Antineoplastic/Antigout
PREGNANCY RECOMMENDATION: Limited Human Data—No Relevant Animal Data
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
The human pregnancy experience with allopurinol is limited because the conditions for which it is indicated are relatively rare in women of childbearing age. No adverse effects were observed in rats and rabbits but, in one study, severe toxicity was noted in mice. However, the only dose comparisons to the human dose were based on body weight and are not interpretable. In one study, the use of allopurinol throughout gestation was associated with multiple major defects in the newborn. Additional data are needed before the association can be classified as causal.
FETAL RISK SUMMARY
Allopurinol, a xanthine oxidase inhibitor, is used for the treatment of symptomatic primary or secondary hyperuricemias. It is in the same antineoplastic subclass of antimetabolites that reduce uric acid levels as rasburicase. Allopurinol is indicated for the management of patients with (a) signs and symptoms of primary or secondary gout; (b) leukemia, lymphoma, and malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels; and (c) recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day in male patients and 750 mg/day in female patients. Allopurinol is rapidly metabolized to oxipurinol, an active metabolite. Allopurinol has a plasma half-life of about 1–2 hours, whereas oxipurinol has a half-life of about 15 hours (1).
Reproduction studies by the manufacturer have been conducted in rats and rabbits. At doses up to 20 times the usual human dose based on body weight, no evidence of impaired fertility or fetal harm was observed (1). In a 1972 study, doses of 50 mg/kg and 100 mg/kg of allopurinol were given intraperitoneally to mice (2). The high dose, but not the low dose, resulted in a significant increase in the number of dead offspring. Both doses were associated with cleft palate and skeletal defects (2). However, it was not determined if the toxicity was a fetal effect or an effect secondary to maternal toxicity (1). In studies involving other animal species, no fetal harm was observed (3).
Consistent with the low molecular weight (about 136 for allopurinol), as well as the plasma half-lives for allopurinol and oxipurinol, both cross the placenta. A group of mothers were given allopurinol 500 mg IV 18–190 minutes before birth (4). The median maternal concentration of allopurinol and oxipurinol were 3.8 mcg/mL (1.2–7.9 mcg/mL) and 3.2 mcg/mL (1.5–6.4 mcg/mL), respectively, whereas arterial cord blood levels were 2.0 mcg/mL (0.2–7.3 mcg/mL) and 1.5 mcg/mL (0.6–7.6 mcg/mL), respectively (4).
The manufacturer is aware of two unpublished reports of women receiving the drug during pregnancy who gave birth to normal infants (1).
Allopurinol, in daily doses of 300–400 mg (unspecified dose in one patient), was combined with cancer chemotherapeutic agents in six patients for the treatment of leukemia occurring during pregnancy (5–9). Treatment in each of these cases was begun in the 2nd or 3rd trimester. The outcomes of these pregnancies were as follows: four normal healthy infants (5–7); one intrauterine fetal death probably a result of severe preeclampsia (8); and one growth-restricted infant with absence of the right kidney, hydronephrosis of the left kidney, and hepatic subcapsular calcifications (9). The cause of the defects in the latter infant was unknown but, because drug therapy was not started until the 20th week of gestation, any relationship to allopurinol can be excluded. The intrauterine growth restriction was thought to be caused by the chemotherapeutic agent, busulfan, that the mother received (9).
A 1976 case report described the use of allopurinol in a woman with type I glycogen storage disease (von Gierke’s disease) (10). One of the characteristics of this inherited disease is hyperuricemia as a result of decreased renal excretion and increased production of uric acid. The woman was receiving allopurinol, 300 mg/day, at the time of conception and during the early portion of the 1st trimester (exact dates were not specified). The drug was stopped at that time. A term female infant was delivered by cesarean section for failed labor. Phenylketonuria, an autosomal recessive disorder, was subsequently diagnosed in the infant (10).
A woman with primary gout and gouty nephropathy was treated with 300 mg/day of allopurinol throughout gestation (11). She delivered an appropriate-for-gestational-age 2510-g healthy female infant at 35 weeks’ gestation. The infant’s weight gain was normal at 10 weeks of age, but other developmental milestones were not provided (11).
A 1997 randomized, double-blind, placebo controlled trial, allopurinol (200 mg/day) was combined with vitamin E (800 IU/day) and vitamin C (1000 mg/day) for women with severe preeclampsia diagnosed between 24 and 32 weeks of gestation (12). The outcomes evaluated were prolongation of pregnancy, infant outcomes, and other factors. The results did not suggest a benefit of the therapy (12).
A 2009 feasibility study evaluated whether allopurinol given to mothers with signs of fetal distress immediately before birth would reduce free radical formation in the fetus, a potential first step to reduce or prevent fetal hypoxia-induced brain injury (4). The study found that therapeutic doses of allopurinol reduced cord blood levels of the protein S-100B, a marker of brain injury. Two other reports described the rationale for this intervention and a new study that was just beginning (13,14).
A 2011 case report described multiple major birth defects in an infant born at 41 weeks’ (15). Birth weight, length, and head circumference were appropriate for gestational age. The mother had taken allopurinol 300 mg/day for recurrent kidney stones and methyldopa for hypertension throughout gestation. External anomalies were as follows: hypertelorism, left-sided microphthalmia and coloboma of upper eyelid, left-sided microtia and absent left external auditory canal, simplified right ear with a preauricular tag, left-sided cleft lip and palate, and bilateral undescended testes. The infant died at 8 days of age. The following internal defects were found at autopsy: hypoplasia of corpus callosum, left optic nerve atrophy, left microphthalmia, small frontal fossa, agenesis of the left diaphragm with intrusion of liver, stomach, and spleen into the diaphragmatic space, mildly enlarged right-sided kidney, absent left kidney, small accessory spleen, and profound left pulmonary hypoplasia. The cerebellum and gyral pattern of the brain surface appeared to be normal, as was the cardiovascular system and skeleton. The infant’s karyotype was a normal 46,XY, but a chromosome microdeletion/duplication syndrome could not be ruled out. Because the anomalies shared some features with those caused by mycophenolate mofetil (see Mycophenolate), and because both allopurinol and mycophenolate interrupt purine synthesis, the authors concluded that allopurinol should be considered a potential teratogen (15).
In contrast to the above report, a 2012 case described a 27-year-old woman with ulcerative colitis who was treated throughout pregnancy with allopurinol 100 mg/day, mercaptopurine 25 mg/day, and mesalazine 4 g/day (16). Pregnancy was complicated by diarrhea and blood loss in the 2nd trimester. An elective cesarean section was performed at 39 weeks’ to give birth to a healthy 3550-g infant (sex not specified) with Apgar score of 9, 10, and 10 at 1, 5, and 10 minutes, respectively. No anomalies were observed in the infant (16).
BREASTFEEDING SUMMARY
Allopurinol and its active metabolite, oxipurinol, are excreted into human milk. A woman with hyperuricemia was taking allopurinol 300 mg/day for 4 weeks while breastfeeding her 5-week-old infant (17,18). Maternal plasma and milk samples were drawn 2 and 4 hours after a 300-mg dose. Her plasma levels of allopurinol and oxipurinol at these times were 1.0 and 13.8 mcg/mL, and 1.0 and 19.9 mcg/mL, respectively. Milk levels of the drug and metabolite at 2 and 4 hours were 0.9 and 53.7 mcg/mL, and 1.4 and 48.0 mcg/mL, respectively. At these times, the milk:plasma ratios for allopurinol were 0.9 and 1.4, respectively, and for oxipurinol were 3.9 and 2.4, respectively. The mother breastfed her infant 2 hours after her dose and a single infant plasma sample was taken 2 hours later. Allopurinol was not detected (detection limit 0.5 mcg/mL) in the infant’s plasma but the concentration of oxipurinol was 6.6 mcg/mL. The average daily dose of allopurinol and oxipurinol ingested by the infant from the milk (based on 150 mL/kg/day) was 0.14–0.20 and 7.2–8.0 mg/kg, respectively. No adverse effects in the nursing infant were observed (18). However, 4 hours after a dose and 2 hours after feeding, the infant’s oxipurinol plasma level was 48% and 33% of the mother’s levels at 2 and 4 hours. As such, the infant should be monitored for allergic reactions, such as rash, periodic blood counts, and other common toxicities observed in adults.
The American Academy of Pediatrics classifies allopurinol as compatible with breastfeeding (19).
References
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