Antihypertensive
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Minoxidil is not teratogenic in rats and rabbits, but some fetotoxicity was observed in rabbits. The human pregnancy experience is too limited, after both oral dosing and topical application, to determine the risk of teratogenicity. A possible exception involves the two infants exposed in utero to oral minoxidil who had hypertrichosis. This is a known adverse effect in adults and, indeed, one of the mothers had hypertrichosis. However, the causes of the multiple congenital malformations observed in one of these infants and the heart defects in the other are unknown. Similarly, the causes of the multiple anomalies observed in two fetuses after minoxidil topical application also are unknown. Although the doses applied in these two cases were not specified, only small amounts of topically applied minoxidil are absorbed into the systemic circulation. Of interest, both mothers had a flu-like illness in the 1st trimester. Even if these malformations are not related to drug exposure, the potential toxicity of oral minoxidil is severe enough to preclude its use in pregnancy. One of these toxicities includes large orthostatic decreases in blood pressure that could severely jeopardize placental perfusion. Although the possibility of a causal relationship to malformations after topical application appears to be remote, the safest course is to avoid applying the agent during the 1st trimester.
FETAL RISK SUMMARY
Minoxidil is a potent antihypertensive peripheral vasodilator. It is indicated for the treatment of hypertension that is symptomatic or associated with target organ damage. Minoxidil is considered a second-line antihypertensive therapy because of the potential for severe adverse effects. After oral dosing, minoxidil is nearly completely (90%) metabolized to metabolites that have much less antihypertensive effects. The average plasma elimination half-life of the parent compound is 4.2 hours (1).
Minoxidil is also used topically for the treatment of androgenetic alopecia (male baldness) and alopecia areata. After topical application, it is poorly absorbed from normal intact skin, with an average of 1.4% (range 0.3%–4.5%) entering the systemic circulation. Steady state concentrations in the plasma are reached at the end of the third dosing interval (36 hours) (2).
Reproduction studies have been conducted in rats and rabbits (1–3). In rats, no evidence of teratogenicity or fetotoxicity was observed after an oral dose that was 5 times the human dose (1,2). Similarly, no teratogenicity was observed with an SC dose (80 mg/kg/day) that produced maternal toxicity (1). The oral dose, however, reduced the conception rate (2). There also was no teratogenicity in the offspring of pregnant rabbits given an oral dose that was 5 times the human dose, but an increased incidence of fetal resorptions was noted (1,2).
Pregnant rats were administered minoxidil at doses of 3 and 10 mg/kg/day on gestational days 6–15 (3). No evidence of teratogenicity or acute toxicity was observed. However, in the 10 mg/kg/day group, there was a higher than expected incidence of retinal folds in the eyes of offspring. Additional studies did not confirm this finding. In pregnant rabbits, similar doses administered on gestational days 6–18 resulted in fewer live pups per litter. At the highest dose, there was a higher incidence of resorptions (3).
It is not known if minoxidil crosses the human placenta. The molecular weight (about 209) is low enough that fetal exposure should be expected. Moreover, the moderately long elimination half-life (4.2 hours) should increase the opportunity for the drug to cross to the fetal compartment. In addition, the two cases of hypertrichosis described below suggest that minoxidil crosses the placenta.
Information on the use of oral minoxidil in human pregnancy is very limited, and only four cases of fetal exposure have been located (4–6). In one report, minoxidil was used throughout gestation with no effect seen in the healthy newborn (4). A second report involved a mother with a history of renal artery stenosis and malignant hypertension who was treated throughout gestation with minoxidil, captopril, and propranolol (5). Three of her four previous pregnancies had ended in midgestation stillbirths. The most recent stillbirth, her fourth pregnancy, involved a 500-g male infant with low-set ears but no gross anomalies. The mother had been treated with the above regimen plus furosemide. In her second pregnancy, she was treated only with hydrochlorothiazide, and delivered a normal term infant. No information was available on the first and third pregnancies, both of which ended in stillbirths.
In her current pregnancy, daily doses of the three drugs were 10, 50, and 160 mg, respectively. The infant, delivered by cesarean section at 38 weeks’ gestation, had multiple abnormalities, including an omphalocele (repaired on the 2nd day), pronounced hypertrichosis of the back and extremities, depressed nasal bridge, low-set ears, micrognathia, bilateral fifth finger clinodactyly, undescended testes, a circumferential midphallic constriction, a large ventriculoseptal defect, and a brain defect consisting of slightly prominent sulci, especially the basal cisterns and interhemispheric fissure. Growth restriction was not evident, but the weight (3170 g, 60th percentile), length (46 cm, 15th percentile), and head circumference (32.5 cm, 25th percentile) were disproportionate. Neurologic, skeletal, and kidney examinations were normal. Marked hypotension (30–50 mmHg systolic) was present, which resolved after 24 hours. Heart rate, blood glucose, and renal function were normal.
The infant’s hospital course was marked by failure to thrive, congestive heart failure, prolonged physiologic jaundice, and eight episodes of hyperthermia (>38.5°C without apparent cause) at 2–6 weeks of age. The hypertrichosis, which was much less prominent at 2 months of age, is a known side effect of minoxidil therapy in both children and adults, and the condition in this infant was thought to be caused by that drug. The cause of the other defects could not be determined, but a chromosomal abnormality was excluded based on a normal male karyotype (46,XY) determined after a midgestation amniocentesis (5).
It is interesting that captopril (see Captopril) is known to cause structural defects (hypocalvaria or acalvaria) and severe renal toxicity (anuria), but none of the anomalies observed in the above infant have been reported with captopril. The relatively low dose of 50 mg/day (recommended dose 50–150 mg/day) may have protected the fetus from the characteristic renal toxicity observed with angiotensin 1-converting enzyme inhibitors.
Two additional cases of in utero exposure to oral minoxidil were reported to the FDA and published in 1987 (6). The first infant was the product of a 32 weeks’ gestation in a 22-year-old woman with severe uncontrolled renal hypertension who was treated during pregnancy with minoxidil, methyldopa, hydralazine, furosemide, and phenobarbital. The 1770-g infant died of congenital heart disease the day after delivery. Defects noted at autopsy were transposition of the great vessels and pulmonic bicuspid valvular stenosis. Hypertrichosis was not observed. No conclusions can be drawn on the cause of the cardiac defects. The second infant, delivered near term and weighing 3220 g, was exposed throughout gestation to minoxidil (5 mg/day) plus metoprolol (100 mg/day) and prazosin (20 mg/day). The mother had severe hypertension secondary to chronic nephritis. Hypertrichosis was evident in both the mother and the newborn, but no other abnormalities were noted in the infant. The excessive hair growth, which was longest in the sacral area, gradually disappeared during the following 2–3 months. Normal development was noted at 2 years of age (6).
Two reports have described the outcomes of pregnancies exposed to topical minoxidil (7,8). A 14 weeks’ gestation was diagnosed in a nondiabetic 28-year-old, primigravid, woman who had used minoxidil 2% topical solution to treat hair loss during the 1st trimester (7). Her pregnancy was terminated at 17 weeks’ gestation because an ultrasound examination had revealed oligohydramnios, a single umbilical artery, and multiple, severe anomalies. The woman also had experienced a flu-like upper respiratory disease during the 7th to 9th weeks of gestation which had been treated with trimethoprim-sulfamethoxazole (2 tablets twice daily for 2 weeks) and erythromycin (500 mg 4 times daily for 1 week). At termination, no evidence of infection was found, with a negative TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex) test. Malformations in the male fetus included a transverse reduction deformity of the lower limbs and pelvis, agenesis of the cloacal membrane, imperforate anus, absence of external genitalia and bladder, renal agenesis, esophageal atresia, tracheoesophageal fistula, hypoplastic left thumb and thenar eminence, 11 ribs and absence of L5, sacrum and pelvis (7). There was no evidence of an amniotic band, and the cause of the malformations remained unknown. Trimethoprim is a folate antagonist and is believed to cause congenital anomalies but not of the type observed in this infant. (See Trimethoprim.) The constellation of defects was thought to represent a severe form of caudal regression syndrome, although the most severe form of this syndrome, the sirenomelia complex, could not be completely excluded (7).
A 28-year-old woman applied a 2% solution of minoxidil on her whole scalp to treat a diffuse bristly hair condition for at least 1 year and throughout her current pregnancy (8). She experienced a brief flu-like syndrome at the 9th week of gestation (maximum temperature 38.5°C). The woman elected to terminate her pregnancy at about 22 weeks’ gestation after an ultrasound examination had revealed a fetus with multiple anomalies. The 450-g female fetus had extradural occipital hematomas, funnel-like posterior cranial base, hypoplastic middle cranial base, underdeveloped cerebellar lobes, fourth ventricle dilation, and diffuse intracerebral hemorrhages. Other defects included a globose heart, partial subaortic stenosis, mesentery commune, and a significantly increased length of the sigmoid colon. Histologic examination of the brain revealed multiple areas of necrosis, diffuse areas of white matter demyelinization with reactive gliosis, with capillary agglomerates. There also was dilation and congestion of cerebral small vessels and capillaries. The woman stopped the minoxidil and gave birth to a normal infant 2 years later. The cause of the malformations could not be determined, but the authors thought they were secondary to minoxidil (8).
BREASTFEEDING SUMMARY
Minoxidil is excreted into breast milk (4). Levels in the milk ranged from 41.7 ng/mL (1 hour) to 0.3 ng/mL (12 hours), with milk:plasma ratios during this interval varying from 0.67 to 1.0. No adverse effects were observed in the infant. The American Academy of Pediatrics classifies minoxidil as compatible with breastfeeding (9).
References
1.Product information. Loniten. Pharmacia & Upjohn, 2002.
2.Product information. Rogaine. RxMed: Pharmaceutical Information, 2004.
3.Carlson RG, Feenstra ES. Toxicologic studies with the hypotensive agent minoxidil. Toxicol Appl Pharmacol 1977;39:1–11.
4.Valdivieso A, Valdes G, Spiro TE, Westerman RL. Minoxidil in breast milk. Ann Intern Med 1985;102:135.
5.Kaler SG, Patrinos ME, Lambert GH, Myers TF, Karlman R, Anderson CL. Hypertrichosis and congenital anomalies associated with maternal use of minoxidil. Pediatrics 1987;79:434–6.
6.Rosa FW, Idanpaan-Heikkila J, Asanti R. Fetal minoxidil exposure. Pediatrics 1987;80:120.
7.Rojansky N, Fasouliotis SJ, Ariel H, Nadjari M. Extreme caudal agenesis. Possible drug-related etiology? J Reprod Med 2002;47:241–5.
8.Smorlesi C, Caldarella A, Caramelli L, Di Lollo S, Moroni F. Topically applied minoxidil may cause fetal malformation: a case report. Birth Defects Res A Clin Mol Teratol 2003;67:997–1001.
9.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.