Fetal loss associated with excess thyroid hormone exposure

Context Maternal hypothyroidism and hyperthyroidism have deleterious effects on the outcome of pregnancy. While the effects of thyroid hormone (TH) deprivation on the fetus, independently from that on the mother, can be studied in infants with congenital hypothyroidism, this is not the case in those with fetal thyrotoxicosis. Objective To study the effects of TH excess on fetuses carried by mothers with resistance to TH (RTH) who are euthyroid despite high TH levels but who may carry normal fetuses that are exposed to high maternal hormone levels. Design, Setting, and Participants Retrospective study of 167 members of an Azorean family with RTH. Affected individuals had the RTH phenotype (high serum concentration of free thyroxine and triiodothyronine without suppressed thyrotropin) confirmed by genotyping to identify the Arg243-->Gln mutation in the TH receptor p gene. Main Outcome Measures Pregnancy outcome of affected mothers vs that of unaffected mothers carrying fetuses conceived by affected fathers, as well as that of unaffected first-degree relatives and outcomes from the general island population. Comparison of birth weights and blood concentrations of thyrotropin (TSH) obtained during routine neonatal screening of infants born to these 3 groups. Results Thirty-six couples with complete information belonged to 1 of 3 groups: affected mothers (n=9), affected fathers (n=9), and unaffected relatives (n=18). Mean miscarriage rates were 22.9%, 2.0%, and 4.4%, respectively (chi(2)=8.66, P=.01). Affected mothers had an increased rate of miscarriage (z=3.10, P=.002, by Wilcoxon rank-sum test). They had marginally higher than expected numbers of affected offspring, ie, 20 affected and 11 unaffected children (P=.07), while affected fathers had 15 affected and 12 unaffected children (P=.35). Unaffected infants born to affected mothers were significantly smaller than affected infants, having a mean SD score for gestational age of -1.79 (SD, 0.86) vs -0.06 (SD, 1.11) to -0.22 (SD, 0.70) for all other groups (P<.001). Only unaffected infants born to affected mothers had undetectable blood levels of TSH. Conclusion There was a higher rate of miscarriage in mothers affected by RTH that may have involved predominantly unaffected fetuses. The lower birth weight and suppressed levels of TSH in unaffected infants born to affected mothers indicates that the high maternal TH levels produce fetal thyrotoxicosis. These data indicate a direct toxic effect of TH excess on the fetus.