TERIS logo TERIS
The Teratogen Information System
© 2018 University of Washington
by J.M. Friedman, M.D., Ph.D.
& Janine E. Polifka, Ph.D.
TERIS Agent Number:2544Bibliographic Search Date:12/2017
Agent Name:PROPYLTHIOURACILRevision Date:01/2018

Propylthiouracil is a thioamide derivative that is administered orally to treat hyperthyroidism.



Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation:
 
GOITER: SMALL TO MODERATE
MALFORMATIONS: UNLIKELY

Quality and Quantity of Data on Which Risk Estimate is Based:
 
GOITER: FAIR TO GOOD
MALFORMATIONS: FAIR TO GOOD

Comments:   

1) A HIGH RISK OF CONGENITAL ANOMALIES IN THE CHILDREN OF WOMEN TREATED WITH PROPYLTHIOURACIL DURING THE FIRST TRIMESTER OF PREGNANCY IS UNLIKELY, BUT A SMALL INCREASE IN THE RISK MAY EXIST.

2) APPROPRIATE TREATMENT OF MATERNAL HYPERTHYROIDISM DURING PREGNANCY REDUCES THE EXCESS PERINATAL AND NEONATAL MORTALITY ASSOCIATED WITH UNTREATED DISEASE IN THE MOTHER.

3) INFANTS OF WOMEN WHO ARE TREATED WITH PROPYLTHIOURACIL FOR GRAVES' DISEASE DURING PREGNANCY ARE AT INCREASED RISK FOR HYPERTHYROIDISM DUE TO PLACENTAL TRANSFER OF THYROID STIMULATING IMMUNOGLOBULINS AS WELL AS FOR HYPOTHYROIDISM AND GOITER DUE TO THE MEDICATION (SEE BELOW).

4) FETAL HYPOTHYROIDISM AND GOITER ARE UNLIKELY TO BE CAUSED BY PROPYLTHIOURACIL TREATMENT PRIOR TO ABOUT TEN WEEKS OF GESTATION, WHEN THE FETAL THYROID BEGINS TO FUNCTION.

5) AN INCREASED RISK FOR LOW BIRTH WEIGHT HAS BEEN ASSOCIATED WITH PROPYLTHIOURACIL TREATMENT, ESPECIALLY DURING THE 2ND TRIMESTER (SEE BELOW).


Summary of Teratology Studies:

FETAL/NEONATAL GOITER

Propylthiouracil, when given to a pregnant woman, crosses the placenta and can cause suppression of fetal thyroid function. Since maternal thyroid hormones do not readily cross the placenta, fetal thyroid hyperplasia and goiter may develop as the fetus attempts to compensate for its hypothyroidism. It has been estimated that 1- 5% of infants born to women treated with propylthiouracil during pregnancy develop significant transient neonatal hypothyroidism (Diav-Citrin & Ornoy, 2002; Cassina et al., 2012), although clinically inapparent mild hypothyroxinemia is much more common (Cheron et al., 1981; Momotani et al., 1997). Neonatal goiter is also seen in a few percent of infants born to women treated with propylthiouracil during pregnancy but is rarely large enough to cause respiratory compromise (Diav-Citrin & Ornoy, 2002; Cassina et al., 2012). Since either hypothyroidism (resulting from the maternal therapy) or hyperthyroidism (resulting from maternal thyroid-stimulating antibodies) may occur among infants of women who have Graves' disease treated with propylthiouracil during pregnancy, thyroid function should be assessed in these children at the time of birth.

Fetal goiter has been identified by prenatal ultrasound examination or magnetic resonance imaging in women with Graves' disease who were treated with propylthiouracil during pregnancy (Polak, 2011). Fetal blood sampling can be used to distinguish hypothyroidism from hyperthyroidism in such cases. Regression of fetal goiter may occur with adjustment of the maternal propylthiouracil treatment (Polak, 2011).

CONGENITAL ANOMALIES

A meta-analysis found no association between the overall frequency of congenital anomalies among a total of 4321 children of women who had been treated with propylthiouracil early in pregnancy in comparison to the children of hyperthyroid women who had not received medical treatment for hyperthyroidism during pregnancy, but an association was seen in comparison to population controls (summary odds ratio=1.29, 95% confidence interval 1.07-1.55, based on analysis of 2189 exposed pregnancies) (Song et al., 2017). In both comparisons, the only reported study that showed an increased risk for congenital anomalies was one performed through linkage of the extensive Danish population-based record system (Andersen et al., 2013). This association was largely driven by an increased prevalence of face and neck anomalies (odds ratio=4.92, 95% confidence interval 2.04-11.86) and obstructive urinary tract abnormalities (odds ratio=2.73, 95% confidence interval 1.22-6.07) among children whose mothers had been treated with propylthiouracil during pregnancy (Andersen et al., 2013; 2014). Although most of these congenital anomalies were not severe (e.g., preauricular sinus or congenital hydronephrosis), the majority required surgical correction (Andersen et al., 2014; Andersen, 2017). Increased frequencies of ear and urinary tract anomalies were also found among 218 infants whose mothers were prescribed propylthiouracil in early pregnancy in a Swedish record linkage study that was not included in the meta-analysis (Andersen et al., 2017). The overall frequency of malformations among the infants of propylthiouracil-treated mothers was not increased in this study.

Maternal use of propylthiouracil during pregnancy was more frequent than expected among 1052 infants with anorectal atresia (odds ratio=8.62, 95% confidence interval 1.71-40.1), 1137 infants with coarctation of the aorta (odds ratio=7.97, 95% confidence interval 1.58-37.1), and 493 infants with aortic valve stenosis (odds ratio=13.8, 95% confidence interval 2.13-71.2) in the National Birth Defects Prevention Study (Howley et al., 2017). All of these associations are based on only three or four exposed and affected cases and, consequently, the risk estimates are imprecise and the confidence intervals very wide. No associations were seen with propylthiouracil treatment during pregnancy among the mothers of infants with craniosynostosis, gastroschisis, or pulmonary valve stenosis in this study. The design of this study does not permit direct comparison of the results to those in other reported epidemiological studies, so the association between malformations and maternal propylthiouracil treatment observed can neither be confirmed nor refuted by other available data.

Associations with situs inversus with or without dextrocardia, unilateral renal agenesis or dysgenesis, and cardiac outflow tract defects were observed among 47 infants whose mothers were treated with propylthiouracil during the first trimester of pregnancy in an exposed case-only study of 18,131 infants with major malformations whose mothers had all been treated with some medication during the first trimester (Clementi et al., 2010). Although statistically significant at a level of p<0.01, these associations were based on only three, two, and five exposed and affected cases, respectively, and there were 52 groups of congenital anomalies compared in this study.

NEURODEVELOPMENT

No differences in intelligence test scores were found between 28 children of women treated with propylthiouracil during pregnancy in one study or 16 such children in another study and their respective sibs who were born of pregnancies without propylthiouracil treatment (Burrow et al., 1978; Eisenstein et al., 1992).

OTHER ADVERSE EFFECTS

Birth weight, length, and gestational age at delivery were no different among 47 infants born to women who had been treated with propylthiouracil during pregnancy than among infants whose mothers were not treated with propylthiouracil in an Italian cohort study (Gianetti et al., 2015). In contrast, low birth weight was a little more frequent among the infants of hyperthyroid women who were treated with propylthiouracil than among the infants of hyperthyroid women who were not treated during pregnancy in a Taiwanese study (odds ratio=1.40, 95% confidence interval 1.00-1.96) (Chen et al., 2011); the effect was more strongly associated with therapy using >150 mg/d of propylthiouracil and treatment during the second trimester.

The rates of spontaneous abortion were no higher than expected among 52 women who were treated with propylthiouracil during pregnancy (Gianetti et al., 2015).

ANIMAL STUDIES

No teratogenic effects were observed among the offspring of mice or rats treated orally during pregnancy with <1-7 or 3-7 times, respectively, the maximum human therapeutic dose of propylthiouracil (Mallela et al., 2014). Developmental landmarks were delayed among the offspring of rats treated intraperitoneally with propylthiouracil during pregnancy and lactation in a dose similar to that used orally in humans (Zhou et al., 2016). Thyroid enlargement but no malformations were observed among the offspring of rabbits treated during pregnancy with propylthiouracil in a dose slightly greater than that used in humans (Krementz et al., 1957).

Congenital hypothyroidism can be induced in the offspring of mice and rats treated during pregnancy with propylthiouracil (Sui & Gilbert, 2003; Negishi et al., 2005; Zoeller & Crofton, 2005; Shafiee et al., 2016).

Selected References (Each paper is classified as a review [R], human case report [C], human epidemiological study [E], human clinical series [S], animal study [A], or other [O]) :

Andersen SL: Risk of embryopathies with use of antithyroidal medications. Curr Opin Endocrinol Diabetes Obes 24(5):364-371 [R]

Andersen SL, Lonn S, Vestergaard P, Torring O: Birth defects after use of antithyroid drugs in early pregnancy: a Swedish nationwide study. Eur J Endocrinol 177(4):369-378, 2017. [E]

Andersen SL, Olsen J, Wu CS, Laurberg P: Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab 98(11):4373-4381, 2013. [E]

Andersen SL, Olsen J, Wu CS, Laurberg P: Severity of birth defects after propylthiouracil exposure in early pregnancy. Thyroid 24(10):1533-1540, 2014. [E]

Burrow GN, Klatskin EH, Genel M: Intellectual development in children whose mothers received propylthiouracil during pregnancy. Yale J Biol Med 51(2):151-156, 1978. [E]

Cassina M, Dona M, Di Gianantonio E, Clementi M: Pharmacologic treatment of hyperthyroidism during pregnancy. Birth Defects Res A Clin Mol Teratol 94(8):612- 619, 2012. [R]

Chen C-H, Xirasagar S, Lin C-C, Wang L-H, Kou YR, Lin H-C: Risk of adverse perinatal outcomes with antithyroid treatment during pregnancy: a nationwide population-based study. BJOG 118(11):1365-1373, 2011. [E]

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 304(9):525-528, 1981. [S]

Clementi M, Di Gianantonio E, Cassina M, Leoncini E, Botto LD, Mastroiacovo P; SAFE-Med Study Group: Treatment of hyperthyroidism in pregnancy and birth defects. J Clin Endocrinol Metab 95(11):E337-E341, 2010. [E]

Diav-Citrin O, Ornoy A: Teratogen update: antithyroid drugs-methimazole, carbimazole, and propylthiouracil. Teratology 65(1):38-44, 2002. [R]

Eisenstein Z, Weiss M, Katz Y, Bank H: Intellectual capacity of subjects exposed to methimazole or propylthiouracil in utero. Eur J Pediatr 151(8):558-559, 1992. [E]

Gianetti E, Russo L, Orlandi F, Chiovato L, Giusti M, Benvenga S, Moleti M, Vermiglio F, Macchia PE, Vitale M, Regalbuto C, Centanni M, Martino E, Vitti P, Tonacchera M: Pregnancy outcome in women treated with methimazole or propylthiouracil during pregnancy. J Endocrinol Invest 38(9):977-985, 2015. [E]

Howley MM, Fisher SC, Van Zutphen AR, Waller DK, Carmichael SL, Browne ML; The National Birth Defects Prevention Study: Thyroid medication use and birth defects in the National Birth Defects Prevention Study. Birth Defects Res 109(18):1471-1481, 2017. [E]

Krementz ET, Hooper RG, Kempson RL: The effect on the rabbit fetus of the maternal administration of propylthiouracil. Surgery 41(4):619-631, 1957. [A]

Mallela MK, Strobl M, Poulsen RR, Wendler CC, Booth CJ, Rivkees SA: Evaluation of developmental toxicity of propylthiouracil and methimazole. Birth Defects Res B Dev Reprod Toxicol 101(4):300-307, 2014. [A]

Momotani N, Yoshimura J, Ishikawa N, Ito K: Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves' hyperthyroidism. J Clin Endocrinol Metab 82(11):3633-3636, 1997. [E]

Negishi T, Kawasaki K, Sekiguchi S, Ishii Y, Kyuwa S, Kuroda Y, Yoshikawa Y: Attention-deficit and hyperactive neurobehavioural characteristics induced by perinatal hypothyroidism in rats. Behav Brain Res 159(2):323-331, 2005. [A]

Polak M: Thyroid disorders during pregnancy: impact on the fetus. Horm Res Paediatr 76(Suppl 1):97-101, 2011. [R]

Shafiee SM, Vafaei AA, Rashidy-Pour A: Effects of maternal hypothyroidism during pregnancy on learning, memory and hippocampal BDNF in rat pups: beneficial effects of exercise. Neuroscience 329:151-161, 2016. [A]

Song R, Lin H, Chen Y, Zhang X, Feng W: Effects of methimazole and propylthiouracil exposure during pregnancy on the risk of neonatal congenital malformations: A meta-analysis. PLoS One12(7):e0180108, 2017. [E]

Sui L, Gilbert ME: Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology 144(9):4195-4203, 2003. [A]

Zhou L, Zhou J, Jiang J, Yang Y, Huang Q, Yan D, Xu L, Chai Y, Chong L, Sun Z: Reproductive toxicity of ZishenYutai pill in rats: Perinatal and postnatal development study. Regul Toxicol Pharmacol 81:120-127 [A]

Zoeller RT, Crofton KM: Mode of action: developmental thyroid hormone insufficiency--neurological abnormalities resulting from exposure to propylthiouracil. Crit Rev Toxicol 35(8-9):771-781, 2005. [R]