American Journal of Medical Genetics 44200-202 (1992)

Esophageal Atresia and Tracheoesophageal Fistula in Two Infants Born to Hyperthyroid Women Receiving Methimazole (Tapazol@) During Pregnancy

Aurora Ramirez, Antonio Espinosa de 10s Monteros, Adalberto Parra, and Beatriz De Leon Department of Endocrinology, Instituto Nacional de Perinatologia (A.R., A.E.M., A.P.) and Department of Pathology, Znstituto Nacwnal de Pediatria (B.D.L.), Mhico, D.F.

We report on 2 newborn infants with esopha- geal atresia and tracheoesophageal fistula (EA + TEF) born to hyperthyroid mothers receiving methimazole (Tapazol a) before and during their entire pregnancies. Both mothers were euthyroid during gestation and developed hydramnios diagnosed during weeks 34 and 33 of gestation. Premature deliv- ery (36.2 weeks of gestation) occurred in one case, and both newborn infants were small for date with palpable goiter; one of them had other associated malformations. Hypo- thyroidism was diagnosed by laboratory tests in both cases. Corrective surgery was under- taken, but both newborn infants developed septicemia and renal insufficiency and died in the first week of life. The EA + TEF and a normally placed enlarged thyroid gland were confirmed at necropsy. These cases represent a previously unreported example of the asso- ciation of maternal ingestion of methimazole during pregnancy and EA + TEF. 0 1992 Wiley-Liss, Inc.

KEY WORDS: esophageal atresia, maternal hyperthyroidism, methim- azole

INTRODUCTION Infants of mothers treated for hyperthyroidism with

methimazole (Tapazol '? during pregnancy are reported to have an increased incidence of scalp defects [Milham, 19851. Nevertheless, up to now it is unclear if such de- fects are due to methimazole, to the thyrotoxicosis, or to other factor associated with thyroid dysfunction.

Received for publication December 3, 1991; revision received February 25, 1992.

Address reprint requests to Aurora Ramirez, M.D., Departa- mento de Endocrinologia, Instituto Nacional de Perinatologia, Montes Urales 800, Lomas Virreyes, Mexico, D.F. CP 11000, Mexico.

0 1992 Wiley-Liss, Inc.

We describe 2 newborn infants born to hyperthyroid women who ingested methimazole before and through- out the pregnancy.

MATERIAL AND METHODS Both cases were selected from a group of 14 pregnant

hyperthyroid women treated with different doses of methimazole throughout pregnancy, with and without thyroid hormone supplementation [Espinosa de 10s Monteros et al., 19861.

CLINICAL REPORTS Case 1

A 25-year-old-woman with 2 previous induced abor- tions developed hyperthyroidism a t age 24. The diag- nosis was confirmed by laboratory tests and meth- imazole treatment (40 mg PO daily) was initiated; 4 months later, when on 30 mgtday she became pregnant. Treatment was continued unchanged until the 18th ges- tational week, when thyroid hormones [180 kg thyrox- ine (T4) equivalents, daily] were added because of a mild rise in serum thyroid stimulating hormone levels (TSH, 7.5 mIUtm1) but normal total triiodothironine (TT3,200 ng/dl) and total T4 (TT4, 16.2 p,g/dl). This treatment continued until delivery and the patient remained eu- thyroid both from a clinical and laboratory point of view. Hydramnios was diagnosed at 34 weeks of gestation by ultrasound. Pregnancy continued normally and the male infant was born prematurely by spontaneous ver- tex vaginal delivery at 36.2 weeks.

The newborn data were as follows: weight 1,560 g, length 44.5 cm, Apgar scores 2 and 4 a t 1 and 5 min, acrocyanosis, sialorrhea, generalized hypotonia, palpa- ble goiter, koilonichia, micrognathia, syndactyly of sec- ond and third fingers, and short fifth fingers. A suspi- cion of EA + TEF arose when a nasogastric tube did not pass into the stomach, with an obstacle at 9 cm; and the diagnosis was confirmed roentgenologically. Primary congenital hypothyroidism was confirmed: TT4 7.6 pg/dl and TSH 110 mIU/ml in cord blood. Surgical cor- rection was unsuccessful because of inability to make the anastomosis; sepsis and renal insufficiency compli- cated the postoperative period and the infant died at age 6 days. No cytogenetic studies were done.

Esophageal Atresia and Methimazole 201

tions. Although we did not perform specific studies to discard an autoimmune process as a cause, there is no evidence of an association of antithyroid antibodies dur- ing pregnancy and fetal malformations, but with recur- rent fetal death [Houck et al., 19811.

The fetal thyroid gland altered by antithyroid medi- cation may have altered its migration and, thus, induced the malformations; however, the causal factor should have been present by 4 to 10 weeks of gestation [Bergs- ma, 19791, at which time, the fetal hypothalamic-pitui- tary-portal circulation has not yet been fully developed [Gluckman et al., 19801 and, thus, it could not be the cause of goiter secondary to fetal TSH overstimulation. Furthermore, at necropsy we found a normal location of the thyroid gland and a diffuse goiter.

To our knowledge, the association of EA + TEF in newborn infants of hyperthyroid women receiving methimazole during gestation has not been reported previously. These 2 cases may be an example of a fortu- itous association between the maternal disease, drug therapy, and malformation. However, it is important to remember that the prevalence of hyperthyroidism com- plicating pregnancy is 0.04-0.6% [Espinoza de 10s Mon- teros et al., 1986; Thomas and Reid, 1987; Wang and Sum, 1989; Arabin et al., 19901, and for the EA + TEF the frequency is 1:3,000-1:4,500 newborn infants [Vaughan et al., 19791, making a fortuitous association less likely.

Primary hypothyroidism is not associated with a greater frequency of congenital malformations [Vaughan et al., 19791; so, the congenital hypothyroid- ism of both infants, probably secondary to methimazole transplacental transfer, hardly can be considered the pathogenesis of these malformations.

Necropsy documented: EA + TEF type C [Holder et al., 19641, right upper mainstem bronchus with a tra- cheal origin 0.5 cm below the carina, ventricular septa1 defect, Meckel diverticulum, and diffise goiter. No other malformations were observed; thus, a VATER associa- tion was eliminated [Emery and Rimoin, 19831.

Case 2 A 23-year-old primigravid woman with family history

of thyroid cancer, and clinical history of hyperthyroid- ism of 7 months duration attended the outpatient clinic and the diagnosis was confirmed by laboratory tests. Treatment with methimazole (Tapazol @) 45 mg PO daily was initiated, and she became pregnant 3 months later, when on 30 mglday. Treatment was continued and by 8 weeks of gestation thyroid hormones (180 pg TT4 equiv- alent, daily) were added since there was clinical and laboratory evidence of hypothyroidism (TT3,llO ng/dl, “4,125 pg/dl, and TSH 10.6 mIU/ml). Treatment with both drugs resulted in a euthyroid state and was contin- ued until delivery. By 33 weeks of gestation hydramnios was shown by ultrasound and the pregnancy ended at 38.2 weeks in a spontaneous vertex vaginal delivery. The birth data were as follows: male, weight 2,455 g, height 49 cm, Apgar scores 8 and 9, cyanosis, tachypnea, sialorrhea, koilonichia, and palpable goiter. EA was sus- pected immediately because of inability to pass the nasogastric tube more than 10 cm; EA + TEF was proven by roentgenograms. Laboratory tests indicated congenital primary hypothyroidism (TT4,3.1 Fgldl and TSH, 87 mIU/ml in cord blood). Surgical correction was performed successfully but sepsis and renal failure de- veloped; death occurred on the fifth day of life.

At necropsy only EA + TEF type C and diffuse goiter were found.

In both cases, there were no other significant medical problems, illness, or other known teratogenic exposures during pregnancy, and there was no family history of these malformations.

DISCUSSION Methimazole intake during pregnancy may be associ-

ated with increased fetal death, intrauterine growth retardation, and congenital malformations, including scalp defects, hypospadias, imperforate anus, aortic at- resia, and choanal atresia with athelia [Greenman et al, 1962; Mujtaba and Burrow, 1975; Greenberg, 1987; Dor- angeon et al., 1989; Khoury et al.; 19891. Nevertheless, methimazole is classified by the Food and Drug Admin- istration with the drugs without clear teratogenic ef- fects [Drug, 19901.

On the other hand, thyrotoxicosis state during preg- nancy has also been associated with a greater frequency of abortions and fetal deaths [Montoro and Mestman, 1981; Espinoza de 10s Monteros et al., 1986; Thomas and Reid, 1987; Houck et al., 19881, although it is not clear if the frequency of congenital malformations in these in- fants is greater than in the general population.

Since the mothers of our patients were euthyroid dur- ing the entire pregnancy, both by clinical and laboratory criteria, it is difficult to postulate that maternal dysthy- roidism was, in some way, the cause of such malforma-

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