Topically Applied Minoxidil May Cause Fetal Malformation: A Case Report Carlo Smorlesi, 1 Adele Caldarella, 2 Laura Caramelli, 1 Simonetta Di Lollo, 2 and Flavio Moroni 1 * 1 Dipartimento di Farmacologia Preclinica e Clinica, Universita ` di Firenze and Azienda Ospedaliera Careggi, Firenze, Italy 2 Dipartimento di Patologia Umana ed Oncologia, Universita ` di Firenze and Azienda Ospedaliera Careggi, Firenze, Italy Received 17 June 2003; Accepted 15 July 2003 BACKGROUND: Minoxidil is a K + channel opener able to cause relaxation of vascular smooth muscles and modify cell growth and cell fate or migration. It is now widely used for its hair growth promoting effects. When locally applied, it is absorbed through the skin and may have systemic pharmacological effects. CASE: A 28-year-old white pregnant woman daily applied minoxidil 2% to her scalp because of hair loss. At the 22nd gestational week, after a routine ultrasound test showing significant brain, heart, and vascular malformations of the fetus, pregnancy was interrupted. The placenta had numerous ischemic areas and a discrepancy between gestational age and villi maturation. In the villi, capillaries were increased in number, significantly enlarged, and excessively marginalized. The fetus’ heart was increased in volume and had a globose shape, the aorta had a distal stenosis. The sigmoid colon was significantly increased in length and a mesentery commune was present. The brain had enlarged ventricles and abundant hemorrhages. Histological examination showed areas of demyelinization with gliosis, signs of excessive and inappropriate angiogenesis, and capillary rearrangement. CONCLUSIONS: Further knowledge on minoxidil-induced fetal toxicity would be beneficial before allowing its use in pregnant women. Birth Defects Research (Part A) 67:997–1001, 2003. © 2003 Wiley-Liss, Inc. Key words: minoxidil; K ATP channels; pathological angiogenesis INTRODUCTION Minoxidil was widely used in the early 1970s because it causes relaxation of vascular smooth muscles and reduces blood pressure. It was even considered one of the drugs of choice for the treatment of malignant renal hypertension (Gilmore et al., 1970; Campese, 1981). A first series of published toxicological studies, performed in mice, rats, and rabbits, showed that repeated minoxidil administra- tion (even at doses higher than those necessary for thera- peutic purposes) was well tolerated (Carlson and Feenstra, 1977). It was soon observed, however, that when chroni- cally administered to dogs or humans, minoxidil may lead to atrophy and degeneration of the atrial septum (Sobota et al., 1980), and this finding suggested limiting minoxidil use only to malignant renal hypertension patients who did not respond to other therapeutic regimens (Campese et al., 1981). A peculiar hypertrichosis affecting the temple, the fore- head areas, and sometimes the entire face or the whole body was another common side effect observed after re- peated minoxidil administration. This side effect was not easily accepted by female patients suffering from high blood pressure syndromes (Ryan et al., 1975; Earhart et al., 1977), but led to the suggestion that direct minoxidil ap- plication to the scalp could be helpful in patients suffering from hair loss (Vanderveen et al., 1984). Topical use rap- idly spread into the general population, was considered sufficiently safe, and is still a rather common medical and nonmedical practice (Price, 1999; Silva-Santos et al., 2002). Minoxidil, however, easily crosses biological barriers and accumulates into lipids, so that brain and fetal concentra- tions may be significantly higher than the concentrations found in plasma (Campese, 1981; Silva-Santos et al., 2002). Its chronic application to the scalp may cause hypotension and tachycardia, thus suggesting that even when topically applied it may reach pharmacologically active concentra- tions in the blood (Vanderveen et al., 1984; Leenen et al., 1988; Silva-Santos et al., 2002). Teratology studies performed in pregnant rabbits or rats receiving minoxidil doses one- to five-fold those adminis- tered to humans did not show a significant increase in offspring malformation rate (Carlson and Feenstra, 1977). Larger doses, however, may cause abnormal fetal growth, skeletal abnormalities, and an increase in the offspring death rate (Yamada et al., 1992). Pronounced hypertrichosis of the back and extremities, dysmorphic facial features, partial clinodactilysm, cryp- torchidism, and omphalocele (4 cm  2 cm) were reported in an infant born to a woman suffering from malignant hypertension and treated with a four-drug hypotensive regimen that included minoxidil. The gradual diminution of the hypertrichosis after delivery suggested the involve- *Correspondence to: Prof. Flavio Moroni, Dipartimento di Farmacologia Pre- clinica e Clinica, Universita ` di Firenze, Viale Pieraccini, 6, 50139 Firenze, Italy. E-mail: flavio.moroni@unifi.it DOI: 10.1002/bdra.10095 © 2003 Wiley-Liss, Inc. Birth Defects Research (Part A) 67:997–1001 (2003) Birth Defects Research (Part A): Clinical and Molecular Teratology 67:997–1001 (2003)