Thyroid and Pregnancy Loss

Prof. Andrea R. Genazzani , MD, PhD, HcD, FRCOG, FACOG

President of the International Society of Gynecological Endocrinology (ISGE) President of the European Society of Gynecology (ESG) General Secretary of the International Academy of Human Reproduction (IAHR) Chairman of the FIGO Working Group on Post Reproductive Health (FIGO) Department of Clinical and Experimental Medicine University of Pisa, Italy -

Declaration for Conflict of Interest

Consultant and occasional presentations for : Abbott, Alfa-Sigma, Bionorica, Endoceutics, Exeltis, Grunenthal, Mithra, MSD, Se-Cure Pharma, Serelys Pharma,

The hypothalamic-pituitary-thyroid axis

The hypothalamic-pituitary-

thyroid axis follows the rules

similarly to all the other

endocrine axes.

TRH receptors are distributed

throughout the brain and

apparently in certain areas

TRH acts as a

neurotransmitter.

TRH is a potent stimulus to

TSH despite a half-life in

blood of less than 1 minute.

T3 and T4 modulates TSH

secretion.

TRH

TSH

T4 - T3

PRL

GnRH

LH - FSH

aromatase

gonadal steroids

SHBG

INTERACTION BETWEEN HYPOTHALAMIC-PITUITARY AXES

Thyroid and reproduction

Thyroid diseases, both hypo or hyper function, may lead to reproductive disturbances.

menstrual irregularities oligomenorrhea

amenorrhea menorrhagia

hyperandrogenism hyperestrinism

chronic anovulation PCOS

Estrogens and TSH secretion

Ramey JN et al., J Clin Endocrinol Metab , 1975

Such control seems to

be exerted mainly at

the hypothalamus-

pituitary levels.

Women taking oral

contraceptive have a

greater TSH response

to TRH, compared to

euthyroid control

women.

Gonadal steroids modulate the control of thyroid function.

•Infertile patients present a greater

prevalence of thyroid autoimmunity than

fertile patients

•Increasing evidence suggest that

spontaneous miscarriage is increased in

women positive for antithyroid antibodies,

regardless of their thyroid function status

Interactions between thyroid and ovary

•The presence of thyroid autoimmunity has

also been related to recurrent embryo

implantation failure and poor prognosis

undergoing assisted reproductive

techniques Poppe K et al., Thyroid 2002.

Stagnaro-Green A et al., JAMA 1990.

Prummel MF et al., Eur J Endocrinol 2004.

De Carolis C et al., Am J Reprod Immunol 2004.

A normal secretion of circulating thiroid

hormones is crucial for normal

reproductive function

Changes in fT3 cause

Gonadotropin altered secretion

Abnormal menstrual cyclicity and consequent

reduction of fertility

T4 promotes angiogenesis

in follicular vascularization in rats through an

up-regulation of mRNA expression of

major angiogenetic factors

Interactions between thyroid and ovary

Oocyte maturation needs normal levels of

thyroid hormones

Essential to obtain:

Good fertilization rates

Embryo development

and

Interactions between thyroid and ovary

Gonadotropin-induced increase in estradiol

during IVF cycles may cause thyroxin-

binding-globulin production to increase.

By consequence, the bioavailability of free

thyroxin decreases.

This would determine a subclinical

hypothyroidism, which in turn may play a role

in the failure of the embryo implantation

Physiopathology

Altered balance between free/bound T4

Altered balance

between free/bound

T and/or E2

“Thyroid Autoimmunity” means

the presence of circulating Auto-

antibodies directed against

thyroid, specifically of antibodies

anti-Tireoperoxidase

(anti-TPO) and/or anti-

Tireoglobulin (anti-TG), with or

without a clinical thyroid

dysfunction

Thyroid AutoImmunity

(TAI) is the more prevalent

autoimmune disease,

concerning about 5 - 20 % of

female population in

reproductive age (principal

cause of thyroid disease)

Many studies in literature have showed a connection

between thyroid autoimmunity (TAI) and infertility.

However, TAI can be present in complete absence of

clinically manifested disease.

Thyroid Autoimmunity

Indeed, active immunization of

mice with human Tg resulted in

the production of anti-Tg

autoantibodies and pregnancy

failure manifested by an

increased fetal resorption rate.

AUTOIMMUNITA’ ANTITIROIDEA Thyroid Autoimmunity:

Animal models

Matalon ST et al., Hum Reprod 2003;

Lee YL et al.,Fertil Steril 2009;

Recent experiments in animals

have shown that antithyroid

antibodies may interfere with

oocyte fertilization and embryo

development.

In a similar experimental

mouse model of

autoimmune thyroiditis,

anti-TPO antibody positivity

was associated with

reduced fertility and litter

size because of a higher

incidence of fetal loss.

Anti-TPO antibodies were

actually evidenced on the

embryo surface.

Thyroid Autoimmunity:

Animal models

Matalon ST et al., Hum Reprod 2003;

Lee YL et al.,Fertil Steril 2009;

Some researchers

studied the effects of

anti-TPO autoantibodies

on embryo development

before and during

implantation.

Antibodies bind embryo

early before

implantation, and they

might hamper embryo

development in early

division steps.

AUTOIMMUNITA’ ANTITIROIDEA Thyroid Autoimmunity

what about pregnancy?

• Thyroid dysfunction and thyroid autoimmunity are prevalent among

women at reproductive age and are associated with adverse

pregnancy outcomes.

• Subclinical hypothyroidism may be associated with ovulatory

dysfunction and adverse pregnancy outcome.

• Even minimal hypothyroidism can increase rates of miscarriage and

fetal death and may also have adverse effects on later cognitive

development of the offspring.

• Pregnancy affects thyroid economy with significant changes in iodine

metabolism, serum thyroid binding proteins, and the development of

maternal goiter, especially in iodine-deficient areas.

• The thyroid gland and gonadal axes interact continuously before and

during pregnancy.

• Autoimmune thyroid disease is present in 5-20% of unselected

pregnant women.

• Isolated hypothyroxinemia has been described in approximately 2% of

pregnancies, without serum TSH elevation and in the absence of

thyroid auto antibodies.

• There is an association of:

• Preeclampsia

• Anemia

• Low birth weigh

• Stillbirth

• Rarely, congestive heart failure can occur

• Miscarriage

• All antithyroid drugs cross the placenta and may potentially affect fetal

thyroid function.

Physiology of Thyroid: Iodine

need of iodine incerases 50%

Yarrington and Pearce, Clinic Obstet and Gynecol 2011

Increase of gland

volume 10-20%

THYROID FISIOLOGY IN PREGNANCY

Gestational transient

hyperthyroidism

clinical approach

Why (do not) studying thyroid

disease in pregnancy?

CONs :

• Today succesfully

treated

• Amelioration during

pregnancy

• Fetus usually

euthyroid

PROs :

• Common in

pregnancy

• Much more common in

women (why?)

• Not being

Endocrinologist-

addicted

HYPERTHYROIDISM TSH:

f-T4:

TSI = thyroid stimulating antibodies

TBII = TSH-binding inhibitory antibodies

PTU = propylthiouracil

MMI = methimazole

IMPACT ON PREGNANCY OUTCOME:

• Preeclampsia x4,7 (Millar 1994, II-2)

• Gestational diabetes x1,8 (Aggarawal 2014, II-2)

• Preterm labor x1,7 (Aggarawal 2014, II-2)

• LBW x9,2 (in donne trattate x2,3) (Millar 1994, II-2)

• Stillbirth x8,4 (Aggarawal 2014, II-2)

(95% Graves

disease)

Prevalence:

0,2%

Thioamides

TRAb = TSH-R antibodies

Fetal hyperthyrodism

Fetal hypothyroidism

HYPERTHYROIDISM TSH:

f-T4:

In most cases of maternal hyperthyroidism, the neonate is euthyroid

Routine evaluation of fetal thyroid function (fetal thyroid US

assessment or Umbilical BS) is NOT RECOMMENDED (ACOG 2015)

HYPERTHYROIDISM TSH:

f-T4:

“EITHER PTU OR MMI CAN BE USED to treat pregnant

women with overt hyperthyrodism” (ACOG 2015)

PTU for I trimester, followed by switch to MMI for II & III trimester (ATA &

AACE)

“The LEVEL OF fT4 should be monitored in pregnant women treated

for hypertyroidism” (ACOG 2015)

“The goal is treatment with the LOWEST POSSIBLE

THIOAMIDE DOSE to maintain fT4 LEVELS SLIGHTLY ABOVE OR

IN THE NORMAL-HIGH RANGE, regardless of TSH levels” (ACOG 2015)

“Serum fT4 concentration are measured EVERY 2-4 WEEKS after

initiation of therapy” (ACOG 2015)

HYPERTHYROIDISM TSH:

f-T4:

DOSE

PTU (Propycil®) – 150-300mg x3/die

MMI (Tapazole®) 5mg cpr – 5-10mg x3/die

Thyroidectomy is reserved for selected cases, and is best performed during the II trimester

Thyroid ablation with 131-I is controindicated in during pregnancy.

Not associated with adverse pregnancy outcome (Casey 2006 III, Tudela 2012 II-3, Wilson 2012 II-3)

Only treated in post-menopausal women or after 65y

“TREATMENT of pregnant women with subclinical hyperthyroidism is NOT WARRANTED” (ACOG 2015)

SUBCLINICAL

HYPERTHYROIDISM TSH:

f-T4: ✔ Prevalence:

1,7%

IMPACT ON PREGNANCY OUTCOME (when it comes out) :

• Stillbirth x13,4 (Su 2011 II-2)

• LBW x9 (Su 2011 II-2), 31% (Davis 1988 III)

• Preeclampsia (Casey 2016 III, Yazbeck 2012 III), 44% (Davis 1988 III)

• Placental abruption (Casey 2016 III, Yazbeck 2012 III), 19% (Davis 1988 III)

• Neuropsychological and cognitive impairment in the child (Pop 1999 II-2, Haddow 1999 II-2)

“Adequate thyroid HORMONE REPLACEMENT THERAPY during pregnancy MINIMIZES THE RISK of adverse outcomes”

(ACOG 2015 from Abalovich 2002 III)

HYPOTHYROIDISM TSH:

f-T4: Prevalence: 0,2-

1% Mostly Hashimoto tyroiditis

Begin with levothyroxine (Eutirox®) 1-2mcg/kg daily (ATA & AACE)

Women with prior thyroidectomy or I-131 ablation may require higher dosages (25% dose increase at pregnancy confirmation) (ACOG2015)

“ASSESSMENT OF THERAPY in pregnant women with

hypothyroidism is guided by measurement of TSH LEVELS” (ACOG 2015)

“TSH levels should be measured AT 4 TO 6 WEEK INTERVALS, and levothyroxine DOSE ADJUSTED BY 25-50mcg increments until TSH becomes normal” (ACOG 2015)

HYPOTHYROIDISM TSH:

f-T4:

IMPACT ON PREGNANCY OUTCOMES:

• Placental abruption x2,1 (Maraka 2016 II-2), x3,3 (Casey 2005 II-2)

• Preterm birth (<34w) x1,7 (Casey 2005 II-2)

• Neonatal admission in ICU x1,8 (Casey 2005 II-2)

• Pregnancy loss x2 (Maraka 2016 II-2)

• PROM x1,4 (Maraka 2016 II-2)

• Neonatal death x2,6 (Maraka 2016 II-2)

FASTER trial (Clearly-Goldman 2008 II) did not found association with adverse obstetrical

outcomes

CATS trial (Lazarus 2012 I) IQ score at 3 years of age of the offspring not improved by

treatment with levothyroxine

“There is no evidence that identification and treatment of subclinical hypothyroidism during

pregnancy improves these outcomes” (ACOG 2015 from Lazarus 2012 I)

SUBCLINICAL

HYPOTHYROIDISM TSH:

f-T4: ✔ Prevalence: 2-5%

Negro et al., BMJ 2014

Goal of the therapy

Normalize TSH levels according to the specific trimester levels, as soon

as possible

Eutiroidism before pregnancy

Hypothiroidism: starting-dose

2014

ISOLATED

HYPOTHYROXINEMIA TSH:

✔

f-T4:

• IQ score at 3 year of age of the offspring not

improved by treatment with levothyroxine (CATS

trial 2012 I)

• Not associated with adverse pregnancy outcome

(Casey 2005 II-2)

• Preterm labor x1,6 (FASTER trial II)

• Gestational diabetes x1,7 (FASTER trial 2008 II)

• Fetal macrosomia x2 (FASTER trial 2008 II)

EUTHYROID AUTOIMMUNE

THYROID DISEASE TSH & f-T4:

✔

anti-TPO: + Prevalence: 4%

IMPACT ON PREGNANCY OUTCOMES:

• Early pregnancy loss x2-5 (Thangaratinam 2011 II-2).

• Preterm labor x2 (Stagnaro-Green 2009 II-2)

• Placental abruption x3 (Abbassi-Ghanavati 2010 II)

“Universal screening for thyroid autoantibodies in pregnancy currently is not recommended” (ACOG 2015, AACE, ATA)

• Personal history of thyroid disease

• Symptoms of thyroid disease

• Significant goiter

• Distinct nodules

• Familiar history of thyroid disease

• Known to have anti-TPO Ab

• Type 1 diabetes mellitus

• Age >30 y

• Prior thyroid surgery

• Use of amiodarone or lithium, or recent administration of iodinated contrast agent

WHICH WOMEN SCREEN

IN PREGNANCY?

ACOG 2015

More from

UpToDate

1. Screen (with TSH) women with known thyroid disease or

symptomatic women

2. Treat hyperthyroidism with the lowest possible dose of

tioamides, according to fT4 levels

3. Treat hypothyroidism with levothyroxine, according to

TSH levels

4. Monitoring thyroid status each 4-6 week

CONCLUSION