Antenatal Thyroid Antenatal Thyroid Screening and Screening and

Childhood Childhood Cognitive FunctionCognitive Function

John H. Lazarus, M.D., Jonathan P. Bestwick, M.Sc., Sue Channon, John H. Lazarus, M.D., Jonathan P. Bestwick, M.Sc., Sue Channon, D.Clin.Psych., Ruth Paradice, Ph.D., Aldo Maina, M.D., Rhian Rees, D.Clin.Psych., Ruth Paradice, Ph.D., Aldo Maina, M.D., Rhian Rees,

M.Sc., Elisabetta Chiusano, M.Psy., Rhys John, Ph.D., Varvara M.Sc., Elisabetta Chiusano, M.Psy., Rhys John, Ph.D., Varvara Guaraldo, M.S.Chem., Lynne M. George, H.N.C., Marco Perona, Guaraldo, M.S.Chem., Lynne M. George, H.N.C., Marco Perona, M.S.Chem., Daniela Dall'Amico, M.D., Arthur B. Parkes, Ph.D., M.S.Chem., Daniela Dall'Amico, M.D., Arthur B. Parkes, Ph.D.,

Mohammed Joomun, M.Sc., and Nicholas J. Wald, F.R.S.Mohammed Joomun, M.Sc., and Nicholas J. Wald, F.R.S.

N Engl J Med 2012; 366:493-N Engl J Med 2012; 366:493-501501

February 9, 2012February 9, 2012

BackgroundBackground

Children born to women with low Children born to women with low thyroid hormone levels have been thyroid hormone levels have been reported to have decreased reported to have decreased cognitive function.cognitive function.

MethodsMethods We conducted a randomized trial in which pregnant We conducted a randomized trial in which pregnant

women at a gestation of 15 weeks 6 days or less women at a gestation of 15 weeks 6 days or less provided blood samples for measurement of provided blood samples for measurement of thyrotropin and free thyroxine. thyrotropin and free thyroxine.

Women were assigned Women were assigned -to a screening group (measurements were

obtained immediately) -or a control group (serum was stored and

measurements were obtained shortly after delivery) Thyrotropin levels above the 97.5th percentile, free Thyrotropin levels above the 97.5th percentile, free

T4 levels below the 2.5th percentile, or both were T4 levels below the 2.5th percentile, or both were considered a positive screening result. considered a positive screening result.

Women with positive findings in the screening Women with positive findings in the screening group were assigned to 150 μg of levothyroxine per group were assigned to 150 μg of levothyroxine per day. day.

The primary outcome was IQ at 3 years of age in The primary outcome was IQ at 3 years of age in children of women with positive results, as children of women with positive results, as measured by psychologists who were unaware of measured by psychologists who were unaware of the group assignments.the group assignments.

MethodsMethods

Study ParticipantsStudy Participants

We invited pregnant women to participate at We invited pregnant women to participate at their first antenatal hospital visit. The their first antenatal hospital visit. The women were recruited from 10 centers in women were recruited from 10 centers in the United Kingdom and 1 center in Italy. the United Kingdom and 1 center in Italy.

Exclusion criteriaExclusion criteria age of less than 18 years, age of less than 18 years, gestational age of more than 15 weeks 6 gestational age of more than 15 weeks 6

days, days, twin pregnancies, twin pregnancies, known thyroid disease. known thyroid disease.

Approval of the study was obtained from Approval of the study was obtained from research ethics committees in the United research ethics committees in the United Kingdom and Italy, and all participants Kingdom and Italy, and all participants provided written informed consent.provided written informed consent.

Study ProceduresStudy Procedures Blood samples were sent to the laboratory at Blood samples were sent to the laboratory at

the University Hospital of Wales, Cardiff, or to the University Hospital of Wales, Cardiff, or to Ospedale Sant'Anna, Turin, Italy, for Ospedale Sant'Anna, Turin, Italy, for measurement of thyrotropin and free T4 levels. measurement of thyrotropin and free T4 levels.

On receipt of samples, women were randomly On receipt of samples, women were randomly assigned with the use of a computer-generated assigned with the use of a computer-generated block design to the screening or control group.block design to the screening or control group.

Serum samples from the screening group were Serum samples from the screening group were immediately assayed for levels of free T4 and immediately assayed for levels of free T4 and thyrotropin. thyrotropin.

Serum samples from women in the control Serum samples from women in the control group, stored at −40°C, were assayed for levels group, stored at −40°C, were assayed for levels of free T4 and thyrotropin after delivery. of free T4 and thyrotropin after delivery.

Women were classified as positive if the serum Women were classified as positive if the serum thyrotropin concentration was above the thyrotropin concentration was above the 97.5th percentile, the serum free T4 97.5th percentile, the serum free T4 concentration was below the 2.5th percentile, concentration was below the 2.5th percentile, or both. or both.

Patients in the screening group who had Patients in the screening group who had positive results were treated with levothyroxine positive results were treated with levothyroxine (recommended starting dose, 150 μg per day). (recommended starting dose, 150 μg per day).

Levels of thyrotropin and free T4 were checked Levels of thyrotropin and free T4 were checked 6 weeks after the start of levothyroxine therapy 6 weeks after the start of levothyroxine therapy and at 30 weeks' gestation, with adjustment of and at 30 weeks' gestation, with adjustment of the dose as necessary. the dose as necessary.

The target thyrotropin level was 0.1 to 1.0 The target thyrotropin level was 0.1 to 1.0 mIU/LmIU/L

Women in the screening and control groups Women in the screening and control groups who had positive test results received standard who had positive test results received standard routine care and were advised to visit their routine care and were advised to visit their family physician after delivery to determine family physician after delivery to determine whether levothyroxine therapy should be whether levothyroxine therapy should be continued or initiated, respectively.continued or initiated, respectively.

In the United Kingdom, In the United Kingdom, The 95% range of thyrotropin - 0.15 The 95% range of thyrotropin - 0.15

to 3.65 mIU/Lto 3.65 mIU/L The 95% range of free T4 levels was The 95% range of free T4 levels was

8.4 to 14.6 pmol/L8.4 to 14.6 pmol/L In Turin, In Turin,

The 95% ranges of thyrotropin 0.11 The 95% ranges of thyrotropin 0.11 to 3.50 Miu/Lto 3.50 Miu/L

free T4 were 7.15 to 11.34 pg/ml.free T4 were 7.15 to 11.34 pg/ml.

Outcomes and AssessmentsOutcomes and Assessments The primary outcome was the IQ, at 3 years The primary outcome was the IQ, at 3 years

of age, of children of the women who tested of age, of children of the women who tested positive. positive.

IQ was assessed with the use of the IQ was assessed with the use of the Wechsler Wechsler Preschool and Primary Scale of Intelligence, Preschool and Primary Scale of Intelligence, third edition (2003) (Psychological third edition (2003) (Psychological Corporation)Corporation) by psychologists who visited by psychologists who visited the children's home and who were unaware the children's home and who were unaware of the group assignments.of the group assignments.

Aspects of child behavior that might affect Aspects of child behavior that might affect the evaluation of IQ were assessed with the the evaluation of IQ were assessed with the use of the use of the Child Behavior Checklist (CBCL) Child Behavior Checklist (CBCL) 20002000 (Achenbach System of Empirically (Achenbach System of Empirically Based Assessment, University of Vermont) Based Assessment, University of Vermont) and the and the Behavior Rating Inventory of Behavior Rating Inventory of Executive Function, preschool version (Brief-Executive Function, preschool version (Brief-P), 2003P), 2003 (Psychological Assessment (Psychological Assessment Resources). Resources).

IQ assessments were performed by two IQ assessments were performed by two psychologists in the United Kingdom and psychologists in the United Kingdom and one in Turin. one in Turin.

To allow for between-psychologist To allow for between-psychologist differences in the assessments, the mean differences in the assessments, the mean IQ score for the controls was set at 100 IQ score for the controls was set at 100 for each psychologist. For example, if the for each psychologist. For example, if the mean IQ score in the control group was mean IQ score in the control group was 105 for a particular psychologist, all IQ 105 for a particular psychologist, all IQ scores assessed by that psychologist were scores assessed by that psychologist were reduced by 5 points. reduced by 5 points.

An analysis based on z scores (the An analysis based on z scores (the observed IQ minus the mean, divided by observed IQ minus the mean, divided by the standard deviation according to the standard deviation according to psychologist) was also performed.psychologist) was also performed.

Statistical AnalysisStatistical Analysis Baseline characteristics of women with Baseline characteristics of women with

positive findings (a high thyrotropin level, a positive findings (a high thyrotropin level, a low free T4 level, or both) in the screening low free T4 level, or both) in the screening and control groups were compared with and control groups were compared with t-tests for continuous variables with a t-tests for continuous variables with a

Gaussian distribution Gaussian distribution Wilcoxon rank-sum test for those with a Wilcoxon rank-sum test for those with a

non-Gaussian distribution. non-Gaussian distribution. The chi-square test was used for The chi-square test was used for

categorical variables.categorical variables. To assess a possible trend, we estimated the To assess a possible trend, we estimated the

relative risk of standardized IQ valuesrelative risk of standardized IQ values A post hoc, on-treatment analysis of IQ A post hoc, on-treatment analysis of IQ

scores was also performed, which included scores was also performed, which included the children of women in whom thyrotropin the children of women in whom thyrotropin levels decreased by at least 10% and free T4 levels decreased by at least 10% and free T4 levels increased by at least 10% from the first levels increased by at least 10% from the first blood sample obtained (at approximately 12 blood sample obtained (at approximately 12 weeks' gestation) to the sample obtained 6 weeks' gestation) to the sample obtained 6 weeks after the initiation of levothyroxine weeks after the initiation of levothyroxine therapy.therapy.

The study protocol specified recruitment of The study protocol specified recruitment of 22,000 women with singleton pregnancies, with 22,000 women with singleton pregnancies, with 440 of the 11,000 women in each study group 440 of the 11,000 women in each study group having positive screening results (a high having positive screening results (a high thyrotropin level, a low free T4 level, or both). thyrotropin level, a low free T4 level, or both).

Among the women with positive results, 22 of the Among the women with positive results, 22 of the children in the screening group (5%) were children in the screening group (5%) were expected to have an IQ of 85 or less, as compared expected to have an IQ of 85 or less, as compared with 66 children in the control group (15%). with 66 children in the control group (15%).

This expectation was based on the results of a This expectation was based on the results of a study by Haddow et al.study by Haddow et al. in which women with a in which women with a high thyrotropin level were three times as likely high thyrotropin level were three times as likely to have children with an IQ that was less than or to have children with an IQ that was less than or equal to 85 as women with normal thyrotropin equal to 85 as women with normal thyrotropin levels during pregnancy. levels during pregnancy.

With an expected 10% loss to follow-up, the With an expected 10% loss to follow-up, the power to detect such a difference in child IQ power to detect such a difference in child IQ between the screening and control groups is between the screening and control groups is greater than 95% at the 5% significance level greater than 95% at the 5% significance level (two-sided test).(two-sided test).

ResultsResults

Randomization and Baseline Measurements

a total of a total of 21,84621,846 women were women were recruited recruited 10,924 women were assigned to the 10,924 women were assigned to the

screening group screening group 10,922 were assigned to the control 10,922 were assigned to the control

group. group. The proportions of women classified The proportions of women classified

as having positive screening results as having positive screening results 4.6% in the screening group 4.6% in the screening group 5.0% in the control group. 5.0% in the control group.

Similar proportions were classified as Similar proportions were classified as having positive results on the basis of a high having positive results on the basis of a high thyrotropin level or a low free T4 level. thyrotropin level or a low free T4 level.

About 5% of women classified as having About 5% of women classified as having positive screening results had both a high positive screening results had both a high thyrotropin level and a low free T4 level. thyrotropin level and a low free T4 level.

Levothyroxine therapy was started in the Levothyroxine therapy was started in the screening group at a median gestation of 13 screening group at a median gestation of 13 weeks 3 days. weeks 3 days.

Psychological testing Psychological testing 78.2% of the children of screening 78.2% of the children of screening

group group 73.3% of the children of control 73.3% of the children of control

group. group.

The groups were similar with respect to The groups were similar with respect to baseline characteristics and baseline characteristics and socioeconomic characteristicssocioeconomic characteristics

There were no significant differences There were no significant differences between the screening and control between the screening and control groups with respect togroups with respect to gestational age at delivery (median, 40.1 gestational age at delivery (median, 40.1

and 40.2 weeks, respectively; P=0.10), and 40.2 weeks, respectively; P=0.10), rates of preterm birth (<37 weeks' rates of preterm birth (<37 weeks'

gestation, 5.6% and 7.9%; P=0.20), gestation, 5.6% and 7.9%; P=0.20), birth weight (mean, 3.5 kg and 3.3 kg; birth weight (mean, 3.5 kg and 3.3 kg;

P=0.15).P=0.15).

Figure 1. Randomization and Follow-up of the Study Figure 1. Randomization and Follow-up of the Study Participants.Participants.

Cognitive FunctionCognitive Function

The mean standardized IQ in children at The mean standardized IQ in children at 3 years of age in the control group was 3 years of age in the control group was 100.0 (by definition), and in the 100.0 (by definition), and in the screening group it was 99.2 (P=0.40). screening group it was 99.2 (P=0.40).

The proportions of children with an IQ of The proportions of children with an IQ of less than 85 were 12.1% in the screening less than 85 were 12.1% in the screening group and 14.1% in the control group group and 14.1% in the control group (P=0.39). (P=0.39).

An analysis adjusting for initial An analysis adjusting for initial thyrotropin measurements (log-thyrotropin measurements (log-transformed) did not show a significant transformed) did not show a significant association between thyrotropin and IQ association between thyrotropin and IQ and yielded results that were not and yielded results that were not materially different. materially different.

We also performed an analysis based on We also performed an analysis based on z scores (the observed IQ score minus z scores (the observed IQ score minus the mean, divided by the standard the mean, divided by the standard deviation according to psychologist) and deviation according to psychologist) and found no significant difference between found no significant difference between groups with respect to the mean IQ z groups with respect to the mean IQ z score or the proportion of children with score or the proportion of children with an IQ z score of less than −1an IQ z score of less than −1

There were likewise no significant There were likewise no significant between-group differences in the results between-group differences in the results of other psychological assessments of other psychological assessments (CBCL and Brief-P scores)(CBCL and Brief-P scores)

ConclusionConclusion Antenatal screening (at a median Antenatal screening (at a median

gestational age of 12 weeks 3 days) gestational age of 12 weeks 3 days) and maternal treatment for and maternal treatment for hypothyroidism did not result in hypothyroidism did not result in improved cognitive function in improved cognitive function in children at 3 years of age.children at 3 years of age.

Maternal Thyroid Deficiency duringMaternal Thyroid Deficiency during Pregnancy and Pregnancy and Subsequent Neuropsychological Development of the Subsequent Neuropsychological Development of the

ChildChildJames E. Haddow et al.James E. Haddow et al.

N Engl J Med 1999; 341:549-555N Engl J Med 1999; 341:549-555

MethodsMethods In 1996 and 1997, we measured thyrotropin in stored In 1996 and 1997, we measured thyrotropin in stored

serum samples collected from 25,216 pregnant serum samples collected from 25,216 pregnant women between January 1987 and March 1990. women between January 1987 and March 1990.

We then located 47 women with serum thyrotropin We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values.and 124 matched women with normal values.

Their seven-to-nine-year-old children, none of whom Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading relating to intelligence, attention, language, reading ability, school performance, and visual–motor ability, school performance, and visual–motor performance.performance.

ResultsResults The children of the 62 women with high serum thyrotropin The children of the 62 women with high serum thyrotropin

concentrations performed slightly less well on all 15 tests. concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control than those of the children of the 124 matched control women (P=0.06); 15 percent had scores of 85 or less, as women (P=0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism.control women had confirmed hypothyroidism.

ConclusionsConclusions Undiagnosed hypothyroidism in Undiagnosed hypothyroidism in

pregnant women may adversely pregnant women may adversely affect their fetuses; therefore, affect their fetuses; therefore, screening for thyroid deficiency screening for thyroid deficiency during pregnancy may be during pregnancy may be warranted. warranted.

Maternal Thyroid Function during Early Maternal Thyroid Function during Early Pregnancy and Cognitive Functioning in Early Pregnancy and Cognitive Functioning in Early

Childhood: The Generation R StudyChildhood: The Generation R StudyEndocrine Care Sept 2010Endocrine Care Sept 2010

Participants:Participants: Participants included 3659 Participants included 3659 children and their mothers in Netherland. children and their mothers in Netherland.

Results:Results: Maternal TSH was not related to the cognitive Maternal TSH was not related to the cognitive

outcomes. outcomes. An increase in maternal FT4 predicted a lower risk of An increase in maternal FT4 predicted a lower risk of

expressive language delay at 30 months only. expressive language delay at 30 months only. However, both mild and severe maternal However, both mild and severe maternal

hypothyroxinemia was associated with a higher risk of hypothyroxinemia was associated with a higher risk of expressive language delay across all ages expressive language delay across all ages

Severe maternal hypothyroxinemia also predicted a Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delayhigher risk of nonverbal cognitive delay

Conclusions:Conclusions: Maternal hypothyroxinemia is a Maternal hypothyroxinemia is a risk factor for cognitive delay in early childhood. risk factor for cognitive delay in early childhood.

cognitioncognition

The term The term cognitioncognition (Latin: (Latin: cognoscerecognoscere, "to know", "to , "to know", "to conceptualize" or "to recognize") conceptualize" or "to recognize") refers to a faculty for the processing refers to a faculty for the processing of information, applying knowledge, of information, applying knowledge, and changing preferences. and changing preferences.

Cognition, or cognitive processes, Cognition, or cognitive processes, can be natural or artificial, conscious can be natural or artificial, conscious or unconscious. or unconscious.