| Objective Pregnancy accompanied by thyroid autoimmune disease is common in clinic. Women with autoimmune hypothyroidism could become conceived after thyroxine replacement. However, thyroid autoimmune antibodies, such as thyroid peroxidase antibody (TPOAb), thyroid globulin antibody (TgAb), and thyroid stimulating hormome receptor blocking antibody (TSBAb) remain positive. TSBAb could transfer freely through placenta, inducing congenital hypothyroidism of the fetus. While TPOAb positivity has been proved to increase the risk of miscarriage. Maternal hypothyroidism is confirmed to have negative effects on offspring’s somatic and neurologic development, and may increase the incidence of metabolic disease in adulthood. The placenta is one of the target organs of maternal autoimmunity and may play a role in miscarriage induced by TPOAb. This study aims to investigate the effect of maternal TSBAb on offspring’s pancreatic development and whether TPOAb affect placental development in early pregnancy.Method In animal research, we used thyrotropin (TSH) receptor knock out mice (Tshr-/-) as model of congenital hypothyroidism to replicate the blockage of TSH action by TSBAb binding to thyrotropin receptor. The development of their offspring and pancreatic function in adulthood were studied.In clinical study, the virtual organ computer-aided analysis (VOCAL) mode in three-dimensional (3D) power Doppler ultrasound was applied to measure placental volume in early pregnancy. Placental quotient (PQ) is calculated to rule out the influence of gestational age on placental development as placental volume (PV) divided by crown-rump length (CRL). PQ values were compared in different TPOAb and TSH groups.Result Tshr-/- mice were born at a similar weight compared to Tshr+/+ mice (1.39±0.06 vs 1.43±0.10g, P=0.708). However, Tshr-/- mice grew significantly slowly than Tshr+/+ mice at 3 weeks and 8 weeks (7.93+0.38 vs 6.53+0.39g, P<0.05; 20.96+0.64 vs 17.36±1.98g,P<0.05). The pancreatic weight of Tshr-/- mice was also remarkably lower (0.23±0.04 vs 0.39±0.03g, P=0.001). The thyroxine levels in adulthood were similar between the two groups, but TSH of Tshr-/- mice was remarkably higher. OGTT test revealed fast blood glucose and postprandial glucose at 30’,60’and 120’ were all significantly lower in Tshr-/- mice. GSIS showed dysfunction of Tshr-/- mice β cells in insulin secretion. Atrophy of islets, decreased number of islet cells, and distortion of acinar architecture were observed in HE staining of Tshr-/- mice pancreas.We found thyroid peroxidase antibody (TPOAb) positive women were at a 3.5-fold risk to have small placental quotient (PQ<0.82 cm3/mm, OR=3.54,95% CI 1.29-9.47), compaired with women without TPOAb. Women with elevated thyrotropin (TSH) levels were found to have similar PQ (OR=1.43,95% CI 0.68-6.74) with euthyriod subjects. CRL values measured revealed high accordance to gestational age specific standard values and showed no difference between TSH and TPOAb subgroups. Small PV was suspected to be the main cause of small PQ.Conclusion Maternal TSBAb may result in congenital hypothyroidism of their offsprings. Retardation of somatic and pancreatic development still occur after thyroxine replacement which lead to islet dysfunction and glucose intolerance in adulthood. We suspect that the absence of TSH modulation may be an important cause. TPOAb positivity, instead of thyroid dysfunction, is associated with maldevelopment of the placenta characterized by small PV in early pregnancy. The underlying mechanism of TPOAb positive affecting placental development warrant further study. |
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