Birth defects after use of antithyroid drugs in early pregnancy: a Swedish nationwide study

Abstract

MMI and PTU were associated with subtypes of birth defects previously reported, but the frequency of ATD exposure in early pregnancy was low and severe malformations described in the MMI embryopathy were rarely observed.

Teratogen update: Antithyroid medications

“…Di Gianantonio et al (2001) did not find a statistically significant increase in risk of anomalies for MMI/CMZ exposure but did find two cases with anomalies consistent with the MMI/CMZ embryopathy. Similarly, Andersen et al (2017) did not find a statistically significant increase in the risk of anomalies for MMI/CMZ and PTU combined exposure but did find four cases with anomalies consistent with MMI/CMZ embryopathy.…”

“…PTU is associated with an increase in congenital anomalies less often than MMI/CMZ but some studies have noted an increased risk (Andersen, Lonn, Vestergaard, & Torring, 2017;Andersen, Olsen, Wu, & Laurberg, 2013;Howley et al, 2017;Leung, Yamamoto, Luca, Beaudry, & McKeen, 2015). A case study identified intestinal malrotation with congenital bands (Leung et al, 2015).…”

“…Cardiac (coarctation of the aorta and aortic valve stenosis) were found in a different study but with four or fewer cases for each anomaly (Howley et al, 2017). PTU alone was associated with anomalies of the face and neck (Andersen et al, 2013;Andersen, Olsen, Wu, & Laurberg, 2014), ear (Andersen et al, 2017), urinary systems (Andersen et al, 2014;Andersen et al, 2017;Korelitz et al, 2013), and musculoskeletal systems (Seo, Kim, & Chung, 2018) using retrospective searches based on ICD codes. Other anomalies have been reported from the Food and Drug Administration's Adverse Event Reporting System including some defects that are part of the MMI/CMZ embryopathy such as aplasia cutis, congenital heart disease, and other gastrointestinal anomalies (Rivkees, 2013).…”

“…CMZ and MMI embryopathy have been described (Clementi et al, 1999;Foulds, Walpole, Elmslie, & Mansour, 2005;Hackmon, Blichowski, & Koren, 2012). Aplasia cutis congenita, microcephaly, choanal atresia, esophageal atresia, athelia or hypothelia (absent or small nipples), hearing loss and ear malformations, developmental delays, facial anomalies (short nose, high and broad nasal bridge, malar hypopoalsia [underdeveloped cheekbones], ocular coloboma, hypoplastic nasal alae, flat philtrum, inverted V-shaped mouth), cardiovascular (ventricular septal) defects, branchial fistula, omphalocele, gastroschisis, patent vitellointestinal duct, other gastrointestinal anomalies, fingernail anomalies, and skin anomalies have been noted in case studies, case series, and epidemiologic studies (Andersen et al, 2013(Andersen et al, , 2017Aramaki et al, 2005;Barbero et al, 2008;Barwell, Fox, Round, & Berg, 2002;Bowman, Osborne, Sturley, & Vaidya, 2012;Bowman & Vaidya, 2011;Clementi et al, 1999;Clementi et al, 2010;Ferraris et al, 2003;Foulds et al, 2005;Guignon, Mallaret, & Jouk, 2003;Hawken et al, 2016;Kancherla et al, 2014;Karlsson, Axelsson, & Melhus, 2002;Koenig et al, 2010;Martin-Denavit et al, 2000;Myers & Reardon, 2005;Ono et al, 2009;Panait, Michel, D'Ercole, & Merrot, 2013;Purnamasari, Setyowati, Yunir, Khumaedi, & Harbuwono, 2019;Seo et al, 2018;Ting, Zhou, & Lao, 2013;Valdez et al, 2007;Wolf, Foulds, & Daya, 2006;Yoshihara et al, 2012;Yoshihara et al, 2015). The cooccurrence of choanal atresia and athelia has been noted without exposure to MMI or CMZ but those cases had other charac...…”

“…Some authors suggested that congenital anomalies may be related to uncontrolled hyperthyroidism, genetic factors, or a combination of genetics and uncontrolled hyperthyroidism or genetics and antithyroid medications (MMI/CMZ or PTU) rather than the antithyroid medications alone that are used to treat hyperthyroidism (Barbero et al, 2008;Koenig et al, 2010;Leung et al, 2015;Momotani et al, 1984;Momotani & Ito, 1991;Seoud et al, 2003;Stanisstreet et al, 1990;Ting et al, 2013;Van Dijke, Heydendael, & De Kleine, 1987;Yoshihara et al, 2012). However, results from studies including untreated hyperthyroidism are mixed with some studies showing no increased risk (Andersen et al, 2013;Andersen et al, 2017;Korelitz et al, 2013;Lo et al, 2015;Yoshihara et al, 2012) and other studies showing increased risk (Barbero et al, 2008;Momotani et al, 1984;Momotani & Ito, 1991;Seoud et al, 2003;Van Dijke et al, 1987). Sometimes, even when there is no statistically significant increased risk for untreated hyperthyroidism, anomalies consistent with MMI/CMZ embryopathy are found in a unexposed group (Andersen et al, 2013).…”