Exposure to Propylthiouracil in the First Trimester of Pregnancy and Birth Defects: A Study at a Single Institution

Abstract

Context Medical treatment of Graves disease during the first trimester has been the subject of controversy ever since treatment with an antithyroid drug during the first trimester was reported to possibly be associated with an increased risk of birth defects in newborns. Objective We investigated whether the incidence of birth defects among newborns born to mothers with Graves disease (GD) treated with propylthiouracil (PTU) during the first trimester of pregnancy was higher than in a control group that was not exposed to any medication. Methods We reviewed the cases of 1913 women with GD who gave birth between January 1, 2015, and May 31, 2019. Detailed information concerning the outcome of pregnancy and the presence of birth defects was collected at the first visit after the delivery and again 1 year after delivery. We classified the mothers and infants into 3 groups according to the treatment the mother had received for GD in the first trimester of pregnancy: a group in which the mothers had been treated with PTU alone (PTU group), a group in which the mothers had not been treated with any medication (control group), and a group in which the mothers had received some other medical treatment, such as thiamazole, potassium iodide, or 2 or more drugs (other treatment group). Results The incidence of malformed infant births was 5.5% (30/541 infants) in the PTU group and 5.7% (27/ 475 infants) in the control group. There were no specific birth defects in the PTU group, and there were no significant differences between PTU dosages or maternal thyroid function according to whether mothers had delivered a child with a birth defect. Conclusion The results of our retrospective study showed that treatment with PTU during the first trimester of pregnancy did not increase the incidence of birth defects among newborns.

Antithyroid drug therapy in pregnancy and risk of congenital anomalies: Systematic review and meta‐analysis

“…In a second study from the same institution, Yoshihara et al reported an increased risk of birth defects in children of hypothyroid compared to euthyroid mothers (9.3% vs 3.8%, p = .03) although this association disappeared after correction for maternal age and treatment 33 . A recent study by the same authors reported no difference in FT4 or TSH concentrations in PTU‐treated mothers who delivered children with birth defects and those who delivered children without birth defects 20 . In a large Danish nationwide study, Andersen et al reported an increased risk of congenital anomalies in a subsection of children of overtly hypothyroid women compared to children of euthyroid mothers although a proportion of these mothers had received ATD treatment (OR, 1.91; 95% CI, 1.12–3.25) 12 …”

“…Three studies evaluated anomaly risk in relation to ATD dose but were not comparable by meta‐analysis. The two hospital studies by Momotani and Yoshihara showed no association between ATD dose and birth defects 14,20 . In contrast, a large Korean nationwide database study by Seo et al reported that children of women who received a high cumulative dose of MMI had an increased anomaly risk compared to those who received lower doses (495 vs. <126 mg, OR, 1.87; 95% CI, 1.06–3.30).…”

“…The search identified 1393 unique articles of which 1324 were excluded after title or abstract screening. A further 53 papers were excluded after full text review, resulting in a final 16 papers in the review 12–14,19–21,26–35 . Papers excluded on full text review are listed in appendix 2 while the characteristics of the selected studies are shown in Table 1.…”

“…A recent meta‐analysis by Morales et al 22 showed an increase in adjusted anomaly risk in the children of women exposed to CMZ/MMI, PTU, as well as those exposed to untreated hyperthyroidism. In contrast however, three recently published studies, not included in the Morales meta‐analyses, reported no excess anomaly risk in association with PTU or untreated hyperthyroidism 19–21 . Thus, the risk of congenital anomalies with ATD therapy, particularly with respect to the PTU and untreated disease groups, remains unresolved.…”

“…Initial meta‐analyses were marked by disparities in comparison groups and the use of crude risk estimates that failed to account for potential confounders 16–18 . Furthermore, earlier meta‐analyses were published over four years ago and do not include a number of relevant studies that have subsequently emerged in the literature 12,13,19–21 . A recent meta‐analysis by Morales et al 22 showed an increase in adjusted anomaly risk in the children of women exposed to CMZ/MMI, PTU, as well as those exposed to untreated hyperthyroidism.…”