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Severe malformations in infant born to hyperthyroid woman on methimazole
THE LANCET
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mice with Creutzfeldt-Jakob disease. J Virol 1991; 65: 6292–95. Lasmezas CI, Cesbron JY, Deslys JP, et al. Immune system-dependent and independent replication of the scrapie agent. J Virol 1996; 70: 1292–95. Outram GW, Dickinson AG, Fraser H. Reduced susceptibility to scrapie in mice after steroid administration. Nature 1974; 249: 855–56. Sailer A, Bueler H, Fischer M, Aguzzi A, Weissmann C. No propagation of prions in mice devoid of PrP. Cell 1994; 77: 967–68.
Institute of Neuropathology, Department of Pathology, Zurich University Hospital, Zurich, Switzerland; Prion Disease Group, Neurogenetics Unit, Imperial College School of Medicine at St Mary’s, London W2 1PG, UK (J Collinge)
Severe malformations in infant born to hyperthyroid woman on methimazole Eva Johnsson, Gerd Larsson, Margareta Ljunggren
Hyperthyroidism complicates up to 0·2% of pregnancies, and if uncontrolled may lead to impaired fetal outcome.1 To reach a euthyroid condition, medical therapy is preferable and methimazole or carbimazole are two commonly used drugs; the antithyroid effect of carbimazole is attributable to its complete bioactivation to methimazole. It is, however, debated if intake of methimazole during pregnancy is associated with an increased number of fetal malformations.1,2 A 33-year-old woman, with a history of asthma requiring inhalation therapy with budesonide and salmeterol, was admitted to an emergency unit with atrial fibrillation. Hyperthyroidism was diagnosed and oral treatment was initiated, first with metoprolol (150 mg per day) and, a few days later, methimazole (30 mg per day) was added. Because of morning sickness and amenorrhoea she had a pregnancy test 3 weeks later, which was positive and a subsequent transvaginal sonogram showed a pregnancy of 5 weeks. The same doses of methimazole and metoprolol were continued for another month. Then metoprolol was discontinued and the dose of methimazole was gradually reduced until 18 gestational weeks when surgery with subtotal thyroidectomy was performed without complications. Levothyroxine was given from gestational week 4 throughout the pregnancy with the exception of between 6 and 12 gestational weeks, and the patient was euthyroid from clinical and laboratory points of view from 14 gestational weeks. Pregnancy proceeded normally until 26 weeks of gestation, but at 27 weeks labour could not be stopped. A boy was born by vaginal delivery with weight 750 g, and Apgar scores 1 at 1 min, 0 at 5 min, and 3 at 10 min. It was difficult to ventilate the infant and he was not adequately oxygenated until intubation was achieved after 13 min. Several malformations were seen such as choanalatresia, oesophageal atresia with tracheo-oesophageal fistula, omphaloenteric connection, and multiple ventricular septal defects. Surgical correction was initially successful but severe infectious complications developed and the infant died at 6 weeks of age. There was no known previous family history of any congenital disorder. The possible relation between serious fetal malformations and therapy with methimazole has previously been noted2 in two infants with oesophageal atresia and tracheo-oesophageal fistula born to hyperthyroid mothers who received methimazole during pregnancies. Furthermore, methimazole teratogenicity in terms of ectodermal defects has been discussed in a case with choanal atresia and athelia.3 An increased incidence of fetal scalp defects, and aplasia cutis congenita has also been associated with intake of methimazole during pregnancy, but this relation is not proven since hyperthyroidism itself may give rise to such
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defects.4 Nevertheless, it was recently concluded that methimazole is as effective and safe as propylthiouracil to use during pregnancy and that the incidence of congenital anomalies is not increased compared with the general population.1 By contrast, on the basis of observations of a possible risk for fetal scalp defects, Vogt et al5 suggest that methimazole should be contraindicated in pregnancy. Our patient was also treated with metoprolol during the first trimester and with inhalations of budesonide and salmeterol throughout the pregnancy, but none of these drugs have been associated with teratogenic effects.4 We conclude that methimazole intake during pregnancy may be associated with severe congenital malformations including oesophaeal atresia and tracheo-oesophaeal fistula. However, thyrotoxicosis during pregnancy has also been related to a higher frequency of abortions and fetal deaths, although it is not clear if congenital malformations in these infants are more frequent than in the general population. Nevertheless, we believe it is important to emphasise the possible risks associated with methimazole for the fetus during pregnancy. 1
2
3
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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; 170: 90–95. Ramirez A, Espinosa de los Monteros A, Parra A, De Leon B. Eosophageal atresia and tracheoesophageal fistula in two infants born to hyperthyroid woman receiving methimazole (Tapazol) during pregnancy. Am J Med Genet 1992; 44: 200–02. Greenburg F. Brief clinical report—Choanal atresia and athelia: methimazole teratogenicity or a new syndrome? Am J Med Genet 1987; 28: 931–34. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation, 4th ed. Baltimore: Williams and Wilkins, 1994: 562–64. Vogt T, Stolz W, Landthaler M. Aplasia cutis congenita after exposure to methimazole: a causal relationship? Br J Dermatol 1995; 133: 994–96.
Departments of Clinical Pharmacology (E Johnsson), Gynaecology and Obstetrics, and Pharmacy, Sahlgrenska University Hospital/Sahlgrenska, 5-41345 Göteborg, Sweden
Neuronally-expressed necdin gene: an imprinted candidate gene in Prader-Willi syndrome James S Sutcliffe, Michael Han, Susan L Christian, David H Ledbetter
Prader-Willi syndrome (PWS) is associated with paternalspecific deficiencies of human chromosome 15q11-q13, caused by paternal deletion, maternal uniparental disomy (UPD), or imprinting mutations. Several imprinted, paternally-expressed genes have been identified within the ~1–1·5 Mb PWS candidate region, including SNRPN, IPW, ZNF127, PAR-5, PAR-1, and PAR-SN.1 Because the three major classes of PWS result in the loss of all paternal-specific gene expression, PWS may well represent a contiguous gene syndrome, with deficiencies of several genes contributing to the phenotype. We mapped the neuronally-expressed gene encoding necdin2 to YAC 495D1 within the PWS-candidate region, placing it telomeric to ZNF127 but centromeric to SNRPN and the 15q imprinting centre (S L Christian and colleagues, unpublished observations). To determine whether necdin was imprinted, we used RT-PCR to assess expression in brain and liver from normal controls and a patient with PWS and a 15q11-q13 deletion (figure A). There was expression in control samples, but not in PWS samples, indicating that necdin is imprinted with paternal-specific expression in these tissues. Detection of control-gene (LDL receptor) expression in all samples confirmed suitable RNA quality in the PWS samples. Although the murine necdin gene was previously
Vol 350 • November 22, 1997
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mice with Creutzfeldt-Jakob disease. J Virol 1991; 65: 6292–95. Lasmezas CI, Cesbron JY, Deslys JP, et al. Immune system-dependent and independent replication of the scrapie agent. J Virol 1996; 70: 1292–95. Outram GW, Dickinson AG, Fraser H. Reduced susceptibility to scrapie in mice after steroid administration. Nature 1974; 249: 855–56. Sailer A, Bueler H, Fischer M, Aguzzi A, Weissmann C. No propagation of prions in mice devoid of PrP. Cell 1994; 77: 967–68.
Institute of Neuropathology, Department of Pathology, Zurich University Hospital, Zurich, Switzerland; Prion Disease Group, Neurogenetics Unit, Imperial College School of Medicine at St Mary’s, London W2 1PG, UK (J Collinge)
Severe malformations in infant born to hyperthyroid woman on methimazole Eva Johnsson, Gerd Larsson, Margareta Ljunggren
Hyperthyroidism complicates up to 0·2% of pregnancies, and if uncontrolled may lead to impaired fetal outcome.1 To reach a euthyroid condition, medical therapy is preferable and methimazole or carbimazole are two commonly used drugs; the antithyroid effect of carbimazole is attributable to its complete bioactivation to methimazole. It is, however, debated if intake of methimazole during pregnancy is associated with an increased number of fetal malformations.1,2 A 33-year-old woman, with a history of asthma requiring inhalation therapy with budesonide and salmeterol, was admitted to an emergency unit with atrial fibrillation. Hyperthyroidism was diagnosed and oral treatment was initiated, first with metoprolol (150 mg per day) and, a few days later, methimazole (30 mg per day) was added. Because of morning sickness and amenorrhoea she had a pregnancy test 3 weeks later, which was positive and a subsequent transvaginal sonogram showed a pregnancy of 5 weeks. The same doses of methimazole and metoprolol were continued for another month. Then metoprolol was discontinued and the dose of methimazole was gradually reduced until 18 gestational weeks when surgery with subtotal thyroidectomy was performed without complications. Levothyroxine was given from gestational week 4 throughout the pregnancy with the exception of between 6 and 12 gestational weeks, and the patient was euthyroid from clinical and laboratory points of view from 14 gestational weeks. Pregnancy proceeded normally until 26 weeks of gestation, but at 27 weeks labour could not be stopped. A boy was born by vaginal delivery with weight 750 g, and Apgar scores 1 at 1 min, 0 at 5 min, and 3 at 10 min. It was difficult to ventilate the infant and he was not adequately oxygenated until intubation was achieved after 13 min. Several malformations were seen such as choanalatresia, oesophageal atresia with tracheo-oesophageal fistula, omphaloenteric connection, and multiple ventricular septal defects. Surgical correction was initially successful but severe infectious complications developed and the infant died at 6 weeks of age. There was no known previous family history of any congenital disorder. The possible relation between serious fetal malformations and therapy with methimazole has previously been noted2 in two infants with oesophageal atresia and tracheo-oesophageal fistula born to hyperthyroid mothers who received methimazole during pregnancies. Furthermore, methimazole teratogenicity in terms of ectodermal defects has been discussed in a case with choanal atresia and athelia.3 An increased incidence of fetal scalp defects, and aplasia cutis congenita has also been associated with intake of methimazole during pregnancy, but this relation is not proven since hyperthyroidism itself may give rise to such
1520
defects.4 Nevertheless, it was recently concluded that methimazole is as effective and safe as propylthiouracil to use during pregnancy and that the incidence of congenital anomalies is not increased compared with the general population.1 By contrast, on the basis of observations of a possible risk for fetal scalp defects, Vogt et al5 suggest that methimazole should be contraindicated in pregnancy. Our patient was also treated with metoprolol during the first trimester and with inhalations of budesonide and salmeterol throughout the pregnancy, but none of these drugs have been associated with teratogenic effects.4 We conclude that methimazole intake during pregnancy may be associated with severe congenital malformations including oesophaeal atresia and tracheo-oesophaeal fistula. However, thyrotoxicosis during pregnancy has also been related to a higher frequency of abortions and fetal deaths, although it is not clear if congenital malformations in these infants are more frequent than in the general population. Nevertheless, we believe it is important to emphasise the possible risks associated with methimazole for the fetus during pregnancy. 1
2
3
4 5
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; 170: 90–95. Ramirez A, Espinosa de los Monteros A, Parra A, De Leon B. Eosophageal atresia and tracheoesophageal fistula in two infants born to hyperthyroid woman receiving methimazole (Tapazol) during pregnancy. Am J Med Genet 1992; 44: 200–02. Greenburg F. Brief clinical report—Choanal atresia and athelia: methimazole teratogenicity or a new syndrome? Am J Med Genet 1987; 28: 931–34. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation, 4th ed. Baltimore: Williams and Wilkins, 1994: 562–64. Vogt T, Stolz W, Landthaler M. Aplasia cutis congenita after exposure to methimazole: a causal relationship? Br J Dermatol 1995; 133: 994–96.
Departments of Clinical Pharmacology (E Johnsson), Gynaecology and Obstetrics, and Pharmacy, Sahlgrenska University Hospital/Sahlgrenska, 5-41345 Göteborg, Sweden
Neuronally-expressed necdin gene: an imprinted candidate gene in Prader-Willi syndrome James S Sutcliffe, Michael Han, Susan L Christian, David H Ledbetter
Prader-Willi syndrome (PWS) is associated with paternalspecific deficiencies of human chromosome 15q11-q13, caused by paternal deletion, maternal uniparental disomy (UPD), or imprinting mutations. Several imprinted, paternally-expressed genes have been identified within the ~1–1·5 Mb PWS candidate region, including SNRPN, IPW, ZNF127, PAR-5, PAR-1, and PAR-SN.1 Because the three major classes of PWS result in the loss of all paternal-specific gene expression, PWS may well represent a contiguous gene syndrome, with deficiencies of several genes contributing to the phenotype. We mapped the neuronally-expressed gene encoding necdin2 to YAC 495D1 within the PWS-candidate region, placing it telomeric to ZNF127 but centromeric to SNRPN and the 15q imprinting centre (S L Christian and colleagues, unpublished observations). To determine whether necdin was imprinted, we used RT-PCR to assess expression in brain and liver from normal controls and a patient with PWS and a 15q11-q13 deletion (figure A). There was expression in control samples, but not in PWS samples, indicating that necdin is imprinted with paternal-specific expression in these tissues. Detection of control-gene (LDL receptor) expression in all samples confirmed suitable RNA quality in the PWS samples. Although the murine necdin gene was previously
Vol 350 • November 22, 1997