Maternal Thyroid Deficiency during Pregnancy and Subsequent Neuropsychological Development of the Child
James E. Haddow, M.D., Glenn E. Palomaki, B.S., Walter C. Allan, M.D., Josephine R. Williams, George J. Knight, Ph.D., June Gagnon, M.A., Cheryl E. O'Heir, M.Ed., Ed.S., Marvin L. Mitchell, M.D., Rosalie J. Hermos, M.P.H., Susan E. Waisbren, Ph.D., James D. Faix, M.D., and Robert Z. Klein, M.D.
Background When thyroid deficiency occurs simultaneously ina pregnant woman and her fetus, the child's neuropsychologicaldevelopment is adversely affected. Whether developmental problemsoccur when only the mother has hypothyroidism during pregnancyis not known.
Methods In 1996 and 1997, we measured thyrotropin in storedserum samples collected from 25,216 pregnant women between January1987 and March 1990. We then located 47 women with serum thyrotropinconcentrations at or above the 99.7th percentile of the valuesfor all the pregnant women, 15 women with values between the98th and 99.6th percentiles, inclusive, in combination withlow thyroxine levels, and 124 matched women with normal values.Their seven-to-nine-year-old children, none of whom had hypothyroidismas newborns, underwent 15 tests relating to intelligence, attention,language, reading ability, school performance, and visualmotorperformance.
Results The children of the 62 women with high serum thyrotropinconcentrations performed slightly less well on all 15 tests.Their full-scale IQ scores on the Wechsler Intelligence Scalefor Children, third edition, averaged 4 points lower than thoseof the children of the 124 matched control women (P=0.06); 15percent had scores of 85 or less, as compared with 5 percentof the matched control children. Of the 62 women with thyroiddeficiency, 48 were not treated for the condition during thepregnancy under study. The full-scale IQ scores of their childrenaveraged 7 points lower than those of the 124 matched controlchildren (P=0.005); 19 percent had scores of 85 or less. Elevenyears after the pregnancy under study, 64 percent of the untreatedwomen and 4 percent of the matched control women had confirmedhypothyroidism.
Conclusions Undiagnosed hypothyroidism in pregnant women mayadversely affect their fetuses; therefore, screening for thyroiddeficiency during pregnancy may be warranted.
The link between hypothyroidism caused by iodine deficiencyduring pregnancy and mental retardation in the offspring hasbeen recognized for nearly 100 years.1 Iodine deficiency isassociated with thyroid deficiency in both mother and fetus,2a situation that makes it impossible to determine whether themental retardation of the fetus is due to maternal hypothyroidismor both maternal and fetal hypothyroidism. In developed countries,chronic autoimmune thyroiditis is the most common cause of hypothyroidismamong women in their childbearing years. Antibodies responsiblefor compromising maternal thyroid function can cross the placentaand, in some instances, compromise fetal and neonatal thyroidfunction.3,4,5,6,7,8 One such antibody, the thyrotropin-receptorblockingantibody, has been implicated in cases of transient congenitalhypothyroidism that were identified by screening programs fornewborns.9
In 1969, Man and Jones suggested that mild maternal hypothyroidismalone was associated with lower IQ levels in the offspring;their study involved a cohort of 1349 children, and measurementsof serum butanol extractable iodine were used to distinguishbetween euthyroidism and hypothyroidism in women.8 A study byMatsuura and Konishi in 1990 documented that fetal brain developmentis adversely affected when both the mother and fetus have hypothyroidismcaused by chronic autoimmune thyroiditis.10 In such cases, transientneonatal hypothyroidism is present.
In an earlier, population-based survey of 2000 pregnancies,we measured serum thyrotropin concentrations during the secondtrimester.11 The concentrations were high (above 6 mU per liter)in 49 of the women, of whom 6 (3 per 1000) had low serum freethyroxine concentrations. If a lowering of the IQ levels ofthe offspring were to occur sufficiently often in associationwith this degree and frequency of maternal thyroid deficiency,then systematically determining the thyroid status of all womenbefore or very early in pregnancy might be justified. The aimof the current study was to determine whether undetected orinadequately treated maternal thyroid deficiency during pregnancyis associated with lower IQ scores in the offspring in the absenceof neonatal hypothyroidism.
Methods
The Foundation for Blood Research administers a statewide, second-trimesterprenatal serum screening program for open neural-tube defectsand Down's syndrome in Maine.12,13 Aliquots of serum that remainafter screening are routinely coded and stored at 20°C.Outcome information is available through a contract with thestate's Bureau of Vital Records. The current study cohort waslimited to women with viable singleton pregnancies, who werescreened between January 1987 and March 1990, and their infantswhose birth weight was at least 1500 g. The serum from the motherswas shipped to the New England Newborn Screening Program inBoston, where serum thyrotropin was measured. Samples from 25,216women were analyzed in five batches over a two-year period.
Selection of Women with Hypothyroidism and Control Subjects
We recruited women with hypothyroidism during pregnancy, asdetermined by a high serum thyrotropin concentration, withoutregard to treatment status, and we tested their children betweenMarch 1996 and December 1997. We contacted 55 of the 75 pregnantwomen with serum thyrotropin concentrations at or above the99.7th percentile of the values for all the pregnant women;47 (85 percent) agreed to participate. In 2 of the 75 pregnancies,the women were enrolled through a previous pregnancy. Of the18 women not contacted, 3 had moved to another state, 1 haddied, and for 1, the child was a ward of the state. The remaining13 were not contacted because of limited funds. At the urgingof a grant review panel, we recruited 18 more women to representa range of milder cases, defined by a serum thyrotropin concentrationbetween the 98th and 99.6th percentiles, inclusive, and a serumthyroxine concentration below 7.75 µg per deciliter (99.7nmol per liter). To identify this second subgroup, we measuredserum thyroxine concentrations in 247 pregnant women with serumthyrotropin concentrations between the 98th and 99.7th percentiles.Fifteen of the 18 women identified (83 percent) agreed to participate.After recruitment, we measured thyroxine, free thyroxine, andantithyroid peroxidase antibodies in the original serum samplesfrom all women in the study.
For each woman with hypothyroidism, we identified potentialcontrol subjects who had serum thyrotropin concentrations belowthe 98th percentile and who were matched according to the followingcriteria: mother's age at delivery (within one year), numberof years of education of the mother (within one year), gestationalage at the time of sampling (same completed week), durationof storage of serum sample (within one month), and sex of thechild. From this group, two women were randomly selected andrecruited for each woman with hypothyroidism. Additional matchedcontrol women were available from the same list, if one initiallydeclined participation.
The protocols for the additional assays and the follow-up studywere approved by the institutional review board at the Foundationfor Blood Research. Enrollment began with a telephone call tothe woman and a letter describing the study. Then an appointmentwas arranged, at which informed consent was requested and, ifconsent was granted, testing was performed on the child. Theneuropsychological test results were provided to the familywithin one month after the child's testing was completed.
At the end of the study, we contacted the women with hypothyroidismand the matched control women again to determine whether hypothyroidismhad been clinically diagnosed since the pregnancy in those whohad not received a diagnosis of hypothyroidism at the time ofpregnancy. The contact was initially by a letter, which alsoincluded information about the thyrotropin concentrations inthe stored serum samples. The letter was followed by a telephonecall, during which a questionnaire was administered and a bloodtest for measuring thyrotropin was offered. For those who agreedto be tested, blood spots were collected on filter paper bya finger prick.
Study Procedures
We collected standardized information about socioeconomic statusand medical history from all women enrolled in the study, usingthe Four Factor Index of Social Status (the Hollingshead score).14Each woman and her husband or partner were assigned an educationcode ranging from 1 (corresponding to less than seven yearsof schooling) to 7 (corresponding to graduate or professionaltraining) and an occupation code ranging from 1 (e.g., "farmworker") to 9 (e.g., "higher executive"). Each couple's individualeducation scores were multiplied by 3, the occupation scoreswere multiplied by 5, and the two values were then added together.The final score was the average of the scores of the woman andher partner. When one partner was not employed, the final scorewas taken to be the score of the employed partner. The womanwas also asked whether her child had repeated a grade and abouther child's school performance, including whether the childhad had learning problems or other difficulties in school.
Neuropsychological testing of the women's children includedassessment of intelligence, attention, language, reading ability,school performance, and visualmotor performance. Oneof two certified psychologists performed the testing, and theproject's consulting psychologist supervised the testing andrescored the tests. The staff involved in the neuropsychologicaltesting did not know whether the children's mothers were womenwith hypothyroidism or control women. Intelligence was measuredwith use of the Wechsler Intelligence Scale for Children, thirdedition,15 the most widely used intelligence test. This testprovides a full-scale IQ score and subscale scores (range, 40to 160) for verbal skills, performance, and freedom from distractibility.To measure hearing deficits in the children, the staff administeredsubtests on word discrimination and word articulation from theTest of Language Development, second edition16 (range of scores,1 to 20). We used the norms for children 8 years 11 months ofage, because the version for older children did not have scalesfor word discrimination or articulation. The Peabody IndividualAchievement Test, revised (PIAT-R),17 was used to measure readingrecognition and reading comprehension (range of scores, 55 to145).
The staff administered the Conners' Continuous Performance Testto measure sustained vigilance and attention,18 using a computerprogram that employs a gono go paradigm (range of overallindex score, 1 to 30). The Developmental Test of Visual-MotorIntegration19 was administered to provide a standard measureof visual perception and fine motor skills (range, 55 to 145).The grooved pegboard test20 was administered to assess visualmotorcoordination and dexterity by measuring the time required toinsert pegs with both the preferred and nonpreferred hand (forthis test, it is recommended that normative data be derivedfrom control children in the study).
Assay Methods
We measured serum thyrotropin using a coated-tube radioimmunoassay(Diagnostic Products, Los Angeles). Thyrotropin was measuredon dried blood spots with a time-resolved immunofluorometricassay (Wallac Oy, Turku, Finland). Serum thyroxine was measuredwith a solid-phase radioimmunoassay21 or a time-resolved immunofluorometricassay (Wallac Oy); serum free thyroxine was measured with atime-resolved immunofluorometric assay. We measured serum antithyroidperoxidase antibodies using the Kalibre enzyme-linked immunosorbentassay (Kronus, San Clemente, Calif.) (normal concentration,2 U per milliliter).
Statistical Analysis
The serum thyrotropin, thyroxine, and free thyroxine concentrationswere logarithmically transformed before analysis. We used geometricmeans and logarithmic standard deviations to summarize the results(after censoring seven measurements that were more than 3 SDabove or below the group mean). We compared categorical variablesusing an exact test of significance or odds ratios, and we comparedcontinuous variables using the Student's t-test. When necessary,the t-test was modified to allow for unequal variances. Theprimary analysis was of all 62 women with hypothyroidism andall 124 control women; we preserved matching by comparing theresult from the child of a woman with hypothyroidism with theaverage result from the two matched control children. No adjustmentwas made for multiple comparisons. All statistical tests weretwo-sided.
Results
According to records from the New England Newborn ScreeningProgram, none of the children of the 62 women with high serumthyrotropin concentrations while pregnant were identified ashaving transient or permanent congenital hypothyroidism. Thedistribution of serum thyrotropin concentrations in the 62 womenwith hypothyroidism and the 124 matched control women is shownin Figure 1. Fifteen of the 62 women with hypothyroidism reportedthat they had received a diagnosis of hypothyroidism beforethe pregnancy, and 14 of these 15 women were treated for hypothyroidismduring that pregnancy. Two of the control women reported thatthey had had hypothyroidism in the distant past but were nevertreated.
Figure 1. Distribution of Serum Thyrotropin Concentrations during Pregnancy in the 62 Women with Hypothyroidism and the 124 Matched Control Women.
Open circles indicate the 14 women who were treated for hypothyroidism during the pregnancy under study. Selected percentiles are shown for the entire cohort of 25,216 pregnant women.
Demographic and pregnancy-related information about the womenwith hypothyroidism and the control women and the remainderof the cohort from which the women were selected is shown inTable 1. There were no significant differences between the womenwith hypothyroidism and the control women for any of the variables.Four of the variables were used for matching: number of yearsof education of the mother, mother's age at delivery, gestationalweek when the serum sample was obtained, and sex of the child.The use of the number of years of education as a matching variablewas intended to control for socioeconomic status. To assessthe effectiveness of this matching, we used the Hollingsheadscore as an additional measure. This score took into accountthe mother's educational level and occupation and also the father'seducational level and occupation. The mean Hollingshead scorein the women with hypothyroidism was one point lower than thatin the control women (P=0.43). The study children were similarin most respects to the remainder of the cohort, but more weregirls, their mothers were older, a higher percentage of theirmothers were married, and more of their mothers were multiparous.
Table 1. Characteristics of the Study Women, the Remainder of the Cohort, and Their Children.
The results of the measurements of thyroid function in the womenwith hypothyroidism and the control women during pregnancy areshown in Table 2. As expected, according to the selection process,the women with hypothyroidism had higher serum thyrotropin andlower serum thyroxine concentrations.
Table 2. Measurements of Thyroid Function in the Study Women during Pregnancy.
The children's neuropsychological test scores are shown in Table 3.All the children were between seven and nine years of agewhen tested, and the child of a woman with hypothyroidism andhis or her matched control children were tested at the sameage. The analysis preserved matching for each of the tests byexpressing the relative performance between case and controlchildren as a mean difference (the value in the case child minusthe average of the values in the two control children). Thecase children performed less well on all the tests; 2 of the15 differences reached statistical significance (P<0.05).
Table 3. Neuropsychological Test Scores among the Children of Women with Hypothyroidism during Pregnancy as Compared with the Children of Matched Control Women.
The results in the children were then grouped according to whetherthe mother's hypothyroidism was treated during the pregnancy(Table 4). The larger deficits in performance were found amongthe children of the untreated women; their scores for all 15tests were worse than those of the control children (their scoresfor 9 tests were significantly worse). Their average full-scaleIQ score on the Wechsler Intelligence Scale for Children, thirdedition, was 7 points lower, and 19 percent of the childrenof women with hypothyroidism had an IQ score of 85 or lower,as compared with 5 percent of the control children. The testscores of the children whose mothers were being treated (albeitinadequately) during pregnancy were similar to those of thecontrol children in most categories, even though the serum thyrotropinconcentrations were at or above the 99.7th percentile in 12of the 14 women. The serum thyroxine and free thyroxine concentrationsin the 14 treated women were very similar to the concentrationsin the 48 women with undiagnosed hypothyroidism.
Table 4. Neuropsychological Test Scores among the Children of Women with Hypothyroidism during Pregnancy as Compared with the Children of Matched Control Women, Stratified According to Whether the Hypothyroidism Was Being Treated.
The mean Hollingshead scores for the women who received treatment(48) and those who were not treated (44, or 45 if one low outlierwas removed) were similar, and these scores were similar tothose of the control women (46). A linear regression analysisof the full-scale intelligence score of the control childrenagainst the Hollingshead score of the control women indicatedthat there was an increase in intelligence of 0.4 point (95percent confidence interval, 0.2 to 0.7) for each 1-point increasein the Hollingshead score (P=0.002). Thus, the 2-point-highermean Hollingshead score of the treated women as compared withthat of the control women could account for a 0.8-point-higherIQ score of their children as compared with the control children,and the 2-point-lower mean Hollingshead score of the untreatedwomen could account for a 0.8-point-lower IQ score. Therefore,differences in maternal intelligence or socioeconomic statusmight account for only a small fraction of the differences shownin Table 4.
At the end of the study, we telephoned the women who were notknown to have hypothyroidism during pregnancy to determine whetherhypothyroidism had been clinically diagnosed subsequently; 120of the 124 control women and 45 of the 48 case women responded.Of those who responded, 5 (4 percent) of the control women and26 (58 percent) of the women with undiagnosed hypothyroidismduring pregnancy were now known to have hypothyroidism (oddsratio, 31; 95 percent confidence interval, 10 to 108). The medianinterval between pregnancy and clinical diagnosis was 5 years(range, 1 to 10). A total of 99 of the 115 control women whoidentified themselves as having normal thyroid function agreedto undergo follow-up testing; all the thyrotropin concentrationsin the blood spots were below 10 mU per liter. Fifteen of the19 women with hypothyroidism during pregnancy who identifiedthemselves as having normal thyroid function agreed to be tested;3 had high thyrotropin concentrations (14, 89, and 243 mU perliter). Altogether, 4 percent of the control women and 64 percentof the women with undiagnosed hypothyroidism during pregnancyhad confirmed hypothyroidism at the time of follow-up about11 years later.
Discussion
The current study shows that hypothyroidism in pregnant womencan adversely affect their children's subsequent performanceon neuropsychological tests. Decreases in performance can occureven when the pregnant woman's hypothyroidism is mild and probablyasymptomatic. The presence of high serum concentrations of antithyroidperoxidase antibodies in 77 percent of the women with hypothyroidismindicates that chronic autoimmune thyroiditis was the most frequentcause of hypothyroidism in these women. Treating maternal hypothyroidismduring pregnancy appears to be beneficial for the child, evenwhen treatment is inadequate as determined by measurements ofthyrotropin.
If our findings were to be confirmed, and routine screeningfor hypothyroidism during pregnancy were to be instituted, whatmight the benefits be? The main benefit an increaseof approximately 4 points in IQ scores would occur inthe children of women with serum thyrotropin concentrationsat or above the 98th percentile. A secondary benefit would bereduced morbidity for women who were systematically identifiedand treated. The present study shows that a large percentageof pregnant women with high serum thyrotropin concentrationssubsequently have clinically apparent hypothyroidism. Becausethe symptoms associated with hypothyroidism are nonspecific,the condition can be difficult to diagnose, as reflected bythe five-year median time to diagnosis in the women.
Before about 12 weeks' gestation, when the fetal thyroid glandbecomes active, the mother is the sole source of thyroid hormones.Maternal thyroid sufficiency might therefore be most importantin the first trimester. This theory is supported by a recentstudy in a small cohort of 220 healthy infants in which lowermaternal serum free thyroxine concentrations at 12 weeks' gestationwere associated with impaired psychomotor development at 10months of age.22 However, the later stages of fetal brain developmentinvolve neuronal migration and organization. Since these processesare responsible for functions measured by the neuropsychologicaltests used in the present study, thyroid insufficiency beyondthe first trimester is also likely to have adverse effects.23In rats, triiodothyronine receptors are first detected in thebrain in the second trimester, and the induction by triiodothyronineof enzymes that are important in nervous-system developmentbegins late in fetal development.24 The current study documentsa relatively long average interval between early biochemicalevidence of hypothyroidism and clinical diagnosis, a findingthat suggests that ongoing maternal health problems might hinderthe child's development after birth. In the absence of objectivedata, the most prudent policy would be to identify and treatmaternal hypothyroidism as early in pregnancy as possible, keepingin mind that the need for thyroxine increases during pregnancy.25
We conclude that systematic screening for hypothyroidism earlyin pregnancy may be worthwhile, even when the degree of deficiencyis mild and does not cause immediate clinical manifestationsin the woman. If routine screening were to be introduced, themost conservative policy would be to perform testing at thefirst prenatal visit, preferably in the first trimester. Follow-upof women with positive screening results would need to be prompt,so that treatment could begin quickly.
Supported by grants from the Thrasher Research Fund (02810-7),Knoll Pharmaceutical Company (SYN-0398-09), and the NationalInstitute of Child Health and Human Development (supplementto RO1-HD31183).
We are indebted to Professor Nicholas J. Wald of the WolfsonInstitute of Preventive Medicine, University of London, forstatistical advice and consultation; to Ms. Sonia Nelson forhelping to locate study participants; and to Ms. Penny Guerinfor her assistance in scheduling and data entry.
Source Information
From the Foundation for Blood Research, Scarborough, Me. (J.E.H., G.E.P., W.C.A., J.R.W., G.J.K., J.G., C.E.O.); the New England Newborn Screening Program, Jamaica Plain, Mass. (M.L.M., R.J.H.); Children's Hospital, Boston (S.E.W.); Beth Israel Deaconess Medical Center, Boston (J.D.F.); and Dartmouth Medical School, Hanover, N.H. (R.Z.K.).
Address reprint requests to Dr. Haddow at the Foundation for Blood Research, 69 U.S. Rte. 1, Scarborough, ME 04074.
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