Symposium francophone

d’endocrinologie de IASI

Symposium of Clinical Endocrinology

6 – 8 may 2009, IASI

Pregnancy and Hypothyroidism:

Disadvantages for Mother and Child

P.Bottermann, Munich

Pregnancy and Hypothyroidism

Disadvantages for Mother and Child

-------------------------------------------

general prevalence in pregnant women

- overt hypothyroidism 0,3 – 0,5 %

autoimmune thyreoiditis ~ 80 %

- subclinical hypothyroidism 2 – 3 %

autoimmune thyreoiditis ~ 55 %

--------------------------------------

Thyroid autoantibodies (TPO) at all

in pregnant women: 5 – 15 %

Chapter 1 – Mother

Pregnancy and Hypothyroidism

Disadvantages for Mother and Child

----------------------------------------------

Decreased fertility

34% become pregnant

11% in case of overt hypothyroidism

89% in case of subclinical hypothyroidism

Increased risk for early and late complications

Abortion

Anemia

Gestational hypertension

Placental abruption

Postpartal hemorrhages

! Adequate thyroxine treatment decreases these risks !

Hypothyroidism - known before pregnancy

Optimal substitution with thyroxine

-------------------------------------------------

During pregnancy thyroxine dosage has to be elevated at 30 – 50 %

The increase of estrogen secretion after conception induces an increase in

TBG production.

The TBG- and therefore the TBG-T4 compartment become enlarged.

The euthyroid pregnant women increases the T4 production until a new

steady state/ balance.

The daily need for iodine increases from 150 µg to 250 µg.

But why it is necessary to elevate the substitution dosage?

What happens in euthyroid women during pregnancy ?

Pregnancy and Hypothyroidism

Disadvantages for Mother and Child

---------------------------------------------

What can we learn from the

pathophysiology of the mother for the child

First, let us look to the fetal development

Chapter 2 - Child

Fetal Brain and Thyroid Development

The fetal thyroid begins to work during the second trimester of

pregnancy.

In the first half of pregnancy thyroid hormone (T4) comes from the

mother; in the second half more and more thyroid hormone (T4) is

added from the fetal thyroid.

Look only to the lower part of this picture

Fetal Brain and Thyroid Development

The fetal thyroid begins to work during the second trimester of

pregnancy.

In the first half of pregnancy thyroid hormone (T4) comes from the

mother; in the second half more and more thyroid hormone (T4) is

added from the fetal thyroid.

It is important to note that for the developing organs (brain included) T3

is necessary.

For sufficient fetal generation of T3 sufficient maternal T4 must be

supplied.

Very early during fetal life deiodinases are detectable for local

generation of T3 (intracellulary) from T4

Early maternal hypothyroxinemia J. Clin. Invest. 111:1073–1082 (2003)

alters histogenesis and cerebral cortex

cytoarchitecture of the progeny Rosalía Lavado-Autric,1 Eva Ausó,2 José Victor García-Velasco,2 María del Carmen Arufe,1

Francisco Escobar del Rey,1 Pere Berbel,2 and Gabriella Morreale de Escobar1

…that maternal hypothyroxinemia clearly results in an alteration of neuronal

migration during neocorticogenesis…

…… availability to the developing brain of maternal T4 is of greater

importance than that of T3, because T3 in the fetal brain is almost entirely

dependent on its local generation from T4 and not on the uptake of

circulating T3….

Case 1: During pregnancy a severe alimentary iodine deficiency exists.

(Mother cannot generate sufficient thyroid hormone. Not enough

iodine for placental transfer from mother to fetus.

Not enough iodine for the fetal thyroid to produce sufficient

amounts of thyroid hormone.)

Child:

endemic cretinism

What happens?

Case 1: During pregnancy a severe alimentary iodine deficiency exists.

(Mother cannot generate sufficient thyroid hormone. Not enough

iodine for placental transfer from mother to fetus.

Not enough iodine for the fetal thyroid to produce sufficient

amounts of thyroid hormone.)

Child: endemic cretinism

Case 2: During pregnancy mother without any problems.

(Mother: TSH, T4 and T3 are normal; euthyroidism)

Child at birth quite normal/euthyroid;

but after 2-4 weeks more and more development of typical signs

of hypothyroidism

congenital hypothyroidism (1: ~3333)

Case 1: During pregnancy a severe alimentary iodine deficiency exists.

(Mother cannot generate sufficient thyroid hormone. Not enough

iodine for placental transfer from mother to fetus.

Not enough iodine for the fetal thyroid to produce sufficient

amounts of thyroid hormone.)

Child: endemic cretinism

Case 2: During pregnancy mother without any problems.

(Mother: TSH, T4 and T3 are normal; euthyroidism)

Child at birth quite normal/euthyroid;

but after 2-4 weeks development of typical signs of

hypothyroidism

congenital hypothyroidism (1: ~3333)

Case 3: During pregnancy overt or subclinical hypothyroidism

(Mother has hypothyroxinemia)

Child:

mentally retardation

Early maternal hypothyroxinemia J. Clin. Invest. 111:1073–1082 (2003)

alters histogenesis and cerebral cortex

cytoarchitecture of the progeny Rosalía Lavado-Autric,1 Eva Ausó,2 José Victor García-Velasco,2 María del Carmen Arufe,1

Francisco Escobar del Rey,1 Pere Berbel,2 and Gabriella Morreale de Escobar1

…that maternal hypothyroxinemia clearly results in an alteration of neuronal

migration during neocorticogenesis…

……also supports previous conclusions that availability to the developing

brain of maternal T4 is of greater importance than that of T3, because T3 in

the fetal brain is almost entirely dependent on its local generation from T4

(4, 44) and not on the uptake of circulating T3….

Click on image to view larger version.

Figure 1. The "inside-out" gradient of cortical lamina is established by neurons migrating farther as development proceeds. Late-born

neurons migrate past early-born neurons, forming six layers. Cortical neurons migrate along scaffolds established by radial glia, which are

attached to the basal lamina of the ventricular zone and extend through to layer I. Cajal-Retzius neurons in layer I are the first neurons to

populate the mantle of the cortex, and they produce and secrete Reelin, which is involved in terminating migration of neurons as they climb

the scaffold. The article by Lavado-Autric et al. (1) indicates that thyroid hormone plays a role in the process of neuronal migration.

Specifically, rats born to dams with moderately low thyroid hormone have "blurred" cortical lamina, and many neurons do not migrate to their

normal destination. Moreover, the action of thyroid hormone in this migration occurs during fetal development. The authors employed this

system to show that maternal hypothyroxinemia can produce specific abnormalities in the cytoarchitecture of the cortex during fetal brain

development. RG, radial glia; SC, subcortical white matter; BL, basal lamina; VI, layer VI. Adapted with permission from ref. 21.

Maternal Thyroid Deficiency during Pregnancy and Subsequent

Neuropsychological Development of the Child

James E. Haddow, M.D., Glenn E. Palomaki, B.S., Walter C. Allan, M.D., Josephine R. Williams, George J. Knight,

Ph.D., June Gagnon, M.A., Cheryl E. O'Heir, M.Ed., Ed.S., Marvin L. Mitchell, M.D., Rosalie J. Hermos, M.P.H.,

Susan E. Waisbren, Ph.D., James D. Faix, M.D., and Robert Z. Klein, M.D.

ABSTRACT

….We then located 47 women with serum thyrotropin concentrations at or above the 99.7th

percentile….

…. Their seven-to-nine- year-old children….,

…..The full-scale IQ scores of their children averaged 7 points lower than those of the 124

matched control children (P=0.005); 19 percent had scores of 85 or less.

Conclusions Undiagnosed hypothyroidism in pregnant women may adversely

affect their fetuses; therefore, screening for thyroid deficiency during pregnancy

may be warranted.

JCEM - Volume 341:549-555 August 19, 1999 Number 8

Low maternal free thyroxine concentrations during early pregnancy

are associated with impaired psychomotor development in infancy*

Victor J. Pop et al. Clinical Endocrinology (1999) 50, 149–155

Clinical Endocrinology (2003) 59, 282–288,

Maternal hypothyroxinaemia during early pregnancy and

subsequent child development: a 3-year follow-up study Victor J. Pop*, Evelien P. Brouwers*, Huib L. Vader†,

Thomas Vulsma‡, Anneloes L. van Baar§ and Jan J. de Vijlder¶

Summary

OBJECTIVE

To evaluate the impact of maternal hypothyroxinaemia

during early gestation (fT4 below the lowest tenth percentile

and TSH within the reference range: 0·15–2·0 mIU/l) on infant

development, together with any subsequent changes in fT4 during

gestation.

RESULTS

Children of women with hypothyroxinaemia

at 12 weeks’ gestation had delayed mental and motor

function compared to controls: …..

CONCLUSIONS

Maternal hypothyroxinaemia during

early gestation is an independent determinant of a

delay in infant neurodevelopment. However, when fT4

concentrations increase during pregnancy in women

who are hypothyroxinaemic during early gestation,

infant development appears not to be adversely affected.

Chapter 3:

What shall we do tomorrow

CLINICAL PRACTICE GUIDELINE

Management of Thyroid Dysfunction during Pregnancy

and Postpartum: An Endocrine Society Clinical Practice Guideline Marcos Abalovich, Nobuyuki Amino, Linda A. Barbour, Rhoda H. Cobin, Leslie J. De Groot,

Daniel Glinoer, Susan J. Mandel, and Alex Stagnaro-Green

Conclusions: Management of thyroid diseases during pregnancy requires

special considerations because pregnancy induces major changes

in thyroid function, and maternal thyroid disease can have adverse

effects on the pregnancy and the fetus. Care requires coordination among

several health care professionals. Avoiding maternal (and fetal) hypothyroidism

is of major importance because of potential damage to fetal

neural development, an increased incidence of miscarriage, and preterm

delivery. Maternal hyperthyroidism and its treatment may be accompanied

by coincident problems in fetal thyroid function. Autoimmune

thyroid disease is associated with both increased rates of miscarriage, for

which the appropriate medical response is uncertain at this time, and

postpartum thyroiditis. Fine-needle aspiration cytology should be performed

for dominant thyroid nodules discovered in pregnancy. Radioactive

isotopes must be avoided during pregnancy and lactation. Universal

screening of pregnant women for thyroid disease is not yet

supported by adequate studies, but case finding targeted to specific

groups of patients who are at increased risk is strongly supported. (J Clin Endocrinol Metab 92: S1–S47, 2007)

Messages for the daily practice

Look for women at risk, especially in childbearing age,

- History of thyroid diseases as hyper- or hypothyrodism, goiter,

struma resection, family history of thyroid diseases,

infertility or preterm delivery,

Risk of thyroid diseases in other autoimmune diseases.

antiTPOAb during or after a former pregnancy (PPTD)

- for overt or subclinical hypothyroidism

Treat with thyroxine

Look for compensatory T3 overproduction as a sign of a relative

iodine deficiency.

(TSH normal; imbalance in the normal range between T3 (higher)

and T4 (lower.)

Treat with iodine – or perhaps, to be on the safe side, with tyroxine.

at all:

Be aware of a possible alimentary iodine deficiency

Treat with 200 µg iodine during pregnancy and breast feeding.

Multumesc frumos