Thyroid antibody positivity in pregnancy is associated with altered reproductive hormone concentrations and placental growth in Lewis rats

Thyroid antibody positivity (TAb+) is common among reproductive-aged women, and TAb+ in pregnancy is associated with complications including miscarriage and gestational diabetes. These associations persist in women with normal thyroid status, but there are minimal studies examining the underlying mechanisms. This study was designed to investigate the effects of TAb+ on maternal, placental and fetal health, with a focus on metabolism, using a Lewis rat model of TAb+ induced before pregnancy. Aspects of maternal fertility, cardiovascular adaptations and placental function were also assessed. Oestrous cycling was monitored prior to pregnancy, and an intraperitoneal glucose tolerance test was performed on embryonic day (E)16. Rats were killed at late pregnancy (E20), with maternal and fetal plasma and tissues collected for analysis of metabolic, endocrine and placental function. TAb+ rats did not have altered glucose tolerance during pregnancy but did have increased oestrous cycle length before pregnancy and altered concentrations of key reproductive hormones at E20, including rat placental lactogen. Placentas exposed to TAb+ were larger, with increased expression of glucose transporters and inflammatory markers. TAb+ dams had a reduced proportion of male fetuses per litter but no changes in litter size or fetal growth. This study demonstrates that although TAb+ was not associated with severe changes to the maternal parameters investigated, several aspects of placental biology were impacted. These findings support further investigation of TAb+ as a thyroid hormone-independent contributor to pregnancy complications, with placental function emerging as a potential mechanistic target. KEY POINTS: Thyroid antibody positivity (TAb+) is associated with an increased risk of complications during pregnancy, including miscarriage and gestational diabetes. Associations are often attributed to thyroid dysfunction, yet risks persist in euthyroid women. Research investigating the effects of TAb+ on glucose metabolism and placental function in models with normal thyroid hormone concentrations is required. In our rodent model of TAb+ during pregnancy, there were limited changes to glucose metabolism or litter size. However, we did see increased placental growth, altered rat placental lactogen and progesterone concentrations, and a reduced proportion of male fetuses. This study suggests the link between TAb+ and gestational diabetes is not driven by elevated antibodies. However, TAb+ impacts aspects of fertility, fetal survival and placental development, which has implications for other pregnancy disorders. The findings from this study highlight that thyroid antibodies are an important factor to consider when managing patients with TAb+ during pregnancy, outside of consequences to thyroid health.