Antithyroid Drug Use in Pregnancy and Birth Defects: Why Some Studies Find Clear Associations, and Some Studies Report None

Laurberg, Peter; Andersen, Stine Linding

doi:10.1089/thy.2015.0182

Cited by 36 publications

(25 citation statements)

References 19 publications

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“…This was consistent with the conclusions of the previous studies [9, 25]. The reasons for the negative findings reported by several trials may have been due to the methods used in their research [26]. …”

Section: Discussionsupporting

confidence: 92%

Effects of methimazole and propylthiouracil exposure during pregnancy on the risk of neonatal congenital malformations: A meta-analysis

Song

Lin²,

Chen

et al. 2017

PLoS ONE

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ObjectiveThe aim of this study was to determine the effect of exposure to different antithyroid drugs during pregnancy on the incidence of neonatal congenital malformations.MethodsA meta-analysis was performed to compare the incidence of neonatal congenital malformations after exposure to different antithyroid drugs during pregnancy. Twelve studies that met the inclusion criteria were included in this meta-analysis. PubMed, Embase, and CENTRAL databases were searched from inception until January 2017. Study designs included case–control studies, prospective cohort studies, and retrospective cohort studies.ResultsTwelve studies involving 8028 participants with exposure to different antithyroid drugs during pregnancy were included in this study; however, only 10 studies involving 5059 participants involved exposure to different antithyroid drugs exactly during pregnancy. Our results indicated that exposure to methimazole (MMI)/carbimazole (CMZ) only during pregnancy significantly increased the risk of neonatal congenital malformations compared to no antithyroid drug exposure (OR 1.88; 95%CI 1.33 to 2.65; P = 0.0004). No differences were observed between propylthiouracil (PTU) exposure and no antithyroid drug exposure only during pregnancy (OR 0.81; 95%CI 0.58 to 1.15; P = 0.24). Exposure to MMI/CMZ only during pregnancy significantly increased the risk of neonatal congenital malformations compared to that associated with exposure to PTU (OR 1.90; 95%CI 1.30 to 2.78; P = 0.001).ConclusionFor pregnant women with hyperthyroidism, exposure to MMI/CMZ significantly increased the incidence of neonatal congenital malformations compared to exposure to PTU and no antithyroid drug exposure; however, no differences were observed between PTU exposure and no antithyroid drug exposure.

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Section: Discussionsupporting

confidence: 92%

Effects of methimazole and propylthiouracil exposure during pregnancy on the risk of neonatal congenital malformations: A meta-analysis

Song

Lin²,

Chen

et al. 2017

PLoS ONE

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“…PTU is generally preferred during the first trimester of pregnancy and then changed to MMI because of the risk of MMI-induced embryopathy, mainly aplasia cutis, esophageal, and choanal atresia (24–26) whose prevalence is reported higher than previously thought (27). The prevalence of the PTU-associated, but less severe, birth defects is not negligible (9, 28). After the first trimester, MMI is the preferred ATD because PTU has a greater risk of hepatotoxicity (9).…”

Section: Graves’ Disease In Pregnancymentioning

confidence: 99%

Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance

2017

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Graves’ disease is the most common cause of thyrotoxicosis in women of childbearing age. Approximately 1% of pregnant women been treated before, or are being treated during pregnancy for Graves’ hyperthyroidism. In pregnancy, as in not pregnant state, thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAbs) are the pathogenetic hallmark of Graves’ disease. TRAbs are heterogeneous for molecular and functional properties and are subdivided into activating (TSAbs), blocking (TBAbs), or neutral (N-TRAbs) depending on their effect on TSHR. The typical clinical features of Graves’ disease (goiter, hyperthyroidism, ophthalmopathy, dermopathy) occur when TSAbs predominate. Graves’ disease shows some peculiarities in pregnancy. The TRAbs disturb the maternal as well as the fetal thyroid function given their ability to cross the placental barrier. The pregnancy-related immunosuppression reduces the levels of TRAbs in most cases although they persist in women with active disease as well as in women who received definitive therapy (radioiodine or surgery) before pregnancy. Changes of functional properties from stimulating to blocking the TSHR could occur during gestation. Drug therapy is the treatment of choice for hyperthyroidism during gestation. Antithyroid drugs also cross the placenta and therefore decrease both the maternal and the fetal thyroid hormone production. The management of Graves’ disease in pregnancy should be aimed at maintaining euthyroidism in the mother as well as in the fetus. Maternal and fetal thyroid dysfunction (hyperthyroidism as well as hypothyroidism) are in fact associated with several morbidities. Monitoring of the maternal thyroid function, TRAbs measurement, and fetal surveillance are the mainstay for the management of Graves’ disease in pregnancy. This review summarizes the biochemical, immunological, and therapeutic aspects of Graves’ disease in pregnancy focusing on the role of the TRAbs in maternal and fetal function.

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“…For example, the PTU-associated defects are relatively mild, and they are often not diagnosed immediately after birth, but first later when they lead to complications such as infections. Thus, studies relying solely on birth defects detected in newborns will not find association with the use of PTU, and also many of the MMI-associated malformations will not be detected (65). The majority of the Danish cases of PTU-associated defects had been detected and registered when the children developed complications and received surgery for the defect later in childhood (60).…”

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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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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Antithyroid Drug Use in Pregnancy and Birth Defects: Why Some Studies Find Clear Associations, and Some Studies Report None

Abstract: Studies finding no associations between early pregnancy exposure to antithyroid drugs and birth defects were either not sufficiently powered or did not study outcomes at optimal ages.

Cited by 36 publications

References 19 publications

Effects of methimazole and propylthiouracil exposure during pregnancy on the risk of neonatal congenital malformations: A meta-analysis

Effects of methimazole and propylthiouracil exposure during pregnancy on the risk of neonatal congenital malformations: A meta-analysis

Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance

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

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