Clinical Review

Hypothyroidism: Should we screen all pregnant women?

OBG Manag. 2004 May;16(5):33-45

What are the practical implications of recent studies linking maternal thyroid deficiency with impaired growth, adverse neurologic outcomes, and fetal death?

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References

1. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol(Oxf). 2003;59:282-288.

2. Blazer S, Moreh-Waterman Y, Miller-Lotan R, Tamir A, Hochberg Z. Maternal hypothyroidism may affect fetal growth and neonatal thyroid function. Obstet Gynecol. 2003;102:232-241.

3. Contempre B, Jauniaux E, Calvo R, Jurkovic D, Campbell S, de Escobar GM. Detection of thyroid hormones in human embryonic cavities during the first trimester of pregnancy. J Clin Endocrinol Metab. 1993;77:1719-1722.

4. Vulsma T, Gons MH, de Vijlder JJ. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to total organification defect or thyroid agenesis. N Engl J Med. 1989;321:13-16.

5. Oppenheimer JH, Schwartz HL. Molecular basis of thyroid hormone-dependent brain development. Endocr Rev. 1997;18:462-475.

6. Morreale De Escobar G, Obregon MJ, Escobar del Rey F. Is neurodevelopment related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab. 2000;85:3975-3987.

7. Kamijo K, Saito T, Sato M, et al. Transient subclinical hypothyroidism in early pregnancy. Endocrinol Jpn. 1990;37:397-403.

8. Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev. 1997;18:404-433.

9. Utiger RD. Maternal hypothyroidism and fetal development. N Engl J Med. 1999;341:601-602.

10. Allan WC, Haddow JE, Palomaki GE, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen. 2000;7:127-130.

11. Mandel SJ, Larsen PR, Seely EW, Brent GA. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med. 1990;323:91-96.

12. Usenko V, Lepekhin E, Lyzogubov V, Kornilovska I, Ushakova G, Witt M. The influence of low doses 131I-induced maternal hypothyroidism on the development of rat embryos. Exp Toxicol Pathol. 1999;51:223-227.

13. Lavado-Autric R, Auso E, Garcia-Velasco JV, et al. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest. 2003;111:1073-1082.

14. Man EB, Jones WS. Thyroid function in human pregnancy. V. Incidence of maternal serum low butanol-extractable iodines and of normal gestational TBG and TBPA capacities; retardation of 8-month-old infants. Am J Obstet Gynecol. 1969;104:898-908.

15. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341:549-555.

16. The Endocrine Society. The Endocrine Society issues recommendations in response to major hypothyroidism study. August 1999. Available at: www.endosociety.org/pubrelations/pressreleases/archives/1999/hypothyroid.cfm. Accessed March 26, 2004.

17. AACE Thyroid Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8:457-469.

18. American College of Obstetricians and Gynecologists. Thyroid disease in pregnancy. Clinical management guidelines for obstetrician-gynecologists. ACOG practice bulletin No. 37. Obstet Gynecol. 2002;100:387-396.

19. Lazarus JH, Wald NJ, Angele C, et al. The controlled antenatal thyroid screening study (CATS): first observations. Endocrine Abstracts. 2003;5:P262.-

20. Brent GA. Maternal thyroid function: interpretation of thyroid function tests in pregnancy. Clin Obstet Gynecol. 1997;40:3-15.

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Emerging research indicates that thyroid hormones play a key role in fetal brain development, and asymptomatic hypothyroidism during pregnancy may have an adverse effect on fetal growth and neurologic development. Findings published in the past year call our attention to the importance of identifying and adequately treating thyroid-deficient gravidas:

Maternal free thyroxine (FT4) concentration below the 10th percentile at 12 weeks is associated with significant impairment of psychomotor development at ages 1 and 2 years.¹
The average serum thyroid-stimulating hormone (TSH) and FT4 levels of neonates born to hypothyroid mothers were significantly higher than those of controls; birth weight and head circumference were significantly lower.²

But given the paucity of data on how maternal hypothyroidism affects the offspring, is universal screening justified? We review the evidence to date, present the current positions of 3 organizations, and offer recommendations for current clinical practice.

Maternal thyroid status is important throughout gestation

The fetal thyroid gland begins to develop at 3 weeks’ gestation; it concentrates iodine and synthesizes thyroid hormone after 10 to 12 weeks.

Prior to this, the mother provides the thyroid hormones through placental diffusion (see “How thyroid needs change during pregnancy”). Indeed, thyroid hormones have been detected in human coelomic and amniotic fluids as early as 8 weeks’ gestation, before the fetal thyroid starts to function.³

New perspective on role of maternal thyroid function. It was previously believed that the mother’s thyroid hormone supply to the fetus was irrelevant after 10 to 12 weeks. However, Vulsma et al⁴ demonstrated that substantial amounts of thyroxine (T4) are transferred from mother to fetus during late gestation. They discovered T4 in the cord blood of fetuses at term who were unable to synthesize T4 due to organification defects or thyroid agenesis. The T4 in these cases (noted at concentrations 25% to 50% of normal) was obviously of maternal origin.

How thyroid hormone needs change during pregnancy

Thyroid hormone requirement increases during pregnancy in normal women, to provide for the added maternal and fetal needs. Thyroxine (T4) requirement also may grow as a result of placental degradation and increased maternal T4 clearance.²⁰

Thyroid hormone turnover is altered during pregnancy, mainly in association with:

lowered iodide availability to the maternal thyroid gland,
increased serum thyroid-binding globulin (TBG) concentration, and
increased production of thyroid-stimulating factors by the placenta.

Maternal serum inorganic iodide levels decrease during pregnancy, possibly due to increased renal clearance of iodide—which stems from increased glomerular filtration rate, and transplacental transfer of iodide and iodothyronines.^8,21 The reduced circulating concentration of iodide leads to decreased availability of iodide to the thyroid gland, and results in a 10% to 20% increase of thyroid volume.²¹ This iodide loss has no clinical importance where iodine intake is sufficient, but may lead to hypothyroidism and goiter in regions of overt iodine deficiency.
The increase in the TBG serum concentration in pregnancy results from estrogen-induced increased synthesis and reduced hepatic clearance of TBG.

Most pregnant women are euthyroid by laboratory evaluation, and their TSH, free T4, and free T3 levels remain within normal values.

Thyroid hormones: Important to brain differentiation and development

In the mammalian embryo, thyroid hormones appear to regulate processes of neuronal proliferation, migration, synaptogenesis and myelination, though the precise mechanism is not fully understood.

Unlike T4, triiodothyronine (T3, the most potent thyroid hormone) does not readily penetrate the brain. Indeed, most brain T3 is produced locally from T4, after which it binds to nuclear thyroid hormone receptors. These in turn bind to specific DNA sequences in the regulatory region of target genes.⁵ A sufficient level of such receptors has been observed in the human fetus as early as 9 weeks’ gestation.

Information comes mostly from animal models, mainly rats. We must thus remain aware that the transfer of thyroid hormones from mother to embryo or fetus may differ between species,⁶ as may the stages of brain development before and after birth.

Hypothyroidism during pregnancy

The frequency of thyroid deficiency in pregnancy varies from 0.19% in Japan⁷ to 2.2% in Belgium⁸ and 2.5% in the United States.⁹

Hypothyroidism in pregnancy may be due to preexisting illness or a disease that evolves during pregnancy; in developed nations, the most common causes are Hashimoto’s thyroiditis, subacute thyroiditis, and surgical or radioactive ablation of the thyroid gland.

The hypothyroid state may be subclinical and can remain undiagnosed throughout pregnancy. The clinical manifestations of hypothyroidism (fatigue, sensitivity to cold, muscle irritability, cramps, constipation, paresthesia of the distal portion of the extremities, dry skin, and hair loss) may be masked in gestation as symptoms of pregnancy. Gestational hypothyroidism can be classified as overt (low FT4 values and elevated TSH) or subclinical (normal FT4 values and elevated TSH).