Drugs in Pregnancy and Lactation: Tenth Edition

PHENTERMINE

Anorexiant

PREGNANCY RECOMMENDATION: Contraindicated

BREASTFEEDING RECOMMENDATION: Contraindicated

PREGNANCY SUMMARY

It is doubtful if any real benefit is derived from the use of phentermine for weight control during pregnancy, and its use during gestation, especially during the 1st trimester, should be considered contraindicated. Moreover, although the causes of the stillbirths cited in one human study were not fully elucidated and may not have been caused by maternal phentermine treatment, the high incidence is disturbing and is another reason to withhold use of the drug during pregnancy.

FETAL RISK SUMMARY

Phentermine (phenyl-tertiary-butylamine) is a sympathomimetic amine that has activity as a CNS stimulant. Similar to other drugs in this class, such as the amphetamines, it is used as an appetite suppressant in the treatment of obesity. In addition to other adverse effects, hypertension has occurred in adults treated with this agent.

Reproduction studies in animals with phentermine have not been conducted. A closely related compound, chlorphentermine (30 mg/kg/day SC), was administered to pregnant rats during the last 5 days of gestation (1). Phospholipidosis was evident in the lungs of the mothers and the newborn rats, and 83% of the latter died within 24 hours of birth. Another group treated with phentermine (30 mg/kg/day SC) in a similar manner did not develop the complication and did not die. A subsequent reference suggested that the chlorphentermine-induced pup mortality was consistent with retardation of fetal pulmonary maturity (2).

No studies have been located that described the placental transfer of phentermine in animals or humans. The molecular weight (about 186) is low enough that exposure of the embryo–fetus should be expected.

A study published in 1962 described the use of phentermine in 118 women who were treated for obesity during the 3rd trimester of pregnancy up to delivery (3). Women weighing <200 pounds were given 30 mg each morning, whereas those >200 pounds were given 30 mg twice daily. The weights of the patients before treatment ranged from 180 to 315 pounds. Adverse outcomes occurred in five women with stillborn infants, one of whom was caused by abruptio placentae. The cause of the other stillborns, whose weights ranged from 9 to 10 pounds, was not mentioned, other than the statement that one mother had mild preeclampsia.

As of 1997, the FDA had received two reports involving the use of the combination, fenfluramine and phentermine, in early pregnancy (F. Rosa, personal communication, FDA, 1997). A spontaneous abortion occurred in one of the pregnancies. In the other, an infant with bilateral valvular abnormalities, both aortic and pulmonary, with moderate stenosis and displacement was born. Because valvular toxicity has been reported in adults taking the combination, a causal relationship in the pregnancy case is potentially possible. No other details of these cases were available.

A 2002 controlled prospective cohort study compared 98 women who had taken phentermine/fenfluramine for weight loss (product withdrawn in 1997) during portions or all of the 1st trimester with 233 nonteratogen-exposed controls (4). About 88% of the subjects had begun the drug combination before conception and the remainder started after conception. The phentermine and fenfluramine daily doses ranged 15–45 mg and 20–60 mg, respectively. Most (96%) stopped the drug combination before the 12th week of gestation. In the two groups, 71% and 65% of the liveborn infants were examined by a dysmorphologist for the presence of major or minor malformations who was blinded to the exposures. There were no statistical differences between the groups in terms of major malformations or ≥3 or more minor malformations, spontaneous abortions, elective abortions, ectopic pregnancies, or preterm delivery. No pattern of malformations was identified. The increased rate of gestational diabetes (11% vs. 4%, p= 0.05) probably reflects the significantly greater prepregnancy body weight and pregnancy weight gain of exposed subjects. The significantly higher mean birth weight and head circumference in full-term infants of subjects were most likely due to the significantly greater mean prepregnancy body weight and weight gain during pregnancy of their mothers as well as to the increased rate of gestational diabetes (4).

BREASTFEEDING SUMMARY

No reports describing the use of phentermine during lactation have been located. The molecular weight (about 186) is low enough that excretion of phentermine into breast milk should be expected. Because CNS stimulation and other adverse reactions may occur in a nursing infant exposed to this drug in milk, breastfeeding should be considered a contraindication if the mother is taking phentermine.

References

1.Thoma-Laurie D, Walker ER, Reasor MJ. Neonatal toxicity in rats following in utero exposure to chlorphentermine or phentermine. Toxicology 1982;24:85–94.

2.Kacew S, Reasor MJ. Newborn response to cationic amphiphilic drugs. Fed Proc 1985;44:2323–7.

3.Sands RX. Obesity and pregnancy. Weight control with a resinate. Am J Obstet Gynecol 1962;83:1617–21.

4.Jones KL, Johnson KA, Dick LM, Felix RJ, Kao KK, Chambers CD. Pregnancy outcomes after first trimester exposure to phentermine/fenfluramine. Teratology 2002;65:125–30.