Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
Table 8. Summary of Pre-Clinical and Human Data on, and Indications for, Opportunistic Infection Drugs During Pregnancy
Last Updated: October 28, 2014; Last Reviewed: October 28, 2014
||Pertinent Animal Reproductive and Human Pregnancy Data||Recommended Use During Pregnancy
||B||No teratogenicity in mice, rats, rabbits at human levels. Large experience in pregnancy (>700 first-trimester exposures reported to registry); well-tolerated.
||Treatment of frequent or severe symptomatic herpes outbreaks or varicella
||C||No increase in malformations at 23 times (rats) and 40 times (rabbits) human dose. Limited experience with human use in pregnancy.
||Not recommended because of limited data in pregnancy. Report exposures during pregnancy to Antiretroviral Pregnancy Registry: http://www.APRegistry.com
||C||Embryotoxic and teratogenic (skeletal malformations) in rats and rabbits, but not in mice or cows. Limited experience in human pregnancy.
||Not recommended, especially in first trimester. Primary therapy for microsporidiosis in pregnancy should be ART.
||C||Not teratogenic in mice, rats, rabbits. Theoretical risk of ototoxicity in fetus; reported with streptomycin but not amikacin.
||Drug-resistant TB, severe MAC infections
|B||Not teratogenic in animals. Large experience in human pregnancy does not suggest an increase in adverse events.
||Susceptible bacterial infections
||B||Not teratogenic in animals or in human experience. Preferred over azole antifungals in first trimester if similar efficacy expected.
||Documented invasive fungal disease
|Antimonials, pentavalent (stibogluconate, meglumine)
||Not FDA approved
||Antimony not teratogenic in rats, chicks, sheep. Three cases reported of use in human pregnancy in second trimester with good outcome. Labeled as contraindicated in pregnancy.
||Therapy of visceral leishmaniasis not responsive to amphotericin B or pentamidine
|Artesunate, artemether, artemether/
|C||Embryotoxicity, cardiovascular and skeletal anomalies in rats and rabbits. Embryotoxic in monkeys. Human experience, primarily in the second and third trimesters, has not identified increased adverse events.
||Recommended by WHO as first-line therapy in second/third trimester for P. falciparum and severe malaria. Pending more data, use for malaria in first trimester only if other drugs not available or have failed. Report cases of exposure to WHO Anti-malarial Pregnancy Exposure Registry when available.
||C||Not teratogenic in rats or rabbits, limited human experience
||Alternate agent for PCP, Toxoplasma gondii, malaria infections
||B||Not teratogenic in animals. Moderate experience with use in human pregnancy does not suggest adverse events.
||Preferred agent for MAC prophylaxis or treatment (with ethambutol), Chlamydia trachomatis infection in pregnancy.
||B||Not teratogenic in rats, rabbits. Limited human experience, but other beta-lactam antibiotics have not been associated with adverse pregnancy outcomes.
||Susceptible bacterial infections
|Bedaquiline||B||Not teratogenic in rats, rabbits. No experience in human pregnancy.||Multidrug resistant TB when effective treatment regimen can not otherwise be provided.|
||Not FDA approved||No animal studies. Increase in chromosomal aberrations in children with treatment; uncertain significance. No human pregnancy data.
||Not indicated for chronic T. cruzi in pregnancy. Seek expert consultation if acute or symptomatic infection in pregnancy requiring treatment.
||B||Not teratogenic in rats, rabbits. No human pregnancy data.
||Treatment of HCV currently generally not indicated in pregnancy.
||C||Increase in skeletal variants in rats. Limited experience in human pregnancy; theoretical risk of fetal ototoxicity.
||C||Embryotoxic, skeletal defects in rats, rabbits. No experience with human use.
||Invasive Candida or Aspergillus infections refractory to amphotericin and azoles
||B||Not teratogenic in animals. Large experience in human pregnancy has not suggested increase in adverse outcomes.
||Bacterial infections; alternate treatment for MAC
||C||Associated with anophthalmia, micro-ophthalmia at fetotoxic doses in animals. Not associated with increased risk in human pregnancy at doses used for malaria.
||Drug of choice for malaria prophylaxis and treatment of sensitive species in pregnancy.
||C||Embryotoxic and teratogenic (meningocele, skeletal abnormalities) in rats and rabbits. No experience in human pregnancy.
|Ciprofloxacin, other quinolones
||C||Arthropathy in immature animals; not embryotoxic or teratogenic in mice, rats, rabbits, or monkeys. More than 1100 cases of quinolone use in human pregnancy have not been associated with arthropathy or birth defects.
||Severe MAC infections; multidrug resistant TB, anthrax, bacterial infections
||C||Cardiovascular defects noted in one strain of rats and cleft palate in mice at high doses, not teratogenic in rabbits or monkeys. Two human studies, each with >100 first-trimester exposures, did not show increase in defects but one study found an increase in spontaneous abortion.
||Treatment or secondary MAC prophylaxis, if other choices exhausted
||B||No concerns specific to pregnancy in animal or human studies.
||Treatment of anaerobic bacterial infections and used with quinine for chloroquine-resistant malaria; alternate agent for secondary prophylaxis of Toxoplasma encephalitis
||C||Not teratogenic in mice, rats, or rabbits. Limited experience reported (19 cases); no anomalies noted but red-brown skin discoloration reported in several infants exposed throughout pregnancy.
||C||Not teratogenic in animals at exposures expected from treatment of oral or vaginal Candida. No increase in adverse pregnancy outcomes with vaginal use.
||Oral or vaginal Candida infections and prophylaxis
||C||Not teratogenic in rats. No data available from human studies.
||C||No animal data. Limited human experience does not suggest teratogenicity; might displace bound bilirubin in the neonate, increasing the risk of kernicterus. Case reports of hemolytic anemia in fetus/infant with maternal treatment.
||Alternate choice for primary or secondary PCP prophylaxis
||C||Limited animal and human data do not indicate teratogenicity.
||Symptomatic treatment of diarrhea
|Doxycycline, other tetracyclines
||D||Risk of hepatic toxicity increased with tetracyclines in pregnancy; staining of fetal bones and teeth contraindicates use in pregnancy.
||B||No concerns in pregnancy from limited animal and human data.
||As part of fully suppressive combination antiretroviral regimen for treatment of HIV, HBV. Report exposures during pregnancy to Antiretroviral Pregnancy Registry: http://www.APRegistry.com.
||C||Animal data do not suggest teratogenicity at human doses; limited experience in human pregnancy.
||Not recommended because of limited data in pregnancy. Use as part of fully suppressive ARV regimen with ARV agents active against both HIV and HBV. Report exposures during pregnancy to Antiretroviral Pregnancy Registry: http://www.APRegistry.com.
||B||Hepatotoxicity with erythromycin estolate in pregnancy; other forms acceptable; no evidence of teratogenicity
||Bacterial and chlamydial infections
||B||Teratogenic, at high doses, in mice, rats, rabbits. No evidence of teratogenicity in 320 cases of human use for treatment of TB.
||Active TB and MAC treatment; avoid in first trimester if possible
||C||Increased rate of defects (omphalocele, exencephaly, cleft palate) in rats, mice, and rabbits with high doses; not seen with usual human doses. Limited human data; case reports of CNS defects.
||Active TB; avoid in first trimester if possible
||B||No evidence of teratogenicity in rats or rabbits, limited human experience.
||Recurrent genital herpes and primary varicella infection. Report exposures during pregnancy to the Famvir Pregnancy Registry (1-888-669-6682).
||C||Abnormal ossification, structural defects in rats, mice at high doses. Case reports of rare pattern of craniofacial, skeletal and other abnormalities in five infants born to four women with prolonged exposure during pregnancy; no increase in defects seen in several series after single dose treatment.
||Single dose may be used for treatment of vaginal Candida though topical therapy preferred. Not recommended for prophylaxis during early pregnancy. Can be used for invasive fungal infections after first trimester; amphotericin B preferred in first trimester if similar efficacy expected.
||C||Facial clefts and skeletal defects in rats; cleft palate in mice, no defects in rabbits. No reports of use in first trimester of human pregnancy; may be metabolized to 5-fluorouracil, which is teratogenic in animals and possibly in humans.
||Use after first trimester if indicated for life-threatening fungal infections.
||C||Skeletal variants in rats, rabbits and hypoplastic dental enamel in rats. Single case report of use in human pregnancy in third trimester.
||Alternate agent for treatment or secondary prophylaxis of life-threatening or sight-threatening CMV infection.
||Not FDA approved||Caused complete litter destruction or growth retardation in rats, depending on when administered. No data in human pregnancy.
||Topical solution can be used for ocular microsporidial infections.
||C||Embryotoxic in rabbits and mice; teratogenic in rabbits (cleft palate, anophthalmia, aplastic kidney and pancreas, hydrocephalus). Case reports of safe use in human pregnancy after transplants, treatment of fetal CMV.
||Treatment or secondary prophylaxis of life-threatening or sight-threatening CMV infection. Preferred agent for therapy in children.
||C/B||Not teratogenic in animals; limited human experience.
||Serious bacterial infections
||B||Not teratogenic in rats and rabbits; 8 case reports of human use, only 2 in first trimester.
||Because of limited experience, other treatment modalities such as cryotherapy or trichloracetic acid recommended for wart treatment during pregnancy.
||C||Not teratogenic. Live vaccines, including intranasal influenza vaccine, are contraindicated in pregnancy.
||All pregnant women should receive injectable influenza vaccine because of the increased risk of complications of influenza during pregnancy. Ideally, HIV-infected women should be on ART before vaccination to limit potential increases in HIV RNA levels with immunization.
(alfa, beta, gamma)
|C||Abortifacient at high doses in monkeys, mice; not teratogenic in monkeys, mice, rats, or rabbits. Approximately 30 cases of use of interferon-alfa in pregnancy reported; 14 in first trimester without increase in anomalies; possible increased risk of intrauterine growth retardation.
||Not indicated. Treatment of HCV currently generally not recommended in pregnancy.
||C||Not teratogenic in animals. Possible increased risk of hepatotoxicity during pregnancy; prophylactic pyridoxine, 50 mg/day, should be given to prevent maternal and fetal neurotoxicity.
||Active TB; prophylaxis for exposure or skin test conversion
||C||Teratogenic in rats and mice at high doses. Case reports of craniofacial, skeletal abnormalities in humans with prolonged fluconazole exposure during pregnancy; no increase in defect rate noted among over 300 infants born after first-trimester itraconazole exposure.
||Only for documented systemic fungal disease, not prophylaxis. Consider using amphotericin B in first trimester if similar efficacy expected.
||D||Associated with club feet in mice, inner ear changes in multiple species. Hearing loss in 2.3% of 391 children after long-term in utero therapy.
||C||Teratogenic in rats, increased fetal death in mice, rabbits. Inhibits androgen and corticosteroid synthesis; may impact fetal male genital development; case reports of craniofacial, skeletal abnormalities in humans with prolonged fluconazole exposure during pregnancy.
||C||Not teratogenic in animals. No evidence of teratogenicity with >3700 first-trimester exposures reported to Antiretroviral Pregnancy Registry.
||HIV and HBV therapy, only as part of a fully suppressive combination ARV regimen. Report exposures to Antiretroviral Pregnancy Registry: http://www.APRegistry.com.
|Ledipasvir/sofosbuvir||B||No evidence of teratogenicity in rats or rabbits. No experience in human pregnancy.
||Treatment of hepatitis C generally not indicated in pregnancy.|
|C||Prevents birth defects of valproic acid, methotrexate, phenytoin, aminopterin in animal models. No evidence of harm in human pregnancies.
||Use with pyrimethamine if use of pyrimethamine cannot be avoided.
||C||Not teratogenic in animals. Decreased fetal weight and neonatal survival at ~ human exposures, possibly related to maternal toxicity. Limited human experience.
||Serious bacterial infections
||B||Not teratogenic in animals. No increase in birth defects among infants born to 89 women with first-trimester exposure in one study; another study suggests a possible increased risk of hypospadias with first-trimester exposure, but confirmation required.
||Symptomatic treatment of diarrhea after the first trimester
||C||Animal data and human data do not suggest an increased risk of birth defects, but miscarriage and stillbirth may be increased.
||Second-line therapy of chloroquine-resistant malaria in pregnancy, if quinine/clindamycin not available or not tolerated. Weekly as prophylaxis in areas with chloroquine-resistant malaria.
||Not FDA approved||See Antimonials, pentavalent
||B||Multiple studies do not indicate teratogenicity. Studies on several hundred women with first-trimester exposure found no increase in birth defects.
||Anaerobic bacterial infections, bacterial vaginosis, trichomoniasis, giardiasis, amebiasis
||C||Teratogenic in rabbits; no human experience.
||Not FDA approved||Embryotoxic in rats, rabbits; teratogenic in rats. No experience with human use.
||Not FDA approved||Not teratogenic in mice and rats. Increased chromosomal aberrations in children receiving treatment; uncertain significance. No experience in human pregnancy.
||Not indicated in chronic infection; seek expert consultation if acute infection or symptomatic reactivation of T. cruzi in pregnancy.
||B||Not teratogenic in animals; no human data
||Severely symptomatic cryptosporidiosis after the first trimester
|Para-amino salicylic acid
|C||Occipital bone defects in one study in rats; not teratogenic in rabbits. Possible increase in limb, ear anomalies in one study with 143 first-trimester exposures; no specific pattern of defects noted, several studies did not find increased risk.
||C||Not teratogenic in mice and rabbits. Limited human experience, but poor oral absorption makes toxicity, teratogenicity unlikely.
||Amebic intestinal infections, possibly cryptosporidiosis
||B||Not teratogenic in multiple animal species. Vast experience with use in human pregnancy does not suggest teratogenicity, other adverse outcomes.
||Syphilis, other susceptible bacterial infections
||C||Embryocidal but not teratogenic in rats, rabbits with systemic use. Limited experience with systemic use in pregnancy.
||Alternate therapy for PCP and leishmaniasis.
||B||Not teratogenic in limited animal studies. Limited experience in pregnancy but penicillins generally considered safe.
||C||No studies in animal pregnancy. Polysaccharide vaccines generally considered safe in pregnancy. Well-tolerated in third-trimester studies.
||Initial or booster dose for prevention of invasive pneumococcal infections. HIV-infected pregnant women should be on ART before vaccination to limit potential increases in HIV RNA levels with immunization.
||C||Increased embryonic and fetal deaths in rats, mice but not teratogenic. Case reports of maternal, fetal deaths after use of podophyllin resin in pregnancy; no clear increase in birth defects with first-trimester exposure.
||Because alternative treatments for genital warts in pregnancy are available, use not recommended; inadvertent use in early pregnancy is not indication for abortion.
||C||Embryotoxic in rabbits; teratogenic in rats at similar to human exposures. No experience in human pregnancy.
||B||Dose-dependent increased risk of cleft palate in mice, rabbits, hamsters; dose-dependent increase in genital anomalies in mice. Human data inconsistent regarding increased risk of cleft palate. Risk of growth retardation, low birth weight may be increased with chronic use; monitor for hyperglycemia with use in third trimester.
||Adjunctive therapy for severe PCP; multiple other non-HIV-related indications
||C||No animal data. Limited experience with use in human pregnancy; theoretical risk for hemolytic anemia if fetus has G6PD deficiency.
||Alternate therapy for PCP, chloroquine-resistant malaria
||C||Not teratogenic in animals. Widely used in malaria-endemic areas with no clear increase in adverse outcomes.
||Alternate therapy and prophylaxis of P. falciparum malaria
||C||Not teratogenic in rats, mice. Limited experience with use in human pregnancy.
||C||Teratogenic in mice, rats, hamsters (cleft palate, neural tube defects, and limb anomalies). Limited human data have not suggested an increased risk of birth defects; because folate antagonist, use with leucovorin.
||Treatment and secondary prophylaxis of toxoplasmic encephalitis; alternate treatment of PCP
||C||Generally considered safe in pregnancy; high doses associated with preterm labor. One case of fetal 8th nerve damage reported.
||Alternate treatment of malaria, control of fetal arrhythmias
||C||High doses, often taken as an abortifacient, have been associated with birth defects, especially deafness, in humans and animals. Therapeutic doses have not been associated with an increased risk of defects in humans or animals. Monitor for hypoglycemia.
||Treatment of chloroquine-resistant malaria
||X||Dose-dependent risk of multiple defects (craniofacial, central nervous system, skeletal, anophthalmia) in rats, mice, hamsters starting at below human doses. Reports of treatment during second half of pregnancy in nine women without incident; first 49 cases in registry did not suggest increased risk, but limited data.
||Contraindicated in early pregnancy; no clear indications in pregnancy. Report exposures during pregnancy to Ribavirin Pregnancy Registry at (800) 593-2214 or www.ribavirinpregnancyregistry.com
||B||Not teratogenic in rats and rabbits; no specific concerns for human pregnancy.
||Treatment or prophylaxis of MAC, active TB
||C||Teratogenic at high doses in mice (cleft palate) and rats (spina bifida) but not in rabbits. No clear teratogenicity in humans.
|Simeprevir||C||Decreased fetal weights and increased skeletal variants in mice at 4x human exposure. Increased deaths and decreased fetal and neonatal growth and developmental delay after in utero exposure in rats. No experience in human pregnancy.||Treatment of HCV currently generally not recommended in pregnancy.|
|Sinecatechin ointment||C||No evidence of teratogenicity in rats and rabbits after oral or intravaginal dosing. No experience in human pregnancy.||Not recommended based on lack of data.|
|Sofosbuvir||B||No evidence of teratogenicity in rats or rabbits. No experience in human pregnancy.||Treatment of HCV generally not indicated in pregnancy. Regimens including ribavirin and interferon are contraindicated in pregnancy.|
||D||No teratogenicity in mice, rats, guinea pigs. Possible increased risk of deafness and VIII nerve damage; no evidence of other defects.
||Alternate therapy for active TB
||B||Sulfonamides teratogenic in some animal studies. No clear teratogenicity in humans; potential for increased jaundice, kernicterus if used near delivery.
||Secondary prophylaxis of toxoplasmic encephalitis
||B||Not teratogenic in mice, rats. No human pregnancy data.
||Treatment of HCV currently generally not indicated in pregnancy.
||B||Not teratogenic in rats, rabbits. Limited experience in human pregnancy.
||Not recommended because of limited data in pregnancy. Use as part of fully suppressive antiretroviral regimen with antiretroviral agents active against both HIV and hepatitis B. Report exposures during pregnancy to Antiretroviral Pregnancy Registry: http://www.APRegistry.com.
||B||No evidence of birth defects in rats, rabbits, or monkeys at high doses; chronic administration in immature animals of multiple species at 6–50 times human doses has led to dose-specific bone changes ranging from decreased mineral density to severe osteomalacia and fractures. Clinical studies in humans (particularly children) show bone demineralization with chronic use; clinical significance unknown. No evidence of increased birth defects in nearly 2000 first-trimester exposures in women.
||Component of fully suppressive antiretroviral regimen in pregnant women. Report exposures during pregnancy to Antiretroviral Pregnancy Registry: http://www.APRegistry.com.
|Trichloracetic acid, bichloracetic acid
||Not rated||No studies. Used topically so no systemic absorption expected.
||Topical therapy of non-cervical genital warts
||C||Not teratogenic in rats, rabbits. Minimal systemic absorption expected with topical ocular use.
||Topical agent for treatment of ocular herpes infections
||C||Teratogenic in rats and mice. Possible increase in congenital cardiac defects, facial clefts, neural tube and urinary defects with first-trimester use. Unclear if higher levels of folate supplementation lower risk. Theoretical risk of elevated bilirubin in the neonate if used near delivery.
||Therapy of PCP during pregnancy. Primary and secondary PCP prophylaxis in the second/third trimester; consider aerosolized pentamidine in first trimester. Recommend fetal ultrasound at 18–20 weeks after first-trimester exposure.
||B||Not teratogenic in mice, rats, and rabbits. Experience with valacyclovir in pregnancy limited; prodrug of acyclovir, which is considered safe for use in pregnancy.
||Treatment of HSV and varicella infections in pregnancy
||C||Not teratogenic in rats, rabbits. Limited human experience.
||Serious bacterial infections
||D||Embryotoxic in rats, rabbits. Teratogenic in rats (cleft palate, hydronephrosis, and ossification defects). No experience with human use.
|Key to Acronyms: ART = antiretroviral therapy; ARV = antiretroviral; CMV = cytomegalovirus; CNS = central nervous system; FDA = Food and Drug Administration; G6PD = Glucose-6-phosphate dehydrogenase; HBV = hepatitis B virus; HCV = hepatitis C virus; HSV = herpes simplex virus; MAC = Mycobacterium avium complex; PCP = Pneumocystis pneumonia; TB = tuberculosis; VIII nerve = vestibulocochlear nerve; WHO = World Health Organization|