Perinatal outcome of children born to mothers with thyroid dysfunction or antibodies: a prospective population-based cohort study.

Abstract

There are only a few large prospective studies involving evaluation of the effect of maternal thyroid dysfunction on offspring and observations are inconsistent.
The objective of the study was to investigate the effects of thyroid dysfunction or antibody positivity on perinatal outcome.
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 T(4) (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.
Outcomes were perinatal mortality, preterm delivery, absolute and gestational age-adjusted birth weight, and absolute and relative placental weight.
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 (1.1-5.9) 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.
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.

Full text

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Perinatal outcome of children born to mothers with thyroid dysfunction or antibodies. A
prospective population-based cohort study.

Short title: Thyroid dysfunction, autoimmunity and perinatal outcome

Tuija Männistö, Med Cand1,3, Marja Vääräsmäki, M.D., Ph.D.1, Anneli Pouta, M.D., Ph.D.1,2, Anna-Liisa
Hartikainen, professor1, Aimo Ruokonen, professor4, Heljä-Marja Surcel, Ph.D.2, Aini Bloigu,
statistician2, Marjo-Riitta Järvelin, professor2,3,5, and Eila Suvanto-Luukkonen*, M.D., Ph.D.1

1Department of Obstetrics and Gynecology, University of Oulu, Finland
2National Public Health Institute, Department of Child and Adolescent Health, Finland
3Institute of Health Sciences, University of Oulu, Finland
4Department of Clinical Chemistry, University of Oulu, Finland
5Department of Epidemiology and Public Health, Imperial College London, UK

*Corresponding author
Eila Suvanto-Luukkonen,
Department of Obstetrics and Gynecology, University of Oulu,
PO Box 5000, 90014 Oulu, Finland.
Phone +358-8-3153627,
Fax +358-8-3154310,
E-mail: Eila.Suvanto-Luukkonen@ppshp.fi

Key words: Thyroid gland, perinatal, autoantibodies, pregnancy complications, TSH

Disclosure statement: Nothing to declare

Précis: Thyroid autoantibodies seem to have an adverse effect on perinatal outcome and their screening
might be advisable.

Word count: 3554
Abstract word count: 248
Number of figures: 1
Number of tables: 5

J Clin Endocrin Metab. First published ahead of print December 23, 2008 as doi:10.1210/jc.2008-1520
Copyright (C) 2008 by The Endocrine Society

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ABSTRACT
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: To investigate the effects of thyroid dysfunction or antibody-positivity on perinatal
outcome.
SETTING AND PARTICIPANTS: Prospective population-based Northern Finland Birth Cohort 1986
including 9247 singleton pregnancies. First trimester maternal serum samples were analyzed for thyroid
hormones (TSH, 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: Perinatal mortality, preterm delivery, absolute and gestational age-adjusted birth
weight, 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 OR 3.1 (95% CI 1.4–7.1) and 3.2 (1.4-7.1) in TPO-Ab- and 2.6 (1.1–
6.2) and 2.5 (1.1-5.9) 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.

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INTRODUCTION
A 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 (5-7). Even subclinical
hypothyroidism in the presence or absence of
thyroid antibodies is regarded as a threat to a
woman’s fertility, pregnancy outcome and to 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, 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 population-
based 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.

SUBJECTS AND METHODS
Study population and data collection
The prospective Northern Finland Birth Cohort
1986 (NFBC 1986) covered 99% of all births
with calculated term between July 1st 1985 and
June 30th 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 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 was obtained by assay of
serum samples from the Finnish Maternity
Cohort (FMC). This is a bio-bank, 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 ºC. The effect of freezing,
thawing and frozen storage on thyroid laboratory
parameters has been reported previously (18).

Quantitative analyses of thyroid hormones (TSH
[thyroid-stimulating hormone], fT3 [free
triiodothyronine] and fT4 [free thyroxine]) and
autoantibodies (TPO-Ab [thyroid-peroxidase
antibody] and TG-Ab [thyroglobulin antibody])
were performed by way of chemiluminescent
micro-particle immunoassays (CMIAs), using an

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Architect i2000 automatic analyzer (Abbott
Diagnostics). The lower limits of detection, and
intra- and interassay coefficients of variation
(CVs) were 0.0025 mlU/L, 1.7 and 5.3% for
TSH, 5.1 pmol/L, 3.6 and 7.8% for fT4, 1.53
pmol/L, 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 (Figure 1). The mean gestational age at
sampling was 11.0 weeks (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
non-pregnant 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 5th 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 (Figure 1):
(i) Group A with TSH over the 95th percentile
and fT4 under the 5th percentile (n=54; clinical
hypothyroidism);
(ii) Group B with TSH over the 95th percentile
and fT4 between the 5th and 95th percentiles
(n=224; subclinical hypothyroidism);
(iii) Group C with TSH under the 5th percentile
and fT4 between the 5th and 95th percentile
(n=204; subclinical hyperthyroidism); and
(iv) Group D with TSH under the 5th percentile
and fT4 over the 95th percentile (n=77; clinical
hyperthyroidism). Groups A–D 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 (Figure 1). The high cut-
off level was used instead of manufacturer’s
reference values, because the samples in this
study were from pregnant women and after
frozen storage (18). The 5th and 95th percentiles
as well as geometric means and 95% confidence
intervals (95% 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 days after birth]), neonatal deaths,
malformations, presentation at birth, mode of
delivery, absolute and relative placental weight
and umbilical cord length.

Statistics
Categorial variables were compared using
Pearson’s χ2 test or Fisher’s exact test, as
appropriate. Student’s 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
analysis of variance followed by pairwise
comparisons with Student’s 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), non-cephalic 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. A p-value of <0.05 was
deemed significant. Statistical analysis was

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performed using SPSS 14.0 software (SPSS Inc.,
Chicago, Illinois, USA).

RESULTS
The demographic data of the mothers in each
group according to their thyroid
hormone/antibody status are presented in Table
2. This 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 to 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 A–D 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-positive 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-Ab-negative
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 to 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 at 5
minutes than infants of the reference group
(Table 3). They had a risk of 0.4 of having low
Apgar scores at 5 minutes when compared with
the reference group (Table 5).

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 5), 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
4). 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 5). In
addition, TPO-Ab-positive mothers had a higher
relative placental weight than TPO-Ab-negative
mothers (Table 4).

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 & 5). In TPO-Ab-positive
group, four out of seven perinatally deceased
infants were born very preterm (before
gestational week 28) and in TG-Ab-positive
group three out of six were born very preterm.
Mothers who were TG-Ab-positive had an
almost 2-fold risk of more often having children
showing non-cephalic presentation at birth
(Tables 4 & 5).

In addition, we did an analysis where 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.