ORIGINAL

E n d o c r i n e

ARTICLE
C a r e

Perinatal Outcome of Children Born to Mothers with

Thyroid Dysfunction or Antibodies: A Prospective
Population-Based Cohort Study
Tuija Mannisto, Marja Vaarasmaki, Anneli Pouta, Anna-Liisa Hartikainen, Aimo Ruokonen,
Helja-Marja Surcel, Aini Bloigu, Marjo-Riitta Jarvelin, and Eila Suvanto-Luukkonen
Departments of Obstetrics and Gynecology (T.M., M.V., A.P., A.-L.H., E.S.-L.) and Clinical Chemistry (A.R.),
and Institute of Health Sciences (T.M., M.-R.J.), University of Oulu, 90014 Oulu, Finland; Department of Child
and Adolescent Health (A.P., H.-M.S., A.B., M.-R.J.), National Public Health Institute, 90101 Oulu, Finland; and Department
of Epidemiology and Public Health (M.-R.J.), Imperial College London, London SW7 2AZ, United Kingdom

Context: There are only a few large prospective studies involving evaluation of the effect of
maternal thyroid dysfunction on offspring and observations are inconsistent.
Objective: The objective of the study was to investigate the effects of thyroid dysfunction or
antibody positivity on perinatal outcome.
Setting and Participants: The study included prospective population-based Northern Finland Birth
Cohort 1986 including 9247 singleton pregnancies. First-trimester maternal serum samples were
analyzed for thyroid hormones TSH, free T4 (fT4) and antibodies thyroid-peroxidase antibody
(TPO-Ab) and thyroglobulin antibody (TG-Ab). Mothers were classified by their hormone and
antibody status into percentile categories based on laboratory data and compared accordingly.
Main Outcomes: Outcomes were perinatal mortality, preterm delivery, absolute and gestational
age-adjusted birth weight, and absolute and relative placental weight.
Results: The offspring of TPO-Ab- and TG-Ab-positive mothers had higher perinatal mortality,
which was not affected by thyroid hormone status. Unadjusted and adjusted (for maternal age and
parity) risk for increased perinatal mortality was an odds ratio of 3.1 (95% confidence interval
1.4 7.1) and 3.2 (1.4 7.1) in TPO-Ab- and 2.6 (1.1 6.2) and 2.5 (1.15.9) in TG-Ab-positive mothers.
TPO-Ab-positive mothers had more large-for-gestational age infants (2.4 vs. 0.8%, P 0.017), as
did mothers with low TSH and high fT4 concentrations vs. reference group (6.6 vs. 2.5%, P 0.045).
Significantly higher placental weights were observed among mothers with low TSH and high fT4
or high TSH and low fT4 levels as well as among TPO-Ab-positive mothers.
Conclusions: First-trimester antibody positivity is a risk factor for perinatal death but not thyroid
hormone status as such. Thyroid dysfunction early in pregnancy seems to affect fetal and placental
growth. (J Clin Endocrinol Metab 94: 772779, 2009)

considerable number of pregnant women have undiagnosed or insufficiently treated thyroid dysfunction during
pregnancy (1 4), and its suspected adverse impact on the outcome of the offspring is currently a subject of much discussion
(57). Even subclinical hypothyroidism in the presence or absence of thyroid antibodies is regarded as a threat to a womans

fertility, pregnancy outcome, and the development of the child.

Several pregnancy and perinatal complications have been considered to be associated with maternal thyroid dysfunction:
spontaneous abortions (1, 8), fetal death (2), preterm delivery (1,
2, 4, 9), small head circumference and low birth weight (10), and
impaired neuropsychological development (11). In addition,

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in U.S.A.
Copyright 2009 by The Endocrine Society
doi: 10.1210/jc.2008-1520 Received July 15, 2008. Accepted December 15, 2008.
First Published Online December 23, 2008

Abbreviations: BMI, Body mass index; CI, confidence interval; fT3, free T3; fT4, free T4; LGA,
large for gestational age; NFBC, Northern Finland Birth Cohort; SGA, small for gestational
age; TG-Ab, thyroglobulin antibody; TPO-Ab, thyroid-peroxidase antibody.

772

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J Clin Endocrinol Metab. March 2009, 94(3):772779

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J Clin Endocrinol Metab, March 2009, 94(3):772779

jcem.endojournals.org

773

Subjects and Methods

NFBC 1986
n=9479 (99%)

Target population
n=9575

Study population and data collection

Denied use of data

n=251 (2.5%)

Multiple pregnancy
n=222 (2.3%)

Insufficient or
missing samples
n=3014 (31.8%)

Gestational week at
FMC sampling >20
n=187 (2.0%)
FMC samples available
n=5805 (61.2%)

TSH and fT4

analyses
Group A (Clinical
hypothyroidism)
n=54
Group B (Subclinical
hypothyroidism)
n=224

TPO-Ab
analyses

TG-Ab
analyses

Reference group
n=4719

TPO-Ab-positive
n=288

TG-Ab-positive
n=285

Group D (Clinical
hyperthyroidism)
n=77

TPO-Ab-negative
n=5475

TG-Ab-negative
n=5420

Group C (Subclinical
hyperthyroidism)
n=204
Reference group: TSH between 5th and 95th percentiles, fT4 between 5th and 95th percentiles
Group A: TSH over 95th percentile, fT4 under 5th percentile
Group B: TSH over 95th percentile, fT4 between 5th and 95th percentiles
Group C: TSH under 5th percentile, fT4 between 5th and 95th percentiles
Group D: TSH under 5th percentile, fT4 over 95th percentile
NFBC 1986=Northern Finland Birth Cohort 1986
FMC=Finnish Maternity Cohort
TSH=thyroid-stimulating hormone, fT4=free thyroxine,
TPO-Ab=thyroid-peroxidase antibody, TG-Ab =thyroglobulin antibody
FIG. 1. Flow chart of the study population.

normal but low concentrations of thyroid hormone in the mother

have been associated with increased prevalence of breech presentation (12). Thyroid autoantibodies have also been hypothesized to be independently related to increased rates of spontaneous abortion and preterm delivery (1, 9, 13). The results of
individual studies on these perinatal outcomes are, however,
controversial, probably because of differences in study design,
populations, and laboratory data.
The precise prevalence of thyroid dysfunction during pregnancy and its suspected association with adverse perinatal outcome can be detected only by means of well-designed populationbased prospective cohort studies with proper documentation. To
our knowledge there are only a few large prospective cohort studies
(2, 4, 14, 15) involving evaluation of the effect of maternal thyroid
dysfunction on offspring and none of these studies provide large
amounts of biochemical data.
In this prospective, population-based cohort study with
comprehensive biochemical measurements from the early
pregnancy, we evaluated the effect of maternal thyroid dysfunction and autoimmunity on perinatal outcomes including
preterm delivery, birth measures, presentation at birth, and
perinatal mortality.

The prospective Northern Finland Birth Cohort

(NFBC) 1986 covered 99% of all births with calculated term between July 1, 1985, and June 30, 1986,
drawn from the two northernmost provinces of Finland (9362 mothers, 9479 children) (16, 17). We included only singleton pregnancies in the present study
(n 9247). The cohort has been followed up since the
12th gestational week of pregnancy. The first questionnaire on demographic, biological, health behavioral, and socioeconomic characteristics of the
mothers/families covered the period up to the 24th
gestational week, when the mothers were enrolled in
the study if still pregnant. The second questionnaire
covered maternal health and health behavior during
pregnancy and the perinatal period. The mothers were
assisted in completion of the questionnaire by the
nurses, who ensured that all questions were answered.
The third questionnaire contained items about pregnancy complications and diseases, delivery, and neonatal outcome and was completed in the maternity
hospitals by the attending midwives. All women gave
birth at hospital. The ethics committees of the University of Oulu and the National Public Health Institute
approved this study. Informed consent was obtained
from all subjects.

Serum samples and laboratory assays

The biochemical data were obtained by assay of

serum samples from the Finnish Maternity Cohort.
This is a biobank, consisting of serum samples collected from all pregnant women in Finland and approved under Finnish law. The law provides the usage
of the samples in studies promoting public health. The
samples were stored at 25 C. The effect of freezing,
thawing, and frozen storage on thyroid laboratory parameters has been reported previously (18).
Quantitative analyses of thyroid hormones TSH,
free T3 (fT3), and free T4 (fT4) and autoantibodies
thyroid-peroxidase antibody (TPO-Ab) and thyroglobulin antibody
(TG-Ab) were performed by way of chemiluminescent microparticle
immunoassays, using an Architect i2000 automatic analyzer (Abbott
Diagnostics, Abbott Park, IL). The lower limits of detection and intraand interassay coefficients of variation were 0.0025 mlU/liter, 1.7 and
5.3% for TSH; 5.1 pmol/liter, 3.6 and 7.8% for fT4; 1.53 pmol/liter, 2.3
and 5.0% for fT3; 1.0 IU/ml, 2.5 and 9.8% for TPO-Ab; and 1.0 IU/ml,
2.7 and 8.2% for TG-Ab.
The number of serum samples analyzed was 5805 (61.2% of the
whole cohort); only samples of a sufficient size (1 ml) were included in
this study (Fig. 1). The mean gestational age at sampling was 11.0 wk (SD
3.6), and only samples drawn before or at the 20th gestational week were
accepted (98% of the samples).

Categorization of the study population and outcomes

For association analyses the data were categorized using percentiles
of laboratory values because the reference values given by the manufacturer of the analyzer (Abbott) apply to a nonpregnant population, and
these values may differ from those in a pregnant population (19). Our
study is population based and large enough to create our own reference
values and to take into account the effect of freezing and storage (18).
Concerning thyroid hormones, the mothers with serum concentrations
of both TSH and fT4 between the fifth and 95th percentiles were considered to have normal thyroid function (reference group, n 4719).
The subjects with thyroid dysfunction were divided into four groups
with respect to thyroid hormone levels (Fig. 1): 1) group A, with TSH

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774

Mannisto et al.

Thyroid Dysfunction, Antibodies, and Perinatal Outcome

J Clin Endocrinol Metab, March 2009, 94(3):772779

TABLE 1. Biochemical characteristics of the samples analyzed

TSH (mU/liter)
fT4 (pmol/liter)
fT3 (pmol/liter)
TPO-Ab (IU/ml)
TG-Ab (IU/ml)

Geometric mean

95% CI

Fifth percentile

95th percentile

5779
5726
5737
5763
5705

1.06
15.3
5.13
6.23
12.5

1.031.08
15.315.4
5.10 5.15
6.03 6.44
12.312.7

0.19
11.96
3.85
2.0
6.4

3.6
20.5
6.63
167.7
47.7

over the 95th percentile and fT4 under the fifth percentile (n 54; clinical
hypothyroidism); 2) group B, with TSH over the 95th percentile and fT4
between the fifth and 95th percentiles (n 224; subclinical hypothyroidism); 3) group C, with TSH under the fifth percentile and fT4 between the fifth and 95th percentile (n 204; subclinical hyperthyroidism); and 4) group D, with TSH under the fifth percentile and fT4 over
the 95th percentile (n 77; clinical hyperthyroidism). Groups AD were
compared with the reference group in the analyses.
With respect to thyroid antibodies, we considered mothers to be
TPO-Ab or TG-Ab positive if the concentration of the antibody was over
the 95th percentile (Fig. 1). The high cutoff level was used instead of
manufacturers reference values because the samples in this study were
from pregnant women and after frozen storage (18). The fifth and 95th
percentiles as well as geometric means and 95% confidence intervals
(CIs) of all laboratory data are presented in Table 1. The mothers positive
for thyroid antibodies were compared with antibody-negative mothers.
All data concerning the mothers and their obstetric histories were
obtained from the questionnaires. The data on perinatal outcomes included gestational age; preterm delivery (birth 37th gestational week);
birth measurements birth weight, small for gestational age (SGA) and
large for gestational age (LGA) infants, birth length, ponderal index
(birth weight/birth length3), head circumference; Apgar scores; perinatal mortality stillborns and early neonatal deaths (7 d after birth);
neonatal deaths; malformations; presentation at birth; mode of delivery;
absolute and relative placental weight; and umbilical cord length.

Statistics
Categorical variables were compared using Pearsons 2 test or Fishers exact test, as appropriate. Students t test for independent samples
was used to compare continuous variables between two groups. When
four thyroid dysfunction groups were compared with reference group,
the comparisons were made by ANOVA followed by pairwise comparisons with Students t test. The concentrations of thyroid parameters
were logarithmically transformed for the calculation of geometric
means. Univariate logistic regression analysis was applied to estimate
susceptibility to LGA infants, low birth weight (2500 g), noncephalic
presentation, low Apgar scores (7), and perinatal mortality in relation
to thyroid parameters. The results were further adjusted for maternal age
and parity by multiple logistic regression. P 0.05 was deemed significant. Statistical analysis was performed using SPSS 14.0 software (SPSS
Inc., Chicago, IL).

Results
The demographic data of the mothers in each group according
to their thyroid hormone/antibody status are presented in Table
2. These data did not differ substantially from that in the whole
cohort. There were clinically minor but statistically significant
differences in the background factors of the mothers whose samples were analyzed compared with those with inadequate samples for analysis with respect to maternal age, body mass index
(BMI), smoking habit, screening time, and prevalence of diabetes. However, the differences were minor considering clinical
significance.

There were significant differences between the reference

group and groups AD in maternal age, BMI, parity, smoking
habits, and prevalence of previous thyroid diseases (Table 2).
The mothers of group C were older; those of group B were heavier; groups B, C, and D had higher parity; the groups A, B, and C
included fewer smokers, and the groups A, B and D had more
often history of thyroid disease than mothers of the reference
group.
When the mothers were stratified according to antibody status, TPO-Ab- and TG-Ab-positive mothers had higher BMIs and
had more often previous thyroid diseases than antibody-negative
mothers. In addition, TG-Ab-positive women were older, had
higher parity, and were less frequently smokers than TG-Abnegative mothers (Table 2). Therefore, the results were adjusted
for maternal age and parity.
The infants in group A (clinical hypothyroidism: high TSH
and low fT4 levels) had a higher mean ponderal index than infants of the reference group. Absolute and relative placental
weights were higher in group A (Table 3).
No significant differences were seen in any of the perinatal
outcomes when group B (subclinical hypothyroidism: high TSH
and normal fT4 levels) was compared with the reference group
(Table 3).
The infants of group C (subclinical hyperthyroidism: low
TSH and normal fT4 levels) less often had Apgar scores of 7 or
less at 5 min than infants of the reference group (Table 3). They
had a risk of 0.4 of having low Apgar scores at 5 min when
compared with the reference group (Table 4).
In group D (clinical hyperthyroidism: low TSH and high fT4
levels) both absolute and relative placental weights as well as
absolute birth weight and number of LGA infants were higher
than in the reference group (Table 3). The infants of group D
were at a 2.7-fold greater risk of being LGA compared with
infants of the reference group (Table 4), but the risk was no
longer significant after adjusting for maternal age and parity.
Mothers who were TPO-Ab positive more often had both low
birth weight infants and LGA infants than TPO-Ab-negative
mothers (Table 5). However, no differences were observed in the
frequencies of SGA infants between the groups. The infants of
TPO-Ab-positive mothers were at a 2-fold increased risk of being
LGA and a 1.7-fold risk of low birth weight (Table 4). In addition, TPO-Ab-positive mothers had a higher relative placental
weight than TPO-Ab-negative mothers (Table 5).
The offspring of TPO-Ab- and TG-Ab-positive mothers
showed 2- to 3-fold greater perinatal mortality than those of
antibody-negative mothers (Tables 4 and 5). In TPO-Ab-positive
group, four of seven perinatally deceased infants were born very
preterm (before gestational wk 28), and in the TG-Ab-positive

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11 (5.3%)
1 (0.4%)
3 (1.3%)
10 (4.5%)
13 (5.8%)a
2 (0.9%)
0

0
0
0
3 (5.6%)
1 (1.9%)a
0
0

262 (5.5%)
65 (1.4%)
56 (1.2%)
253 (5.4%)

34 (0.7%)
10 (0.2%)
6 (0.1%)

36 (16.1%)
8 (3.6%)

12 (22.2%)
1 (1.9%)

919 (19.5%)
212 (4.5%)

4 (1.9%)
0
0

9 (4.4%)
1 (0.5%)
1 (0.5%)
14 (6.9%)

45 (22.1%)
9 (4.4%)

22.5 (3.5)
45 (22.1%)a
1.9 (0 12)a
31 (15.2%)a
10 (4.9%)

22.5 (3.8)
12 (22.2%)
1.5 (0 7)
3 (5.6%)a
3 (5.6%)

22.1 (3.4)
1628 (34.5%)
1.3 (0 15)
1307 (27.7%)
271 (5.7%)

22.6 (3.7)a
69 (30.8%)
1.6 (0 13)a
40 (17.9%)a
11 (4.9%)

28.7 (5.1)
10.9 (3.3)

29.5 (5.5)a
10.5 (2.2)

Group C
(n 204)

28.6 (5.8)
10.9 (2.8)

Group B
(n 224)

28.0 (5.3)
10.7 (2.8)

Group A
(n 54)

2 (2.6%)a
0
0

7 (9.1%)
1 (1.3%)
2 (2.6%)
4 (5.2%)

12 (15.6%)
5 (6.5%)

22.0 (2.9)
17 (22.1%)a
2.1 (0 12)a
17 (21.1%)
3 (3.9%)

28.9 (5.8)
10.4 (2.2)

Group D
(n 77)

12 (4.2%)a
1 (0.3%)
1 (0.3%)

19 (6.6%)
4 (1.3%)
3 (1.0%)
18 (6.3%)

59 (20.5%)
13 (4.5%)

22.7 (4.0)a
81 (28.1%)
1.3 (0 13)
74 (25.7%)
16 (5.6%)

28.6 (5.1)
10.3 (2.4)

TPO-Ab positive
(n 288)

33 (0.6%)
11 (0.2%)
5 (0.1%)

293 (5.3%)
67 (1.3%)
63 (1.1%)
290 (5.3%)

1063 (19.4%)
246 (4.5%)

22.2 (3.4)
1842 (33.6%)
1.4 (0 15)
1486 (27.1%)
310 (5.7%)

28.2 (5.4)
10.8 (2.8)

TPO-Ab negative
(n 5475)

6 (2.2%)a
0
1 (0.4%)

39 (0.7%)
12 (0.2%)
5 (0.1%)

294 (5.4%)
64 (1.2%)
60 (1.1%)
287 (5.3%)

1045 (19.3%)
242 (4.5%)

67 (23.5%)a
15 (5.3%)
16 (5.3%)
6 (2.2%)
5 (1.8%)
17 (6.0%)

22.2 (3.4)
1828 (33.7%)
1.4 (0 15)
1491 (27.5%)
310 (5.7%)

28.1 (5.4)
10.7 (2.8)

TG-Ab negative
(n 5420)

22.7 (4.0)a
73 (25.6%)
1.7 (0 13)a
45 (15.8%)a
15 (5.3%)

29.1 (5.4)a
10.4 (2.7)

TG-Ab positive
(n 285)

P 0.05 when comparing groups AD together or separately with the reference group or comparing the antibody-positive group with the antibody-negative group.

Values are mean (SD) or n (%). Reference group had TSH between the 5th and 95th percentile and fT4 between the 5th and 95th percentile; group A (clinical hypothyroidism) had TSH over the 95th percentile, fT4 under 5th
percentile; group B (subclinical hypothyroidism) had TSH over 95th percentile, fT4 between 5th and 95th percentile; group C (subclinical hyperthyroidism) had TSH under the 5th, fT4 between the 5th and 95th percentile; group
D (clinical hyperthyroidism) had TSH under the 5th percentile, fT4 over the 95th percentile.

Age (yr)
Gestational week at
screening
BMI (kg/m2)
Nulliparous
Parity
Smokers
Alcohol use during
pregnancy
Obstetric history
Spontaneus abortions
Low birth weight
infants
Preterm births
Fetal deaths
Neonatal deaths
Infertility treatments
Previous diseases
Thyroid diseases
Diabetes
Autoimmune diseases

Reference group
(n 4719)

TABLE 2. Demographic characteristics of the pregnant women

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775

776

Mannisto et al.

Thyroid Dysfunction, Antibodies, and Perinatal Outcome

J Clin Endocrinol Metab, March 2009, 94(3):772779

TABLE 3. Perinatal outcome of children grouped according to maternal thyroid hormone status

Birth weight (g)

Low birth weight
SGA
LGA
Birth length (cm)
Ponderal index (kg/m3)
Head circumference (cm)
Gestational weeks at birth
Preterm births
Less than 37 gestational
weeks
Less than 34 gestational
weeks
Noncephalic presentation
Apgar score 7 or less
At 5 min
At 10 min
At 15 min
Perinatal mortality
Fetal death
Neonatal death
Malformations
Placental weight (g)
Relative weight of
placenta (%)
Umbilical cord length (cm)
Cesarean sections

Reference group
(n 4719)

Group A
(n 54)

Group B
(n 224)

Group C
(n 204)

Group D
(n 77)

3568 (548)
149 (3.2%)
93 (2.0%)
116 (2.5%)
50.5 (2.4)
27.6 (2.4)
35.2 (1.5)
39.4 (1.7)

3676 (657)
2 (3.7%)
0
3 (5.6%)
50.6 (2.7)
28.4 (2.8)a
35.4 (2.4)
39.4 (2.3)

3514 (542)
8 (3.6%)
5 (2.3%)
4 (1.8%)
50.2 (2.5)
27.5 (2.3)
35.0 (1.6)
39.3 (1.8)

3564 (524)
7 (3.4%)
2 (1.0%)
3 (1.5%)
50.5 (2.2)
27.5 (2.1)
35.1 (1.6)
39.4 (1.5)

3703 (568)a
2 (2.6%)
1 (1.4%)
5 (6.6%)a
50.9 (2.3)
27.9 (2.2)
35.2 (1.2)
39.4 (1.5)

204 (4.3%)

4 (7.4%)

7 (3.1%)

9 (4.4%)

2 (2.6%)

64 (1.4%)

1 (1.9%)

5 (2.2%)

3 (1.5%)

1 (1.3%)

175 (3.7%)

1 (1.9%)

7 (3.2%)

6 (3.0%)

4 (5.2%)

317 (6.7%)
102 (2.7%)
42 (1.3%)
39 (0.8%)
24 (0.5%)
17 (0.4%)
141 (3.0%)
642 (132)
18.1 (3.3)

6 (11.1%)
1 (2.6%)
1 (2.3%)
1 (1.9%)
1 (1.9%)
0
1 (1.9%)
688 (142)a
19.1 (4.3)a

14 (6.3%)
5 (2.9%)
3 (2.0%)
4 (1.8%)
1 (0.4%)
3 (1.4%)
8 (3.6%)
636 (133)
18.2 (3.2)

6 (2.9%)a
4 (2.5%)
2 (1.3%)
0
0
0
3 (1.5%)
644 (139)
18.1 (3.3)

4 (5.2%)
2 (3.4%)
0
0
0
0
2 (2.6%)
696 (140)a
18.9 (2.9)a

56.1 (12.0)
620 (14.1%)

56.0 (9.9)
8 (15.7%)

56.6 (12.0)
29 (14.0%)

56.5 (13.6)
27 (13.8%)

55.6 (11.5)
7 (9.5%)

Values are mean (SD) or n (%). Reference group had TSH between the 5th and 95th percentile, fT4 between the 5th and 95th percentile; group A (clinical
hypothyroidism) had TSH over the 95th percentile, fT4 under the 5th percentile; group B (subclinical hypothyroidism) had TSH over the 95th percentile, fT4 between
the 5th and 95th percentile; group C (subclinical hyperthyroidism) had TSH under the 5th, fT4 between the 5th and 95th percentile; group D (clinical hyperthyroidism)
had TSH under the 5th percentile, fT4 over the 95th percentile.
a

P 0.05 when comparing groups AD together or separately with the reference group.

group, three of six were born very preterm. Mothers who were
TG-Ab positive had an almost 2-fold risk of more often having
children showing noncephalic presentation at birth (Tables 4
and 5).
In addition, we did an analysis in which we evaluated the
perinatal outcomes of thyroid dysfunction groups after including
and excluding the antibody-positive mothers from the reference
group. The results did not differ from those reported.
We evaluated independently the effect of maternal underweight (BMI 20 kg/m2) and overweight (BMI 25 kg/m2) on
the outcomes presented in Table 4. Maternal underweight was
not associated with any of the adverse perinatal outcomes. However, maternal overweight was a significant risk factor odds
ratio 1.7 1.22.5 for LGA. No association was found between
maternal overweight and perinatal mortality and low birth
weight in our study population.

Discussion
Maternal thyroid autoantibody positivity but not thyroid hormone status at the end of first trimester was associated with
elevated perinatal mortality rate in our study. Preterm delivery
was not associated with either thyroid autoantibodies or thyroid
hormone status. Greater placental weight and an increased num-

ber of LGA infants were associated with both low TSH and high
fT4 levels and presence of autoantibodies.
We are aware of only four prospective cohort studies (2, 4, 14,
15) in which the effect of thyroid hormone status on perinatal
outcome has been investigated. In the study by Allan et al. (2), all
thyroid function measurements were made among a small subcohort (n 627), and the women were classified only according
to their TSH levels. The large study by Matalon et al. (15) involved evaluation of the perinatal outcome of levothyroxinetreated women, but there were no laboratory data. The two
studies by Casey et al. (4, 14) did not include thyroid antibody
testing. Thus, the present work is the only large populationbased prospective cohort study with extensive laboratory data
concerning the effect of maternal thyroid dysfunction and autoimmunity on perinatal outcome. Although our cohort is large,
the rarity of some outcomes such as perinatal mortality and the
fact that serum samples could be obtained only once can be
regarded as a limitation of the study. However, the most changes
in thyroidal function can be observed in the first trimester and are
due to placental hormone stimulation (20). In addition, screening programs in routine maternity care usually take place in the
first trimester. Our study population is a cohort of normal population, in which thyroid dysfunction and antibody positivity are
presumably mostly asymptomatic. The mothers with overt thyroid dysfunction (hypo- or hyperthyroidism) have an increased

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J Clin Endocrinol Metab, March 2009, 94(3):772779

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777

TABLE 4. Estimated risks of perinatal outcomes in association with maternal thyroid dysfunction (presented as odds ratios)
Perinatal outcome
LGA

Birth weight 2500 g

Noncephalic presentation
at birth
Apgar score at 5 min 7 or
less

Perinatal mortality

n (% of total)

Univariate OR (95% CIs)

TSH and fT4 between fifth-95th

percentiles
TSH fifth percentile, fT4 95th
percentile
TPO-Ab negative
TPO-Ab positive
TPO-Ab negative
TPO-Ab positive
TG-Ab negative

Thyroid status

116 (2.5%)

1.0

130 (2.4%)
14 (5.0%)
168 (3.1%)
15 (5.2%)
186 (3.5%)

1.0
2.1 (1.23.7)
1.0
1.7 (1.013.0)
1.0

TG-Ab positive
TSH and fT4 between fifth-95th
percentiles
TSH fifth percentile, fT4 between
fifth and 95th percentile
TPO-Ab negative
TPO-Ab positive
TG-Ab negative
TG-Ab positive

18 (6.3%)
317 (6.7%)

1.9 (1.13.1)
1.0

1.9 (1.13.1)

6 (2.9%)

0.4 (0.2 0.95)

0.5 (0.21.1)

43 (0.8%)
7 (2.4%)
44 (0.8%)
6 (2.1%)

1.0
3.1 (1.4 7.1)
1.0
2.6 (1.1 6.2)

5 (6.6%)

2.7 (1.1 6.9)

Adjusted OR (95% CIs)

2.5 (0.96 6.3)

2.2 (1.23.8)
1.7 (1.013.0)

3.2 (1.4 7.1)

2.5 (1.15.9)

ORs adjusted for maternal age and parity. OR, Odds ratio.

risk for adverse perinatal outcomes, and hence, they require a

more extend follow-up during pregnancy and possibly alterations in their treatment (3).
Finland is one of the few countries in the Western world in
which iodine deficiency practically does not exist because iodine
has been provided as a supplement in the population since the
1940s. The greatest iodine sources in the Finnish diet are dairy
products and table salt. Studies from the early 1980s (21, 22)

have shown that the daily iodine intake was sufficient, and the
iodine intake exceeds the recommended amount, even in the
pregnant population (23). Therefore, we presume that the iodine
intake was sufficient during the pregnancies of NFBC 1986
mothers, and it can be supposed that cases of thyroid dysfunction
arise from thyroid diseases and not from environmental factors.
In addition, because practically all pregnant Finnish women have
maternity care that is well organized and free of charge, provide

TABLE 5. Perinatal outcome of children grouped according to maternal thyroid antibody status

Birth weight (g)

Low birth weight
SGA
LGA
Birth length (cm)
Ponderal index (kg/m3)
Head circumference (cm)
Gestational weeks at birth
Preterm births
Less than 37 gestational weeks
Less than 34 gestational weeks
Noncephalic presentation
Apgar score 7 or less
At 5 min
At 10 min
At 15 min
Perinatal mortality
Fetal death
Neonatal death
Malformations
Placental weight (g)
Relative weight of placenta (%)
Umbilical cord length (cm)
Cesarean sections

TPO-Ab positive
(n 288)

TPO-Ab negative
(n 5475)

TG-Ab positive
(n 285)

TG-Ab negative
(n 5420)

3551 (658)
15 (5.2%)a
8 (2.9%)
14 (5.0%)a
50.3 (2.8)
27.6 (2.5)
35.1 (2.1)
39.2 (2.3)

3570 (543)
168 (3.1%)
106 (2.0%)
130 (2.4%)
50.5 (2.3)
27.6 (2.4)
35.2 (1.5)
39.4 (1.7)

3606 (596)
7 (2.5%)
7 (2.6%)
11 (4.0%)
50.5 (3.0)
27.8 (2.6)
35.2 (1.9)
39.3 (1.9)

3567 (548)
174 (3.2%)
107 (2.0%)
132 (2.5%)
50.5 (2.3)
27.6 (2.4)
35.2 (1.5)
39.4 (1.7)

17 (5.9%)
8 (2.8%)
11 (3.9%)

237 (4.3%)
70 (1.3%)
197 (3.6%)

20 (7.0%)
8 (3.6%)
5 (2.3%)
7 (2.4%)a
4 (1.4%)
3 (1.1%)
8 (2.8%)
654 (146)
18.7 (3.9)a
56.9 (11.1)
40 (15.1%)

354 (6.5%)
117 (2.7%)
49 (1.3%)
43 (0.8%)
26 (0.5%)
19 (0.3%)
165 (3.0%)
642 (131)
18.1 (3.3)
56.1 (12.0)
708 (13.8%)

12 (4.2%)
5 (1.8%)
18 (6.3%)a
17 (6.0%)
8 (3.6%)
6 (2.7%)
6 (2.1%)a
4 (1.4%)
2 (0.7%)
7 (2.5%)
641 (128)
18.1 (4.0)
56.4 (11.0)
36 (13.5%)

238 (4.4%)
73 (1.3%)
186 (3.5%)
352 (6.5%)
116 (2.7%)
48 (1.3%)
44 (0.8%)
26 (0.5%)
20 (0.4%)
163 (3.0%)
643 (133)
18.1 (3.3)
56.1 (12.0)
703 (13.9%)

Values are mean (SD) or n (%). Perinatal mortality was death during pregnancy or during the first week of life.
a

P 0.05 when comparing the antibody-positive group with the antibody-negative group.

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778

Mannisto et al.

Thyroid Dysfunction, Antibodies, and Perinatal Outcome

serum samples, and give birth in public hospitals, studies on

perinatal outcome are relatively reliable in our country.
Perinatal mortality was 2- to 3-fold greater in the infants of
thyroid autoantibody-positive mothers compared with those in
the antibody-negative groups. This association remained, even
after adjusting for maternal age and parity. There were no differences between the groups A-D (hormonal thyroid dysfunction) and the reference group with respect to perinatal mortality.
Therefore, thyroid hormone status did not affect the perinatal
mortality rate in our study. It is likely that autoimmunity is associated with increased perinatal mortality, not thyroid hormone levels as such. However, there were three mothers with
both subclinical hypothyroidism (in group B) and TPO-Ab positivity in the perinatal mortality group. Previously, increased
rates of fetal death have been considered to be associated with
high TSH levels (2), but 80% of the women with high TSH levels
were thyroid antibody positive in that study. It seems that subclinical hypothyroidism and TPO-Ab positivity together may be
a risk factor for perinatal mortality, but TPO-antibodies in itself
may also have an independent effect. In addition, all the TGAb-positive mothers having perinatally deceased newborns were
euthyroid. We conclude that the presence of thyroid autoantibodies during pregnancy indicated increased risk for perinatal
mortality. This risk may, however, be explained by preterm
births. The perinatally deceased infants in both TPO-Ab- and
TG-Ab-positive groups were more often born preterm.
Regarding preterm deliveries we found no significant differences between the groups. Just a slight tendency toward an increase in preterm deliveries (34th gestational week) was seen
among TPO-Ab-positive mothers. Stagnaro-Green et al. (9) previously reported a similar finding, but they could not confirm
their results statistically due to small sample size. In a study by
Negro et al. (24), TPO-Ab positivity was significantly related to
preterm delivery, the rate of which decreased with levothyroxine
treatment. These findings, as well as those reported by Casey et
al. (4), who found an increased rate of preterm delivery among
women with subclinical hypothyroidism, suggest that an increase rate of preterm delivery among TPO-Ab-positive women
may be related to impaired thyroid function.
The mothers with high TSH combined with low fT4 levels
also showed a nonsignificant tendency to have an increased rate
of preterm delivery, but this was not the case when fT4 levels
were normal. Antibodies could possibly explain this because
50% of the mothers with high TSH and low fT4 levels were
antibody positive. Because preterm delivery is a relatively rare
event and the reasons for it are multifactorial, an association with
thyroid dysfunction cannot be confirmed in our study. The role
of autoimmunity and thyroid autoantibodies in preterm deliveries needs further research.
The TPO-Ab-positive mothers had an increased rate of low
birth weight infants (2500 g), but after adjusting birth weight
by gestational age, no increase in the rate of SGA infants was
seen. Therefore, the increased rate of low birth weight infants in
the TPO-Ab-positive mothers might be explained by preterm
delivery because almost 65% of low birth weight infants in this
group were also born preterm. Three of the fifteen low birth
weight infants in the TPO-Ab-positive group were born to moth-

J Clin Endocrinol Metab, March 2009, 94(3):772779

ers with subclinical hypothyroidism (group B). Thus, it seems

that TPO-Ab positivity in itself associated with increased rates of
low birth weight infants, probably through preterm births.
Recently in a large study in which normal-weight, overweight, and obese pregnant women were compared (25), it was
shown that an overweight condition and obesity are significant
risk factors with regard to fetal death, premature delivery, low
Apgar scores, and low birth weight. In the studies by Casey et al.
(4, 14) and Allan et al. (2), maternal weight was substantially
greater than in our study. The mean BMI of 22.3 kg/m2 in our
study reflected the normal range. Thyroid diseases may have an
effect on the BMI of the mother, and BMI is possibly an confounding or intervening factor when evaluating the effect of thyroid dysfunction. Therefore, no adjustment for maternal BMI
was done.
We found the growth of the fetus and the placenta to be
affected by thyroid dysfunction and autoimmunity. To our
knowledge, the association of thyroid dysfunction or autoimmunity with gestational age-adjusted birth measurements has
not been reported earlier. Mothers with low TSH and high thyroid hormone levels (group D, clinical hyperthyroidism) had an
almost 3-fold increased risk, and TPO-Ab-positive mothers had
a 2-fold increased risk of having LGA infants. Multiparity is a
known risk factor for LGA (26), and our results are in accordance with this because the risk for LGA infants in mothers with
low TSH and high fT4 disappeared after adjusting the results for
parity. Maternal gestational diabetes, which is associated with
LGA infants as well, was found in only one case in group D and
none in the TPO-Ab-positive group. The effect of clinical hyperthyroidism or TPO antibodies on the rates of LGA infants is
unknown. The relationship is probably multifactorial and maternal BMI and placental function may have an effect on the rates
of LGA infants.
Placental weight was associated with thyroid dysfunction in
an U-shaped manner. Greater placental weight was observed in
mothers with high TSH and low fT4 levels (group A, clinical
hypothyroidism), mothers with low TSH and high fT4 levels
(group D, clinical hyperthyroidism), and TPO-Ab-positive
mothers. To our knowledge, this is the first study in which the
effect of thyroid dysfunction or autoimmunity on placental
weight has been reported. Explanatory factors for higher placental weights could be smoking, maternal weight, and birth
weight. These factors may have had an effect on our results because TPO-Ab-positive mothers were slightly heavier, mothers
with clinical hypothyroidism smoked less often and their infants
had higher ponderal indexes, and mothers with clinical hyperthyroidism had a higher prevalence of LGA infants. The role of
thyroid hormone or antibody concentrations on placental
growth is unknown, but placenta may have an active role on
thyroid hormone metabolism through enzyme function and
transportation (27).
Noncephalic presentation at birth was more common among
TG-Ab-positive mothers, although breech presentation alone
was not statistically significantly more frequent. The difference
in the rates of noncephalic presentations persisted between TGAb-positive and -negative women, even after adjusting for maternal age and parity. Mothers who are TG-Ab positive show an

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J Clin Endocrinol Metab, March 2009, 94(3):772779

increased incidence of subclinical hypothyroidism during pregnancy (1), which may be related to increased rates of breech
presentation (12), but no differences in the rates of noncephalic
presentation were observed in our study in relation to thyroid
hormones. In Finland there is an active policy with regard to
external manipulation of the fetus to cephalic presentation,
which may have affected the rate of noncephalic presentation in
our study.
Subclinical hyperthyroidism during pregnancy is probably
transient and due to placental hormone stimulation (20). In our
study fewer children with low Apgar scores were born to mothers
with low TSH levels together with normal fT4 concentrations
(group C, subclinical hyperthyroidism) compared with the reference group. The relationship between pregnancy complications and Apgar scores are multifactorial and the effect of subclinical hyperthyroidism on Apgar scores is unclear. Casey et al.
(14) also reported that women with subclinical hyperthyroidism
did not have any adverse outcomes.
In conclusion, thyroid autoimmunity detected during the first
trimester of pregnancy seems to be independently associated
with increased perinatal mortality, probably through preterm
births. Thyroid autoantibodies are also associated with an increased rate of LGA infants. Therefore, it seems that rather than
thyroid hormones themselves, thyroid autoantibodies more often have an adverse effect on perinatal outcome. Testing for them
might be advisable, at least in risk pregnancies.

jcem.endojournals.org

5.
6.
7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

Acknowledgments
We thank Ms. Sarianna Vaara and Ms. Tuula Ylitalo for their valuable work regarding NFBC 1986. We also thank Mr. Jouni Sallinen
and Mr. Frank Quinn (Abbott Laboratories) for providing laboratory
reagents.
Address all correspondence and requests for reprints to: Eila Suvanto-Luukkonen, Department of Obstetrics and Gynecology, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland. E-mail: eila.suvantoluukkonen@ppshp.fi.
This work was supported in part by grants from the Alma and K. A.
Snellman Foundation (Oulu, Finland); the Jalmari and Rauha Ahokas
Foundation (Finland); the Lilly Foundation (Finland); Oulu University
Scholarship Foundation (Oulu, Finland); the Finnish Medical Association of Clinical Chemistry; the Foundation of Northern Ostrobothnia
Hospital District (Finland); and the Academy of Finland.
Disclosure Statement: The authors have nothing to declare.

17.

18.

19.

20.

21.

22.
23.

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