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

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.

Hyperthyroidism

“…Propylthiouracil-associated anomalies include facial or neck cysts and urinary tract abnormalities, whereas those associated with methimazole include aplasia cutis, esophageal atresia, abdominal wall defects, and ventricular septal defects. In a meta-analysis of 16 cohorts that included 5 367 601 people, the adjusted relative risk among neonates born to mothers in the methimazole group compared with the control group was 1.28 (95% CI, 1.06-1.54) and for the propylthiouracil group compared with the control group was 1.16 (95% CI, 1.08-1.25; absolute rates were not provided) . Therefore, propylthiouracil is preferred in the first trimester of pregnancy .…”

“…In a meta-analysis of 16 cohorts that included 5 367 601 people, the adjusted relative risk among neonates born to mothers in the methimazole group compared with the control group was 1.28 (95% CI, 1.06-1.54) and for the propylthiouracil group compared with the control group was 1.16 (95% CI, 1.08-1.25; absolute rates were not provided). 93 Therefore, propylthiouracil is preferred in the first trimester of pregnancy. 90,91 Because antithyroid drugs cross the placenta and have more pronounced effects on fetal than on maternal thyroid function, the lowest antithyroid drug dose necessary should be used to maintain the maternal FT 4 level at or just above the upper reference limit.…”

How to manage Graves’ disease in women of childbearing potential

“…PTU could then be switched to MMI after the first trimester (5 mg CBZ or 3 mg MMI is equivalent to 50 mg PTU) to reduce maternal hepatotoxic risk. The potential for destabilisation of hyperthyroidism by switching should be weighed against the ATD risks 16 . In women with overt GD hyperthyroidism newly diagnosed in the first trimester, we suggest commencing PTU, but when diagnosed later in pregnancy, commence MMI.…”

“…Exposure in the first trimester is associated with increased risk of congenital malformation. 16,[18][19][20] MMI exposure is associated with foetal aplasia cutis, choanal atresia, omphalocoele and dysmorphic features at a rate 2%-4% higher than unexposed neonates. 18,20 PTU exposure has been associated with urinary tract, face and neck malformations, 18,21 but more evidence is needed to establish the degree of risk.…”

“…In women with overt GD hyperthyroidism newly diagnosed in the first trimester, we suggest commencing PTU, but when diagnosed later in pregnancy, commence MMI. Block and replace therapy using ATD and levothyroxine has no routine role due to risk of foetal hypothyroidism with high dose ATD, dose‐dependent ATD risks 16 and insufficient transplacental levothyroxine transfer 6,17 ; but may be considered in foetal hyperthyroidism.…”