THERAPY OF ENDOCRINE DISEASE: Antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk?

Laurberg, Peter; Andersen, Stine Linding

doi:10.1530/eje-14-0135

Cited by 105 publications

(61 citation statements)

References 43 publications

(84 reference statements)

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“…In this study, the highest relative risk was seen for various types of abdominal wall defects (Fig. 3), followed by skin defects (aplasia cutis), digestive (oesophageal and other atresias), eye, urinary tract, respiratory (choanal atresia), and circulatory (ventricular septum) defects (57,58).…”

Section: Therapy Of Graves' Disease and The Risk Of Birth Defectsmentioning

confidence: 54%

“…In recent years, large studies from Japan (55, 56) and Denmark (57,58) have shown that MMI/CMZ-associated birth defects are more common than anticipated, and may affect ~1/30 of children exposed to the drug in the weeks 6-10 of pregnancy. This is considerably below 10% of the effect of thalidomide, the prime drug example of teratogenicity (59), but still enough to raise serious concern.…”

Section: Therapy Of Graves' Disease and The Risk Of Birth Defectsmentioning

confidence: 99%

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ENDOCRINOLOGY IN PREGNANCY: Pregnancy and the incidence, diagnosing and therapy of Graves’ disease

Laurberg

Andersen

2016

European Journal of Endocrinology

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Thyroid hormones are essential developmental factors, and Graves' disease (GD) may severely complicate a pregnancy. This review describes how pregnancy changes the risk of developing GD, how early pregnancy by several mechanisms leads to considerable changes in the results of the thyroid function tests used to diagnose hyperthyroidism, and how these changes may complicate the diagnosing of GD. Standard therapy of GD in pregnancy is anti-thyroid drugs. However, new studies have shown considerable risk of birth defects if these drugs are used in specific weeks of early pregnancy, and this should be taken into consideration when planning therapy and control of women who may in the future become pregnant. Early pregnancy is a period of major focus in GD, where pregnancy should be diagnosed as soon as possible, and where important and instant change in therapy may be warranted. Such change may be an immediate stop of anti-thyroid drug therapy in patients with a low risk of rapid relapse of hyperthyroidism, or it may be an immediate shift from methimazole/carbimazole (with risk of severe birth defects) to propylthiouracil (with less risk), or maybe to other types of therapy where no risk of birth defects have been observed. In the second half of pregnancy, an important concern is that not only the mother with GD but also her foetus should have normal thyroid function.Thyroid hormones are essential developmental factors as first shown by Gudernatsch when he, in 1912, fed tadpoles thyroid tissue and observed metamorphosis (1). In mammals, thyroid hormones are especially of importance for brain development (2, 3), and even a few months with lack of thyroid hormones in infant life may lead to irreversible brain damage. This is the background for the universal screening for congenital hypothyroidism performed in many countries. However, thyroid hormones are also important for normal pregnancy, and maternal thyroid disease may severely increase the risk of pregnancy complications, including Invited author's profile Peter Laurberg was Clinical Professor of Internal Medicine and Endocrinology, Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark. His research mainly focused on thyroid disease prevention, epidemiology, diagnosing and therapy, including studies on iodine and thyroid, and pregnancy and thyroid. He had special research interest on the risk from and optimal management of autoimmune hypo-and hyperthyroidism in pregnancy and post-partum, management of Graves' disease in general, and how the burden of thyroid disease can be minimized by adjusting the population's iodine intake. He has coauthored several international guidelines on thyroid disease management, including management of thyrotoxicosis, and thyroid disease in pregnancy. Peter Laurberg died June 20, 2016.

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Section: Therapy Of Graves' Disease and The Risk Of Birth Defectsmentioning

confidence: 54%

Section: Therapy Of Graves' Disease and The Risk Of Birth Defectsmentioning

confidence: 99%

ENDOCRINOLOGY IN PREGNANCY: Pregnancy and the incidence, diagnosing and therapy of Graves’ disease

Laurberg

Andersen

2016

European Journal of Endocrinology

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“…Such birth defects are observed in about 3% of the neonates, and some birth defects may be detected later, resulting in a total prevalence of about 6% at 2 years of age. It has, therefore, recently been suggested that the use of ATDs at 6-10 weeks of gestation should be limited as much as possible to decrease the risk of birth defects [15] .…”

Section: Treatmentmentioning

confidence: 99%

“…PTU and MMI/CMZ cross the placenta and are equally effective for treating hyperthyroidism in pregnancy. PTU is the most widely used during pregnancy, generally with a shift onto this drug from MMI/CMZ shortly before conception [15] . The fetus benefits directly from the maternal ingestion of these drugs, which cross the placenta and act on the fetal thyroid gland.…”

Section: Treatmentmentioning

confidence: 99%

Management of Fetal and Neonatal Graves' Disease

Léger¹

2016

Horm Res Paediatr

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Fetal and neonatal autoimmune hyperthyroidism is a rare, serious but transient disorder. Early diagnosis and treatment are key objectives for an optimal prognosis and the well-being of the child. This review focuses on the management of these patients during the fetal and neonatal periods. We propose a diagnostic algorithm for high-risk pregnancies in mothers with current or past hyperthyroidism related to Graves' disease, involving repeated fetal thyroid gland assessments from 20 weeks of gestation onwards and maternal serum thyroid-stimulating hormone receptor antibody (TRAb) determination, with close monitoring if TRAb levels exceed 2 to 3 times the upper limit of the normal range. In fetuses with goiter, the main clinical issue is determining whether the cause is (1) maternal antithyroid drug (ATD) treatment that is appropriate for achieving normal maternal thyroid function but inappropriate and excessive for the fetus, resulting in hypothyroidism and necessitating a decrease in the ATD dose during pregnancy, or (2) the presence of TRAbs resulting in fetal thyroid stimulation and hyperthyroidism, requiring an increase in the maternal ATD dose. Methimazole/carbimazole treatment should be initiated as soon as possible during the neonatal period, carefully managed and maintained over a period of 1-3 months and then stopped when TRAb is no longer detectable in serum.

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“…PTU and methimazole have similar placental transfer kinetics (DiavCitrin et al 2002). Due to the fetal teratogenicity associated with methimazole (Laurberg and Andersen 2014), PTU is considered the first-line in the treatment of Graves' disease during pregnancy (Chattaway and Klepser 2007). PTU could, however, induce hepatitis in fetus (Taylor and Vaidya 2012) and sometimes, changing from PTU therapy after first trimester to methimazole is considered to be the optimum treatment during pregnancy (Taylor and Vaidya 2012).…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic properties and arterial structure in male rat offspring with fetal hypothyroidism

Ghanbari

Bagheripuor²,

Piryaei³

et al. 2016

gpb

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Abstract. Thyroid hormones (THs) play a crucial role in the development of different systems during fetal life; fetal hypothyroidism (FH) is associated with reduced cardiac function and dimensions in neonates. The aim of this study is to determine whether TH deficiency during fetal life is associated with arterial structural and hemodynamic changes during adulthood. Hypothyroidism was induced by adding 0.025% 6-propyl-2-thiouracil in drinking water throughout pregnancy, while controls consumed only tap water. Hemodynamic parameters, cross-sectional area, intima-media thickness (IMT), and density of nuclei of smooth muscle cells and endothelial cells (ECs) in the aorta and mesenteric arteries were measured. Compared to controls, in the FH group, baseline systolic blood pressure (105.7 ± 3.1 vs. 87.9 ± 3.3 mm Hg, p < 0.01), diastolic blood pressure (64.4 ± 1.7 vs. 53.2 ± 2.1 mm Hg, p < 0.05), and mean arterial pressure (80.9 ± 2.1 vs. 67.1 ± 2.1 mm Hg, p < 0.01) were significantly lower. In addition, in the FH group, intensity and latency of response to phenylephrine were significantly lower and longer, respectively, as were the IMT and density of ECs in the aorta and superior mesenteric arteries. In conclusion, this study showed that TH deficiency during fetal life can have long-lasting functional and histological effects, which can compromise cardiovascular function during adulthood.

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THERAPY OF ENDOCRINE DISEASE: Antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk?

Cited by 105 publications

References 43 publications

ENDOCRINOLOGY IN PREGNANCY: Pregnancy and the incidence, diagnosing and therapy of Graves’ disease

ENDOCRINOLOGY IN PREGNANCY: Pregnancy and the incidence, diagnosing and therapy of Graves’ disease

Management of Fetal and Neonatal Graves' Disease

Hemodynamic properties and arterial structure in male rat offspring with fetal hypothyroidism

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