Maternal Thyroid Dysfunction During Pregnancy and Thyroid Function of Her Child in Adolescence

Maternal Thyroid Dysfunction During Pregnancy andThyroid Function of Her Child in Adolescence

Fanni Pakkila, Tuija Mannisto, Helja-Marja Surcel, Aimo Ruokonen, Aini Bloigu,Anneli Pouta, Anna-Liisa Hartikainen, Marja Vaarasmaki, Marjo-Riitta Jarvelin,and Eila Suvanto

Department of Obstetrics and Gynecology (F.P., T.M., A.-L.H., M.V., E.S.), Oulu University and OuluUniversity Hospital, Oulu 90029, Finland; Institute of Health Sciences (F.P., M.-R.J.), Oulu University, Oulu90029, Finland; National Institute for Health and Welfare (F.P., H.-M.S., A.B., A.P., M.-R.J.), Departmentof Children, Young People, and Families, Oulu 90101, Finland; Department of Clinical Chemistry (T.M.,A.R.), Oulu University and Oulu University Hospital, Oulu 90029, Finland; and Department ofEpidemiology and Biostatistics (M.-R.J.), Imperial College London, London SW7 2AZ, United Kingdom

Context: Normal maternal thyroid function is important for fetal development. No knowledgeexists on how maternal thyroid function and thyroid antibodies during early pregnancy affectthyroid function of the offspring.

Objective: The aim of this study was to investigate the relationship between maternal and ado-lescent thyroid function parameters.

Design, Setting, and Participants: A total of 3673 mother-child pairs from the prospective, population-based Northern Finland Birth Cohort 1986 participated in the study. Maternal serum samples weredrawn in early pregnancy (�20th gestational week), and children’s samples were drawn at the age of16 years and analyzed for TSH, free T4 (fT4), and thyroid peroxidase antibodies (TPO-Abs).

Main Outcome Measures: TSH, fT4, and TPO-Ab concentrations were measured at the age of 16years. Children of mothers with thyroid dysfunction (hypothyroidism, hyperthyroidism, or hypo-thyroxinemia) or TPO-Ab positivity were compared to those of euthyroid or TPO-Ab-negativemothers. The distributions are expressed as medians with 5th to 95th percentiles.

Results: Boys of hypothyroid mothers had higher TSH concentrations than those of euthyroid mothers:2.0 (0.9–4.0) vs 1.7 (0.8–3.3) mU/L; P � .001. Children of hyperthyroid mothers had lower TSH concen-trations than those of euthyroid mothers: 1.3 (0.6–4.2) vs 1.7 (0.8–3.3) mU/L, P � .013, for boys; and 1.3(0.5–3.5) vs 1.6 (0.7–3.4) mU/L, P � .034, for girls. There were no differences in TSH or fT4 concentrationsbetween children of hypothyroxinemic and euthyroid mothers. TPO-Ab-positive mothers more oftenhad TPO-Ab-positive children (prevalence, 9.0 vs 3.7% among boys, and 22.7 vs 7.5% among girls).

Conclusions: Maternal thyroid dysfunction and TPO-Ab positivity during pregnancy seem to mod-ify thyroid function parameters of offspring even in adolescence. Whether this increases the thy-roid disease risk of the children is still unknown. (J Clin Endocrinol Metab 98: 965–972, 2013)

Maternal thyroid dysfunction affects up to 5% ofpregnant women, and thyroid antibodies are prev-

alent in 5–10% of fertile-aged women (1). Maternal thy-roid hormones and antibodies cross the placenta and are

important to fetal development during the first trimes-ter (2– 4). However, research on the impact of maternalthyroid status on later thyroid function of the child isscarce (5).

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2013 by The Endocrine Societydoi: 10.1210/jc.2012-2028 Received April 23, 2012. Accepted December 13, 2012.First Published Online February 13, 2013

Abbreviations: CI, confidence interval; fT4, free T4; OR, odds ratio; TPO-Ab, thyroid per-oxidase antibody.

O R I G I N A L A R T I C L E

E n d o c r i n e C a r e

J Clin Endocrinol Metab, March 2013, 98(3):965–972 jcem.endojournals.org 965

It is known that circulating TSH levels in the newborn risespontaneously after birth and decrease within a few days (6).During the first 3 years of life, children show wide variabilityof TSH concentrations, and they are higher both in prepu-berty and in puberty compared with those in adults (6). Cur-rently there are no data concerning possible associations be-tween maternal thyroid hormone levels during pregnancyand thyroid hormone levels of offspring in later life.

In iodine sufficiency, 3% of schoolchildren are positivefor thyroid peroxidase antibodies (TPO-Abs) and thyro-globulin antibodies, with a higher prevalence among girls(7). Children of women with autoimmune thyroiditis areat risk of having thyroid dysfunction and thyroid antibod-ies later in life (5, 8, 9). Children positive for TPO-Abs alsomore often have TPO-Ab-positive mothers (5), but thereare no studies concerning maternal serum sampling con-ducted during pregnancy.

The aim of this study was to evaluate the impact ofmaternal thyroid function parameters and thyroid anti-bodies during pregnancy on thyroid function parametersand thyroid autoantibody levels of the offspring inadolescence.

Subjects and Methods

Study population and data collectionThe prospective, population-based Northern Finland Birth

Cohort 1986 (NFBC 1986) covers 99% of all births in northernFinland with an expected delivery date between July 1, 1985, andJune 30, 1986, from the 2 northernmost provinces of Finland(9362 mothers and 9479 children). Only singleton pregnancies(n � 9247) were included in this study. The cohort mothers wererecruited by 24 weeks gestation, but they were followed sincetheir first visit to free-of-charge maternity welfare clinics (from10th to 12th gestational week onward). Demographic, biologi-cal, health behavior, and socioeconomic as well as maternalhealth data and data related to birth and neonatal outcome havebeen collected via questionnaires, which were filled in by themothers, nurses, or midwives (10, 11).

Data on children have been collected prospectively antena-tally, at birth, and at the ages of 7 and 16 years. The latestfollow-up, in 2001–2002 when the children were 16 years old,involved questionnaires for parents and children (participationrate, 80%) and clinical examination of the children (participa-tion rate, 74%) among those participants who were alive andtraceable (n � 6798).

The Ethics Committees of the Northern Ostrobothnia Hos-pital District and the National Institute of Health and Welfareapproved this study. Informed written consent was obtainedfrom all subjects.

Serum samples and laboratory assaysIn 2001–2002, the children had serum sampling included in

their clinical examination. The samples were drawn in the morn-ing after overnight fasting, went through primary analyses, andhave been stored thereafter at �80°C. The samples have been

further thawed 1 to 6 times for various analyses; 14% of thesamples were thawed for the second time and 84% for the thirdtime for analyses connected with this study in 2010. To study theeffect of repeated freezing and thawing, 7 samples with a 5-yearstorage time at �80°C from healthy nonpregnant volunteerswere analyzed after up to 9 freeze-thaw cycles. Concentrations ofTSH, free T4 (fT4), and TPO-Ab were measured after every othercycle (after thaw numbers 1, 3, 5, 7, and 9), and their concen-trations did not change even after repeated freezing and thawing(data not shown).

Altogether, 5765 adolescent samples were analyzed for atleast 1 thyroid function test in year 2011. When the sample sizewas not sufficient for all analyses, TPO-Ab analyses were carriedout primarily.

Maternal serum samples were obtained from the Finnish Ma-ternity Cohort (FMC), a serum bank with early pregnancy serumsamples from all Finnish pregnant women. Data concerning ma-ternal serum sample collection has been published earlier (12,13). A total of 5805 maternal samples with sufficient serumsamples and sampling conducted before the 20th gestationalweek (61.2% of the whole cohort with mean gestational ageat sampling of 10.7 weeks [SD, 2.8]) were analyzed for at least1 thyroid function test in year 2006. The excluded population(gestational week at sampling �20; n � 187, insufficient se-rum sample; n � 3014) did not differ significantly from thoseincluded regarding maternal demographic characteristics orpregnancy or neonatal outcomes (data not shown). Ninety-eight mothers were under some thyroid medication during theindex pregnancy or had used thyroid medication previously.Ninety-four mothers used levothyroxine, and four mothersused thyrostatic drugs.

Quantitative analyses of TSH, fT4, and TPO-Ab from bothmaternal and adolescent serum samples were performed by wayof chemiluminescent microparticle immunoassays using an Ar-chitect i2000 automatic analyzer (Abbott Diagnostics, AbbottPark, Illinois). Lower limits of detection and intra- and interassaycoefficients of variation were: 0.0025 mU/L, 1.7 and 5.3% forTSH; 5.1 pmol/L, 3.6 and 7.8% for fT4; and 1.0 IU/mL, 2.5 and9.8% for TPO-Ab, respectively.

Maternal-adolescent sample pairs and definitionof thyroid dysfunction

A total of 3673 adolescent samples had matching maternalsample pairs (1746 boys, 1927 girls) with at least TPO-Ab con-centrations analyzed (all tests were performed to 3586 pairs).There were no statistically significant differences in maternalTSH, fT4, or TPO-Ab concentrations when comparing adoles-cent samples with missing or matching maternal sample pair(data not shown).

The manufacturer’s reference intervals for TPO-Ab used inconnection with children are �5.61 IU/mL. For mothers, earlierpublished reference intervals for TSH and fT4 are 0.07–3.1mU/L and 11.4–22.4 pmol/L in the first trimester and 0.10–3.5mU/L and 11.09–18.9 pmol/L in the second trimester, respec-tively. The limit for maternal TPO-Ab positivity was TPO-Abconcentration over the 95th percentile (�167.7 IU/ml) (14).

Mothersweredividedinto6groupsaccordingtotheir fT4,TSH,and TPO-Ab concentrations (Figure 1): 1) euthyroidism, maternalTSH and fT4 both between the reference intervals (n � 3189); 2)hypothyroidism, TSH above its upper limit with low or normal fT4concentrations (n�207); 3)hyperthyroidism,TSHbelow its lower

966 Pakkila et al Maternal and Adolescent’s Thyroid Function J Clin Endocrinol Metab, March 2013, 98(3):965–972

reference limit with high or normal fT4 concentrations (n � 81); 4)hypothyroxinemia, TSH between its reference intervals with lowfT4 concentration (n � 45); 5) TPO-Ab-negative, with TPO-Abconcentration �167.7 IU/mL (n � 3481); and 6) TPO-Ab-positive,with TPO-Ab concentration �167.7 IU/mL (n � 164).

Reference intervalsThere were 5765 (60.8% of the NFBC 1986) children’s sam-

ples available for calculations of reference intervals. Data fromboys and girls were analyzed together and separately.

Among the TPO-Ab-negative children, outliers were identi-fied by using the detection method described by Horn et al (15)after log-transformation of the data to achieve normality. Alloutliers were evaluated, and all cases with high outlying TSHconcentrations (�5.28 mU/L) were excluded from all analysesbecause they were assumed to have subclinical hypothyroidism.No identification of outliers was performed among the TPO-Ab-positive children.

The calculated new reference intervals were used to identifythe prevalence of thyroid dysfunction among children and to

Figure 1. Flow chart of the study population in the Northern Finland Birth Cohort 1986.


evaluate whether this prevalence was different among thosewhose mothers had had thyroid dysfunction during pregnancy.Hypothyroidism was identified as having a TSH concentrationover the upper reference limit with normal or low fT4 concen-trations; hyperthyroidism as having a TSH concentration underthe lower reference limit with normal or high fT4 concentrations;and hypothyroxinemia as having fT4 concentration under thelower reference limit with normal TSH concentrations.

Statistical analysisStudent’s t test and Fisher’s exact test were used when eval-

uating differences in background factors among those includedand excluded from the study due to missing values.

Comparison of children’s TSH, fT4, and TPO-Ab concentra-tions as continuous variables among all children and betweengenders was conducted by using the Mann-Whitney U test. Be-cause statistically significant differences were seen in TSH andTPO-Ab concentrations, all further analyses were performed forboys and girls separately.

Mann-Whitney U test was used to compare serum TSH, fT4,and TPO-Ab concentrations in children born to mothers with orwithout thyroid dysfunction or TPO-Ab positivity or negativity.Similarly, this test was used to compare TSH and fT4 concentra-tions among TPO-Ab-positive and -negative children. Pearson’s �2

test and Fisher’s exact test were used to evaluate the prevalence ofTPO-Ab positivity in children between genders and to evaluate thedifferences of prevalence of TPO-Ab positivity and thyroid dys-function among children born to mothers with and without thyroiddysfunction and TPO-Ab positivity. All distributions are presentedas medians with the 5th-95th percentile range.

Odds ratios (ORs) with 95% confidence intervals (CIs) forchildren having the same thyroid dysfunction as their motherswere calculated with logistic regression analysis. To avoid somemisclassification error due to categorization of the data, we alsoperformed linear regression analysis with logarithmically trans-formed continuous TSH levels to estimate the effects of increasesin maternal TSH levels on children’s thyroid function. The re-sults were adjusted for maternal continuous TPO-Ab levels. Fur-ther risk estimates were performed after excluding TPO-Ab-pos-itive mothers.

Sensitivity analyses were performed after excluding moth-ers under thyroid medication before or during pregnancy (n �98) and by categorizing mothers using only data on TSHconcentration.

Reference intervals were calculated as 2.5th and 97.5th per-centiles separately for TPO-Ab-negative and -positive children.Bias-corrected and accelerated 95% CIs of the percentiles werecalculated with 1000 bootstrap resamples. Statistical analyseswere performed using SPSS version 18.0 software (SPSS Inc, Chi-cago, Illinois).

Results

At the age of 16 years, children of hypothyroid mothershad higher median TSH concentrations (1.8 [5th–95thpercentiles, 0.8–3.9] mU/L; P � .001) and children ofhyperthyroid mothers had lower median TSH concentra-tions (1.3 [0.6–3.5] mU/L; P � .001) than those of euthy-roid mothers (1.6 [0.8–3.4] mU/L). Children of hypothy-

roid mothers also had lower median fT4 concentrations(13.2 [11.3–15.6] pmol/L; P � .05) and higher TPO-Abconcentrations (0.24 [0.00–94.4] IU/mL; P � .004) com-pared with those of euthyroid mothers (13.4 [11.4–16.0]pmol/L for fT4, and 0.1 [0.00–9.4] IU/mL for TPO-Ab).No statistically significant differences were seen in TSH orfT4 concentrations among children of hypothyroxinemicmothers compared with euthyroid mothers, but childrenof hypothyroxinemic mothers had higher median TPO-Abconcentrations: 0.4 (0.0–157.1) vs 0.1 (0.0–9.4) IU/mL;P � .004. The results remained the same after excludingmothers with thyroid medication and categorizing moth-ers using only data on TSH concentration (data notshown).

Boys had significantly higher median serum TSH concen-trations than girls: 1.67 (5th–95th percentiles, 0.82–3.37)mU/L compared with 1.57 (0.71–3.54) mU/L; P � .001.However, girls had higher median TPO-Ab concentrationsthan boys: 0.14 (0.00–44.27) IU/mL compared with 0.08(0.00–3.94) IU/mL; P � .002.

Boys of hypothyroid mothers had higher median TSHconcentrations (2.0 [5th–95th percentiles, 0.9–4.0] vs 1.7[0.8–3.3] mU/L; P � .001), and girls had higher medianTPO-Ab concentrations (0.3 [0.0–255.5] vs 0.1 [0.0–33.9] IU/mL; P � .015) than those born to euthyroidmothers. Children of hyperthyroid mothers had signifi-cantly lower median TSH concentrations (1.3 [0.6–4.2]vs 1.7[0.8–3.3] mU/L; P � .013, for boys; and 1.3 [0.5–3.5] vs 1.6 [0.7–3.4] mU/L; P � .034, for girls). Boys ofhypothyroxinemic mothers had higher median TPO-Abconcentrations: 0.5 (0.0–160.6) vs 0.1 (0.0–3.9) IU/mL;P � .016 (Table 1).

When comparing children of TPO-Ab-positive and-negative mothers, both boys and girls had significantlyhigher median TPO-Ab concentrations: 0.2 (5th–95thpercentiles, 0.0–51.1) vs 0.1 (0.0–3.9) IU/mL; P � .05, forboys; and 0.6 (0.0–387.1) vs 0.1 (0.0–33.9) IU/mL; P �.001, for girls (Table 1).

There were 223 (6.0%) TPO-Ab-positive children, ofwhom 74 (33.2%) were boys and 149 (66.8%) were girls.TPO-Ab-positive mothers more often had TPO-Ab-posi-tive children (Figure 2), 9.0 vs 3.7% among boys (P �.021), and 22.7 vs 7.5% among girls (P � .001). TPO-Ab-positive boys had higher median serum TSH and lowermedian fT4 concentrations than TPO-Ab-negative boys(TSH, 1.84 vs 1.67 mU/L, P � .04; and fT4, 13.00 vs 13.41pmol/L, P � .03), and TPO-Ab-positive girls had highermedian TSH concentrations than TPO-Ab-negative girls(TSH, 2.10 vs 1.53 mU/L; P � .001) (Table 2).

Children’s reference intervals are presented in Table 3and are 0.64–3.74 mU/L for TSH and 11.01–16.63pmol/L for fT4. When using these reference values of TSH


and fT4 concentrations to evaluate the prevalence of thy-roid dysfunction in children, there were 125 (2.2%) casesof overt or subclinical hypothyroidism (of whom 26.2%or 32 of 122 were TPO-Ab-positive), 86 (1.5%) cases ofovert or subclinical hyperthyroidism, and 82 (1.4%) casesof hypothyroxinemia.

The ORs (95% CIs) for children to have the same thy-roid dysfunction as their mothers are presented in Table 4.Hypothyroid mothers more often had hypothyroid chil-dren than euthyroid mothers: 8.1 vs 3.2%, P � .001 (3.4[1.8–6.5]) for all children; 6.6 vs 3.1%, P � .081, for boys(2.9 [1.1–7.7]); and 9.9 vs 3.4%, P � .005, for girls (3.9[1.7–9.0]). Between children of hypothyroid and euthy-roid mothers, the percentage difference (95% CI) of chil-dren’s TSH concentrations was 13.6% (5.7–22.1); amongboys, it was 19.1% (8.7–30.5); and among girls, it was8.11% (�3.3 to 20.9) with all mothers included, and it didnot change after adjusting for TPO-Ab or excludingTPO-Ab-positive mothers from the analysis.

Hyperthyroid mothers had hyperthyroid children moreoften than euthyroid mothers: 8.0 vs 2.3%, P � .009, forall children (OR [95% CI], 4.1 [1.7–9.8]); 6.9 vs 1.6%,P � .082 (5.9 [1.3–26.7]) for boys; and 8.7 vs 3.0%, P �.057 (3.1 [1.1–9.1]) for girls. Between children of hyper-thyroid and euthyroid mothers, the percentage difference(95% CI) of children’s TSH concentrations was �17.6%(�26.1 to �8.0); among boys, �18.0 (�30 to �4.0); andamong girls, �16.6% (�28.4 to 2.8), with all mothersincluded; it did not change after adjusting for TPO-Ab orexcluding TPO-Ab-positive mothers from the analysis.The results of OR analyses did not substantially changeafter the following sensitivity analyses: excluding motherswith thyroid medication, and categorizing mothers byonly using data on TSH concentration (data not shown).

Hypothyroxinemic mothers also had hypothyroxine-mic children more often, but the differences were not sta-tistically significant: 5.1 vs 2.4%, P � .251 for all children;

Figure 2. Prevalence of TPO-Ab-positive children (%) grouped bymaternal antibody status.

Table 2. Comparison of TSH and fT4 ConcentrationsBetween TPO-Ab-Negative and TPO-Ab-Positive Childrenin the Northern Finland Birth Cohort 1986

TPO-Ab-Negative TPO-Ab-PositiveBoys

n 1770 74TSH, mU/L 1.67 (0.95–2.80) 1.84 (0.91–4.70)a

fT4, pmol/L 13.41 (11.80–15.81) 13.00 (11.44–14.72)a

Girlsn 1691 149TSH, mU/L 1.53 (0.83–2.89) 2.10 (1.01–3.97)b

fT4, pmol/L 13.48 (11.85–15.42) 13.28 (11.50–15.26)

Distributions are expressed as median (5th–95th percentiles).P values were obtained with the Mann-Whitney U test whencomparing TPO-Ab-positive and -negative children.a P � .05; b P � .001.

Table 1. Comparison of Thyroid Function Parameters in Boys and Girls According to Maternal Thyroid Status in theNorthern Finland Birth Cohort 1986

Maternal Thyroid Status

Euthyroid Hypothyroid Hyperthyroid HypothyroxinemicTPO-Ab-Negative

TPO-Ab-Positive

Boysn (mother-child pairs) 1589–1591 107–108 32 27 1735 89TSH, mU/L 1.7 (0.8–3.3) 2.0 (0.9–4.0)c 1.3 (0.6–4.2)b 1.6 (0.6–5.1) 1.7 (0.8–3.4) 1.8 (0.9–3.4)fT4, pmol/L 13.4 (11.4–15.9) 13.1 (11.4–15.7) 13.0 (10.7–15.1) 13.1 (10.8–16.9) 13.4 (11.4–15.8) 13.2 (11.7–16.2)TPO-Ab, IU/mL 0.1 (0.0–3.9) 0.2 (0.0–6.5) 0.0 (0.0–4.3) 0.5 (0.0–160.6)a 0.1 (0.0–3.7) 0.2 (0.0–51.1)b

Girlsn (mother-child pairs) 1589–1598 96–99 49 18 1746 75TSH, mU/L 1.6 (0.7–3.4) 1.6 (0.5–3.9) 1.3 (0.5–3.5)a 1.5 (0.6–3.9) 1.6 (0.7–3.5) 1.6 (0.7–3.8)fT4, pmol/L 13.5 (11.5–16.0) 13.3 (11.2–15.5) 13.6 (11.6–15.8) 13.1 (10.1–15.1) 13.5 (11.5–16.0) 13.7 (11.5–16.2)TPO-Ab, IU/mL 0.1 (0.0–33.9) 0.3 (0.0–255.5)a 0.3 (0.0–506.5) 0.4 (0.0–72.4) 0.1 (0.0–32.9) 0.6 (0.0–387.1)c

Numbers vary due to missing samples. Distributions are expressed as median (5th–95th percentiles). Euthyroid indicates both TSH and fT4 betweenthe trimester-specific reference intervals. Hypothyroid indicates TSH above its upper reference limit and low or normal fT4. Hyperthyroid indicatesTSH below its lower reference limit and high or normal fT4. Hypothyroxinemic indicates TSH between its reference intervals and fT4 below itslower limit. P values were obtained with the Mann-Whitney U test when comparing individual groups with the maternal euthyroid group or anantibody-positive group with an antibody-negative group.a P � .05; b P � .01; c P � .001.


4.3 vs 2.8%, P � .488 for boys; and 6.3 vs 2.0%, P � .289for girls.

Discussion

Previous information concerning the impact of maternalthyroid function on thyroid function parameters of thechild is scarce, although thyroid dysfunction during preg-nancy is widely studied. Our study describes the associa-tion between maternal thyroid status during pregnancyand thyroid function parameters in adolescent offspring.Serum TSH and fT4 concentrations in the children weresignificantly in accordance with maternal TSH and fT4concentrations during pregnancy. When comparing thechildren of hypothyroid and hyperthyroid mothers withthe children of euthyroid mothers, significant differenceswere seen between the groups even after adjusting for ma-ternal TPO-Abs, showing that maternal thyroid statusduring pregnancy might associate with later thyroid func-tion of the child. To our knowledge, our study is the firstto show this association.

Individual levels of fT4 and TSH are largely geneticallycontrolled (16, 17), although variations in fT4 concentra-tions may be more environmentally driven than previouslythought (18). Aggregation of thyroid antibodies in first-

degree relatives has been suggested to be controlled bygenes (19–21), and female gender seems to be a predictivefactor as regards consistently elevated TSH levels (22). Inour study, the effect of gender on thyroid function of thechild was clear because boys had higher TSH concentra-tions and girls had a higher prevalence of TPO-Abs. Wecannot explain why adolescent boys had higher TSH con-centrations than girls, but similar association has beenseen in other studies (23). Women seem to be particularlyat risk of elevated TSH concentrations later in life, whenthe prevalence of thyroid disease exceeds that in men (23).The fact that maternal thyroid dysfunction was indepen-dently associated with children’s TSH concentrations af-ter adjusting for maternal TPO-Ab or excluding TPO-Ab-positive mothers might be a manifestation of the geneticcontrol of TSH.

There are currently limited data on reference intervalsof serum TSH and fT4 concentrations in adolescent pop-ulations, and therefore adult reference intervals are widelyused. Our results suggest a decrease in the upper limit ofTSH levels from 4.0 mU/L (as reported by the manufac-turer) to 3.74 mU/L, and also an increase in the lower limitfrom 0.4 to 0.64 mU/L among the adolescents. In a recentFinnish study concerning the adult population (24), it wasalso proposed that a decrease of 10% in the current upper

Table 3. Reference Intervals (2.5th–97.5th Percentiles With 95% CIs) for TSH and fT4 in TPO-Ab-Positive and-Negative Children in the Northern Finland Birth Cohort 1986

n

TSH, mU/L fT4, pmol/L

2.5th Percentile(95% CI)




TPO-Ab-negativeBoys 2764 0.69 (0.65–0.7) 3.76 (3.61–3.95) 11.02 (10.86–11.14) 16.44 (16.24–16.76)Girls 2633 0.59 (0.57–0.61) 3.66 (3.56–3.83) 11.08 (10.90–11.22) 16.75 (16.51–16.98)

All TPO-Ab-negativechildren

5764 0.64 (0.62–0.65) 3.74 (3.62–3.84) 11.01 (10.91–11.12) 16.63 (16.45–16.79)

TPO-Ab-positiveBoys 122 0.35 (0.00–0.88) 11.79 (7.58–64.22) 10.04 (9.26–10.95) 16.23 (15.45–17.29)Girls 246 0.14 (0.03–0.68) 9.06 (6.08–14.13) 10.57 (9.44–11.21) 17.92 (16.60–21.14)

Reference intervals were calculated as 2.5th and 97.5th percentiles separately for TPO-Ab-negative and -positive children and presented with 95%CIs. Bias-corrected and accelerated 95% CIs of the percentiles were calculated with 1000 bootstrap resamples.

Table 4. Estimated Risks of Children to Have the Same Thyroid Dysfunction as Their Mothers in the NorthernFinland Birth Cohort 1986

MaternalThyroidStatus

OR (95% CIs) OR (95% CIs)

No. ofMothers

AllChildren Boys Girls

No. ofMothersa

AllChildren Boys Girls

Hypothyroid 207 (108/99) 2.7 (1.5–4.6) 2.2 (1.0–5.1) 3.1 (1.5–6.6) 118 (60/58) 3.4 (1.8–6.5) 2.9 (1.0–5.1) 3.9 (1.7–9.0)Hyperthyroid 81 (32/49) 3.7 (1.5–8.8) 4.7 (1.0–20.8) 3.0 (1.0–8.8) 67 (23/44) 4.1 (1.7–9.8) 5.9 (1.3–26.7) 3.1 (1.1–9.0)

Number of mothers includes mothers of all children (boys/girls). Hypothyroid indicates TSH above its upper reference limit and low or normal fT4.Hyperthyroid indicates TSH below its lower reference limit and high or normal fT4.a TPO-Ab-positive mothers (TPO-Ab concentration �167.7 IU/mL) excluded from analysis.


limit of TSH levels would be suitable. In our study, the fT4reference intervals in adolescents (11.01–16.63 pmol/L)are considerably narrower than the clinically used refer-ence intervals for adults. This may be a result of the ado-lescent population being healthier than adults, and in ad-dition, exclusion of TPO-Ab-positive subjects reduces thenumber of cases of subclinical thyroid disease among thestudy population.

In our study, the girls of TPO-Ab-positive mothersshowed a particularly higher prevalence of TPO-Ab positiv-ity. Among girls, the prevalence of TPO-Ab positivity was3.0-foldhigherandamongboys2.4-foldhigher if themotherwasTPO-Abpositive. Similar resultshavebeenreportedear-lier, although in a smaller population and with serum sam-pling of the mothers not carried out during pregnancy (5). Inaddition, in another study children diagnosed with autoim-mune thyroiditis had measurable concentrations of TPO-Abin cord blood sera more often than controls (9).

The early effects of maternal thyroid antibodies on thechild are better known than the effects in later life. Ma-ternal TSH receptor antibodies may cause transient con-genital thyroid dysfunction (25). Maternal TPO-Ab pos-itivity has been associated with high TSH concentrationsin the child 1 week after birth (26). The mothers of con-genitally hypothyroid children have been reported to havea high prevalence of decreased fT4 and increased TSHlevels and TPO-Ab positivity (27), and 50% of childrenwith subclinical hypothyroidism have been reported tohave a positive family history of thyroid disease (28).

One third of TPO-Ab-positive children have been re-ported to have subclinical hypothyroidism (7), and 15–37% of children with abnormal serum TSH concentra-tions are TPO-Ab positive (22). Our results confirm thatTPO-Ab-positive children have higher TSH concentra-tions than TPO-Ab-negative children, suggesting that sub-clinical thyroid diseases affect even adolescents.

The strengths of our current study lie in the well-docu-mented population-based NFBC 1986 cohort with its nearly3700mother-child samplepairsand in thehighparticipationrate of the subjects. These mother-child pairs represent thewhole cohort for all important background factors. Ourstudy setting is reliable when comparing the various thyroidfunction groups and observing the analogous nature of thy-roid hormone levels in mother-child pairs. All actions havebeen strictly supervised, and the methods are convergent. Inaddition, Finland has been iodine-sufficient since the 1940s(29–31). It is also highly important that we were able to useour own population-based trimester-specific reference inter-vals for maternal serum samples and most of the maternalsamples were drawn during the first trimester.

Unfortunately, we were not able to study genetics andpaternal impact. The number of mother-child pairs was

lower than the number of maternal and adolescent sam-ples available independently, but it was also verified thatthe adolescent samples without maternal pair did notshow any difference in overall TSH, fT4, or TPO-Ab con-centrations or maternal background factors compared tothe adolescent samples with matching maternal sample.We acknowledge that serum fT4 measurements may notbe totally reliable during pregnancy (32–34), althoughthey are clinically used in addition to TSH measurements.To avoid this problem, our classification of study mothersis mostly based on TSH concentrations, and we also per-formed sensitivity analysis categorizing the data withoutusing data on fT4 concentrations.

There is a possibility that some of the study mothersmay have been misclassified by using trimester-specificreference intervals because individual variation in thyroidfunction during pregnancy is small (35, 36). However,using trimester-specific reference intervals is a more accu-rate estimate of thyroid function during pregnancy thanusing reference intervals obtained in nonpregnant popu-lations. We also estimated the linear effects of increases inmaternal TSH concentrations on adolescents’ thyroidfunction parameters, and the results were in the same di-rection as in our categorized analyses.

We also do not know whether the mothers or children withaltered thyroid function parameters suffer any symptoms frompossible thyroid disease or whether the adolescents with highvalues are at a higher risk of overt thyroid disease.

In conclusion, altered maternal thyroid function param-eters and TPO-Ab positivity during early pregnancy appeartoassociatewith thyroid functionof the child inadolescence.Children of hypothyroid mothers had a higher risk of beinghypothyroid, and children of hyperthyroid mothers had ahigher risk of being hyperthyroid than those born to euthy-roid mothers. The children, especially girls, of TPO-Ab-pos-itive mothers had a higher prevalence of TPO-Ab positivitythan those of TPO-Ab-negative mothers, and it seems thatantibodies may affect the child as early as in utero. Thisknowledge might help in recognizing risk groups for thyroiddysfunction and in making earlier diagnosis. However, thelong-term effects of these changes in thyroid function in ad-olescence are still unknown.

Acknowledgments

We thank Sarianna Vaara, Aljona Amelina, Jenna Aavavirta,and all other personnel from the National Institute for Healthand Welfare and Tuula Ylitalo from the Institute of Health Sci-ences, Oulu University, for their valuable work regarding theNorthern Finland Birth Cohort 1986 and the Finnish MaternityCohort serum bank. We also thank Jouni Sallinen and Frank


Quinn (Abbott Laboratories) for providing laboratory reagentsfor the maternal serum sample analyses.

Address all correspondence and reprint requests to: Eila Su-vanto, Department of Obstetrics and Gynecology, Post Box 23,90029 OYS, Oulu, Finland. E-mail: [email protected].

This work was supported in part by grants from the Alma andK. A. Snellman Foundation (Oulu, Finland), the Jalmari andRauha Ahokas Foundation (Finland), the Northern Ostroboth-nia Hospital District (Finland), the Finnish Medical Associationof Clinical Chemistry, and the Academy of Finland.

Disclosure Summary: The authors have nothing to disclose.

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Maternal Thyroid Dysfunction During Pregnancy and Thyroid Function of Her Child in Adolescence