Therapeutic Drug Monitoring of Antithyroid Drugs in Pregnancy

Koren, Gideon

doi:10.1097/01.ftd.0000192135.54477.d9

Cited by 12 publications

(3 citation statements)

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“…Despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have yet to be performed in humans [37]. There has been some investigation of the effects of ATDs in animal models.…”

Section: Introductionmentioning

confidence: 99%

Propylthiouracil Is Teratogenic in Murine Embryos

et al. 2012

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BackgroundHyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed.MethodsWe examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis.ResultsWhen dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss of malformed embryos. These data show that PTU exposure during embryogenesis is associated with delayed neural tube closure and cardiac abnormalities. In contrast, we did not observe structural or cardiac defects associated with MMI exposure except at the higher dose. We find that PTU exposure during embryogenesis is associated with fetal loss. These observations suggest that PTU has teratogenic potential.

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Section: Introductionmentioning

confidence: 99%

Propylthiouracil Is Teratogenic in Murine Embryos

et al. 2012

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“…Despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed (12). Some investigation of ATDs has been conducted in animal models on embryos, including studies of E9.5 to E11.5 rat embryos cultured with MMI, which revealed abnormal head morphology and defects in neural tube closure in some specimens (13).…”

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confidence: 99%

Embryonic exposure to propylthiouracil disrupts left‐right patterning inXenopusembryos

Veenendaal¹,

Ulmer

Boskovski³

et al. 2012

FASEB j.

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Antithyroid medications are the preferred therapy for the treatment of Graves' disease during pregnancy. Propylthiouracil (PTU) is favored over methimazole (MMI) due to potential teratogenic concerns with MMI. This study was to determine the teratogenic potential of MMI and PTU using a validated Xenopus tropicalis embryo model. Embryos were exposed to 1 mM PTU (EC(50)=0.88 mM), 1 mM MMI, or vehicle control (water) from stages 2 to 45. Treated embryos were examined for gross morphological defects, ciliary function, and gene expression by in situ hybridization. Exposure to PTU, but not MMI, led to cardiac and gut looping defects and shortening along the anterior-posterior axis. PTU exposure during gastrulation (stage 8-12.5) was identified as the critical period of exposure leading to left-right (LR) patterning defects. Abnormal cilia polarization, abnormal cilia-driven leftward flow at the gastrocoel roof plate (GRP), and aberrant expression of both Coco and Pitx2c were associated with abnormal LR symmetry observed following PTU exposure. PTU is teratogenic during late blastula, gastrulation, and neurulation; whereas MMI is not. PTU alters ciliary-driven flow and disrupts the normal genetic program involved in LR axis determination. These studies have important implications for women taking PTU during early pregnancy.

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“…During gestation the thyroid is hyperstimulated which causes changes in thyroid hormone concentration; also, hypothyroidism is common and consistently lower serum concentrations of propylthiouracil have been observed in pregnant women compared with non-pregnant (8).…”

Section: Introductionmentioning

confidence: 97%