Definition of hypothyroidism in pregnancy

• TSH > 10 mU/L with normal or low free T4

• TSH >2.5 mU/ L with low free T4

Overt hypothyroidism

• TSH >2.5 mU/L with normal free T4

Subclinical hypothyroidism (SH)

• Normal TSH and free T4 below 5th centile

Isolated hypothyroxinaemia

Prevalence of hypothyroidism in pregnancy • Prevalence of TSH >6 mUI/ml in 2000 women between

15 - 18 weeks of gestation

• Prevalence of H- according to TSH trimester-specific reference intervals in 117,892 pregnant women

Klein RZ et al. Clin. Endocrinol. 1991 35:41

Prevalence TPOab+

SH 2.2% 58 %

Overt H 0.3% 90%

Prevalence TPOab+ Gestational hypothyroidism 15.1% 65%

Blatt AJ. et al. National Status of Testing for Hypothyroidism during Pregnancy and Postpartum .J Clin Endocrinol Metab 97: 777–784, 2012.

Risk groups for hypothyroidism Women > 30 years of age

Presence of other autoimmune diseases

Previous cervical irradiation

Use of drugs that interfere with thyroid function (amiodarone, lithium)

Use of iodinated contrast media

Brenta G. et al. Clinical practice guidelines for the management of hypothyroidism. Arq Bras Endocrinol Metab. 2013;57/4

Risk groups for hypothyroidism Presence of circulating TPOAb

Personal history of previous thyroidectomy or thyroid disease

Family history of thyroid disease

Goiter and signs and symptoms of hypothyroidism

Brenta G. et al. Clinical practice guidelines for the management of hypothyroidism. Arq Bras Endocrinol Metab. 2013;57/4

Pregnancy complications of subclinical hypothyroidism (SH)

• 35 pregnancies with SH

• Without adequate treatment 71%: miscarriage and 7% premature delivery

• With adequate treatment no excess complications observed

Abalovich et al. Thyroid

12:63, 2002

• 25 766 pregnancies

• Prevalence SH 2.3% at week 20

• RR of abrupto placentae 3x

• RR of premature delivery before week 34: 1.8x

Casey et al. Obst-

Gynecol 105:239,

2005

Thangaratinam S et al. BMJ 2011 May 9;342

Association between thyroid autoantibodies and miscarriage and preterm birth:

meta-analysis of evidence.

• 52% relative risk reduction in miscarriages with levothyroxine (relative risk 0.48, 0.25 to 0.92; P=0.03).

• 69% relative risk reduction in preterm birth (relative risk 0.31, 0.11 to 0.90).

Conclusions of this metanalysis…

• In women with normal thyroid function and thyroid autoantibodies the risk of miscarriage is more than tripled and the risk of preterm birth is doubled

• Treatment with levothyroxine can halve the risk of miscarriage in women with normal thyroid function and thyroid autoantibodies

Thangaratinam S et al. BMJ 2011;342:bmj.d2616

In the Generation R study…

• Cohort study from the Netherlands

• 3,659 children and their mothers.

• Maternal hypothyroxinemia was associated with a higher risk of expressive language delay and higher risk of nonverbal cognitive delay

• An association between increasing maternal TSH in early pregnancy and behavioural problems in their offspring.

Henrichs J, et al. J Clin Endocrinol Metab 2010; 95: 4227–4234.

Ghassabian A,. et al. Pediatr Res 2011; 69: 454–459.

Moreover… in the Generation R study…

• Prenatal enrollment between 2002 and 2006.

• Six years later, parents reported behavioral and emotional symptoms in 4,039 children (79%) using the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist and/or the Social Responsiveness Scale (SRS).

• Severe maternal hypothyroxinemia (n=136) was associated with an almost 4-fold increase in the odds of having a probable autistic child

Roman GC et al. Ann Neurol.2013 Nov;74(5):733-42.

Condition ATA 20111 ES 20122 LATS 20133 ETA 20144

Overt hypothyroidism

LT4 recommended

LT4 recommended

LT4 recommended

LT4 recommended

Subclinical hypothyroidism (TPOAb+)

LT4 recommended

LT4 recommended

LT4 recommended

LT4 recommended

Subclinical hypothyroidism (TPOAb-)

Insufficient evidence to

recommend for or against LT4

LT4 recommended

Insufficient evidence to

recommend for or against LT4

LT4 recommended

HypoT4 Should not be

treated Not issued

Not issued

May be considered in the

first trimester

Conclusions: Recommendations for treting hypothyroidism in pregnancy

1. Stagnaro-Green A, et al. Thyroid. 2011, 2. De Groot L, et al. J Clin Endocrinol Metab. 2012; 3. Brenta et al. Arq Bras Endocrinol Metab. 2013, 4. Lazarus J, et al. Eur Thyroid J. 2014

Treatment of hypothyroidism in pregnancy according to international guidelines

Abalovich M, et al.Thyoid 2013;23(11):1479-83

Newly diagnosed hypothyroidism during pregnancy

Levothyroxine dose to achieve TSH trimester target

2.5

2.0

1.5

1.0

0.5

0.0

2.33 ± 0.59

1.31 ± 0.36

Ug

/Kg

/day

overt hypothyroidism

n: 13

subclinical hypothyroidism

n: 64

Diagnosis Dosis (mcg/kg/day)

Overt Hypothyroidism 2.33

Subclinical Hypothyroidism • TSH between 2.5 - 4.2

uUI/L

• TSH between 4.2 – 10 uUI/L

1.20

1.42

85% of pregnant women met their TSH target in the same trimester they were started on LT4.

90% did not require further adjustments.

Abalovich M, et al.Thyoid 2013;23(11):1479-83

• When planning to conceive, the dose of LT4 should be adjusted to maintain plasma TSH

< 2.5 mU/L. Grade D.

• Hypothyroid women who become pregnant and do not have immediate access to the physician must increase the dose of LT4 by 25%-30% or increase by two additional LT4 tablets per week. Grade B.

Brenta G. et al.. Clinical practice guidelines for the management of hypothyroidism. Arq Bras Endocrinol Metab. 2013;57/4.

Recommendation 26

After delivery…

• 523 women without known thyroid disease.

• 65 (12.4%) with SCH during pregnancy defined as TSH greater than 3 mU/l.

• 75.4% had normal thyroid function when studied 5 years after delivery

• Only 24.6% had persistent high TSH (TSH >4.5 mU/l after pregnancy)

• Women with TPOAb and TSH greater than 5 mU/l in pregnancy were more likely to have persistently

elevated TSH.

Shields BM et al. J Clin Endocrinol Metab 2013; 98:E19411–E1945.