Risk Factor: D
Class: Hormones/ Antithyroid agents
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
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
The American Academy of Pediatrics considers PTU to be compatible with breast feeding (57).
- Astwood EB, VanderLaan WP. Treatment of hyperthyroidism with propylthiouracil. Ann Intern Med 1946;25:81321.
- Bain L. Propylthiouracil in pregnancy: Report of a case. South Med J 1947;40:10201.
- Lahey FH, Bartels EC. The use of thiouracil, thiobarbital and propylthiouracil in patients with hyperthyroidism. Ann Surg 1947;125:57281.
- Reveno WS. Propylthiouracil in the treatment of toxic goiter. J Clin Endocrinol Metab 1948;8:86674.
- Eisenberg L. Thyrotoxicosis complicating pregnancy. NY State J Med 1950;50:16189.
- Astwood EB. The use of antithyroid drugs during pregnancy. J Clin Endocrinol Metab 1951;11:104556.
- Aaron HH, Schneierson SJ, Siegel E. Goiter in newborn infant due to mother’s ingestion of propylthiouracil. JAMA 1955;159:84850.
- Waldinger C, Wermer OS, Sobel EH. Thyroid function in infant with congenital goiter resulting from exposure to propylthiouracil. J Am Med Wom Assoc 1955;10:1967.
- Bongiovanni AM, Eberlein WR, Thomas PZ, Anderson WB. Sporadic goiter of the newborn. J Clin Endocrinol Met 1956;16:14652.
- Krementz ET, Hooper RG, Kempson RL. The effect on the rabbit fetus of the maternal administration of propylthiouracil. Surgery 1957:41:61931.
- Branch LK, Tuthill SW. Goiters in twins resulting from propylthiouracil given during pregnancy. Ann Intern Med 1957;46:1458.
- Man EB, Shaver BA Jr, Cooke RE. Studies of children born to women with thyroid disease. Am J Obstet Gynecol 1958;75:72841.
- Becker WF, Sudduth PG. Hyperthyroidism and pregnancy. Ann Surg 1959;149:86774.
- Greenman GW, Gabrielson MO, Howard-Flanders J, Wessel MA. Thyroid dysfunction in pregnancy. N Engl J Med 1962;267:42631.
- Herbst AL, Selenkow HA. Combined antithyroid-thyroid therapy of hyperthyroidism in pregnancy. Obstet Gynecol 1963;21:54350.
- Reveno WS, Rosenbaum H. Observations on the use of antithyroid drugs. Ann Intern Med 1964;60:9829.
- Herbst AL, Selenkow HA. Hyperthyroidism during pregnancy. N Engl J Med 1965;273:62733.
- Burrow GN. Neonatal goiter after maternal propylthiouracil therapy. J Clin Endocrinol Metab 1965;25:4038.
- Burrow GN, Bartsocas C, Klatskin EH, Grunt JA. Children exposed in utero to propylthiouracil. Am J Dis Child 1968;116:1615.
- Talbert LM, Thomas CG Jr, Holt WA, Rankin P. Hyperthyroidism during pregnancy. Obstet Gynecol 1970;36:77985.
- Hollingsworth DR, Austin E. Thyroxine derivatives in amniotic fluid. J Pediatr 1971;79:9239.
- Ayromlooi J. Congenital goiter due to maternal ingestion of iodides. Obstet Gynecol 1972;39:81822.
- Worley RJ, Crosby WM. Hyperthyroidism during pregnancy. Am J Obstet Gynecol 1974;119:1505.
- Refetoff S, Ochi Y, Selenkow HA, Rosenfield RL. Neonatal hypothyroidism and goiter in one infant of each of two sets of twins due to maternal therapy with antithyroid drugs. J Pediatr 1974;85:2404.
- Mestman JH, Manning PR, Hodgman J. Hyperthyroidism and pregnancy. Arch Intern Med 1974;134:4349.
- Goluboff LG, Sisson JC, Hamburger JI. Hyperthyroidism associated with pregnancy. Obstet Gynecol 1974;44:10716.
- Mujtaba Q, Burrow GN. Treatment of hyperthyroidism in pregnancy with propylthiouracil and methimazole. Obstet Gynecol 1975;46:2826.
- Serup J, Petersen S. Hyperthyroidism during pregnancy treated with propylthiouracil. Acta Obstet Gynecol Scand 1977;56:4636.
- Petersen S, Serup J. Case report: neonatal thyrotoxicosis. Acta Paediatr Scand 1977;66:63942.
- Serup J. Maternal propylthiouracil to manage fetal hyperthyroidism. Lancet 1978;2:896.
- Wallace EZ, Gandhi VS. Triiodothyronine thyrotoxicosis in pregnancy. Am J Obstet Gynecol 1978;130:1067.
- Weiner S, Scharf JI, Bolognese RJ, Librizzi RJ. Antenatal diagnosis and treatment of a fetal goiter. J Reprod Med 1980;24:3942.
- Sugrue D, Drury MI. Hyperthyroidism complicating pregnancy: results of treatment by antithyroid drugs in 77 pregnancies. Br J Obstet Gynaecol 1980;87:9705.
- Cheron RG, Kaplan MM, Larsen PR, Selenkow HA, Crigler JF Jr. Neonatal thyroid function after propylthiouracil therapy for maternal Graves’ disease. N Engl J Med 1981;304:5258.
- Check JH, Rezvani I, Goodner D, Hopper B. Prenatal treatment of thyrotoxicosis to prevent intrauterine growth retardation. Obstet Gynecol 1982;60:1224.
- Kock HCLV, Merkus JMWM. Graves’ disease during pregnancy. Eur J Obstet Gynecol Reprod Biol 1983;14:32330.
- Hollingsworth DR, Austin E. Observations following I131 for Graves disease during first trimester of pregnancy. South Med J 1969;62:15556.
- Burrow GN. The management of thyrotoxicosis in pregnancy. N Engl J Med 1985;313:5625.
- Momotani N, Noh J, Oyanagi H, Ishikawa N, Ito K. Antithyroid drug therapy for Graves’ disease during pregnancy. Optimal regiment for fetal thyroid status. N Engl J Med 1986;315:248.
- American Hospital Formulary Service. Drug Information 1997. Bethesda, MD: American Society of Health-System Pharmacists, 1997:24878.
- Marchant B, Brownlie EW, Hart DM, Horton PW, Alexander WD. The placental transfer of propylthiouracil, methimazole and carbimazole. J Clin Endocrinol Metab 1977;45:118793.
- Gardner DF, Cruikshank DP, Hays PM, Cooper DS. Pharmacology of propylthiouracil (PTU) in pregnant hyperthyroid women: Correlation of maternal PTU concentrations with cord serum thyroid function tests. J Clin Endocrinol Metab 1986;62:21720.
- Ramsay I, Kaur S, Krassas G. Thyrotoxicosis in pregnancy: Results of treatment by antithyroid drugs combined with T4. Clin Endocrinol (Oxf) 1983;18:7385.
- Burr WA. Thyroid disease. Clin Obstet Gynecol 1981;8:34151.
- Burrow GN. Hyperthyroidism during pregnancy. N Engl J Med 1978; 298:1503.
- Burrow GN. Maternal-fetal considerations in hyperthyroidism. Clin Endocrinol Metab 1978;7:11525.
- Burrow GN, Klatskin EH, Genel M. Intellectual development in children whose mothers received propylthiouracil during pregnancy. Yale J Biol Med 1978;51:1516.
- Momotani N, Ito K, Hamada N, Ban Y, Nishikawa Y, Mimura T. Maternal hyperthyroidism and congenital malformations in the offspring. Clin Endocrinol (Oxf) 1984;20:695700.
- Heinonen OP, Slone D, Shapiro S.Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:388400.
- Wing D, Millar L, Koonings P, Montoro M, Mestman J. A comparison of PTU versus Tapazole in the treatment of hyperthyroidism (abstract). Am J Obstet Gynecol 1992;166:308.
- Wing DA, Millar LK, Koonings PP, Montoro MN, Mestman JH. A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 1994;170:905.
- Anonymous. Transplacental passage of thyroid hormones. N Engl J Med 1967;277:4867.
- Low LCK, Lang J, Alexander WD. Excretion of carbimazole and propylthiouracil in breast milk. Lancet 1979;2:1011.
- Kampmann JP, Johansen K, Hansen JM, Helweg J. Propylthiouracil in human milk. Lancet 1980;1:7368.
- Cooper DS. Antithyroid drugs: to breast-feed or not to breast-feed. Am J Obstet Gynecol 1987;157:2345.
- Lee A, Moretti ME, Collantes A, Chong D, Mazzotta P, Koren G, Merchant SS, Ito S. Choice of breastfeeding and physicians’ advice: a cohort study of women receiving propylthiouracil. Pediatrics 2000;106:2730.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.