a comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy

A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy Deborah A. Wing, MD, Lynnae K. Millar, MD, Paul P. Koonings, MD, Martin N. Montoro, MD, and Jorge H. Mestman, MD'' Los Angeles, California

OBJECTIVE: Our purpose was to demonstrate that propylthiouracil and methimazole are equally effective and safe In the treatment of hyperthyroidism during pregnancy. STUDY DESIGN: Between 1974 and 1990 records were available on 185 pregnant patients with a history or diagnosis of hyperthyroidism. Ninety-nine patients were treated with propylthiouracil and 36 with methimazole. 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. RESULTS: The time to normalization of the free thyroxine index was compared in the two groups by

means of survival analysis. The median time to normalization of the free thyroxine index on propyithiouracil and methimazole was 7 and 8 weeks, respectively (p = 0.34, log-rank test). The incidence of major congenital malformations in mothers treated with propylthiouracil and methimazole was 3.0% and 2.7%, respectively. No neonatal scalp defects were seen. One infant was overtly hypothyroid at delivery. CONCLUSION: Propylthiouracil and methimazole are equally effective and safe in the treatment of hyperthyroidism in pregnancy. (Ani J OBSTET GmECOL 1994; 170: 90-5. )

Key words: Hyperthyroidism, propylthiouracil, methimazole, congenital anomalies

Hyperthyroidism in pregnancy has a prevalence of approximately 0.2%, ' and in the United States it is generally treated with one of the thioamides, propylthiouracil or 1-methyl-2-mercaptoimidazole (methimazole). Both block thyroid hormone synthesis by prevent- ing iodination of tyrosine residues in thyroglobulin; additionally, propylthiouracil acts peripherally to in- hibit the conversion of thyroxine to triiodothyronine. Both agents cross the placenta, although propylthiouracil does so to a lesser degree than does methimazole. ̀ ' Additionally, methimazole has been associated with neonatal aplasia cutis, a scalp defect. '- ' For these reasons some clinicians may choose to avoid prescribing methimazole. There is a paucity of literature comparing propylthiouracil with methimazole with regard to maternal and fetal outcomes. This study was performed to compare the efficacy of these two agents in the pregnancy outcomes of hyperthyroid patients.

From the Division of Maternal-Fetal Medicine, Department of Ob- stetr: cs and Gynecology" and the Division of Diabetes, Hypertension, and Nutrition, Department of Medzlne, ̀ Los Angeles County/Uni- versity of Southern California Medical Center, Women's Hospital. Received for publication April 20,1993; revised July 9,1993; accepted August 10,1993. Reprint requests: Jorge H. Mestman, MD, USC Health Care Con- sultation Center, 1355 San Pablo St., Los Angeles, CA 90033. Copyright ® 1994 by Mosby-Year Book, Inc. 0002-9378/94 $1.00 + . 20 6/1/50626

Methods A total of 227 patients with a history or diagnosis of

hyperthyroidism were evaluated in our high-risk obstet- rics clinic between July 1974 and June 1990. The patients were followed up prospectively during pregnancy with physical examinations and thyroid function tests to monitor the disease process and treatment efficacy. The patients were considered to be hyperthy-

roid on the basis of history, physical examination, free thyroxine index, free triiodothyronine index, and, since 1985, sensitive thyroid-stimulating hormone (TSH). The normal range for the free thyroxine index in our laboratory is 4.5 to 13.2. The free triiodothyronine index was used to assess the progress of treatment. The normal range is 70 to 235. The normal range for TSH is 0.4 to 5.0 mU/ml. We attempted to maintain the free thyroxine index in the upper normal range. 6 7 An attempt was made to wean patients from thioamide therapy in the last 4 to 8 weeks of pregnancy if their thyroid function tests were normal and if they had been

maintained on a regimen of low doses of medication. Total thyroxine and total triiodothyronine were mea-

sured by radioimmunoassay. Resin triiodothyronine uptake was measured with a commercial kit (Biomedicus, Costa Mesa, Calif. ). The free thyroxine index and the free triiodothyronine index were calculated as the prod- uct of the thyroxine or triiodothyronine concentrations

90

Volume 170, Number 1, Part I Am J Obstet Gynecol

227 hyperuryrow patrnes '""ý

Wing et al. 91

15 euUryrokl lhrotighmA

135 Pxt u treated 99 Petients pegnWICY with PTU or methýmemle

treated with PTU 32 hyperthyroid

throughout 6 crosaowrs pregnancy (PTU and methwnazole

185 d th 52 hyperthyroa ring e same, gestation)

(83% chart recall) at presentation. 43 Patients: No suU+rob at medications daIrmry

(48 complete 1 Patent received PTU data sets) LM 15 weeks EGA, then 1311 before known to be pregnant, thereafter 21

hyperthyroid maintained on thyroid at presentation, replacement. authyroid at

delivery

36 patients (18 complete treated with

data sets)

Methimazole U t"rthyrola thm hau

pregnancy

3 euthyrokl throughout pregnancy

Fig. 1. Breakdown of patients by treatment group. PTU Propylthiouracil; EGA, estimated gestational age.

and the resin triiodothyronine uptake, as described

previously. " Before February 1990 TSH was measured by immunoradiometric assay with human TSH kits (Abbott, Chicago). Since then TSfi has been measured by chemiluminescence (Nichols Institute, San Juan Capistrano, Calif. ). The interassay variation for TSH

was 0.5 mU/ml and 2.7%, respectively. Retrospectively, the maternal and fetal outcomes

were reviewed from clinic, labor, delivery, and postpar- tum records. Of the 227 charts recalled, 83% were

available for review; this represented 185 patients (Fig.

1). A cohort was established to compare the outcome of

patients treated with propylthiouracil and methimazole. When the patients were first seen, free thyroxine index,

free triiodothyronine index, TSH, and medication dos-

ages were recorded. Outcomes measured included time

to normalization of free thyroxine index on medication, incidence of congenital anomalies, and incidence of

congenital hypothyroidism. A major congenital anom-

aly was defined as a gross structural lesion detected by

the pediatrician, which required surgical repair or had

a significant impact on the infant's life. Neonatal thy-

roxine screening was performed under the California

state screening program by means of a filter paper blood spot assay; neonatal TSH measurements were

performed only if the thyroxine levels were found to be

abnormal. Statistical significance of time to normalization of free

thyroxine index was analyzed by survival analysis. The

X` test was used to analyze the incidence of congenital

anomalies between the two treatment groups. Differ-

ences and correlations were considered significant at a

level of p50.05. No statistical adjustment was made for multiple end points. We accepted an increased chance of a type I error to minimize whatever type II error existed. This was to maximize the power in the study.

Results There was no statistically significant difference in

treatment groups with respect to age, parity, and eth- nicity. The prevalence of hyperthyroidism in the pregnant population at Los Angeles County/University of Southern California Medical Center was 0.1% during the study period. There were 241,036 births during this time interval. One hundred thirty-five hyperthyroid patients were treated with either propylthiouracil (99 patients) or methimazole (36 patients) on the basis of the personal choice of their physicians (Fig. 1). Forty- three patients were either euthyroid throughout pregnancy and required no medications or were hyperthyroid but were seen late in pregnancy. These latter patients were delivered before therapy could be insti- tuted. One patient received propylthiouracil until 5 weeks of gestation, then received iodine 131 before she was known to be pregnant. She was maintained on thyroid replacement for the duration of her pregnancy. Six patients received both medications during their pregnancies. These patients were not included in the data analysis regarding treatment effectiveness.

In two patients propylthiouracil was discontinued secondary to allergic skin rashes. These patients were then placed on methimazole for the remainder of their pregnancies. One patient had non-A, non-B hepatitis

92 Wing et al. January 1994 Am J Obstes Gynecol

100

J

Ö

z 75 PTU (N=48)

------------------- Methimazole (N=18) V Note: As treatment continued, the

ts in each rou t f ti 50 g p en percen age o pa who remained hyperthyroid decreased.

D '- --

LL 0

Z 0 25 P=0.34 ä

7 14 21

WEEKS OF FOLLOW-UP

Fig. 2. Time to normalization of free thyroxine index. PTU, Propylthiouracil.

and was switched from propylthiouracil to methimazole. Three other patients changed medications for unknown reasons. At delivery 32 patients (32%) treated wtih propylthiouracil remained hyperthyroid, compared with 12 (33%) in the methimazole-treated group.

Maternal. Of the 185 hyperthyroid women in the study 60% of patients who achieved euthyroid status by the time of delivery were seen in our clinic during the second trimester. Of the remainder, equal percentages were seen in the first and third trimesters. The gestational age at presentation did not affect the time to normalization of free thyroxine index. None of the patients seen after 34 weeks' estimated gestational age in whom medications were begun became euthyroid by

parturition. The median maximal daily medication dose of pro-

pylthiouracil was 450 mg with a range of 150 to 600

mg; the median maximal daily dose of methimazole was 40 mg (range 10 to 60 mg). The median minimal daily dose of propylthiouracil was 100 mg with a range of 100

to 600 mg; the median minimal daily dose of methimazole was 10 mg (range of 10 to 60 mg). These doses are comparable.

The time to normalization of free thyroxine index

was compared in patients who were hyperthyroid when first seen and euthyroid at delivery. The median time to normalization of free thyroxine index in 48 propylthiouracil- and 18 methimazole-treated patients was 7 (range 0 to 20) and 8 (range 0 to 23) weeks, respectively (Fig. 2). This difference was not statistically significant by log-rank test with ap value of 0.34. Patients placed

on propylthiouracil had a lower free thyroxine index

when they were first examined. The mean initial free thyroxine index on propylthiouracil was 24.5 (SD ± 8.03), whereas the mean initial free thyroxine index in the methimazole-treated group was 27.2 (SD ± 13.04, two-group t test with log transformation) (Table I). The Cox proportional hazard model was used to compare the time of normalization of free thyroxine index in the two treatment groups after adjusting for the initial

measurements. These results confirmed no statistical difference in the rate of normalization between propylthiouracil- and methimazole-treated patients (p = 0.52).

Fetal. Of the 185 pregnant women who were diag-

nosed with or had a history of hyperthyroidism during

pregnancy with available records, six infants were delivered with major congenital anomalies (Table II). None of the mothers delivered of anomalous fetuses had other medical complications of the pregnancies as confounding factors in this analysis. Three of these six anomalies occurred in 154 mothers who were hyperthy-

roid during the period of embryogenesis (1.9%), and the other three occurred in mothers who were euthyroid. The incidence of major congenital anomalies in the general population ranges from 2% to 5%; therefore the incidence of congenital anomalies in patients who were hyperthyroid during embryogenesis in our study was consistent with the national average.

The frequency of congenital anomalies in the two treatment groups was compared in the 99 patients who were treated wtih propylthiouracil with the 36 patients

Volume 170, Number 1, Part I Am J Obstet Gynecol

Table I. Summary of data for time to normalization of free thyroxine index

Wing et al. 93

Propylthiouracil Methimazole (n = 48) (n = 18) Significance

Initial free thyroxine index (mean ± SD) 24.5 ± 8.03 27.2 ± 13.04 p=0.46* Treatment time (wk)

Median 7 8p=0.34t Range 0-20 0-23

Note: Cox proportional hazard model was used to compare the time to normalization of free thyroxine index in the two treatment groups adjusting for the initial measurements. The p value is 0.52 and not statistically significant.

"Two-group t test with log transformation. tLog-rank test.

Table II. Congenital anomalies in hyperthyroid patients

Medication No. of

patients Anomalies Thyroid status at presentation

Time medication initiated

Propylthiouracil 99 Severe pulmonic Hyperthyroid stenosis All 3 patients were > 15

Ventricular septal Hyperthyroid wk estimated gesta- defect tional age before ini-

Patent ductus arterio- Hyperthyroid tiation of propylthio- sus in a term infant uracil

Methimazole 36 Congenital inguinal Euthyroid Before conception hernia

Crossovers 6 None Not applicable Not applicable Multiple therapeutic I Congenital inguinal Euthyroid Before conception

modalities* hernia None 43 Hydrocephalus (nor- Euthyroid (spontane- Not applicable

mal chromosomes) ous remission)

This patient received propylthiouracil until 5 weeks' estimated gestational age; then she received therapeutic ''I before she was known to be pregnant and euthyroid status was achieved. She was maintained on a regimen of thyroid replacement for the remainder of the pregnancy.

in the methimazole-treated group (Table II). The incidence of major congenital anomalies in infants of propylthiouracil-treated mothers was 3.0% (three of 99),

whereas the incidence of anomalies in infants of methimazole-treated mothers was 2.7% (one of 36). No cases of aplasia cutis were reported among neonates of mothers receiving either medication.

One infant was delivered with overt congenital hy-

pothyroidism, presumably secondary to maternal inges-

tion of propylthiouracil during pregnancy. This infant had an initial total thyroxine level of 3 µgm/dl and an initial TSH level of 38 mU/ml. The mother of this infant

was hyperthyroid when first seen, with a free thyroxine index of 20.2. She was treated with 100 mg of propyl-

thiouracil three times a day until severe preeclampsia

occurred at 34 weeks of gestation, necessitating deliv-

ery. The infant was treated for prematurity for several

weeks in the neonatal intensive care unit but was even- tually discharged home with normal thyroid function

tests.

Comment The outcomes of pregnancies complicated by hyper-

thyroidism treated with either propylthiouracil or methimazole were compared with respect to the time to

normalization of the free thyroxine index, the incidence

of congenital anomalies, and the incidence of congenital hypothyroidism. Notably, side effects from either medication were uncommon. Propylthiouracil was dis-

continued in two patients secondary to allergic skin reactions. Skin rash is known to occur in approximately 5% of patients treated with these medications. ' Cross

reactions rarely occur with the thioamides, and both of these patients did well on methimazole. No cases of agranulocytosis, the most severe complication of thioamide therapy, were seen.

No significant difference in the time to normalization

of the free thyroxine index was noted in the two

treatment groups, after adjusting for the initial mea-

surements (p = 0.52). The median time to normalization in the propylthiouracil-treated group was 7 weeks (range 0 to 20), and the median time to normalization in the methimazole-treated group was 8 weeks (range 0

to 23). Thus it appears that each medication functions

at the same rate to normalize thyroid function tests. This result differs from a prior report by Okamura et al. '° in nonpregnant patients; they showed methimazole

normalizes serum triiodothyronine and thyroxine levels

much faster than propylthiouracil does.

We found that the incidence of major congenital

94 Wing et al.

anomalies in infants of propylthiouracil-treated mothers was 3%, whereas the incidence of anomalies in infants in methimazole-treated mothers was 2.7%. These findings are not statistically different, are consistent with the incidence of major anomalies in the general population, and are consistent with previous findings by Khoury et al. " They demonstrated no increased risk of birth defects for pregnant women with thyroid disease, regardless of the presence or absence of treatment, in a population-based, case-control study. Obviously, because congenital malformations occur rarely, it would be necessary to evaluate large numbers of patients to elucidate subtle increases in number of anomalies in medicated patients.

Momotani et al., ̀ with a study base of 643 neonates born to mothers with Graves' disease, observed the influence of maternal ingestion of methimazole during

the first trimester versus the presence of uncontrolled hyperthyroidism on the incidence of congenital anomalies. They showed that uncontrolled maternal hyperthyroidism may cause congenital malformations in as many as 6% of infants of afflicted mothers. However,

our study did not confirm this finding. Only 1.9% of our mothers who were hyperthyroid during embryogenesis gave birth to infants with anomalies.

Our study did not substantiate previous reports of aplasia cutis associated with the maternal use of methimazole. Nor were umbilical defects seen. A recent review of the literature reveals only 11 cases demon- strating the association between the maternal ingestion of methimazole during pregnancy and congenital scalp defects. ' Furthermore, it should be noted that congenital skin defects often have a familial occurrence. "- 14 Milham documented that four of these 11 cases were the offspring of only two mothers. ' Van Dijke et al. 's demonstrated that the occurrence risk for congenital scalp defects was not statistically different for those patients with hyperthyroidism treated with methimazole or its analog carbimazole when compared to euthyroid untreated controls. This risk is < l%. " In this retrospective study review of records for all patients with congenital skin defects born during a 27-year period revealed a 0.05% incidence of congenital skin defects with a 0.03% incidence of congenital skin defects confined to the scalp. None of the 25 infants with congenital skin defects were born to mothers treated with antithyroid drugs, whereas in 24 patients treated during the first trimester with thioamides no cases of congenital skin defects were detected. This conclusion is supported by the data of biomotani et al., 12 which failed to demonstrate any cases of the skin defect in 243 neonates of methimazole-treated mothers. The alleged propensity of methimazole to cause congenital scalp defects is insufficiently supported to preclude its use in pregnancy.

January 1994 Am J Obstet Gynecol

Other researchers have clearly delineated the safety of using methimazole or carbimazole during pregnancy. Studies on the offspring of mothers treated with thioamides have failed to demonstrate any adverse effects on neonatal thyroid function, neonatal outcome, long-term growth, and intellectual development. Bur- row et al. 15 revealed no discernible impairment in intellectual development, physical development, or thyroid function studies when matching offspring exposed to propylthiouracil in utero with their nonexposed siblings. Furthermore, McCarroll et al. " reached simi- lar conclusions in surveying the long-term effects of carbimazole exposure in utero. No differences have been noted in the effects of propylthiouracil or methimazole on fetal thyroid function. " Long-term sur- veillance of maternal thioamide therapy on the somatic growth and psychologic and intellectual development of children born to these mothers has failed to demonstrate any detrimental effects in the offspring. "

Congenital hypothyroidism may result from maternal administration of antithyroid medication. " Only one overtly hypothyroid infant was born to a hyperthyroid mother managed with propylthiouracil in our study. Because the California state screening program per- forms TSH levels only when thyroxine levels are found to be abnormal, it is possible that several cases of subclinical neonatal hypothyroidism secondary to maternal thioamide use, as evidenced by normal thyroxine and elevated TSH levels, were missed.

Several factors, addressed by Cooper, ' should be considered when prescribing medication for hyperthyroidism during pregnancy. Pharmacologically, propylthiouracil has a much shorter serum half-life than does methimazole, 1 hour versus 6 to 8 hours, respectively, and accordingly must be administered more frequently. ' Propylthiouracil is extensively protein bound, whereas there is little appreciable binding of methimazole to serum albumin; accordingly, there is little trans- placental transfer of propylthiouracil compared with methimazole. 2 The less frequent dosing of methimazole increases patient compliance with the medication regimen. It also appears that at low doses methimazole is associated with less major toxicity, including agranulocytosis, hepatic damage, and lupus-like syndromes, than is propylthiouracil. 9 The cost of methimazole is also less than that of propylthiouracil, and patients report less metallic aftertaste with methimazole.

Medication choice in breast-feeding mothers is ex- tremely important. Both agents are excreted in breast

milk, but propylthiouracil crosses to a lesser degree than does methimazole secondary to higher protein binding at physiologic pH; it is correspondingly found in lesser concentrations in breast milk than is methimazole. zO" Y' Therefore propylthiouracil is the drug of choice in breast-feeding patients, although it is sug-

Volume 170, Number 1, Part I Am j Obstet Gynecol

gested that either drug may be used in breast-feeding

patients if infant thyroid function status is surveyed on

a regular basis. 22 Several small studies attest to the

safety of maternal thioamide ingestion while breast-

feeding. Lamberg et al. Y9 found no cases of neonatal hypothyroidism in 13 breast-fed infants of mothers maintained on low-dose carbimazole post partum. Mo-

motani et al. 24 evaluated eight hypothyroid neonates

whose mothers had been treated with propylthiouracil during their pregnancies and who were later breast-fed

while their mothers continued on propylthiouracil. Res-

olution of the fetal hypothyroidism was attributed to the disappearance of the effects of in utero exposure to

propylthiouracil. There are limitations to this study. The power of this

study is inadequate to assess equivalence of the two medications. However, the data represented here was collected over a 16-year period; a much more lengthy

period of time would be required to obtain enough data

to give this study adequate power. Also in this study selection bias is present, because the medications to treat the hyperthyroid patients were chosen by physi- cian preference. The mean initial free thyroxine index in the methimazole-treated patients was slightly higher

than that in the propylthiouracil-treated patients. It is

possible methimazole was used to treat less compliant patients because it can be dosed less frequently. ' Also, because 17% of the charts were unavailable for review, ascertainment bias was possible.

In summary, propylthiouracil and methimazole are equally safe and effective in the treatment of hyperthy-

roidism. Both medications are well tolerated. The rate of normalization of the free thyroxine index is equal with each medication. There is no difference in maternal and fetal morbidity in patients treated with either drug. No increased incidence in congenital anomalies in the offspring of patients exposed to either medication was detected over the incidence in the general population.

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a comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy

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