Antenatal therapeutic drug exposure and fetal/neonatal tumours: review of 89 cases

Abstract

Although case reports on the association between neonatal tumours and maternal therapeutic drug use during pregnancy are cited regularly, no systematic review has been published. In a systematic search of the literature on fetal and neonatal tumours, we identified 36 malignant and 54 benign tumours in 89 fetuses and neonates prenatally exposed to various drugs. Six associations with in utero exposure are noteworthy: (1) phenytoin and neuroblastoma, as already suspected; (2) antibiotics and leukaemias; (3) hormonal treatment and vascular tumours; (4) acetaminophen (paracetamol) and fusocellular sarcoma; (5) acetaminophen in combination with petroleum products and hepatoblastoma; and (6) dicyclomine hydrochloride and teratomas. In view of the high level of consumption of drugs by pregnant women and the rarity of neonatal tumours, a possible carcinogenic effect is difficult to establish. However, some associations already observed in older infants, children and adults after antenatal and postnatal exposure to the same drugs are of note. We suggest that these drugs may act as carcinogens or as co-carcinogens in association with other physical and chemical agents and/or a particular genetic background. We therefore feel it is important to encourage the systematic collection, registration and publication of case reports on this subject. The hypotheses generated thereby could then be tested by formal epidemiological studies.

Teratogenic exposures

“…Polytherapy with anti‐epileptic drugs is associated with a higher likelihood of fetal adverse effects than is monotherapy [Samren et al, 1999]. Use of phenytoin during pregnancy has been associated by case reports with a neuroectodermal tumors, specifically neuroblastomas, in the offspring [Satgé et al, 1998]. Without controlled studies, this association remains tentative at best.…”

Association between antiepileptic drugs and hepatocellular carcinoma in patients with epilepsy: a population‐based case–control study

“…Initial reports described the use of phenytoin associated with lymphoma after prolonged exposure (Abbondazo, Irey, & Frizzera, ; Gleichmann, Pals, Radaszkiewicz, & Wasser, ; Johns, Moscinski, & Sokol, ). Some reports have described the incidence of neuroblastoma among children with fetal hydantoin syndrome following prenatal exposure to phenytoin (al‐Shammri, Guberman, & Hsu, ; Satgé, Sasco, & Little, ). Liver cancer (87% incidence) and hepatoblastoma (33% incidence) were found with high doses of phenytoin (500 ppm) treatment in a rodent model (Diwan, Henneman, & Nims, ).…”