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Clinical Reviews


What you need to know about thyroid disorders in pregnancy

Managing overt disorders is straightforward, but even subclinical disease warrants heightened scrutiny

May 2007 · Vol. 19, No. 05

IN THIS ARTICLE

Until recently, thyroid dysfunction was thought to have little influence on pregnancy as long as it was treated, and management was straightforward. That was before case-control studies in prominent journals suggested an association between even subclinical hypothyroidism and impaired neonatal neurodevelopment.1-4

The risk associated with hyperthyroidism in pregnancy is less clear. Currently, it is believed to cause no adverse effects; the low thyroid-stimulating hormone (TSH) resolves in most women within 4 to 12 weeks.

As for the nonpregnant state, there is no agreement between the American College of Physicians and its British counterpart as to whether isolated, subclinical hyperthyroidism leads to morbidity or mortality, although some investigators have found an excess risk of atrial fibrillation and possibly increased bone loss in postmenopausal women. Treatment of hyperthyroidism in non-pregnant women is recommended only if low TSH persists after 4 to 12 weeks and the level is less than 0.1 mIU/L.5

This article discusses the detection and management of thyroid disease in pregnancy, concentrating on 2 representative cases. (See TABLE 1, for a list of the full spectrum of thyroid disorders.)

TABLE 1

The spectrum of thyroid disorders is wide

Hypothyroidism

Hashimoto’s or subacute thyroiditis

Subclinical hypothyroidism

Subclinical hypothyroxemia

Postpartum thyroiditis

Secondary hypothyroidism

  • Hypothalamic dysfunction
  • Radioactive iodine therapy
  • Thyroidectomy
  • Iodine deficiency
  • TSH receptor resistance/mutation

Hyperthyroidism

Grave’s disease

Subclinical hyperthyroidism

Thyroid storm

Secondary hyperthyroidism

  • TSH-producing pituitary adenoma
  • Toxic multinodular goiter
  • Toxic adenoma
  • Subacute thyroiditis
  • Metastatic follicular thyroid cancer
  • Iodine excess
  • Factitious/iatrogenic
  • Thyroid hormone resistance syndrome
  • Struma ovarii
  • Gestational trophoblastic neoplasia
  • Hyperemesis gravidarum

CASE 1: History of Graves’ disease

S.H., 32, is 6 weeks’ pregnant with her first child. She has a history of Graves’ disease, and underwent radioactive iodine treatment 10 years ago. She then became hypothyroid and has been on levothyroxine replacement for the past 9 years. She visits her endocrinologist annually and reports good control on 125 μg daily of oral levothyroxine sodium.

How should her pregnancy be managed?

When the mother has a history of Graves’ disease, regardless of her current thyroid state, 1% to 5% of newborns develop hyperthyroidism due to transplacental passage of thyroid-stimulating immunoglobulins (TSI). Fetal or neonatal hyperthyroidism is associated with fetal tachycardia (heart rate >160 bpm), poor growth, goiter, craniosynostosis, and advanced bone age. Therefore, fetal growth and heart rate should be monitored throughout pregnancy in these women. Investigators have published monograms on fetal thyroid measurement,6 and even argued that Doppler ultrasonography can differentiate between fetal hypo- and hyperthyroidism caused by drugs or disease processes.7 However, measurement of TSI levels (poor predictive value) and ultrasonography for fetal goiter (low yield) are controversial.

Another important consideration: The requirement for thyroxine hormone increases by approximately 30% in women on thyroid supplementation during pregnancy.8 This has been demonstrated in more than 9 studies, with athyrotic women experiencing greater increases than women with autoimmune hypothyroidism.9 The need for thyroxine increases as early as 5 weeks’ gestation and plateaus by 16 weeks.

Because hypothyroxemia or hypothyroidism (clinical or subclinical) may be associated with adverse neurodevelopment in the newborn, I recommend increasing the dosage of levothyroxine at the first encounter with this patient to 150 μg/day (<25% dosage increase). I also suggest measuring the baseline TSH level, if no reading is available from the past 3 months. If baseline TSH is less than 2.5 mIU/L, the dosage increase is probably adequate. If the TSH exceeds 2.5 mIU/L, however, I would ask the patient to take 1 extra pill (125 μg) on 2 days of the week (>30% dosage increase) and measure TSH again 4 to 6 weeks later (thyroxine takes 5 weeks to equilibrate after a change in dosage). Once the dosage has been adequately adjusted, I would monitor TSH every 6 to 8 weeks until delivery. At that time, the dosage should be reduced to the prepregnancy level, with TSH measured again in 4 to 6 weeks to confirm that the dosage is adequate.

Levothyroxine absorption is hampered by ferrous sulfate, aluminum hydroxide antacids, proton-pump inhibitors, and cholestyramine. Levothyroxine should be ingested at least 4 hours before or after the prenatal vitamin. The metabolism of levothyroxine is altered by phenytoin, carbamazepine, and rifampin.

Subclinical hypothyroidism can progress to overt disease

The majority of women with hypothyroidism are asymptomatic, with only 20% to 30% having any complaints, usually nonspecific (TABLE 2). Women with 1 or 2 symptoms are no more likely to have abnormal thyroid function tests than are asymptomatic women.

Overt hypothyroidism is primarily diagnosed with laboratory tests—specifically, low free thyroxine (FT4) or free triiodothyronine (FT3), or both, resulting in elevated TSH levels.

If untreated, overt hypothyroidism is associated with significant morbidity in both the nonpregnant and pregnant states (TABLE 3). Levothyroxine is easily administered and well tolerated, with no to few adverse effects with appropriate follow-up.10

In women with subclinical hypothyroidism, only 1 of the thyroid function tests is elevated—either elevated TSH with normal free thyroid hormone levels (mild thyroid failure) or normal TSH with low FT4 levels (hypothyroxemia). Most cases of mild thyroid failure are thought to be related to thyroid dysfunction, whereas hypothyroxemia is usually associated with a deficiency of iodine.

Subclinical hypothyroidism can occur in women with a history of thyroid disease, after surgery or radioactive iodine therapy for toxic goiter, or as the result of an inadequate dosage of thyroid medication. It can also occur in women with no history of thyroid dysfunction, detected in routine testing in women with no symptoms or with nonspecific complaints that could be related to thyroid disease. Experts agree that women with secondary subclinical disease should be treated to achieve a euthyroid state because approximately 5% per year will develop overt disease. Considerable controversy clouds management of women with primary subclinical hypothyroidism.

Subclinical hypothyroidism is more common among white women (~67%) than among black women.

TABLE 2

Know these signs and symptoms of thyroid dysfunction

HYPOTHYROIDISM

HYPERTHYROIDISM

Fatigue

Resting tremors

Constipation

Hyperdefecation

Somnolence

Insomnia

Cold intolerance

Heat intolerance

Hair loss

Diaphoresis

Depression

Nervousness

Decreased libido

Palpitations

Menstrual irregularities

 

Weight gain despite poor appetite

Weight loss

Dry skin

Warm, moist skin

Deafness

Ophthalmopathy

Hoarseness

Sinus tachycardia

Paresthesia

 

Carpal tunnel syndrome

 

Periorbital puffiness

 

Slow cerebration or movement

 

Slowing ankle jerk

Hyperreflexia

Goiter

Thyromegaly

TABLE 3

Consequences of untreated thyroid dysfunction are significant

HYPOTHYROIDISM

HYPERTHYROIDISM

Nonpregnant state

Hyperlipidemia

Atrial fibrillation

Atherosclerosis

Congestive heart failure

Osteoporosis

 

Neuropsychiatric disorders

Neuropsychiatric disorders with or without dementia/Alzheimer’s disease

Reduced functional status and quality of life

Reduced functional status and quality of life

Pregnancy

Spontaneous abortion

Spontaneous abortion

Preterm delivery <32 weeks

Preterm labor

Low birth weight

Low birth weight

Perinatal morbidity and mortality

Stillbirth

Preeclampsia/gestational hypertension

Preeclampsia

Anovulation

 

Cesarean delivery

 

Postpartum hemorrhage

 

Placental abruption

 

Nonreassuring fetal heart rate tracing

 

Impaired neurodevelopment

 

Subclinical disease

 

Risk factor for overt disease

Risk factor for overt disease

Subclinical hyperthyroidism is more elusive

Overt hyperthyroidism can be detected through symptom-based screening (TABLE 2).

Subclinical hyperthyroidism is defined as low TSH with normal thyroid hormone levels. The pituitary appears to be more sensitive to the presence of thyroid hormones than to their absence. Subclinical hyperthyroidism is most common in black women and smokers. Approximately 50% of women with subclinical disease will have normal TSH levels several weeks to 1 year later.

Because subclinical hyperthyroidism can occur in up to 20% of women on thyroid replacement therapy, the dosage should be adjusted to achieve a euthyroid state.

CASE 2 Diabetes, with a family history of hypothyroidism

M.H., 30, is 12 weeks’ pregnant with her second child and reports a 12-year history of diabetes. Before she became pregnant, she was taking insulin, with HbA1C=8.5%. Her history includes a mother with hypothyroidism.

How should she be managed?

Besides the obvious need for good diabetes control, this case merits screening for thyroid dysfunction, as the patient has 2 risk factors (TABLE 4).

One prominent controversy of the 21st century is whether all pregnant women should undergo routine screening for hypothyroidism. The controversy extends to screening all women of childbearing age.

TABLE 4

Risk factors for hypothyroidism include other autoimmune disorders

Family history of thyroid disease

More than 3 symptoms

History of postpartum thyroid disease

Type 1 diabetes mellitus

Recurrent spontaneous abortions

Unexplained intrauterine fetal demise

Other autoimmune disorders

  • Vitiligo
  • Addison’s disease
  • Pernicious anemia
  • Multiple sclerosis
  • Rheumatoid arthritis
  • Sjögren’s disease

$64,000 question: Should all women be screened?

Screening would involve testing thyroid function in women with no history and few or no signs and symptoms of thyroid dysfunction. Such screening could be population-based (using special methods to recruit, contact, and follow patients) or case-finding (performed on patients who present for unrelated reasons). The decision to screen a woman who is pregnant or planning to conceive should be based on many factors, most notably whether treatment prevents impaired neonatal neurodevelopment and preterm delivery.

A mother’s elevated TSH level can have lasting effects in the child

Haddow and colleagues1 measured the IQ of 47 children, ages 7 to 9 years, whose mothers had had an elevated serum TSH concentration in the second trimester, 15 children whose mothers had high serum TSH values in combination with low thyroxine levels in the second trimester, and 124 children whose mothers had normal TSH values. None of these children had hypothyroidism at birth. The children of the women with an elevated TSH concentration had lower IQs. Interestingly, the group with hypothyroxemia was not evaluated at the time, and the mean FT4 level was low in the entire group, suggesting overt hypothyroidism rather than subclinical disease.

In a study from the Netherlands, Pop and associates2 found impaired psychomotor function in 22 infants (age 10 months) whose mothers had had FT4 below the 10th percentile at 12 weeks of gestation, compared with 194 infants whose mothers had normal readings. When these children were reevaluated at 2 years, no neurodevelopmental delay was found in the infants whose mothers had a spontaneously increased free thyroxine level after the first trimester.

There is much speculation about precisely when thyroid hormone is critical for fetal brain development. The study by Pop and associates2 would suggest it is important after the first trimester. That study also recommends exogenous thyroxine for FT4 values below 0.96 ng/mL (12 pmol/L).

In Italy, Vermiglio and coworkers11 conducted behavioral and neuropsychological testing in 27 children at ages 18 to 36 months and again at 8 to 10 years. Mothers of 16 of these children were from a moderately iodine-deficient area (group A), and the mothers of 11 children were from a marginally iodine-sufficient area and were monitored with thyroid function tests in the first trimester (group B). Attention-deficit and hyperactivity disorders were more prevalent in group A.

Two studies published in 2006 also suggest that maternal free thyroxine levels in the first trimester of pregnancy correlate with impaired neonatal behavior at 3 months, and impaired mental development at ages 6, 9, and 12 months.3,4

How common?


Thyroid disorders affect approximately 5% of the general population, two thirds of them women.17 Subclinical hypothyroidism occurs in an additional 4.3%, and subclinical hyperthyroidism in 0.7%.

In pregnancy, subclinical disease is present in 3.6% of women; overt hypothyroidism, in 2.5%; and overt hyperthyroidism, in 0.2%. In addition, thyroid disease affects 5% to 9% of postpartum women.14

No consensus on whom to test or what test is best

There is no clear agreement about which population should be targeted for screening or what test to use. Most medical societies do not recommend routine screening, including the American College of Obstetricians and Gynecologists, which recommends TSH testing only in women with a history of thyroid disease and in women with “symptoms” (but does not specify which symptoms or how many symptoms warrant testing). A majority of organizations agree that all high-risk women should be tested when pregnancy is planned or as soon as pregnancy is confirmed.

TABLE 5

Comparison of screening recommendations highlights lack of consensus (and, in pregnancy, the absence of guidance)

YEAR

ORGANIZATION

NONPREGNANT STATE

PREGNANCY

1994

American Association of Clinical Endocrinologists (AACE), American Academy of Family Physicians

Periodic assessment via thyroid function tests in older women

No recommendation

1998

American College of Physicians

Office screening of women >50 years of age

No recommendation

2000

American Thyroid Association (ATA)

Measure TSH every 5 years in women age 35 and older (probably men also)

No recommendation

2002

American College of Obstetricians and Gynecologists

Measure TSH every 5 years in women age 65 and older

No screening recommended

2003

Institute of Medicine

Screening is not cost-effective in Medicare population

No recommendation

2004

United States Preventive Services Task Force

Routine screening of children and adults is not recommended

No recommendation

2004

AACE, ATA, the Endocrine Society Consensus Group

No population-based screening, but “aggressive case finding” in women at high risk and those over age 60

Do not support routine testing; recommend “aggressive case finding” and screening pregnant women at high risk

Proponents of routine screening argue that it may limit health risks to children and save money in the long run, and they point out that thyroid disease is easy to treat with pills. Opponents note that no cost-benefit analysis has been performed, the benefits of treating mild disease are unclear, and screening a large population could be a significant expense ($40–100 per person) and would necessitate a lifelong commitment to daily medication in asymptomatic patients.

Continued...
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