Substituting Potassium Iodide for Methimazole as the Treatment for Graves' Disease During the First Trimester May Reduce the Incidence of Congenital Anomalies: A Retrospective Study at a Single Medical Institution in Japan

Abstract

Background:

To control hyperthyroidism due to Graves' disease, antithyroid drugs should be administered. Several studies have shown that exposure to methimazole (MMI) during the first trimester of pregnancy increases the incidence of specific congenital anomalies that are collectively referred to as MMI embryopathy. Congenital anomalies associated with exposure to propylthiouracil (PTU) have also recently been reported.

Methods:

This study investigated whether substituting potassium iodide (KI) for MMI in the first trimester would result in a lower incidence of major congenital anomalies than continuing treatment with MMI alone. The cases of 283 women with Graves' disease (GD) were reviewed whose treatment was switched from MMI to KI in the first trimester (iodine group), as well as the cases of 1333 patients treated with MMI alone (MMI group) for comparison. Another major outcome of interest was the incidence of neonatal thyroid dysfunction. The subjects of the analysis of major congenital anomalies and neonatal thyroid dysfunction were live-born infants.

Results:

The incidence of major anomalies was 4/260 (1.53%) in the iodine group, which was significantly lower than the incidence of 47/1134 (4.14%) in the MMI group. Two neonates in the iodine group had anomalies consistent with MMI embryopathy (0.8%), as opposed to 18 neonates in the MMI group (1.6%). None of the neonates exposed to KI had thyroid dysfunction or goiter.

Conclusions:

Substituting KI for MMI as a means of controlling hyperthyroidism in GD patients during the first trimester may reduce the incidence of congenital anomalies, at least in iodine-sufficient regions.

Introduction

Thyrotoxicosis occurs in approximately 0.2% of pregnancies, and the most common cause of the thyrotoxicosis is Graves' disease (GD) (1,2). GD is common in young women of childbearing age, and poorly controlled GD during pregnancy can cause serious complications in both the mother and the fetus. A number of observational studies have consistently linked overt hyperthyroidism during pregnancy to higher risks of miscarriage, pregnancy-induced hypertension, prematurity, low birth weight (3), intrauterine growth restriction, and preterm birth (4,5).

Because of the possible associations of methimazole (MMI) with specific congenital anomalies (choanal atresia, aplasia cutis, esophageal atresia), propylthiouracil (PTU) is recommended as the first-line antithyroid drug for the treatment of hyperthyroidism during the first trimester of pregnancy (6 –11). PTU has been found to be hepatotoxic, and the guidelines of the Endocrine Society and the American Thyroid Association (ATA) recommend restricting treatment with PTU during pregnancy to the first trimester and that a switch be made to MMI thereafter (12,13). Andersen et al. reported finding that exposure to PTU in early pregnancy was associated with an increased prevalence of congenital anomalies, including face and neck anomalies and urinary system anomalies (14,15).

For GD patients treated with MMI who cannot tolerate PTU because of adverse effects, treatment for hyperthyroidism during the first trimester of pregnancy becomes a problem. To minimize the risk to both the mother and the fetus in such cases, the authors have been switching patients from MMI to potassium iodide (KI) to control hyperthyroidism in the first trimester. Inorganic iodide is usually used to treat GD patients before surgery or during a thyroid storm (16). Treatment of GD with KI is widely approved in Japan, and its efficacy widely acknowledged (17 –19). Although treatment of GD patients with KI is usually considered contraindicated during pregnancy in other countries, Momotani et al. reported that KI therapy is an effective and safe method of treating mild hyperthyroidism during pregnancy (20). An association between exposure to antithyroid drugs (ATDs) during early pregnancy and congenital anomalies became a concern in 2000, and some patients were switched from treated with MMI to KI at their first visit after conception.

This was a retrospective study to determine whether switching from MMI to KI in the first trimester of pregnancy would decrease the incidence of major congenital anomalies in comparison to treatment with MMI alone, and to determine the incidence of neonatal goiter accompanied by abnormal thyroid function in the neonates. Pregnancy outcome, birth weight, and gestational age at delivery were also evaluated.

Subjects and Methods

The cases of 283 women with GD were reviewed who were switched from MMI to inorganic iodide to control hyperthyroidism in the first trimester (iodine group) between January 1, 2000, and March 31, 2013. The diagnosis of GD was based on the clinical findings, that is, the presence of a goiter and/or ophthalmopathy, elevated free triiodothyronine (fT3) and free thyroxine (fT4) levels, a suppressed thyrotropin (TSH) level, and a positive TSH receptor antibody test. In some patients, radioactive iodine uptake was measured as a diagnostic test before pregnancy.

The thyroid hormone status of each woman was evaluated during the first trimester of pregnancy by reviewing the fT3, fT4, and TSH levels obtained in measurements made before the switch from MMI to KI. Their thyroid hormone levels were measured again two to four weeks after the switch to iodine. KI was prescribed as an inorganic iodine dose of 10–30 mg/day in the form of a solution (10 mg of KI per drop of the infusion) or KI tablets (38 mg of KI per tablet). When the fT4 level after the substitution was within the reference range, the KI dose was tapered, and when the fT4 level had risen, the KI dose was increased during the first trimester. When a patient being treated with KI was still hyperthyroid in the second trimester, an ATD was added to KI, or an ATD was substituted for KI.

An association between exposure to MMI during early pregnancy and congenital anomalies became a concern in 2000, and that is when the authors started to substitute KI for MMI in some patients in the first trimester, but most patients continued to be treated with MMI. Since a clear association was noticed between MMI and congenital anomalies early in 2004, at that point, KI began to be substituted for MMI in the first trimester whenever possible, regardless of the patient's thyroid size or TRAb titer.

Of the 283 patients in the iodine group, 222 (78%) patients conceived in or after 2004. As a control group, the cases of 1333 patients with GD were also reviewed who became pregnant during the same period and were treated with MMI alone (MMI group). Even after 2004, when KI began to be substituted for MMI, GD patients who came to the authors' hospital after the second trimester of pregnancy and who had been treated with MMI at a previous hospital were continued on MMI, and they constituted the MMI group in this study. Of the 1333 patients in the MMI group, 330 (24.8%) conceived in or after 2004, and the number of patients being treated with MMI decreased year by year until 2013.

The subjects of the analysis for the presence of major congenital anomalies were live-born infants. The information concerning the neonates was collected from patients at their first visit to the authors' hospital after delivery. Patients are routinely asked to fill out a diagnostic questionnaire related to their delivery, and the information is confirmed by their physician. If a malformation is reported, their physician corresponds with their gynecologist. Another major outcome of interest was the incidence of neonatal thyroid dysfunction with or without goiter. Thyroid hormone levels of mother and umbilical cords in the infants were measured at the time of delivery. To investigate the influence of KI and ATD on fetal thyroid function, the cases of women who were exposed to KI or an ATD beyond the third trimester of pregnancy were reviewed. Secondary endpoints were pregnancy outcome (live birth, miscarriage, elective abortion, or perinatal loss), rate of preterm delivery (i.e., delivery at <37 weeks gestational age), gestational age at delivery, and birth weight.

Laboratory methods

TSH, fT3, and fT4 levels were measured by electrochemiluminescence immunoassays (ECLusys TSH, ECLusys fT3, and ECLusys fT4, respectively; Roche Diagnostics GmbH, Mannheim, Germany). The manufacturer's reference limits were: TSH 0.2–4.5 mIU/L, fT3 2.2–4.3 pg/mL, and fT4 0.8–1.6 ng/dL. Based on the results of a previous study of a large population, the reference intervals for maternal TSH and fT4 in the first trimester of pregnancy were 0.01–3.35 mIU/L and 0.77–1.91 ng/dL, respectively, and in the third trimester of pregnancy, they were 0.01–3.67 mIU/L and 0.44–1.61 ng/dL, respectively. The reference range for umbilical cord serum TSH was 0.09–18.0 mUI/L, and for fT4 it was 1.04–1.62 ng/dL.

Statistical analysis

The statistical analysis was performed with JMP software v11.0 (SAS Institute, Inc., Cary, NC). Dichotomous data were compared with chi square or Fisher's exact tests, whichever was appropriate, and were expressed as percentages. p-Values of < 0.05 were considered significant.

Results

Maternal characteristics and pregnancy outcomes

Maternal characteristics in the iodine group (n = 283) and the MMI group (n = 1333) are compared in Table 1. There were 15 miscarriages, 4 elective abortions, and 4 perinatal losses in the iodine group, and 164 miscarriages, 30 elective abortions, and 5 perinatal losses in the MMI group. A higher proportion of women in the MMI group (12.3%) had a miscarriage than in the iodine group (5.3%; p < 0.05). Gestational age at the time of the miscarriage was 8.7 ± 3.0 weeks (M ± SD) in the MMI group and 10.0 ± 2.9 weeks in the iodine group, and the difference was not significant (p = 0.128). Of the four perinatal losses in the iodine group, one was due to placental abruption, one to acrania, and two to coiling of the umbilical cord. All four mothers were euthyroid throughout their pregnancy. Of the five perinatal losses in the MMI group, two were due to coiling of the umbilical cord, and the causes of the other three are unknown. The reason for the higher incidence of perinatal loss in the iodine group remains unclear. There were no significant differences between the iodine group and the MMI group in either the percentage of perinatal losses or elective abortions.

Table 1.

Comparison Between the Maternal Characteristics of the Iodine Group and the MMI Group

	Iodine group	MMI group
Total no. of cases	283	1333
Maternal age (years), mean (SD)	32.8 (4.6)	31.9 (4.3)	NS
fT4 (ng/dL), mean (SD)	1.65 (1.01)	1.39 (0.97)	NS
Pregnancy outcome
Live birth, n	260 (91.9%)	1134 (85.1%)	p < 0.05
Perinatal loss, n	4 (1.4%)	5 (0.4%)	NS
Miscarriage, n	15 (5.3%)	164 (12.3%)	p < 0.05
Abortion, n	4 (1.4%)	30 (2.2%)	NS
MMI dose^ in the first trimester (mg/day)*			NS
Median	7.5	5
Range	1.4–60	0.5–75

MMI dose before the switch to iodine.

MMI, methimazole; fT4, free thyroxine; NS, not significant.

The switch from MMI to KI was made at the first visit after conception. Most of the patients in the iodine group (243/283, 85.9%) were switched from MMI to KI within the first eight weeks of gestation. The maternal fT4 levels of both groups according to gestational weeks are shown in Table 2. The fT4 levels of the iodine group were higher than in the MMI group at every gestational week measured. Of the 260 patients who remained in the iodine group after excluding the patients who had a miscarriage, abortion, or perinatal loss, 64 patients (24.6%) had been switched to an ATD after the second trimester, 65 patients (25%) continued taking KI until delivery, and 127 patients (48.8%) stopped taking KI during pregnancy and their thyroid hormone levels remained within their normal ranges without medication until delivery. Four patients (1.5%) had been treated with levothyroxine because their TSH level was slightly elevated.

Table 2.

The Maternal fT4 Levels of the Iodine Group and the MMI Group According to Gestational Weeks

	fT4 (M ± SD; ng/dL)
Gestational week (w)	Iodine group	MMI group
4–7	1.55 ± 0.90	1.38 ± 0.80	p < 0.01
8–11	1.66 ± 0.85	1.44 ± 0.83	p < 0.01
12–15	1.71 ± 1.02	1.27 ± 0.62	p < 0.0001
16–19	1.74 ± 1.24	1.17 ± 0.49	p < 0.0001
20–23	1.67 ± 1.02	1.13 ± 0.44	p < 0.0001
24–27	1.60 ± 1.03	1.16 ± 0.43	p < 0.0001
28–31	1.56 ± 0.64	1.16 ± 0.43	p < 0.0001
32–36	1.36 ± 0.49	1.16 ± 0.38	p < 0.0001
36–40	1.38 ± 0.38	1.34 ± 0.49	NS

The thyroid hormone levels of the patients who had been switched to KI were measured again two to four weeks after the switch. The thyroid hormone levels at the first visit after conception showed that 60 patients were hyperthyroid, 189 patients were euthyroid, and 11 patients were hypothyroid. Among the 60 hyperthyroid patients, 26 patients remained hyperthyroid after the switch to KI, and 19 of them required treatment with MMI or PTU after the second trimester. Among the 189 euthyroid patients, 33 became hyperthyroid after the switch to KI, 16 patients became euthyroid after adjustment of the KI dose, and 17 patients required treatment with MMI or PTU after the second trimester. Among the11 hypothyroid patients being treated with MMI, four became hyperthyroid after switching to KI, and three of these required treatment with MMI after the second trimester. The median number of weeks of gestation at the time of the switch to KI was six weeks (range 4–12 weeks). The initial dose of KI was 25 mg (SD = 17.3 mg).

Pregnancy outcome

As shown in Table 3, the incidence of major congenital anomalies in the iodine group was 4/260 (1.53%) and significantly lower than the 47/1134 (4.14%) in the MMI group (p < 0.05). Two neonates in the iodine group had findings consistent with MMI embryopathy (2/260, 0.8%), as opposed to 18 neonates in the MMI group (18/1134, 1.6%).

Table 3.

Numbers and Incidences of Congenital Anomalies in Each of the Treatment Groups

	Iodine group	MMI group
Total number of newborns	260	1134
Mean birth weight	2965 g	2943 g	NS
Mean gestational age at birth	38.9 weeks	39 weeks	NS
Congenital anomaly present	4 (1.53%)	47 (4.14%)	p < 0.05
Ventricular septal defect	0	9
Aplasia cutis	1	6
Omphalomesenteric duct anomaly	0	6
Omphalocele	1	5
Patent ductus arteriosus	0	5
Cheiloschisis, palatoschisis	1	0
Accessory ear	0	2
Congenital esophageal stenosis	0	2
Polydactyly	1	0
Other	0	14

Detailed information regarding the mothers of the infants with each of the malformations is provided in Table 4. The one newborn with an omphalocele had been exposed to MMI during the first seven weeks of gestation, then to KI until 15 weeks of gestation, and thereafter to MMI again. The one newborn with aplasia cutis congenita had been exposed to MMI during the first four weeks of gestation, then to KI, and to MMI again at 25 weeks of gestation. The one newborn with cheiloschisis had been exposed to MMI during the first seven weeks of gestation and to KI thereafter. The one newborn with polydactyly had been exposed to MMI during the first four weeks of gestation and then to KI until eight weeks. All neonates with a congenital anomaly in the iodine group were born to euthyroid mothers.

Table 4.

Detailed Information Regarding the Mothers of the Infants with Congenital Malformations in the Iodine Group

			Dose			Thyroid status
Age (years)	Congenital anomaly of the infant	Duration of treatment with MMI	MMI	Iodine	fT4^ (ng/dL)*	With MMI	With iodine
37	Aplasia cutis	4 weeks	15	30	0.97	Euthyroid	Euthyroid
36	Omphalocele	7 weeks	15	38	1.11	Euthyroid	Euthyroid
33	Cheiloschisis	7 weeks	2.5	19	0.97	Euthyroid	Euthyroid
27	Polydactyly	4 weeks	5	38	1.30	Euthyroid	Euthyroid

Serum fT4 level before the switch to iodine.

The subjects in the MMI group gave birth to 47 neonates with a congenital anomaly: nine had a ventricular septal defect, six had aplasia cutis, six had an omphalomesenteric duct anomaly, five had an omphalocele, five had a patent ductus arteriosus, two had an accessory ear, and two had congenital esophageal stenosis. The thyroid status of their mothers during the first trimester of pregnancy was hyperthyroid in eight cases, euthyroid in 33 cases, and hypothyroid in six cases. Gestational age at delivery was 39.0 ± 0.5 weeks in the MMI group and 38.9 ± 1.1 weeks in the iodine group, and the difference was not significant (p = 0.24). Median birth weight was 2943 ± 428 g in the MMI group and 2965 ± 482 g in the iodine group, and the difference was not significant (p = 0.47).

Neonatal thyroid status

Data on neonatal thyroid function were available for 41 neonates in the iodine group and 142 neonates in the MMI group. Neonates who had been exposed to KI or an ATD beyond the third trimester of pregnancy were included. Of the 41 neonates born to mothers in the iodine group, 14 had been exposed to KI alone in the third trimester (Figs. 1A and 2A), four had been exposed to both KI and MMI (Figs. 1B and 2B), and 23 had been exposed to an ATD in the third trimester (20 to MMI alone and three to PTU; Figs. 1C and 2C). All 142 neonates born to mothers in the MMI group had been exposed to MMI alone throughout pregnancy (Figs. 1D and 2D). The fT4 levels of the mothers and neonates in each group are shown in Figure 1, and their TSH levels are shown in Figure 2. The cord fT4 level was lower in the MMI group (Fig. 2D) than in the KI group (Fig. 2A), but the difference was not significant. There were no significant differences between the cord TSH levels of the four groups. None of the infants exposed to KI in the third trimester had a goiter. Severe neonatal hypothyroidism (fT4 <0.9 ng/dL) was detected only in neonates who had been exposed to an ATD in the third trimester.

FIG. 1.

Free thyroxine (fT4) levels of mothers and neonates in the iodine group (potassium iodide [KI] → methimazole [MMI]) (A–C) and MMI group (D). The iodine group is divided into three subgroups according to the treatment during the third trimester: KI alone group (A), KI and antithyroid drug (ATD) group (B), and ATD alone group (C). The difference between the cord fT4 levels in the KI group (A) and the MMI group (D) was not statistically significant.

FIG. 2.

TSH levels of mothers and neonates in the iodine group (KI → MMI; A–C) and MMI group (D). The iodine group is divided into three subgroups according to the treatment during the third trimester: KI alone group (A), KI and ATD group (B), and ATD alone group (C). There were no significant differences in cord TSH levels among the four groups.

Discussion

This is the first study to evaluate whether switching from MMI to KI in the first trimester of pregnancy decreases the incidence of major congenital anomalies in comparison with continuing treatment with MMI alone. The results show that the incidence of major congenital anomalies was 4/260 (1.53%) in the iodine group and 47/1134 (4.14%) in the MMI group. The incidence of major congenital anomalies in the iodine group was significantly lower than in the MMI group. Of the 47 neonates with major anomalies in the MMI group, 18 had MMI embryopathy (18/1134, 1.6%), four had an omphalocele, six had an omphalomesenteric duct anomaly, two had esophageal atresia, and six had aplasia cutis congenita. Switching from MMI to KI in the first trimester of pregnancy did not completely prevent MMI embryopathy, but the incidence of MMI embryopathy and incidence of major anomalies were lower in the iodine group.

In recent years, PTU has been the preferred drug for the treatment of GD during the first trimester of pregnancy because of concerns about the teratogenicity of MMI during the first trimester of pregnancy (12,13). The ATA recommends using PTU during the first trimester and MMI during the second trimester. Recent analyses by the United States Food and Drug Administration indicate that PTU may rarely be associated with severe liver toxicity. It has been estimated that 4/4000 pregnant women treated with PTU each year in the United States develop PTU-related severe liver injury (21). Six cases of PTU-induced hepatitis during pregnancy have been reported in the medical literature (22 –25). One case of neonatal hepatitis as an adverse effect of maternal treatment with PTU has also been reported (26). Moreover, a recently published study from Denmark showed that exposure to either MMI or PTU or to both in early pregnancy was associated with an increased prevalence of birth defects (14).The birth defects seen after prenatal exposure to PTU were milder and minor compared with those observed after prenatal exposure to MMI, and usually were not detected at birth but later in infancy (27). These reports suggest that switching from MMI to PTU during pregnancy may not reduce the incidence of congenital anomalies and may increase the risk of liver dysfunction.

Treatment of GD with KI is widely accepted by Japanese thyroid specialists, and its efficacy has been reported (17 –20). Treatment with KI during pregnancy has usually been considered contraindicated, because iodine is known to cross the placenta readily and possibly to have an inhibitory effect on fetal thyroid hormone synthesis. Although several cases of neonatal hypothyroidism caused by excessive maternal iodine intake have been reported (28,29), none of their mothers had GD. Momotani et al. reported that iodine administration is an effective and safe means of treating mild hyperthyroidism due to GD in pregnant women, and the result indicated that exposure of the fetus to iodine during the treatment of maternal hyperthyroidism due to GD did not increase the risk of hypothyroidism in the neonate (20). This study yielded similar results, and hypothyroidism was more common and severe among the neonates whose mothers had been treated with an ATD than with KI. There were 15 miscarriages (5.3%) and four perinatal losses (1.4%) in the iodine group, and 164 miscarriages (12.3%) and five perinatal losses (0.4%) in the MMI group. All four mothers with a perinatal loss in the iodine group were euthyroid throughout their pregnancy. The reason for the higher incidence of perinatal loss in the iodine group remains unclear.

A higher proportion of women in the MMI group (12.3%) had a miscarriage than in the iodine group (5.3%; p < 0.05). As shown in Table 2, maternal fT4 levels were higher in the first trimester in the iodine group. In addition, the proportion of subjects with maternal hypothyroidism was 5.6% in the MMI group and 1.3% in the iodine group, and the higher proportion of subjects with hypothyroidism in the MMI group may have been related to the higher miscarriage rate in the MMI group.

This study has the limitation of being a retrospective, nonrandomized study, which has the potential for introducing biases. Further limitations include that the dose of KI at the time of substitution differed from patient to patient, and that the treatment protocol with KI varied in terms of continuation throughout pregnancy, the addition of ATD to KI, or the switch to an ATD after the second trimester of pregnancy. In addition, the subjects were Japanese women, whose dietary iodine intake is higher than in most other countries. Since this study was performed in an iodine-sufficient country, this result cannot be automatically transferred to populations exposed to mild to moderate iodine deficiency.

In summary, switching from MMI to KI to control hyperthyroidism in GD patients during the first trimester of pregnancy may reduce the risk of congenital anomalies, at least in iodine-sufficient regions.

Footnotes

Acknowledgment

Portions of this manuscript were presented at the 84th Annual Meeting of the ATA held in California 2014.

Author Disclosure Statement

The authors declare that they have no competing financial interests.

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