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 β 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
(χ2 = 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.