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Three Part Question

In [pregnant women with hyperthyroidism], are [thioamides safe and effective] at [treating symptoms of maternal hyperthyroidism, maintaining maternal FT4 and FTI in the high-normal range, and/or reducing complications of pregnancy and harm to the mother, fetus, and neonate]?

Clinical Scenario

The patient is a 39 yo Afr-Am G3P0Ab2 with IUP at about 22 weeks with hyperemesis gravidarium and clinical Grave's disease. At 20 weeks, blood tests show that her serum TSH is suppressed at 0.02 mIU/ml (0.4-3.5), free T4 is 3.0 ng/dL (0.8-1.8) and free T3 is 2.6 ng/dL (0.2-0.6), her pulse is about 120. Ultrasound shows borderline normal fetal growth with a fetal heart rate of 170 (120-160). She is currently being treated with PTU (propylthiouracil) 200 mg TID. At about 22 weeks, targeted ultrasound reveals low normal fetal weight, a fetal anterior neck mass consistent with fetal goiter, normal amniotic fluid volume, and fetal heart rate of 150. How should the mother be treated?

Search Strategy

Search PubMed for: "treatment of hyperthyroidism in pregnancy with propylthiouracil and methimazole."
Limits: English, Female, Humans.

Search Outcome

Altogether 49 papers were found in PubMed, of which 7 were relevant to answering the question. Two of these papers were of insufficient quality. The remaining 5 papers are summarized in the table below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Azzizi F, et al. 2000 Iran	139 thyrotoxic lactating mothers and their infants were studied. 51 were treated with MMI during pregnancy, and MMI was continued during breast-feeding. 88 mothers were given 10 mg MMI (n 46) or 20 mg MMI (n = 42) daily for 1 month, 10 mg daily for the second month, and 5-10 mg daily thereafter.	Clinical Trial	Serum T4, T3, and TSH concentrations in mothers and their infants. Serum MMI in the infants of mothers taking 20 mg MMI. Thyroid function, urinary iodine, thyroid antibodies, IQ on 14 children 48-74 months of age and on 17 controls.	Mean +/- SD of FT4I in thyrotoxic lactating mothers treated with 10 mg MMI for 1 month decreased from 19.4 +/- 4.1 to 11.6 +/- 4.4 and from 20.5 +/- 4.7 to 9.8 +/- 1.5 when treated with 20 mg MMI. In all infants FT4I, FT3I, and TSH concentrations were normal before and up to 12 months of MMI therapy in their lactating mothers. The mean IQ was 107 +/- 14 vs. 106 +/- 16 (Goodenough test) and 103 +/- 10 vs. 103 +/- 16 (Wechsler test) for infants of thyrotoxic lactating mothers and control infants, respectively. No deleterious effects occur in thyroid function and physical and intellectual development of breast-fed infants whose lactating mothers were treated with doses of MMI up to 20 mg daily.	Not randomized or blinded.
Momotani N, et al. 1997 Japan	77 mothers with Graves' hyperthyroidism who were receiving thionamides (34 PTU, 43 MMI) and whose free T4 (FT4) levels were within the normal range. 32 healthy women who had no history of thyroid disease and who were delivered at term served as normal controls.	Clinical Trial	Fetal thyroid status; Dose effects.	No significant difference in the occurrence of low and mean fetal FT4 or TSH levels between group P and group M. Little relationship was observed between maternal doses and fetal thyroid status. Higher doses were associated with normal or low fetal TSH levels. In terms of fetal hypothyroidism-inducing potential, there is little reason to choose PTU over MMI. Individualized doses should be used.	Not randomized or blinded. Small sample.
Mandel SJ, et al. 1994. USA.	N/A	Review, Case Report	Occurrence of Aplasia Cutis Congenita (ACC); impairment of fetal thyroid function.	Reports 1 example of ACC. There is insufficient evidence either to establish or eliminate a direct causal relationship between ACC and MMI use. Since propylthiouracil is equally effective and has not been associated with ACC, it is the preferred thioamide for hyperthyroidism during pregnancy. Impairment of neonatal thyroid function may be minimized by using a thioamide dose that is just sufficient to maintain the maternal serum free thyroxine concentration in the high normal or slightly thyrotoxic range.	Single case report; review/not trial.
Wing DA, et al. 1994 USA	185 pregnant patients with a history or diagnosis of hyperthyroidism. 99 patients were treated with propylthiouracil and 36 with methimazole.	Retrospective chart review.	The response to therapy was compared with respect to the time to normalization of the free thyroxine index and the incidences of congenital anomalies and hypothyroidism.	The median time to normalization of the free thyroxine index on PTU and MMI was 7 and 8 weeks, respectively (p = 0.34, log-rank test). The incidence of major congenital malformations in mothers treated with PTU and MMI was 3.0% and 2.7%, respectively. No neonatal scalp defects were seen. PTU and MMI are equally effective and safe in the treatment of hyperthyroidism in pregnancy.	Retrospective; no controls. Not randomized or blinded.
Eisenstein Z, et al. 1992. Israel.	31 subjects aged 4-23 years, born to women with Grave's disease who received antithyroid drugs (15 MMI, 16 PTU) throughout pregnancy. 25 unexposed siblings served as controls.	Clinical Trial	I.Q. was assessed using the Wechsler test appropriate for age.	The exposed and unexposed groups did not differ with respect to the total I.Q. Both groups scored equally in verbal and performance skills and in each of six main subcategories of the tests. There was no difference between exposure to MMI and PTU or between the higher and lower dosages. All children were euthyroid at birth and none had goiter. Conclude that exposure to MMI or PTU during pregnancy in doses sufficient to control maternal hyperthyroidism does not pose any threat to intellectual capacity of the offspring.	Small sample. Not randomized or blinded.

Comment(s)

There have been no randomized, double-blind, placebo controlled clinical trials comparing MMI to PTU. The studies discussed above have found no significant difference between PTU and MMI in mean FT4 or TSH levels in newborn cord-blood samples, as well as no cases of aplasia cutis and similar rates of fetal anomalies for both agents. Women treated with PTU or MMI can breastfeed safely. Further, the goal of treatment should be to maintain FT4 or FTI in the high-normal range using the lowest possible thioamide dosage. Since propylthiouracil is equally effective and has not been associated with ACC, it is the preferred thioamide for hyperthyroidism during pregnancy. (Practice Guidelines: ACOG Practice Bulletin on Thyroid Disease in Pregnancy http://www.aafp.org/afp/20020515/practice.html).

Clinical Bottom Line

Thioamides (propylthiouracil or methimazole) are used to treat hyperthyroidism in pregnant women. According to the practice guidelines, the lowest possible thioamide dosage should be used to maintain FT4 or FTI in the high-normal range. It can be beneficial to measure FT4 or FTI every 2-4 weeks. A beta blocker (e.g., propanolol) can be used to treat symptoms until the thioamide therapy begins to have an effect. Side effects of thioamides include agranulocytosis, hepatitis, vasculitis, and thrombocytopenia. The fetus and neonate should be monitored for signs of both thyroid suppression (hypothyroidism) and hyperthyroidism. Thyroidectomy is an option for women who do not respond to thioamide therapy. Iodine 131 (I-131) is contraindicated in pregnant women. (Practice Guidelines: ACOG Practice Bulletin on Thyroid Disease in Pregnancy http://www.aafp.org/afp/20020515/practice.html).

References

1. Azizi F, Khoshniat M, Bahrainian M, Hedayati M. Thyroid function and intellectual development of infants nursed by mothers taking methimazole. J Clin Endocrinol Metab. 2000 Sep;85(9):3233-8.
2. Momotani N, Noh JY, Ishikawa N, Ito K. Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves' hyperthyroidism. J Clin Endocrinol Metab. 1997 Nov;82(11):3633-6.
3. Mandel SJ, Brent GA, Larsen PR. Review of antithyroid drug use during pregnancy and report of a case of aplasia cutis. Thyroid. 1994 Spring;4(1):129-33.
4. 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 Jan;170(1 Pt 1):90-5.
5. Eisenstein Z, Weiss M, Katz Y, Bank H. Intellectual capacity of subjects exposed to methimazole or propylthiouracil in utero. Eur J Pediatr. 1992 Aug;151(8):558-9.