Endocrine

DOI 10.1007/s12020-015-0564-3

RESEARCH LETTER

Maternal hypothyroidism and subsequent neuropsychological

outcome of the progeny: a family portrait
Daniela Pasquali Marco Carotenuto Paola Leporati
Maria Esposito Lorenzo Antinolfi Daniela Esposito
Giacomo Accardo Carlo Carella Luca Chiovato Mario Rotondi

Received: 22 December 2014 / Accepted: 27 February 2015

Springer Science+Business Media New York 2015

Introduction
Normal neuropsychological development depends upon
adequate function of both maternal and foetal thyroid gland
[1]. Previous studies suggested that even mild hypothyroidism can interfere with normal brain development [2, 3].
Maternal hypothyroidism is not a rarely diagnosed
condition during pregnancy [4]. The diagnosis and the
treatment of such condition are not troublesome [57], but
the possibility to predict what will be going on in the
newborn, once maternal hypothyroidism is discovered,
remains difficult. As a result it is not rare that some
pregnant women with severe hypothyroidism during gestation could consider early termination of pregnancy fearing that their infant might have significant mental
retardation [8, 9].
We are here reporting the early and long-term neuropsychological development of the progeny of a thyroidectomized woman displaying different degrees of
hypothyroidism in three subsequent pregnancies.

D. Pasquali
D. Esposito
G. Accardo
C. Carella

Department of Cardiothoracic and Respiratory Science, Second
University of Naples, Naples, Italy
M. Carotenuto
M. Esposito
L. Antinolfi
Clinic of Child and Adolescent Neuropsychiatry, Department of
Mental Health, Physical and Preventive Medicine, Second
University of Naples, Naples, Italy
P. Leporati
L. Chiovato (&)
M. Rotondi
Unit of Internal Medicine and Endocrinology, Fondazione
Salvatore Maugeri I.R.C.C.S., Laboratory for Endocrine
Disruptors, University of Pavia, Via S. Maugeri 10, 27100 Pavia,
Italy
e-mail: luca.chiovato@fsm.it

Even if limited to three patients, analysis of this family

is of potential clinical relevance in that the three sisters,
besides the parents, shared the same social and cultural
environment, which would prevent the confounder effects
of the environment thus, allowing a more bias-free comparison of the effects of maternal hypothyroidism on their
neurodevelopment outcome. Furthermore, the comparisons
of the early versus long-term neuropsychological outcome,
provides some clinically useful informations.

Patients and methods

The case history of three sisters (F.F., A.F. and C.F.) born
to a thyroidectomized mother under levothyroxine substitutive treatment are reported. Briefly, the mother had been
thyroidectomized for Graves disease at the age of 12 years
and was under replacement therapy with levothyroxine
(200 mcg/day). The case history of the first pregnancy was
previously reported [10]. Throughout the three pregnancies
LT4 doses were adjusted up to 300 lg/day. The LT4 dose
adjustments were performed at variable timing at each
pregnancy because the patient did not attend regular follow-up and displayed a poor compliance to the treatment.
In particular, the patient was found to be severely hypothyroid at 29 weeks gestation in the first pregnancy (TSH
level of 79 lU/ml, FT4 6.0 pg/ml). A mild hypothyroidism
was found at 24 weeks gestation in the the second pregnancy (TSH 15 lU/ml), while euthyroidism resulted at 6
weeks gestation in the third pregnancy (TSH 3.5 lU/ml).
(1)

F.F. The case history of the first daughter was

previously reported [10]. Briefly, she had been found
to be growth-retarded at her 29 week of intrauterine
life, when the mother was severely hypothyroid

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(TSH level of 79 lU/ml, FT4 6.0 pg/ml). Structural

ultrasounds, were performed at the 34th, 36th and
39th weeks of gestation. All parameters analysed by
ultrasound (head and abdominal circumferences,
biparietal diameter, humerus and femur length), at
the 34th week showed a marked growth delay,
(values \5th centiles), with normalisation of extremities ([50th centiles) but not head measurements by 39th weeks. At the age of 4 years the child
showed normal thyroid function parameters and
negative tests for circulating thyroid Ab. She also
had undergone a complete neuropsychological evaluation with the following results:
Neurological status The neurological examination
performed using a standardised form [11] did not
reveal any kind of abnormality.
Psychometric assessment The psychological testing
included the Wechsler-Preschool and Primary Scale
of Intelligence [12]. The full scale IQ was 93, with
verbal IQ = 92 and performance IQ = 96. The
standard score for each subtest is reported in
Table 1.
Language Speech and language evaluation revealed
mild expressive impairments with most skills clustering at the early 3-year range. Receptive language
was normal.
Behaviour The Child Behaviour Checklist [13]
completed by parents showed scores in the normal
range. We could evidence only a minor separation
anxiety which did not interfere with the social
adjustment by direct observation. There were also
present oppositional behaviours related to an egocentric attitude. The standard score of WPPI subtest
obtained at the age of 4 years are reported in
Table 1.
In conclusion, the patient was found to be rather
normal for the age-related neurological and psychological development. At the age of 15 years, she
underwent a new cognitive evaluation applying the
Italian version of the Wechsler Intelligence Scale or
Children Third Edition (WISC-III) [14] for subjects
aged 616 years. According to the WISC-III performance, girl result affected by Mild Level of
Table 1 Standard score of
Wechsler Intelligence Scale for
Children Third Edition subtests

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(2)

(3)

After delivery, all of the infants underwent routine

screening program for neonatal hypothyroidism. Thyroid
hormones and TSH were found to be normal (compared to
age-related range) at all evaluations (1, 5, 30 days).
Both parents gave their informed consent to the study.
We obtained local Research Ethics Board approval for the
study.

Results
The anthropometric parameters and the cognitive evaluations of the three sisters performed at the age of 15, 11
and 10 years, respectively, by full Wechsler Intelligence
Scale for Children Third Edition are shown in Table 2.
Height, weight and BMI of the three sisters at the time of
their first assessment as well as the genetic target for height
are also shown in Table 2.
All the available informations regarding maternal thyroid function during each pregnancy were recollected and
are shown in Table 3. Although no systematic evaluation
had been performed, the results shown in Table 3, allow to
assume reasonably, that the mother had been severely hypothyroid during the first pregnancy, a less severe hypothyroidism was found during the second pregnancy

Verbal scale
Subtest

Intellectual Disability (Total-IQ 63) with a high

discrepancy between performance (PIQ 80) and
verbal (VIQ 54) subscales results. Only after the
results of the neurocognitive tests performed at the
age of 15 years (child 1), parents were asked to give
permission to extend the evaluation to the remaining
two sisters.
F.A. is a 11-year-old girl who showed, according to
the WISC-III evaluation, a Borderline Intellectual
Functioning (Total-IQ 77) with a mild discrepancy
between performance (PIQ 85) and verbal (VIQ 71)
subscales results.
F.C. is a 10-year-old girl who showed, according to
the WISC-III evaluation, a normal range of cognitive
functioning (Total-IQ 98) with a mild discrepancy
between performance (PIQ 106) and verbal (VIQ 92)
subscales results.

Performance scale
Standard score

Subtest

Standard score
10

Information

Animal pegs

Vocabulary

Picture completion

Arithmetic

Mazes

10

Similarities

10

Geometric design

10

Comprehension

10

Block design

Endocrine
Table 2 Auxological data and cognitive evaluations of the sisters performed at the age of 15 years, 11 years and 10 years, respectively, by full
Wechsler Intelligence Scale for Children Third Edition
Sisters

Age (years)

Height (cm)

Weight (kg)

BMI

TIQ

PIQ

F.F.

15

155a

52

21.6

63

F.A.

11

142

40

19.8

77

85

71

F.C.

10

140a

46

23.4

98

106

92

80

VIQ
54

TIQ total intelligence quotient, PIQ performance intelligence quotient, VIQ verbal intelligence quotient
a

The calculated final height target was 155 4 cm

Table 3 Maternal thyroid function parameters throughout three subsequent pregnancies

Pregnancy

Week of gestation

TSH lU/ml (0.44.0)a

FT3 pmol/l (5.521.6)a

FT4 pmol/l (19.158.0)a

First

Pre-conception

\0.05

5.9

58.0

29

72.4

3.9

18.3

32

14.0

5.5

32.3

34

10.4

5.8

33.0

36

3.2

6.5

34.8

Pre-conception

2.9

6.7

36.0

Second

Third

24

15.0

6.2

26.1

32

2.8

6.6

35.9

Pre-conception

2.4

7.1

40.3

3.5

5.9

34.1

21

3.4

7.0

37.0

39

2.9

6.2

39.2

Non-pregnant normal range

while euthyroidism had been present throughout the third

pregnancy. It is interesting noting that the outcome of the
neuropsychological evaluation paralleled maternal thyroid
status over the three gestations. Indeed, a relevant intellectual disability was found in the first daughter
(documented severe maternal hypothyroidism), a normal
cognitive functioning was found in the third daughter
(documented maternal euthyroidism) and an intermediate
clinical feature such as a Borderline Intellectual functioning was found in the second daughter (surely not maternal
euthyroidism, likely not maternal overt hypothyroidism;
one documented finding of subclinical hypothyroidism).
Another interesting finding relates to the high discrepancy
between performance (PIQ 80) and verbal (VIQ 54) subscales results observed in the first daughter. Similar discrepancy in the second and in third daughter, showing
performance (PIQ 85) and verbal (VIQ 71) and performance (PIQ 106) and verbal (VIQ 92) subscale results,
respectively, was also revealed (Table 2).

Discussion
The present study describes the family history of three
daughters born from three subsequent pregnancies

characterised by different maternal thyroid function status.

The principal finding emerging from our description is that
the repercussions on the progeny of maternal hypothyroidism may be underestimated in early childhood. In the
first daughter [10], the first NPS evaluation performed at 4
years age showed normal/low normal findings, while a
severe impairment was clearly demonstrated at the 16 years
age. The fact that early neuropsychological evaluation
(4 years of age) had been performed only for the first
daughter could be viewed as a limitation of our study.
However, changes in the scores obtained at the neuropsychological tests between the age of 4 and 16 years should
be viewed in light of the differences in intellective profile
between pre-school children and adolescent subjects. In
fact, the intellective profile among pre-school children is
focused on pragmatic competencies and motor abilities
more than cognitive styles. On the other hand, adolescents
are more focused on verbal competencies and imaginative
reasoning [15]. Thus, it appears unlikely that major changes in the scores obtained by the other two patients (who
were evaluated at the age of 11 and 10 years) will occur by
the time they will be 15 years old .
The most important aspect of the present study stems
from the fact that the progeny, besides the parents, shared
the same social and cultural level which allows a better

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between subjects neuropsychological comparison [16].

Furthermore, the similar genetic background of three sisters reduces the relative contributions of genes and environment on the association between intellectual abilities
and thyroid functioning during pregnancy [17].
Although a certain dose response effect of maternal
hypothyroidism on the subsequent neurodevelopment of
the progeny might be derived from the observation of the
three sisters, it should be remembered that both severity
and timing of the development of the maternal hypothyroidism may potentially impair subsequent neuropsychological status [18].
The above aspects evidence how complex is the issue of
the neuropsychological development of progeny and how
no simplistic model can be applied to predict possible longterm outcome [18]. Thus, description of every single case
may be helpful in the clinical management of occasionally
diagnosed gestational hypothyroidism. Owing to the fact
that the occurrence of severe hypothyroidism during gestation has become rather rare nowadays, it seems clear that
it will be difficult that large series studies will be available
in the literature.
In this view, we could attempt to compare our patients
with those described by Downing et al. [8] and Momotami
et al. [9]. In the first study, Downing et al. administered
neuropsychological tests to assess intelligence, language,
memory and visual-motor performance in three children
born to three mothers with overt hypothyroidism in the first
half of pregnancy reporting average/above average scores
[8]. It should be noted that all the mothers were promptly
substituted to normalise thyroid hormone levels and that
the three infants had a mean of 5.4 years of age (range
5.16.1) which would appear in line with the neuropsychological evaluation obtained by the first of our patient at
the age of 4 years. Similarly, Momotami et al. reported
normal neurodevelopment scores in 5 children born to
severely hypothyroid mothers [9]. Besides the fact that
only one patient was older than 10 years, the most likely
explanation accounting for discrepancy between the here
reported and Momotamis patients might be the different
iodine intake between the two areas, iodine deficiency in
our region [19, 20] and iodine sufficiency in Japan. Indeed,
it was recently demonstrated that even marginal maternal
iodine deficiency (\150 lg/l) during gestation can result in
mild but still measurable and irreversible impairment of
foetal neurocognitive development [2123].
On the other hand, the mothers of subjects described by
Momotami et al. obtained a significantly clinical improvement in hypothyroidism in the early weeks of pregnancy, while the mother of our subjects achieved
euthyroidism later in gestation [9]. This could suggest that
normal development in the progeny studied by Momotami
could have been realised through restoration of maternal

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T4 levels, whereas in our patients, maternal hypothyroidism might have had a greater impact on the neuropsychological development, as it was not promptly
corrected in the early stages of gestation.
This last point suggests could suggest considering early
screening for maternal thyroid dysfunction during pregnancy. Another finding derived from description of this
family, stems from the observation of the increased impairment of the verbal subscale results compared to the
performance scale. This result is in line with the importance of thyroid hormones level for language/verbal performance among men [24], underlying their key role during
developmental life.
In conclusion, by description of these patients, it appears
that the potential harmful repercussions of gestational hypothyroidism in terms of neurodevelopmental outcome of
the progeny may be delayed and that normal/mildly low
performances at the WPPSI subtests score obtained at the
age of 4 years do not exclude that severe impairment of
neurocognitive function will be detected in the subsequent
years.

Conflict of interest

The authors have no conflict of interest.

References
1. J.H. Oppenheimer, H.L. Schwartz, Molecular basis of thyroid
hormone-dependent brain development. Endocr. Rev. 18,
462475 (1997)
2. J.E. Haddow, G.E. Palomaki, W.C. Allan, J.R. Williams, G.J.
Knight, J. Gagnon, C.E. OHeir, M.L. Mitchell, R.J. Hermos, S.E.
Waisbren, J.D. Faix, R.Z. Klein, Maternal thyroid deficiency
during pregnancy and subsequent neuropsychological development of the child. N. Engl. J. Med. 341, 549555 (1999)
3. V.J. Pop, E.P. Brouwers, H.L. Vader, T. Vulsma, A.L. van Baar,
J.J. de Vijlder, Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up
study. Clin. Endocrinol. 59, 282288 (2003)
4. D. Glinoer, The regulation of thyroid function in pregnancy:
pathways of endocrine adaptation from physiology to pathology.
Endocr. Rev. 18, 404433 (1997)
5. S.J. Mandel, P.R. Larsen, E.W. Seely, G.A. Brent, Increased need
for thyroxine during pregnancy in women with primary hypothyroidism. N. Engl. J. Med. 323, 9196 (1990)
6. A. Stagnaro-Green, M. Abalovich, E. Alexander, F. Azizi, J.
Mestman, R. Negro, A. Nixon, E.N. Pearce, O.P. Soldin, S.
Sullivan, W. Wiersinga, American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum
Guidelines of the American Thyroid Association for the diagnosis
and management of thyroid disease during pregnancy and postpartum. Thyroid 21, 10811125 (2011)
7. L. De Groot, M. Abalovich, E.K. Alexander, N. Amino, L.
Barbour, R.H. Cobin, C.J. Eastman, J.H. Lazarus, D. Luton, S.J.
Mandel, J. Mestman, J. Rovet, S. Sullivan, Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine
Society clinical practice guideline. J. Clin. Endocrinol. Metab.
97, 25432565 (2012)

Endocrine
8. S. Downing, L. Halpern, J. Carswell, R.S. Brown, Severe maternal hypothyroidism corrected prior to the third trimester is
associated with normal cognitive outcome in the offspring.
Thyroid 22, 625630 (2012)
9. N. Momotani, S. Iwama, K. Momotani, Neurodevelopment in
children born to hypothyroid mothers restored to normal thyroxine (T4) concentration by late pregnancy in Japan: no apparent
influence of maternal T4 deficiency. J. Clin. Endocrinol. Metab.
97, 11041108 (2012)
10. M. Rotondi, C. Caccavale, C. Di Serio, A. Del Buono, F. Sorvillo,
D. Glinoer, A. Bellastella, C. Carella, Successful outcome of
pregnancy in a thyroidectomized-parathyroidectomized young
woman affected by severe hypothyroidism. Thyroid 9,
10371040 (1999)
11. B.C.L. Touwen, Examination of the child with minor neurological dysfunction (William International Medical Publications,
London, 1979), p. 71
12. D. Wechsler, The Wechsler Preschool and Primary Scale of Intelligence (Organizzazioni Speciali, Firenze, 1998)
13. T.M. Achenbach, The Child Behaviour Checklist (University of
Vermont, Burlington, 1991)
14. D. Wechsler, Wechsler Intelligence Scale for Children, 3rd edn.
(The Psychological Corporation, San Antonio, 1991)
15. J. Piaget, Main Trends in Psychology (George Allen & Unwin,
London, 1973)
16. A.W. Siegman, The effect of cultural factors on the relationship
between personality, intelligence, and ethnocentric attitudes.
J. Consult. Clin. Psychol. 22, 375377 (1958)
17. M.M. Bohlken, R.M. Brouwer, R.C. Mandl, N.E. van Haren, R.G.
Brans, G.C. van Baal, E.J. de Geus, D.I. Boomsma, R.S. Kahn,
H.E. Hulshoff Pol, Genes contributing to subcortical volumes and

18.

19.

20.

21.

22.
23.

24.

intellectual ability implicate the thalamus. Hum. Brain Mapp. 35,

26322642 (2014)
D. Glinoer, Potential consequences of maternal hypothyroidism
on the offspring: evidence and implications. Horm. Res. 55,
109114 (2001)
M. Rotondi, G. Amato, B. Biondi, G. Mazziotti, A. Del Buono,
M.R. Nicchio, S. Balzano, A. Bellastella, D. Glinoer, C. Carella,
Parity as a thyroid size-determining factor in areas with moderate
iodine deficiency. J. Clin. Endocrinol. Metab. 85, 45344537
(2000)
M. Rotondi, G. Mazziotti, F. Sorvillo, M. Piscopo, M. Cioffi, G.
Amato, C. Carella, Effects of increased thyroxine dosage preconception on thyroid function during early pregnancy. Eur.
J. Endocrinol. 151, 695700 (2004)
K.L. Hynes, P. Otahal, I. Hay, J.R. Burgess, Mild iodine deficiency during pregnancy is associated with reduced educational
outcomes in the offspring: 9-year follow-up of the gestational
iodine cohort. J. Clin. Endocrinol. Metab. 98, 19541962 (2013)
M. Moleti, F. Trimarchi, F. Vermiglio, Thyroid physiology in
pregnancy. Endocr. Pract. 21, 126 (2014)
S.C. Bath, C.D. Steer, J. Golding, P. Emmett, M.P. Rayman,
Effect of inadequate iodine status in UK pregnant women on
cognitive outcomes in their children: results from the Avon
Longitudinal Study of Parents and Children (ALSPAC). Lancet
382, 331337 (2013)
M.A. Beydoun, H.A. Beydoun, M.H. Kitner-Triolo, J.S. Kaufman, M.K. Evans, A.B. Zonderman, Thyroid hormones are associated with cognitive function: moderation by sex, race, and
depressive symptoms. J. Clin. Endocrinol. Metab. 98, 34703481
(2013)

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