Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, Chiusano E, John R, Guaraldo V, George LM, Perona M, Dall'Amico D, Parkes AB, Joomun M, Wald NJ.
Antenatal thyroid screening and childhood cognitive function.
N Engl J Med. 2012 Feb 9;366(6):493-501.
ABSTRACT--Children born to women with low thyroid hormone levels have been reported to have decreased cognitive function.
We conducted a randomized trial in which pregnant women at a gestation of 15 weeks 6 days or less provided blood samples for measurement of thyrotropin and free thyroxine (T(4)). Women were assigned to a screening group (in which measurements were obtained immediately) or a control group (in which serum was stored and measurements were obtained shortly after delivery). Thyrotropin levels above the 97.5th percentile (nl=0.15 - 3.65mIU/l in UK), free T(4) levels below the 2.5th percentile (fT4 8.4 - 14.6 pmol/l), or both were considered a positive screening result. Women with positive findings in the screening group were assigned to 150 μg of levothyroxine per day. The primary outcome was IQ at 3 years of age in children of women with positive results, as measured by psychologists who were unaware of the group assignments.
Of 21,846 women who provided blood samples (at a median gestational age of 12 weeks 3 days), 390 women in the screening group and 404 in the control group tested positive. The median gestational age at the start of levothyroxine treatment was 13 weeks 3 days; treatment was adjusted as needed to achieve a target thyrotropin level of 0.1 to 1.0 mIU per liter. Among the children of women with positive results, the mean IQ scores were 99.2 and 100.0 in the screening and control groups, respectively (difference, 0.8; 95% confidence interval [CI], -1.1 to 2.6; P=0.40 by intention-to-treat analysis); the proportions of children with an IQ of less than 85 were 12.1% in the screening group and 14.1% in the control group (difference, 2.1 percentage points; 95% CI, -2.6 to 6.7; P=0.39). An on-treatment analysis showed similar results.
Antenatal screening (at a median gestational age of 12 weeks 3 days) and maternal treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age.
COMMENT-This is the long-awaited report of an excellent study, and a disappointment to those who favor universal screening of pregnant women. Screening and treatment were done very early (12,and 13--20 weeks, respectively). In both screened and observed groups, approximately 5% had abnormal results, but deviation from “normal” appears modest. Among the 404 control women (not-screened and not-treated with abnormal tests), whose progeny were evaluated, median TSH was only 3.2 mIU/l and interquartile range 1.2-4.2, while median fT4 was 11.2 pmol/l, with interquartile range 10.5-13.2. Twenty-four percent of women were lost to follow up.
It is uncertain why this study fails to support previous findings indicating untreated hypothyroidism was detrimental to offspring’s IQ. Perhaps testing at 3 years age is inadequate to detect abnormalities, but this seems not likely. Perhaps the women in this study had on average more mild abnormalities in TSH or fT4 than in prior studies, some of which used older and less sensitive assays with different cut-off levels. Perhaps in the 2 decades between original and recent studies women are more effectively screened and treated prior to pregnancy, leaving fewer individuals with serious hypothyroidism at the start of pregnancy. Perhaps prior studies failed to sort out confounding differences in the control subjects. Or, perhaps this study is the correct answer. And we should remember that effects of hypothyroidism on the fetus are just part of the problems, the aqdverse effects of hypothyroidism on outcome of pregnancy being the other important aspect. Time and ongoing studies may provide an answer. L De Groot, MD


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