Thyroid hormones in pregnancy

Dr Suman Bijlani, MD, DGO, FCPS

Impact of thyroid on the female reproductive system

Relevant in menstruation, ovulation, fertility and pregnancy

Thyroid and pregnancy

• 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.

• Thyroid dysfunction affects 2–3% of pregnant women.

TBG during normal pregnancy (mean ± 2 SD) in 2-week intervals

Acta Endocrinol1982;100:504–11. © Society of the European Journal of Endocrinology

Feto-maternal unit and thyroid

THYROID ADAPTATION DURING NORMAL PREGNANCY

Thyroid hormone levels in pregnancy

Recommended trimester specific reference ranges for TSH

• Trimester TSH range

• First 0.1–2.5 mIU/L

• Second 0.2–3.0 mIU/L

• Third 0.3–3.0 mIU/L

Algorithm for the evaluation of hypothyroidism during pregnancy

Definitions

• Stagnaro-Green A, ert al. 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. 2011 Oct;21(10):1081-125.PMID

SCH is defined as a serum TSH between 2.5 & 10 mIU/L with a normal FT4 concentration.Women with a TSH concentration above the trimester-specific reference interval with a decreased FT4, and all women with a TSH concentration above 10.0 mIU/L irrespective of the level of FT4 are also considered to have OH.

Etiology of hypothyroidism in pregnancy

Iodine deficiency - Combined maternal and fetal hypothyroidism

• Iodine deficiency is, by a large margin, the most common preventable cause of mental retardation in the world. Without adequate maternal iodine intake, both the fetus and mother are hypothyroid, and if supplemental iodine is not provided, the child may well develop cretinism, with mental retardation, deaf-mutism and spasticity.

• The WHO recommends 250 μg/day of iodine in pregnancy and lactation to meet the increased demands.

Iodine deficiency in India

In India, the entire population is prone to IDD due to deficiency of iodine in the soil of the subcontinent and consequently the food derived from it. To combat the risk of IDD, salt is fortified with iodine. However, an estimated 350 million people do not consume adequately iodized salt. Of the 325 districts surveyed in India so far, 263 are IDD-endemic. The current household level iodized salt coverage in India is 91 per cent with 71 per cent households consuming adequately iodized salt.

Iodine deficiency disorders (IDD) control in India Chandrakant S. Pandav et al Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, Department of Social & BehavioralSciences, School of Public Health, Harvard University, Boston, Massachusetts, USA & **Department of Indian Coalition for Control of Iodine Deficiency Disorders, New Delhi, India October 5, 2011

Overt untreated hypothyroidism

• Fetal loss

• Gestational hypertension

• Placental abruption

• Neurodevelopmental delay

• Poor perinatal outcome

Subclinical hypothyroidism adverse outcomes

• At present, the majority of high-quality evidence suggests that SCH is associated with increased risk of adverse pregnancy outcomes (miscarriage, late fetal loss)

• The detrimental effect of SCH on fetalneurocognitive development is less clear. An association between maternal SCH and adverse fetal neurocognitive development is biologically plausible , though not clearly demonstrated.

SCH and neurocognitive development

• Data from a large, case–control study (Haddow et al) demonstrated a 7-point reduction in IQ among children born to untreated hypothyroid women when compared with euthyroid controls(in addition to delays in motor, language, and attention at 7–9 years of age). Similar retrospective data were previously published by Man and colleagues.

• Preliminary data from the Controlled Antenatal Thyroid Screening trials, presented at the International Thyroid Congress in 2010, have questioned these findings. Primary outcomes of the study were the mean IQ of children at 3.5 years and the percentage of children with an IQ < 85 at 3.5 years among children whose mothers were treated for SCH and/or isolated hypothyroxinemia as compared to children whose mothers were not treated. They found that there was no difference in mean IQ. However, the percentage of children with IQs < 85 was higher in the untreated group vs. the treated group (15.6% vs. 9.2%, p = 0.009).

• Between 50% and 85% of hypothyroid women being treated with exogenous LT4 need to increase dosing during pregnancy.

• Thyroxine should be increased by two additional doses per week (or 30%) on suspicion or confirmation of pregnancy in women already taking thyroxine.

• All treated hypothyroid women (currently receiving LT4) optimize thyroid status preconception. Maternal serum TSH concentration of <2.5 mIU/L is a reasonable goal for all such women.

• In pregnant patients with treated hypothyroidism, maternal serum TSH should be monitored approximately every 4 weeks during the first half of pregnancy because further LT4 dose adjustments are often required.

• Therefore, following delivery, maternal LT4 dosing should be reduced to prepregnancy levels, and a serum TSH assessed 6 weeks thereafter.

• There are no data to suggest that women with adequately treated SCH or OH have an increased risk of any obstetrical complication. Consequently, there is no indication for any additional testing or surveillance in pregnancies of women with either SCH or OH who are being monitored and being treated appropriately.

Controversy

• Universal versus targeted screening

• How to and whether to treat SCH

• How to manage the thyroid antibody positive euthyroid woman

• OH should be treated in pregnancy. The goal of LT4 treatment is to normalize maternal serum TSH values within the trimester-specific pregnancy reference range.

• Thyroid auto-antibodies were detected in ∼50% of pregnant women with SCH and in more than 80% with OH.

• There is insufficient evidence to recommend for or against screening all women for thyroid antibodies in the first trimester of pregnancy.

Management of hypothyroidism in pregnancy

Monitoring Hypothyroidismin Pregnancy

• Ideally women with hypothyroidism should be seen pre-pregnancy to ensure that they are euthyroid. They should also be encouraged to present as soon as they become pregnant in order that their thyroxine dose may be increased and TSH and FT4 are monitored regularly. For patients with established hypothyroidism the ideal monitoring regimen is thus:-

• Before conception (if possible)

• Test FT4 and TSH at diagnosis of pregnancy or at antenatal booking

• Test 2 weeks after the dose of T4 has been increased

• At least once in each trimester

• 2-6 weeks postpartum

• If TFTs are unstable refer to Consultant Endocrinologist as early as possible as growth scans may be required

• Reduce T4 treatment to pre-pregnancy dose at 2-6 weeks post-partum and recheck TSH/Free T4 6-8 weeks later

Should SCH be treated in pregnancy?

• SCH has been associated with adverse maternal and fetal outcomes. However, due to the lack of randomized controlled trials there is insufficient evidence to recommend for or against universal LT4 treatment in TAb−vepregnant women with SCH (Level I-USPSTF)

Should SCH be treated in pregnancy?

• Benefit of thyroxine treatment has been demonstrated for thyroid peroxidase antibody (TPOab) positive women with SCH, but there is little prospective data on intervention in TPOabnegative women. Until prospective data are available to guide management, some clinicians may choose to consider low dose thyroxinereplacement, which is safe in pregnancy, aiming for TSH values within the trimester specific reference ranges in all women with SCH.

Should SCH be treated in pregnancy?

• Women who are positive for TPOAb and have SCH should be treated with LT4. Level B-USPSTF

If pregnant women with SCH are not initially treated, how should they be monitored through gestation?

• Women with SCH in pregnancy who are not initially treated should be monitored for progression to OH with a serum TSH and FT4 approximately every 4 weeks until 16–20 weeks gestation and at least once between 26 and 32 weeks gestation. This approach has not been prospectively studied. Level I-USPSTF

Should isolated hypothyroxinemia be treated in pregnancy?

To date, no randomized, interventional trial of LT4 therapy has been performed in pregnant women with isolated hypothyroxinemia (this will change with the publication of the Controlled Antenatal Thyroid Study). Thus, because only limited data exist suggesting harm from isolated hypothyroxinemia and no interventional data have been published, the committee does not recommend therapy for such women at present.

Isolated hypothyroxinemia

Isolated hypothyroxinemia is defined as a normal maternal TSH concentration in

conjunction with FT4 concentrations in the lower 5th or 10th percentile of the reference range.

Isolated hypothyroxinemia

• It is debated whether isolated hypothyroxinemia causes any adverse effects on the developing fetus.

• Pop and colleagues reported a decrease in psychomotor test scores among offspring born to women with FT4 indices in the lowest 10th percentile.

• Li et al. observed a similar reduction in the IQ of the offspring whose mothers experienced either hypothyroidism or isolated hypothyroxinemia during the first trimester.

• Henrichs and colleagues recently published data from the Generation R study, conducted in the Netherlands. This prospective, nonrandomized investigation evaluated communication development in children born to women with isolated hypothyroxinemia. A 1.5- to 2-fold increased risk of adverse findings (at 3 years of age) was associated with maternal FT4 in the lower 5th and 10th percentiles.

Hyperthyroidism in pregnancy

Etiology of hyperthyroidism in pregnancy

Low TSH in pregnancy

Hyperthyroidism (Graves' disease)

Stimulation of the TSH receptor by hCG (first trimester of pregnancy, hyperemesis gravidarum, molar pregnancy/choriocarcinoma)

Exogenous thyroid hormone

Thyroiditis

Autonomous thyroid nodule

Dopamine, glucocorticoids

Secondary hypothyroidism

Serum TSH and hCG as a function of gestational age

J Endocrinol Metab 1990;71:276–87. © The Endocrine Society.

Significance of an “Undetectable” TSH in Pregnancy

• Some “normal” pregnancies are associated with a mild transient “physiological” hyperthyroidism during the first trimester. This is caused by very high levels of hCG, that have a mild stimulatory effect on the thyroid. In approximately 3% of pregnancies the TSH will be suppressed to <0.01mU/L and FT4/FT3 may be slightly elevated. It is essential to exclude Graves’ disease in such pregnancies and as such TSH-receptor antibodies should be (TRAbs) measured and an endocrine opinion sought.

Gestational thyrotoxicosis

• The appropriate management of women with gestational hyperthyroidism and hyperemesis gravidarum includes supportive therapy, management of dehydration, and hospitalization if needed.

• ATDs are not recommended for the management of gestational hyperthyroidism.

Hyperthyroidism in pregnancy

• In the presence of a suppressed serum TSH in the first trimester (TSH <0.1 mIU/L), a history and physical examination are indicated. FT4 measurements should be obtained in all patients. Measurement of TT3 and TRAb may be helpful in establishing a diagnosis of hyperthyroidism.

Algorithm for management of hyperthyroidism during pregnancy

NL, within the reference interval; ↓, decreased; ↑, increased.

Hyperthyroid pre-pregnancy

• The optimal time to conceive is once a euthyroid state is reached.

• Prepregnancy counseling is imperative, and use of contraception until the disease is controlled is strongly recommended.

• Prior to conception, a hyperthyroid patient may be offered ablative therapy (131I or surgery) or medical (anti-thyroid drugs) therapy.

Ablative therapy

• If TrAB titres are high and the prospective mother is planning a pregnancy in the next 2 years, surgery is better than 131I as the latter causes increase in antibody titres which may remain for several months.

• After surgery, pregnancy should be postponed for 6 months to allow time for adjustment of LT4 dose for optimal control.

Course of Grave’s Disease in pregnancy

• In the first trimester of pregnancy some women with Graves' disease will experience an exacerbation of symptoms. Afterwards, there is a gradual improvement in the second and third trimesters.

• Typically, this will result in a need to decrease the dose of ATDs. Discontinuation of all ATD therapy is feasible in 20%–30% of patients in the last trimester of gestation.

• The exceptions are women with high levels of TRAbvalues, in which cases ATD therapy should be continued until delivery.

• Aggravation of symptoms often occurs after delivery.

Goals of management

• Maintaining euthyroid status with minimal effective dose of antithyroid drugs

• Prediction and prevention of neonatal hypo-and hyperthyroidism

• Prevention of postpartum flare of thyrotoxicosis

• Optimising fetal outcome in uncontrolled cases

Anti-thyroid drugs

• PTU drug of choice in first trimester

• Switch to MMI after first trimester

• Free T4 and TSH should be measured approximately every 2–4 weeks at initiation of therapy and every 4–6 weeks after achieving the target value.

Hyperthyroidism in pregnancy

Patients with detectable TRAbs

• Measure TrAB between 24-28 weeks. If negative, the test need not be repeated.

• Fetal surveillance with serial growth scans should be performed in women who have uncontrolled hyperthyroidism and/or women with high TRAb levels (greater than three times the upper limit of normal).

• Mother needs to be watched for flare of Grave’s thyrotoxicosis postpartum.

• Neonates of TrAB positive mothers need to be followed up for thyroid function. Cord blood should be taken for TSH, FT4 and Total T3 at delivery and the baby should have a resting heart rate checked and remain in hospital for at least 24 hours. Further management should be carried out on the advice of the Paediatrician

Postpartum management

• Moderate doses of antithyroid medications (ie. carbimazole 25–30 mg/day or PTU less than 300 mg/day) appear to be safe for the breastfed infant.

• Monitoring of thyroid function in breastfeeding infants of mothers taking antithyroid medications (particularly those taking high doses) should be considered.

Postnatal management

Many women will not require to return to their CBZ/PTU post-natal but all should be seen in the

Endocrine Clinic 8-12 weeks post partum or sooner if they have symptoms.

Postpartum thyroiditis

Postpartum thyroiditis

Postpartum thyroiditis

Management

• ATDs are not recommended for the treatment of the thyrotoxic phase of PPT.

• Following the resolution of the thyrotoxic phase of PPT, TSH should be tested every 2 months (or if symptoms are present) until 1 year postpartum to screen for the hypothyroid phase.

• Women with a prior history of PPT should have an annual TSH test performed to evaluate for permanent hypothyroidism.

• Women who are symptomatic with hypothyroidism in PPT should either have their TSH level retested in 4–8 weeks or be started on LT4 (if symptoms are severe, if conception is being attempted, or if the patient desires therapy). Women who are asymptomatic with hypothyroidism in PPT should have their TSH level retested in 4–8 weeks.

• If LT4 is initiated for PPT, future discontinuation of therapy should be attempted. Tapering of treatment can be begun 6–12 months after the initiation of treatment. Tapering of LT4 should be avoided when a woman is actively attempting pregnancy, is breastfeeding, or is pregnant.

Controversy

• How to manage the thyroid antibody positive euthyroid woman

The thyroid antibody positive euthyroid woman

1 in 10 women of childbearing age with normal thyroid function have underlying thyroid

autoimmunity, which may indicate reduced functional reserve, but antenatal antibody

screening is not routine. Screening for TPOaband TSH is advisable in women with recurrent

miscarriage.

The thyroid antibody positive euthyroid woman

• A two–threefold increased risk of spontaneous miscarriage • The risk of preterm birth is approximately doubled • A risk factor for perinatal death• However, prospective intervention data are limited and the

decision to treat with thyroxine or monitor for overt or subclinical hypothyroidism is controversial.

• In these cases, monitoring of thyroid function every 4 weeks during the first half of pregnancy and once between 26 and 32 weeks gestation has been suggested. In the case of recurrent miscarriage, it is acceptable to treat with low dose thyroxine with judicious monitoring of thyroid function as there is potential benefit from this safe treatment.

Controversy

• Universal versus targeted screening

Screening recommendation for thyroid disease in pregnancy

High risk attributes for thyroid dysfunction

• A history of thyroid dysfunction or surgery

• Family history of thyroid disease

• Goitre

• Antithyroid antibodies present

• Symptoms or signs of hypothyroidism

• Women with type 1 diabetes

• History of miscarriage or preterm delivery

• Autoimmune disorder

• Infertility

• Prior head or neck irradiation

• Morbid obesity

• Age 30 years or older

• Treatment with amiodarone/ lithium

• Recent exposure to iodinated contrast

Take home messages

• Serum TSH is a more accurate indication of thyroid status in pregnancy than any alternative method.

• Pregnancy specific reference ranges should be used to guide diagnosis and monitoring of thyroid conditions in pregnancy.

Take home messages

• The World Health Organization recommends a daily intake of iodine 250 µg during pregnancy and lactation.

• Hypothyroid states should be treated with thyroxineaiming for a TSH <2.5 prior to conception and in the first trimester and TSH <3.0 for the second and third trimesters.

• Gestational thyrotoxicosis needs to be differentiated from Graves disease and rarely requires thionamidetreatment.

• It is important to maintain a high index of suspicion for postpartum thyroiditis, especially in those with known thyroid antibodies or autoimmune conditions.

A new study finds that not only low but also high maternal thyroid hormone levels during early pregnancy may significantly lower the infant's IQ later in childhood. The study results suggest that the common practice of treating pregnant women who have mild thyroid hormone deficiency may pose unexpected risks to the developing baby's brain.

High-normal thyroid hormone level in pregnancy may affect fetal brain developmentMarch 6, 2015:The Endocrine Society