Liver injury associated with drug intake during pregnancy

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 cholestasis	Recovery without sequelae	Birth by caesarean section
Chlorpromazine	Severe 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 therapy	Fulminant 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]	Cholestasis	Recovery without sequelae	Premature birth by cesarean section
Methyldopa	Cytolytic hepatitis and cholestasis, toxic hepatitis[106]; hepatitis[73,74,107,108]	Improved following drug withdrawal[72-74]	-
Nitrofurantoin[109]	Toxic liver damage	Recovery without sequelae	Normal
Paracetamol	Acute 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]
Propylthiouracil	Liver 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 liver	Death	-

Table 2 Studies other than case reports describing effect of drugs on maternal/fetal/neonatal liver function

Ref.	Study design	Study population	Suspected medication (s)	Study outcome
Snijdewind et al[68]	Retrospective, comparative	Pregnant women	Antiretroviral therapy and hepatitis C virus co-infection	Nevirapine 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, comparative	Pregnant vs non-pregnant	Antitubercular drug	Severe hepatotoxicity and temporary drug withdrawal more frequent in pregnant women compared to non-pregnant women
Mandelbrot et al[113]	Retrospective, comparative	Pregnant women	Atazanavir	Three 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-control	General population including pregnant women	Doxycycline, tetracycline	Doxycycline potentially less hepatotoxic than tetracycline
McCormack et al[114]	Prospective, placebo-controlled	Pregnant women	Erythromycin estolate, clindamycin hydrochloride, placebo	Erythromycin estolate resulted in raised liver enzymes; use not advised in pregnancy
Tempelman et al[115]	Retrospective, comparative	Pregnant women	Highly active antiretroviral therapy	Nelfinavir or nevirapine containing regimens are safe and effective in pregnant women with HIV
Franks et al[77]	Retrospective	Women with isoniazid hepatitis	Isoniazid	A 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 trial	Women with HIV (efavirenz-based antiretroviral therapy) receiving isoniazid preventive therapy either during pregnancy or after delivery	Isoniazid	Risk 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 interventional	Pregnant women with choriocarcinoma and high-risk gestational trophoblastic neoplasia	Methotrexate, etoposide, actinomycin D	Of 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, interventional	Pregnant women	Nelfinavir	Of the 16 women studied, one developed serious adverse event of elevated AST; the drug was well tolerated in general.
Timmermans et al[59]	Retrospective, comparative	Pregnant and non-pregnant women	Nelfinavir, nevirapine	Nevirapine related hepatotoxicity more frequent in pregnant than in non-pregnant women.
Joy et al[119]	Single-cohort, retrospective, observational	Pregnancy women in third trimester	Nevirapine	Incidence of adverse events lower; study in larger cohorts recommended to determine the relationship between nevirapine hepatotoxicity and trimester use.
Natarajan et al[58]	Retrospective, comparative	Pregnant women	Nevirapine	Risk of nevirapine-associated toxicity not higher in pregnancy; CD4 counts not predictive of toxicity.
Kondo et al[65]	Retrospective, comparative study	Pregnant women	Nevirapine	Hepatotoxicity 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, comparative	General population including pregnant women	Nevirapine	Pregnant women with high CD4 counts have higher rate of symptomatic hepatotoxicity.
Kondo et al[67]	Single-cohort, retrospective, observational	Pregnant women	Nevirapine	No 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, comparative	Pregnant women	Nevirapine	No significant association between nevirapine use and liver enzyme elevation regardless of pregnancy status; pregnancy associated with increased hepatotoxicity.
Ouyang et al[27]	Retrospective, comparative	Pregnant women	Nevirapine	No increased risk of hepatotoxicity among HIV-infected pregnant women on nevirapine versus other drugs, including in those treatment naïve.
Peters et al[64]	Prospective, comparative	Pregnant women	Nevirapine	Severe hepatotoxicity and rash higher with nevirapine than with nelfinavir; no association with CD4 counts.
Lyons et al[62]	Single-cohort, retrospective, observational	Pregnant women	Combination antiretroviral therapy	Women with more severe hepatotoxicity had higher pretreatment CD4 counts.
Jamisse et al[63]	Single-cohort, prospective, observational	Pregnant women	Nevirapine-containing combination antiretroviral therapy	Severe hepatotoxicity more common at higher CD4 counts in pregnancy.
Sheng et al[121]	Prospective, comparative	Pregnant women with high viral loads of hepatitis B virus	Nucleos(t)ide analogues	Telbivudine therapy was safe in pregnant women.
Zhang et al[122]	Disproportionality analysis	Pregnant women	Omeprazole, lansoprazole, amoxicillin	The risk of cholestasis associated with these drugs higher in pregnant women; re-assessment of safety recommended.
Cecchi et al[88]	Single-cohort, prospective, observational	Pregnant women	Organophosphate pesticides	Subclinical hepatotoxicity during the second trimester in spraying period.
Trakulsrichaia et al[123]	Single-cohort, retrospective, observational	Pregnant women	Paraquat poisoning	Hepatotoxicity more common in patients who died.
Andersen et al[57]	Single-cohort, observational	General population including pregnant women	Antithyroid drugs	Antithyroid drug-associated liver failure observed less frequently in pregnant women than in the general population.
Brunet et al[124]	Single-cohort, prospective, observational	Pregnant women	Saquinavir/ritonavir	Among 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, observational	Pregnant women	6-Thioguanine nucleotide, 6-methylmercaptopurine	Fetal exposure to 6-thioguanine but not to 6-methylmercaptopurine; 60% had anemia at birth; no major congenital abnormalities.

HIV: Human immunodeficiency virus.

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 rupture	Prolonged hospital stay	Emergency caesarian delivery
Paracetamol	Raised 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 activity	Recovery without sequelae	Normal
Mountain germander (Teucrium polium)[128]	Raised liver enzymes	Recovery without sequelae	Normal