Propylthiouracil Risk Summary

Fetal Risk Summary

Propylthiouracil (PTU) has been used for the treatment of hyperthyroidism during pregnancy since its introduction in the 1940s (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22, 23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38 and 39). The drug prevents synthesis of thyroid hormones and inhibits peripheral deiodination of levothyroxine (T4) to liothyronine (T3) (40).

PTU crosses the placenta. Four patients undergoing therapeutic abortion were given a single 15-mg 35S-labeled oral dose 2 hours before pregnancy termination (41). Serum could not be obtained from two 8-week-old fetuses, but 0.0016%0.0042% of the given dose was found in the fetal tissues. In two other fetuses at 12 and 16 weeks of age, the fetal:maternal serum ratios were 0.27 and 0.35, respectively, with 0.020% and 0.025% of the dose in the fetuses. A 1986 report described the pharmacokinetics of PTU in six pregnant, hyperthyroid women (42). Serum concentrations of PTU consistently decreased during the 3rd trimester. At delivery in five patients, 19 hours after the last dose of 100150 mg, the mean maternal serum concentration of PTU was 0.19 g/mL (range <0.020.52 g/mL) compared with a mean cord blood level of 0.36 g/mL (range 0.030.67 g/mL). The cord:maternal serum ratio was 1.9 (42).

The primary effect on the fetus from transplacental passage of PTU is the production of a mild hypothyroidism when the drug is used close to term. This usually resolves within a few days without treatment (34). Clinically, the hypothyroid state may be observed as a goiter in the newborn and is the result of increased levels of fetal pituitary thyrotropin (24). The incidence of fetal goiter after PTU treatment in reported cases is approximately 12% (29 goiters/241 patients) (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22, 23, 24,25,26,27,28,29,30,31,32,33,34,35,36 and 37,43). Some of these cases may have been caused by coadministration of iodides (9,11,18,22). Use of PTU early in pregnancy does not produce fetal goiter because the fetal thyroid does not begin hormone production until approximately the 11th or 12th week of gestation (44). Goiters from PTU exposure are usually small and do not obstruct the airway as do iodide-induced goiters (see also Potassium Iodide) (43,44 and 45). However, two reports have been located that described PTU-induced goiters in newborns that were sufficiently massive to produce tracheal compression resulting in death in one infant and moderate respiratory distress in the second (7,10). In two other PTU-exposed fetuses, clinical hypothyroidism was evident at birth with subsequent retarded mental and physical development (10,11 and 12). One of these infants was also exposed to high doses of iodide during gestation (12). PTU-induced goiters are not predictable or dose dependent, but the smallest possible dose of PTU should be used, especially during the 3rd trimester (19,33,44,45 and 46). No effect on intellectual or physical development from PTU-induced hypothyroxinemia was observed in comparison studies between exposed and nonexposed siblings (19,47).

Congenital anomalies have been reported in seven newborns exposed to PTU in utero (14,17,21,27,34). This incidence is well within the expected rate of malformations. Maternal hyperthyroidism itself has been shown to be a cause of malformations (48). No association between PTU and defects has been suggested. The reported defects were as follows: Congenital dislocation of hip (14) Cryptorchidism (17) Muscular hypotonicity (17) Syndactyly of hand and foot (131I also used) (21) Hypospadias (27) Aortic atresia (27) Choanal atresia (34) In a large prospective study, 25 patients were exposed to one or more noniodide thyroid suppressants during the 1st trimester, 16 of whom took PTU (49). From the total group, 4 children with nonspecified malformations were found, suggesting that this group of drugs may be teratogenic. However, because of the maternal disease and the use of other drugs (i.e., methimazole in 9 women and other thiouracil derivatives in 2), the relationship between PTU and the anomalies cannot be determined. This study also noted that independent confirmation of the data was required (49).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 35 newborns had been exposed to PTU during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (2.9%) major birth defect was observed (one expected), a case of hypospadias (none expected).

A 1992 abstract and a later full report described a retrospective evaluation of hyperthyroid pregnancy outcomes treated with either PTU (N=99) or methimazole (N=36) (50,51). Three (3.0%) defects were observed in those exposed to PTU (ventricular septal defect; pulmonary stenosis; patent ductus arteriosus in a term infant), whereas one newborn (2.8%) had a defect (inguinal hernia) in the methimazole group. No scalp defects were observed.

In comparison with other antithyroid drugs, propylthiouracil is considered the drug of choice for the medical treatment of hyperthyroidism during pregnancy (see also Carbimazole, Methimazole, Potassium Iodide) (34,36,44,45 and 46). Combination therapy with thyroid-antithyroid drugs was advocated at one time but is now considered inappropriate (25,26,34,36,44,45 and 46,52). Two reasons contributed to this change: (a) use of thyroid hormones may require higher doses of PTU to be used, and (b) placental transfer of T4 and T3 is minimal and not sufficient to reverse fetal hypothyroidism (see also Levothyroxine and Liothyronine).

Breast Feeding Summary

Propylthiouracil (PTU) is excreted into breast milk in low amounts. In a patient given 100 mg of radiolabeled PTU, the milk:plasma ratio was a constant 0.55 for a 24-hour period, representing about 0.077% of the given radioactive dose (53). In a second study, nine patients were given an oral dose of 400 mg (54). Mean serum and milk levels at 90 minutes were 7.7 g/mL and 0.7 g/mL, respectively. The average amount excreted in milk during 4 hours was 99 g, about 0.025% of the total dose. One mother took 200300 mg daily while breast-feeding. No changes in any of the infant's thyroid parameters were observed (54).

Based on these two reports, PTU does not seem to pose a significant risk to the breast-fed infant, but periodic evaluation of the infant's thyroid function would be prudent. A 1987 review of antithyroid medication during lactation considered PTU the drug of choice because it is ionized at phyiologic pH and protein bound (80%); both limiting its transfer into milk (55).

An interesting study published in 2000 found that the physician's advice was the only significant predictor of a woman's choice to breast-feed during PTU therapy (56). In the postpartum period, a group of 36 hyperthyroid women who required PTU were compared with 30 women who no longer required PTU therapy and 36 healthy women (controls). The breast feeding initiation rates in the three groups were 44%, 83%, and 83% (p<0.01), respectively. In 15 of the women receiving PTU who breast-fed, advice on breast feeding was given by 22 physicians (20 in favor, 1 against, and 1 equivocal). In those women taking PTU who formula fed, 11 received advice from 17 physicians (4 in favor, 12 against, and 1 equivocal) (56).

The American Academy of Pediatrics considers PTU to be compatible with breast feeding (57).

References

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