Copyright ©The Author(s) 2021.
World J Hepatol. Jul 27, 2021; 13(7): 747-762
Published online Jul 27, 2021. doi: 10.4254/wjh.v13.i7.747
Table 1 Data available from case reports regarding drug-induced liver injury in pregnant women
Suspect drug
Pathological finding(s)
Outcome in mother
Outcome in child
Azithromycin[78]Intrahepatic cholestasisRecovery without sequelaeBirth by caesarean section
ChlorpromazineSevere reduction in the number of bile ducts; marked cholestasis and pseudoxanthomatous transformation of ductular epithelia and hepatocytes in the region of the limiting plate; progressed to cirrhosis[85]; Ductopenia, long-standing cholestasis with pseudoxanthomatous transformation of hepatocytes and ductular epithelia[84]Prolonged liver disease culminating in vanishing bile duct syndrome and cirrhosis[85]; Gradual resolution with non-active periportal and septal fibrosis[84]Premature birth by cesarean section[84,85]
Combination antiretroviral therapyFulminant hepatitis[105]Recovery without sequelae[70,105]; death[105]Nonreassuring fetal testing; improved following drug withdrawal; normal delivery[70]
Human chorionic gonadotropin and follicle stimulating hormone for in vitro fertilization[87]CholestasisRecovery without sequelaePremature birth by cesarean section
MethyldopaCytolytic hepatitis and cholestasis, toxic hepatitis[106]; hepatitis[73,74,107,108]Improved following drug withdrawal[72-74]-
Nitrofurantoin[109]Toxic liver damageRecovery without sequelaeNormal
ParacetamolAcute fatty liver of pregnancy and toxin-induced injury[43]; fulminant hepatitis[45]Liver transplantation[43,45]Fetal death[43]; intrauterine fetal demise with extensive pericerebral and intraventricular hemorrhage with extensive periventricular leukomalacia[45]; intracranial hemorrhage, fetal hepatotoxicity[110]; preterm birth[111]
PropylthiouracilLiver necrosis[50,53,54,112]; widened portal triads, and lymphoplasmocytic infiltrate[50]; hepatitis[52]; portal hepatitis[112]; acute liver failure[55] Liver transplantation[53,55]; recovered[52,54]; death[50]Miscarriage[50,54]; Antenatal ischemic encephalopathy, delayed developmental milestones[53]; normal[52,55]; caesarian delivery[112]
Tetracycline[83]Fatty liverDeath-
Table 2 Studies other than case reports describing effect of drugs on maternal/fetal/neonatal liver function
Study design
Study population
Suspected medication (s)
Study outcome
Snijdewind et al[68]Retrospective, comparativePregnant womenAntiretroviral therapy and hepatitis C virus co-infectionNevirapine use related to hepatotoxicity in pregnant as well as non-pregnant women; the risk is significantly associated with hepatitis C coinfection during pregnancy
Beck-Friis et al[26]Retrospective, comparativePregnant vs non-pregnantAntitubercular drugSevere hepatotoxicity and temporary drug withdrawal more frequent in pregnant women compared to non-pregnant women
Mandelbrot et al[113]Retrospective, comparativePregnant womenAtazanavirThree women had abnormal liver enzyme levels; grade 3 bilirubin elevations in 5 patients; jaundice in 5 neonates requiring phototherapy.
Heaton et al[82]Retrospective, case-controlGeneral population including pregnant womenDoxycycline, tetracycline Doxycycline potentially less hepatotoxic than tetracycline
McCormack et al[114]Prospective, placebo-controlledPregnant womenErythromycin estolate, clindamycin hydrochloride, placeboErythromycin estolate resulted in raised liver enzymes; use not advised in pregnancy
Tempelman et al[115]Retrospective, comparativePregnant womenHighly active antiretroviral therapyNelfinavir or nevirapine containing regimens are safe and effective in pregnant women with HIV
Franks et al[77]RetrospectiveWomen with isoniazid hepatitisIsoniazidA 2.5-fold increased risk of isoniazid hepatitis and 4-fold higher mortality rate in the prenatal clinic group compared to non-pregnant women.
Gupta et al[116]Multicenter, double-blind, placebo-controlled, noninferiority trialWomen with HIV (efavirenz-based antiretroviral therapy) receiving isoniazid preventive therapy either during pregnancy or after deliveryIsoniazidRisk of composite adverse pregnancy outcome was greater in those who initiated isoniazid preventive therapy during pregnancy than those during postpartum period; majority of liver enzyme elevations and symptomatic hepatitis occurred in postpartum period.
Sato et al[117]Single-cohort interventionalPregnant women with choriocarcinoma and high-risk gestational trophoblastic neoplasiaMethotrexate, etoposide, actinomycin DOf the 23 patients who received methotrexate, etoposide and actinomycin D, treatment changed to etoposide and actinomycin D in 14 patients due to leukocytopenia, hepatotoxicity, and stomatitis.
Fang et al[118]Single-cohort, prospective, interventionalPregnant womenNelfinavirOf the 16 women studied, one developed serious adverse event of elevated AST; the drug was well tolerated in general.
Timmermans et al[59]Retrospective, comparativePregnant and non-pregnant womenNelfinavir, nevirapineNevirapine related hepatotoxicity more frequent in pregnant than in non-pregnant women.
Joy et al[119]Single-cohort, retrospective, observationalPregnancy women in third trimesterNevirapineIncidence of adverse events lower; study in larger cohorts recommended to determine the relationship between nevirapine hepatotoxicity and trimester use.
Natarajan et al[58]Retrospective, comparativePregnant womenNevirapineRisk of nevirapine-associated toxicity not higher in pregnancy; CD4 counts not predictive of toxicity.
Kondo et al[65] Retrospective, comparative studyPregnant womenNevirapineHepatotoxicity occurred in those with pre-treatment CD4 counts ≥ 250 cells/µL; no correlation between high CD4 counts and adverse events.
Phanuphak et al[66]Retrospective, comparativeGeneral population including pregnant womenNevirapinePregnant women with high CD4 counts have higher rate of symptomatic hepatotoxicity.
Kondo et al[67] Single-cohort, retrospective, observationalPregnant womenNevirapineNo correlation between high CD4 counts and adverse events; hepatotoxicity occurred only in pregnant women with CD4 counts > 250 cells/µL
Ouyang et al[120]Prospective, comparativePregnant womenNevirapineNo significant association between nevirapine use and liver enzyme elevation regardless of pregnancy status; pregnancy associated with increased hepatotoxicity.
Ouyang et al[27]Retrospective, comparativePregnant womenNevirapineNo increased risk of hepatotoxicity among HIV-infected pregnant women on nevirapine versus other drugs, including in those treatment naïve.
Peters et al[64] Prospective, comparativePregnant womenNevirapineSevere hepatotoxicity and rash higher with nevirapine than with nelfinavir; no association with CD4 counts.
Lyons et al[62]Single-cohort, retrospective, observationalPregnant womenCombination antiretroviral therapyWomen with more severe hepatotoxicity had higher pretreatment CD4 counts.
Jamisse et al[63]Single-cohort, prospective, observationalPregnant womenNevirapine-containing combination antiretroviral therapySevere hepatotoxicity more common at higher CD4 counts in pregnancy.
Sheng et al[121] Prospective, comparativePregnant women with high viral loads of hepatitis B virusNucleos(t)ide analoguesTelbivudine therapy was safe in pregnant women.
Zhang et al[122]Disproportionality analysisPregnant womenOmeprazole, lansoprazole, amoxicillinThe risk of cholestasis associated with these drugs higher in pregnant women; re-assessment of safety recommended.
Cecchi et al[88] Single-cohort, prospective, observationalPregnant womenOrganophosphate pesticidesSubclinical hepatotoxicity during the second trimester in spraying period.
Trakulsrichaia et al[123]Single-cohort, retrospective, observationalPregnant womenParaquat poisoningHepatotoxicity more common in patients who died.
Andersen et al[57]Single-cohort, observationalGeneral population including pregnant womenAntithyroid drugsAntithyroid drug-associated liver failure observed less frequently in pregnant women than in the general population.
Brunet et al[124]Single-cohort, prospective, observationalPregnant womenSaquinavir/ritonavirAmong the 58 women who received the drug, one developed severe grade 3 hepatotoxicity; in general, the drug was effective and safe.
Jharap et al[125]Single-cohort, prospective, observationalPregnant women6-Thioguanine nucleotide, 6-methylmercaptopurineFetal exposure to 6-thioguanine but not to 6-methylmercaptopurine; 60% had anemia at birth; no major congenital abnormalities.
Table 3 Case reports of drug poisoning/abuse and alternative medicine use resulting in liver injury during pregnancy
Suspect drug
Clinical finding(s)
Maternal outcome
Fetal outcome
Cocaine[126]Hepatic ruptureProlonged hospital stayEmergency caesarian delivery
ParacetamolRaised liver enzymes[46,47]; coagulopathy[46]Recovery without sequelae[46,47]Normal[47]; prematurity, respiratory distress, metabolic acidosis, full recovery[46]
Mushroom (Amanita species)[127]Low prothrombin activityRecovery without sequelaeNormal
Mountain germander (Teucrium polium)[128]Raised liver enzymesRecovery without sequelaeNormal