By La Lura White MD

Maternal Fetal Medicine

A normal pregnancy results in a number of important reversible physiological and hormonal changes that alter thyroid structure and more importantly function.

Understanding these change are important to interpreting, identifying and managing of thyroid disease in pregnancy.

The thyroid gland is located in the anterior neck below the hyoid bone.

Consist of two lobes connected by an isthmus.

Each lobe is divided into lobules that contain 20-40 follicles each.

Follicles consist of follicular cells which surround a glycoprotein material (colloid).

Thyroid hormone is produced by the follicular cells.

The production of thyroid hormone functions on a negative feedback loop.

The hypothalamus releases thyrotropin-releasing hormone (TRH) from paraventricular nucleus.

Stimulates the anterior pituitary gland to secrete thyroid-stimulating hormone (TSH).

This in turn causes the thyroid gland to produce and release thyroid hormone.

The thyroid gland produces thyroxine (T4), deiodinated primarily by the liver to its active form, triiodothyronine (T3).

The thyroid gland also produces a small amount of T3 directly.

Increase in dietary iodine from 80-100 mcg/d to 200 mcg./day.

Dietary iodine uptake by thyroid gland is reduced to iodide.

This is the rate limiting step for hormone synthesis.

Iodide binds to thyroglobulin catalyzed by thyroid peroxidase to produce monoidotyrosine (MIT) or di-iodotyrosine (DIT).

T4: coupling 2 DIT. T3: coupling DIT+MIT. Stored bound to thyroglobulin as a colloid.

Under TSH control, thyroglobulin is digested and T3 30 mcg/d) and T4 (90 mcg./d) released into capillary circulation.

T4(thyroid origin) and T3(T4 deiodinated by liver and kidneys to T3, only 20% thyroid production)

99% hormone bound mostly to thyroxine-binding globulin (TBG).

Other binding proteins include thyroxine-binding pre-albumin and albumin.

Physiological Changes in ThyroidStructure

20% increase in thyroid gland size due to hyperplasia and increased vascularity.

T4 production increases approximately 50% starting in early pregnancy.

Rarely thyroid gland enlargement causes goiter unless iodine-deficient.

Plasma iodide levels decrease as a result of fetal iodide use, placental losses and increased maternal renal clearance resulting in a deficit.

Physiological Changes in Thyroid Function: Influenced by two hormones: hCG

and estrogen.

hCG: Shares some structural homology

with thyrotropin (TSH).

Binds to thyroid gland TSH receptors, exhibit weak thyrotropic stimulation with subsequent hormone production, especially first trimester.

Week from the Last Menstrual Period Amount of HCG in mIU/ml

3 5 -50 4 3 - 426 5 19 - 7,340 6 1,080 - 56,500 7 - 8 7,650 - 229,000 9 - 12 25,700 - 288,000 13 - 16 13,300 - 254,000 17 - 24 4,060 - 165,400 25 - 40 3,640 - 117,000

Peaks end first trimester and then declines.

Increased hCG will stimulate thyroid hormone production and produce a negative feedback, suppress and decrease levels of thyroid stimulating hormone (TSH) in the first trimester.

Serum TSH drops to undetectable levels in up to 15% of normal pregnancies.

Mistakenly diagnose hyperthyroidism with physiologic decrease in TSH and increase in thyroid hormone.

By the second trimester, serum TSH levels return to normal

Estrogen

Stimulates the liver to produce thyroid binding proteins, especially (TBG), major transport protein for thyroid hormone and extend its half-life.

Significant increase in secretion TBG (levels ~200 %).

Results in lower free thyroid hormone and stimulate positive feedback H-P-T axis.

Reduced peripheral TBG degradation rate. 80% TBG (greater affinity) 15% TBPA (greater

binding). Increase in total but not free thyroid hormone

which remains within normal limits.

Gestational Transient Thyrotoxicosis)

Seen in 10% to 15% of pregnant women during early pregnancy. Mildly increased free T4 and suppressed TSH early in pregnancy

not due to intrinsic thyroid pathology. Characterized by mild or no symptoms, and resolves

spontaneously by the second half of pregnancy. No evidence of thyroid autoimmunity, when evaluating thyroid

antibodies (thyroid peroxidase antibodies ) or immunoglobulin's (thyroid-stimulating immunoglobulins).

Associated with hyperemesis gravidarum. Also with hydatidiform mole, secondary to high levels of hCG that

lead to TSH receptor stimulation. Rarely symptomatic, no treatment with anti-thyroxine

medications.

Fetal thyroid: Form as a midline

outpouching of the anterior pharyngeal floor, migrates and reaches its final position by 7 weeks.

Lateral contributions from the 4th and 5th pharyngeal pouches give its bilateral shape by week 8-9.

Fetal Thyroid

The fetal thyroid begins concentrating iodine by 10 to 12 weeks and produces thyroid hormones (T4 and T3) between 15 and 18 weeks of gestation, with the fetal pituitary also producing TSH beginning around this time.

Although fetal thyroid is functional, it still depends on adequate amounts of iodide from mother.

Placental transfer of maternal T4,T3 is believed to occur prior to fetal thyroid hormone synthesis and continue thereafter.

May be the only source of thyroid hormone during early fetal life, and it is important to maintain normal maternal thyroid status for brain maturation of the developing child.

Hypothyroidism

Complicates 1-3/1000 pregnancies.

Most common cause of primary hypothyroidism in women of child-bearing age is chronic autoimmune thyroiditis (Hashimoto’s thyroiditis).

Painless inflammation with progressive enlargement of the thyroid gland (diffuse lymphocytic infiltration, fibrosis, parenchymal atrophy, eosinpohilic changes).

Normal

Hashimoto’s thyroiditis

Other causes primary hypothyroidism (thyroid gland)

Endemic iodine deficiency Ablative radioiodine therapy Thyroidectomy

Secondary hypothyroidism (pituitary) Lymphocytic hypophysitis Hypophysectomy

Tertiary hypothyroidism (hypothalamus) Rare

Hypothyroid Symptoms: (similar to pregnancy complaints)

Fatigue Constipation Cold intolerance Muscle cramps

Insomnia Weight gain Hair loss Carpel tunnel Voice changes Intellectual

slowness

Signs of hypothyroiddism:

Peri-orbital edema Dry skin Goiter Prolonged relaxation

phase of DTR’s

Maternal/Fetal Risk

Infertility Spontaneous abortion Pre-eclampsia Placental abruption Low birth weight Prematurity Stillbirth

Fetal Risk: Impaired neurodevelopment

Initial phase of the fetal brain (neuronal multiplication, migration, and organization) during the second trimester, the supply of thyroid hormones to the growing fetus is almost exclusively of maternal origin.

During the next phase of fetal brain development (glial cell multiplication, migration and myelinisation), from the third trimester up to 2-3 years postnatally, the supply of thyroid hormones to the fetus is essentially of fetal origin.

While severe maternal hypothyroidism during the second trimester will result in irreversible neurologic deficits, maternal hypothyroxinemia occurring at later stages will result in less severe, and also partially reversible, fetal brain damage.

Diagnosis

TSH (most sensitive): Non-pregnant normal range for TSH (.45-

4.5 mIU/ml). 95% have levels <2.5 mIU/ml., and those

with levels 2.5-4.5 mIU/ml are at greater risk for overt disease.

T4: (nl 0.7-1.8 ng/dl)

For diagnosis of hypothyroidism, elevated TSH and decreased T4.

Management: Levothyroxine sodium

(Synthyroid) 1-2 mcg/kg/d (100 mcg/d). Measure TSH every 6-8

weeks (.5-2.5 mIU/L). T4 can be helpful to

determine response to treatment.

Adjust medication dose on 25-50 mcg increments.

Newly diagnosed hypothyroid patient, a full replacement dose of levothyroxine should be instituted immediately, assuming there are no abnormalities in cardiac function.

To normalize the T4 pool more rapidly (when clinically required), therapy may be initiated by giving for two-three days a levothyroxine dose which is two-three times the estimated final replacement daily dose.

This will allow more rapid normalization of the circulating T4 levels and a more rapid return to the euthyroid state.

Thyroxine requirements of women with preexisting hypothyroidism increase during pregnancy and about 30-50% will need adjustment of their medication:

estrogen-induced increased TBG concentrations increased volume of distribution increased placental T4 degradation and transport

Check TSH levels on first prenatal visit Adjustment of levothyroxine dosage should be

implemented as early as possible during gestation and certainly within the first trimester.

Those well-controlled can have TSH levels checked each trimester.

Drugs that interfere with levothyroxine: absorption: (cholestyramine, ferrous sulfate,

aluminum hydroxide antacids) metabolism: (phenytoin, carbamazepine,

rifampin)

After delivery: Levothyroxine dose should progressively be

reduced to its pregestational level. TSH concentration rechecked at the 6th-8th week

postpartum visit. Patient can breastfeed.

Subclinical hypothyroidism:(elevated TSH/normal T4)

Some suggest treat to restore TSH to normal range due to possible increase in fetal wastage or impaired neurodevelopment but no consensus or ACOG recommended.

Isolated hypothyroxinemia: (normal TSH/lowT4)

May suggest central hypothyroidism (pituitary macroadenoma, pituitary surgery or radiation).

Associated with iodine insuffiency causes autoregulatorty response that leads to low T4.

Possible treatment for impaired fetal neurodevelopment with central hypothydoidism conditions otherwise no treatment.

New guidelines of the American Thyroid Association (ATA) reported online July 25, 2010

Women who are already receiving thyroid replacement therapy should increase their dose by 25% to 30% when they become pregnant.

Women with subclinical hypothyroidism in pregnancy who are not initially treated should be monitored for progression to overt hypothyroidism.

Serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels should be measured approximately every 4 weeks until 16 to 20 weeks' gestation and at least once between 26 and 32 weeks' gestation.

In the first trimester, normal range for TSH level is 0.1 to 2.5 mIU/L; this level increases to 0.2 to 3.0 mIU/L in the second trimester and 0.3 to 3.0 mIU/L in the third trimester.

During pregnancy and lactation, the minimal suggested daily recommended allowance for iodine is 250 μg.

The risk for fetal hypothyroidism may increase when total daily iodine intake from diet and/or supplements is or exceeds 500 μg.

Congenital hypothyroidism Cretinism: "Jonny druitt syndrome" Dull look Puffy face Thick tongue that sticks out Choking episodes Constipation Dry, brittle hair Jaundice Lack of muscle tone Low hairline Poor feeding Short height Sleepiness Sluggishness

Other caues congenital hypothyroidim:

Thyroid agenesis, inborn errors of metabolism, maternal blocking antibodies, congenital pituitary and hypothalamic hypothyroidism.

Neurological impairment if not treated before 3 months postnatal.

Neonatal Hypothyroidism

Hyperthyroidism

Hyperthyroidism affects 2/1000 pregnancies

Graves disease (diffuse toxic goiter) is the most common form of overt hyperthyroidism.

Organ-specific autoimmune process where thyroid stimulating autoantibodies attach to and activate TSH receptors.

In some with history of Graves disease, thyroid stimulating autoantibodies activity may decrease with chemical remission.

Other etiologies: Functional adenoma or toxic nodular

goiter, thyroiditis or excess thyroid intake.

Symptoms

Nausea/Vomiting Weight loss Nervousness Heat intolerance Insomnia Breathlessness Diaphoresis Fatigue Anxiety

Signs: Thyromegaly Diffuse goiter Exophthalmos Pretibial myxedema Increased cardiac output Systolic flow murmur Resting pulse >100

(tachycardia)

Maternal Risk:

Congestive heart failure Thyroid storm Pre-eclampsia

Fetal Risk

Early pregnancy loss (increased risk congenital anomalies untreated)

IUGR LBW PTB

Neonatal hyperthyroidism 1-2% Thyrotropin receptor-stimulating

antibodies (TSHR-SAb), can cross the placenta, and cause an overactive thyroid in the fetus.

small head circumference, prominent forehead

Enlarged thyroid (goiter) Difficulty breathing High blood pressure Tachycardia Arrythmia Emesis Diarrhea

Hyperthyroidism: Diagnosis

Depressed serum TSH (< .45mIU/L) Elevated T4 (>1.8 ng/dl) Rare T3 thyrotoxicosis (check for if

depressed TSH but normal T4) Check TSH receptor antibodies, may be

increased risk neonatal hypothyroidism)

Antithyroid drugs: inhibit iodination of thyroglobulin and thyroglobulin synthesis:

Propylthiouracil(PTU): Also some blocking T4 to T3 conversion Crosses the placenta less readily Initial daily dose 100-600 mg, suggest start

300 mg/d 100-150 mg q 8 hr. 50 mg. qid 150 mg/d Maintain 50mg bid

Methimazole :10-40 mg daily dose

Management: Maintain T4 in upper normal range using

lowest possible dose. May be able to discontinue 32-34 weeks. Improvement in T4 in 4 weeks Normalization TSH 6-8 weeks

Methamizole: ? Aplasia cutis, esophageal and choanal atresia

PTU: severe liver toxicity

Thiomide Risk: Rash, hepatitis,drug fever 10% transient leukopenia .1-0.2% agranulocytosis

(acute onset, not dose related but others feel related to higher doses and increased maternal age)

Other treatments: (unable to take medication)

Surgery: subtotal thyroidectomy after 1st trimester hypothyroidism recurrent laryngeal nerve paralysis

Radioactive iodine ablation is contraindicated and women should avoid pregnancy for at least 6 months

Monitor closely after delivery.

Can get recurrence or aggravation of symptoms first few months.

Check TSH and T4 6 weeks postpartum.

Can breast feed, most medication protein bound.

Acute, life-threatening exacerbation of Acute, life-threatening exacerbation of thyrotoxicosisthyrotoxicosis

1-2% of patients with hyperthyroidism 1-2% of patients with hyperthyroidism progress to thyroid stormprogress to thyroid storm

Precipitated by a physiologically stressful Precipitated by a physiologically stressful event, labor, delivery, C/Section, infectionsevent, labor, delivery, C/Section, infections

If untreated, thyroid storm may be fatalIf untreated, thyroid storm may be fatal is is as high as 20%as high as 20%

FeverFever TachycardiaTachycardia TremorTremor DeliriumDelirium ComaComa

NauseaNausea VomitingVomiting DiarrheaDiarrhea DehydrationDehydration

Up to one half of patients presenting to the ED in thyroid storm Up to one half of patients presenting to the ED in thyroid storm report a dramatic weight loss of more than 40 lb.report a dramatic weight loss of more than 40 lb.

Tachycardia (out of proportion to the fever)Tachycardia (out of proportion to the fever) Diaphoresis (often profuse)Diaphoresis (often profuse) Widened pulse pressureWidened pulse pressure Congestive heart failure (may be a high Congestive heart failure (may be a high

output failure)output failure) Atrial fibrillation (may be refractory to Atrial fibrillation (may be refractory to

attempted rate control with digitalis; attempted rate control with digitalis; converts after antithyroid therapy in converts after antithyroid therapy in 20-50% of patients20-50% of patients

ShockShock

1 gm PTU p.o. or crushed in NG tube the continued 200 mg. q. 6 hours or 600 mg. b.i.d.

One hour later give Sodium iodide 500-1000mg IV q. 8 (block release T3 and T4)

oral 5gtts KI or 10 gtts Lugol’s solution q. 8 hrs.If hx iodide anaphylaxis, give lithium carbonate

300 mg. q. 6 hrs.

Propranolol: 40 mg.p.o q 6 hr. (1-2 mg IV) for tachycardia >120 bpm.

Dexamethasone 2 mg q. 6 hrs. X 4 doses (block peripheral conversion T4 to T3)

Fluid and nutritional support Treat hyperthermia

Post-partum Thyroditis

3-6 months postpartum. Up to 10% women first year after childbirth. Secondary to thyroid autoantibodies. Depression, memory impairment,

carelessness.

Risk: Family hx of thyroid or other autoimmune

diseases, 25% +IDDM will develop disease Transient hypo or hyper thyroidism

Two Phases: 1) 1-4 months post delivery: glandular

disruption leads to hormone release (4% transient thyrotoxicosis)

abrupt; develop small, painless goiter, fatigue, palpitations

antithyroid meds ineffective, can give b-blockers

2) 4-8 months postpartum (2-5% develop hypothyroidism)

treat with thyroxine 6-12 months

Most recover within 12 months 30% permanent hypothyroidism

Subclinical Hyperthyroidism

Depressed TSH with normal T4 1.7% of pregnancies More common in iodine deficient areas Long-term sequale:

Osteoporosis, cardiovascular morbidity, overt thyrotoxicosis, thyroid failure.

No adverse pregnancy affects

Obstetrix Professor

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