamide (C)
Animal reproduction tests have not been conducted with this synthetic derivative of niacinamide. The very low molecular weight of pyrazinamide suggests that it crosses the human placenta. Only a single case report has noted the use of this drug in pregnancy. Although no adverse effects were mentioned, the lack of other reports prevents an assessment of the fetal risk. Pyrazinamide is excreted into breast milk. The effects of exposure on a nursing infant from the drug are unknown.
H. Rifampin (C)
Dose-related teratogenicity in mice (spina bifida and cleft palate), in rats (spina bifida), but not in rabbits, have been observed with rifampin. Rifampin crosses the human placenta to the fetus. Although birth defects have been reported in pregnant women exposed to rifampin, other reports have not found an association with malformations. Further, most reviewers have concluded that rifampin was not a proven teratogen and recommended the agent be used in pregnancy if necessary. Rifampin, however, has been implicated as an agent capable of causing hemorrhagic disease of the newborn. Prophylactic vitamin K1 (phytonadione) should be given to the newborn. No reports of adverse effects have been described in nursing infants exposed to the small amounts of rifampin excreted into breast milk. The AAP classifies the drug as compatible with breast-feeding.
I. Rifapentine (C)
Rifapentine is indicated for the treatment of pulmonary tuberculosis. The agent is teratogenic in rats (cleft palate, aortic arch defect, delayed ossification, and increased number of ribs) and rabbits (ovarian agenesis, pes varus – inward angulation of the feet, arhinia – absent nose, microphthalmia – small eyes, and other facial defects) at doses less than the recommended human dose. Rifapentine also caused embryo toxicity in rats (abortion, stillbirth, and retarded growth). It is not known if rifapentine crosses the human placenta, but the molecular weight suggests that some degree of transfer will occur. Reported use in pregnancy is limited to six cases: two spontaneous abortions (one in a woman abusing alcohol and the other in an HIV-infected patient), one elective abortion, one lost to follow up, and two normal infants. Hemorrhagic disease of the newborn may occur when rifapentine is used in the last few weeks of pregnancy. As with rifampin, vitamin K1 should be given to the newborn soon after birth. No information is available on the excretion of rifapentine into human breast milk or on the potential for toxicity in a nursing infant.
J. Streptomycin (D)
(see Aminoglycoside section in Part I)
References or Suggested Reading:
- Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 6th ed. Philadelphia:Lippincott Williams and Wilkins, 2001.
- Schardein JL. Chemically Induced Birth Defects. 3rd ed. New York:Marcel Dekker, 2000.
- Rama Sastry BV. Techniques to study human placental transport. Adv Drug Deliver Sys 1999;38:17-39.
- American College of Obstetricians and Gynecologists. Antimicrobial therapy for obstetric patients. ACOG Educational Bulletin. Number 245, March 1998.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.
- Mantovani A, Ricciardi C, Stazi AV, et al. Effects observed on gestational day 13 in rat embryos exposed to albendazole. Reprod Toxicol 1995;9:265-73.
- Product information. Stromectol. Merck, 2002.
- Chippaux JP, Gardon-Wendel N, Gardon J, et al. Absence of any adverse effect of inadvertent ivermectin treatment during pregnancy. Trans R Soc Trop Med Hyg 1993;87:318.
- de Silva N, Guyatt H, Bundy D. Anthelmintics. A comparative review of their clinical pharmacology. Drugs 1997;53:769-88.
- Ogbuokiri JE, Ozumba BC, Okonkwo PO. Ivermectin levels in human breast milk. Eur J Clin Pharmacol 1994;46:89-90.
- de Silva NR, Sirisena JLGJ, Gunasekera DPS, et al. Effect of mebendazole therapy during pregnancy on birth outcome. Lancet 1999;353:1145-9.
- Product information. Cancidas. (Caspofungin) Merck, 2002.
- Holdiness MR. Transplacental pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1987;13:125-9.
- Product information. Priftin. Aventis, 2002.
Gerald G. Briggs is a Pharmacist Clinical Specialist in the Perinatal Center of Women's Hospital, Long Beach Memorial Medical Center in Long Beach, California. He is also a Clinical Professor of Pharmacy for the University of California, San Francisco and an Adjunct Associate Clinical Professor of Pharmacy at the University of Southern California, Los Angeles.
He is the primary author of the textbook entitled Drugs in Pregnancy and Lactation, currently in its 6th Edition, copyright 2001, Lippincott, Williams, and Wilkins, Philadelphia, Pennsylvania. He also has several publications in peer-review medical journals and has lectured at many institutions across the United States and Canada regarding the use of drugs in pregnancy and lactation.