Antithyroid Drug Therapy in Pregnancy and Risk of Congenital Anomalies

Systematic Review and Meta-Analysis

Medha Agrawal; Steffan Lewis; Lakdasa Premawardhana; Colin M. Dayan; Peter N. Taylor; Onyebuchi E. Okosieme

Disclosures

Clin Endocrinol. 2022;96(6):857-868. 

In This Article

Abstract and Introduction

Abstract

Objectives: The risk of congenital anomalies following in utero exposure to thionamide antithyroid drugs (ATDs) is unresolved. Observational studies are contradictory and existing meta-analyses predate and preclude more recent studies. We undertook an updated meta-analysis of congenital anomaly risk in women exposed to carbimazole or methimazole (CMZ/MMI), propylthiouracil (PTU), or untreated hyperthyroidism in pregnancy.

Methods: We searched Medline, Embase, and the Cochrane database for articles published up till August 2021. We pooled separate crude and adjusted risk estimates using random effects models and subgroup analyses to address heterogeneity.

Results: We identified 16 cohort studies comprising 5957, 15,785, and 15,666 exposures to CMZ/MMI, PTU, and untreated hyperthyroidism, respectively. Compared to nondisease controls, adjusted risk ratio (RR) and 95% confidence intervals (95% CIs) for congenital anomalies was increased for CMZ/MMI (RR, 1.28; 95% CI, 1.06–1.54) and PTU (RR, 1.16; 95% CI, 1.08–1.25). Crude risk for CMZ/MMI was increased relative to PTU (RR, 1.20; 95% CI, 1.01–1.43). Increased risk was also seen with exposure to both CMZ/MMI and PTU, that is, women who switched ATDs in pregnancy (RR, 1.51; 95% CI, 1.14–1.99). However, the timing of ATD switch was highly variable and included prepregnancy switches in some studies. The excess number of anomalies per 1000 live births was 17.2 for patients exposed to CMZ/MMI, 9.8, for PTU exposure, and 31.4 for exposure to both CMZ/MMI and PTU. Risk in the untreated group did not differ from control or ATD groups. The untreated group was however highly heterogeneous in terms of thyroid status. Subgroup analysis showed more positive associations in studies with >500 exposures and up to 1-year follow-up.

Conclusions: ATD therapy carries a small risk of congenital anomalies which is higher for CMZ/MMI than for PTU and does not appear to be reduced by switching ATDs in pregnancy. Due to key limitations in the available data, further studies will be required to clarify the risks associated with untreated hyperthyroidism and with switching ATDs in pregnancy.

Introduction

Hyperthyroidism is common in women of reproductive age and affects about 0.1%–0.5% of pregnant women.[1] Uncontrolled hyperthyroidism has adverse effects on pregnancy outcomes including an increased risk of pre-eclampsia, preterm delivery, and low birth weight.[2–4] The thionamide antithyroid drugs (ATD), namely methimazole (MMI), its prodrug derivative, carbimazole (CMZ), and propylthiouracil (PTU), are effective in the treatment of hyperthyroidism.[5] CMZ/MMI is the recommended ATD in the nonpregnant population while PTU is reserved as second line due to the potentially serious adverse effect of hepatotoxicity.[5] One drawback of CMZ/MMI however is the risk of offspring congenital anomalies when administered in early pregnancy, that is, during the critical phase of organogenesis.[6,7] CMZ/MMI has been linked with a broad range of defects including the so called CMZ/MMI embryopathy, a cluster of anomalies comprising aplasia cutis, choanal atresia, trachea-oesophageal fistula, and dysmorphic facial features.[8]

Accordingly, international guidelines recommend that PTU is used instead of CMZ/MMI in early gestation or in the preconception period.[9–11] Guidelines also suggest that ATDs can be discontinued altogether in women with mild disease in pregnancy.[9–11] However, the benefits of these approaches remain uncertain. Congenital anomaly risk is well established for CMZ/MMI but increased anomaly risk has also been reported in PTU treated women including those who switch from CMZ/MMI to PTU on conception.[12,13] To compound matters, some studies have suggested that hyperthyroidism by itself has teratogenic potential independent of ATD exposure.[14] Randomised controlled trials are now unlikely to be conducted given the potential ethical dilemmas that such trials will entail. Thus, a meta-analysis of observational studies represents the next best level of evidence for evaluating the safety of ATDs in pregnancy.

Findings from observational studies have been conflicting and challenging to synthesize due to methodological discrepancies across studies.[15] 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. 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. Our objective was therefore to present an updated meta-analysis of all available studies to date. To optimise the use of available data, we have pooled separate crude and adjusted risk estimates using random effects models and subgroup analyses to address heterogeneity.

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