Increased Levothyroxine Requirements in Pregnancy — Why, When, and How Much?
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《新英格兰医药杂志》
Those with sufficiently long memories must be somewhat bemused by the successive controversies surrounding the treatment of primary hypothyroidism, a condition viewed by many as simple, satisfying to manage, and very much within the purview of the primary care physician, rather than the specialist. The development of sensitive assays for measuring thyrotropin has led to a reduction in levothyroxine doses; in most patients, a dose of only 100 to 125 μg daily restores serum thyrotropin levels to the reference range, thereby satisfying the 1990 recommendations of the American Thyroid Association,1 which have since been reinforced.2 There is no consensus, however, about whether treatment with "a little too much" levothyroxine, resulting in a low or undetectable serum thyrotropin concentration, is detrimental in the long run.3 Nor is there agreement about the effectiveness of combination treatment with levothyroxine and triiodothyronine, prescribed in an attempt to reproduce normal thyroid secretion more closely.4 In addition, there is now concern that even borderline maternal hypothyroxinemia early in pregnancy may compromise fetal neuropsychological development,5 inevitably raising the prospect of screening for changes in thyroid function in women of reproductive age.
Early in pregnancy in normal women, as a consequence of the weak thyroid-stimulating activity of chorionic gonadotropin, serum free thyroxine concentrations may increase and thyrotropin concentrations may fall. In a small proportion of women, gestational thyrotoxicosis is the result. For reasons that are not entirely clear, free thyroid hormone concentrations then decrease as pregnancy progresses, necessitating the use of trimester-related reference ranges. The other important change in thyroid hormone economy is the estrogen-driven increase (by 100 percent or more) in the concentration of thyroxine-binding globulin, the key thyroid hormone–binding protein. It has been determined that ordinarily some two thirds of circulating thyroxine is carried by thyroxine-binding globulin and that the proportion increases to 75 percent during pregnancy.6 The increased number of binding sites for thyroxine would result in an even more marked fall in serum free thyroxine concentrations during pregnancy, unless there were a compensatory increase in thyroidal secretion and restoration of the equilibrium between the free (metabolically active) hormone and bound hormone. The raised concentration of chorionic gonadotropin may play an important role in this homeostasis. In pregnant women with primary hypothyroidism, however, the thyroid cannot respond to stimulation adequately. Consequently, there is little or no appropriate compensation for the increased availability of binding sites on thyroxine-binding globulin, which effectively "mops up" substantial amounts of free thyroxine.
In this issue of the Journal, Alexander et al.7 elegantly demonstrate the interrelated changes in thyroid hormone, chorionic gonadotropin, and estradiol concentrations in pregnant women who are taking levothyroxine for primary hypothyroidism. The authors not only reaffirm the need for an increased dose of levothyroxine in most such women in order to restore the preconception serum thyrotropin concentration,8 but they also make the important clinical observation that this increased requirement may be evident as early as the fifth week of gestation — an important time for maternal provision of thyroxine to the fetus. Indeed, Pop et al.9 showed that the offspring of women with serum free thyroxine concentrations in the lowest decile of the reference range at 12 weeks of gestation, without a subsequent increase, had significant delays in neurodevelopment when assessed at one and two years of age, even when the maternal serum thyrotropin concentration had been normal. The likely explanation, at least according to studies in animals, is that until a point toward the end of the first trimester, when the hypothalamic–pituitary–thyroid axis becomes functional, the fetal brain is dependent on local monodeiodination of maternal thyroxine for triiodothyronine. A relatively low serum thyroxine concentration may be associated with a normal serum thyrotropin concentration in iodine deficiency when the thyroid preferentially secretes triiodothyronine, but maternal triiodothyronine cannot be used by the fetal brain during early pregnancy.5
In a retrospective analysis of stored serum samples obtained during pregnancy from women who had delivered many years earlier, Haddow et al.10 found impaired neuropsychological development among children seven to nine years of age whose mothers had had a high serum thyrotropin concentration (but a low-normal free thyroxine concentration) during pregnancy. Nineteen percent of the children whose mothers had received no levothyroxine had IQ scores below 85, as compared with 5 percent of the children whose mothers had had normal thyroid-function status.
The changes in thyroid function recorded by Alexander and colleagues in a cohort of pregnant women with primary hypothyroidism are relatively minor in comparison. For example, serum thyrotropin concentrations increased from a mean of 1.0 μU per milliliter before conception to a maximum of 4.2 μU per milliliter during pregnancy — a change within the reference range of 0.8 to 5.0 μU per milliliter; in contrast, the mean serum thyrotropin concentration in the study by Haddow et al. was 13.2 μU per milliliter.10 Similarly, the free thyroxine index, a surrogate measure of free thyroxine, did not appear to be in the lowest decile of the reference range. It is not known, of course, how much greater these changes might have been had there been no increase in the dose of levothyroxine. However, in a previous, smaller study from the same institution, the mean serum thyrotropin concentration of 2.0 μU per milliliter before pregnancy increased to 13.5 μU per milliliter during pregnancy.8
Untreated overt hypothyroidism is associated with fetal loss, gestational hypertension, abruptio placentae, and a poor perinatal outcome.11 There are no outcome measures for women who continue throughout pregnancy to take the dose of replacement therapy that was considered appropriate before conception, and it is now unlikely that any controlled, interventional studies will be conducted.
The current recommendation for levothyroxine therapy during pregnancy is to increase the dose such that the serum thyrotropin concentration is between 0.5 and 2.0 μU per milliliter and the serum free thyroxine concentration is within the upper third of the reference range, ideally after adjustment for the trimester.2 However, because the increased requirement for levothyroxine is evident as early as the fifth week of gestation, it is not sufficient to recommend thyroid-function testing once each trimester. Ideally, women with primary hypothyroidism should be counseled before pregnancy, with emphasis on the need for complete and exact compliance with the regimen of levothyroxine therapy at the established dose.
The suggestion by Alexander and colleagues that women should increase their dose of levothyroxine by the equivalent of two daily doses each week as soon as pregnancy is confirmed will do no harm and should preempt any tendency toward early hypothyroxinemia. However, it would be more practical to increase the dose by 25 to 50 μg daily and to request thyroid-function testing within the following four to six weeks. Although the current consensus is that thyroid function should be tested every six to eight weeks during pregnancy,12 it appears that the requirement for an increase (of up to 50 percent) in the levothyroxine dose peaks midway through pregnancy and remains constant thereafter, until delivery. Surveillance of thyroid function can therefore be more relaxed after the 20th week of gestation, during which time one additional test is probably sufficient.
A raised serum thyrotropin concentration, in excess of 6 μU per milliliter, has been reported in 2.5 percent of all pregnant women, with overt hypothyroidism in more than 10 percent of that group.13 Although the debate continues about the wisdom of screening women of childbearing age by measuring serum thyroxine, thyrotropin, or both in order to detect unrecognized thyroid failure in advance of pregnancy, the evidence is beginning to stack up in favor of doing so. If screening is not to be performed universally, it would be reasonable to test those under the age of 35 years who already have one or more of the organ-specific autoimmune diseases, such as type 1 diabetes mellitus, or who have a strong family history of thyroid disease.
Source Information
From the Royal Infirmary, Edinburgh, Scotland.
References
Surks MI, Chopra IJ, Mariash CN, Nicoloff JT, Solomon DH. American Thyroid Association guidelines for use of laboratory tests in thyroid disorders. JAMA 1990;263:1529-1532.
Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf) 2003;58:138-140.
Toft AD, Beckett GJ. Thyroid function tests and hypothyroidism. BMJ 2003;326:295-296.
Hennemann G, Docter R, Visser TJ, Postema PT, Krenning EP. Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid 2004;14:271-275.
Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 2000;85:3975-3987.
Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-433.
Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004;351:241-249.
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.
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.
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.
Davis LE, Leveno KJ, Cunningham FG. Hypothyroidism complicating pregnancy. Obstet Gynecol 1988;72:108-112.
Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific reviews and guidelines for diagnosis and management. JAMA 2004;291:228-238.
Klein RZ, Haddow JE, Faix JD, et al. Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol (Oxf) 1991;35:41-46.(Anthony Toft, M.D.)
Early in pregnancy in normal women, as a consequence of the weak thyroid-stimulating activity of chorionic gonadotropin, serum free thyroxine concentrations may increase and thyrotropin concentrations may fall. In a small proportion of women, gestational thyrotoxicosis is the result. For reasons that are not entirely clear, free thyroid hormone concentrations then decrease as pregnancy progresses, necessitating the use of trimester-related reference ranges. The other important change in thyroid hormone economy is the estrogen-driven increase (by 100 percent or more) in the concentration of thyroxine-binding globulin, the key thyroid hormone–binding protein. It has been determined that ordinarily some two thirds of circulating thyroxine is carried by thyroxine-binding globulin and that the proportion increases to 75 percent during pregnancy.6 The increased number of binding sites for thyroxine would result in an even more marked fall in serum free thyroxine concentrations during pregnancy, unless there were a compensatory increase in thyroidal secretion and restoration of the equilibrium between the free (metabolically active) hormone and bound hormone. The raised concentration of chorionic gonadotropin may play an important role in this homeostasis. In pregnant women with primary hypothyroidism, however, the thyroid cannot respond to stimulation adequately. Consequently, there is little or no appropriate compensation for the increased availability of binding sites on thyroxine-binding globulin, which effectively "mops up" substantial amounts of free thyroxine.
In this issue of the Journal, Alexander et al.7 elegantly demonstrate the interrelated changes in thyroid hormone, chorionic gonadotropin, and estradiol concentrations in pregnant women who are taking levothyroxine for primary hypothyroidism. The authors not only reaffirm the need for an increased dose of levothyroxine in most such women in order to restore the preconception serum thyrotropin concentration,8 but they also make the important clinical observation that this increased requirement may be evident as early as the fifth week of gestation — an important time for maternal provision of thyroxine to the fetus. Indeed, Pop et al.9 showed that the offspring of women with serum free thyroxine concentrations in the lowest decile of the reference range at 12 weeks of gestation, without a subsequent increase, had significant delays in neurodevelopment when assessed at one and two years of age, even when the maternal serum thyrotropin concentration had been normal. The likely explanation, at least according to studies in animals, is that until a point toward the end of the first trimester, when the hypothalamic–pituitary–thyroid axis becomes functional, the fetal brain is dependent on local monodeiodination of maternal thyroxine for triiodothyronine. A relatively low serum thyroxine concentration may be associated with a normal serum thyrotropin concentration in iodine deficiency when the thyroid preferentially secretes triiodothyronine, but maternal triiodothyronine cannot be used by the fetal brain during early pregnancy.5
In a retrospective analysis of stored serum samples obtained during pregnancy from women who had delivered many years earlier, Haddow et al.10 found impaired neuropsychological development among children seven to nine years of age whose mothers had had a high serum thyrotropin concentration (but a low-normal free thyroxine concentration) during pregnancy. Nineteen percent of the children whose mothers had received no levothyroxine had IQ scores below 85, as compared with 5 percent of the children whose mothers had had normal thyroid-function status.
The changes in thyroid function recorded by Alexander and colleagues in a cohort of pregnant women with primary hypothyroidism are relatively minor in comparison. For example, serum thyrotropin concentrations increased from a mean of 1.0 μU per milliliter before conception to a maximum of 4.2 μU per milliliter during pregnancy — a change within the reference range of 0.8 to 5.0 μU per milliliter; in contrast, the mean serum thyrotropin concentration in the study by Haddow et al. was 13.2 μU per milliliter.10 Similarly, the free thyroxine index, a surrogate measure of free thyroxine, did not appear to be in the lowest decile of the reference range. It is not known, of course, how much greater these changes might have been had there been no increase in the dose of levothyroxine. However, in a previous, smaller study from the same institution, the mean serum thyrotropin concentration of 2.0 μU per milliliter before pregnancy increased to 13.5 μU per milliliter during pregnancy.8
Untreated overt hypothyroidism is associated with fetal loss, gestational hypertension, abruptio placentae, and a poor perinatal outcome.11 There are no outcome measures for women who continue throughout pregnancy to take the dose of replacement therapy that was considered appropriate before conception, and it is now unlikely that any controlled, interventional studies will be conducted.
The current recommendation for levothyroxine therapy during pregnancy is to increase the dose such that the serum thyrotropin concentration is between 0.5 and 2.0 μU per milliliter and the serum free thyroxine concentration is within the upper third of the reference range, ideally after adjustment for the trimester.2 However, because the increased requirement for levothyroxine is evident as early as the fifth week of gestation, it is not sufficient to recommend thyroid-function testing once each trimester. Ideally, women with primary hypothyroidism should be counseled before pregnancy, with emphasis on the need for complete and exact compliance with the regimen of levothyroxine therapy at the established dose.
The suggestion by Alexander and colleagues that women should increase their dose of levothyroxine by the equivalent of two daily doses each week as soon as pregnancy is confirmed will do no harm and should preempt any tendency toward early hypothyroxinemia. However, it would be more practical to increase the dose by 25 to 50 μg daily and to request thyroid-function testing within the following four to six weeks. Although the current consensus is that thyroid function should be tested every six to eight weeks during pregnancy,12 it appears that the requirement for an increase (of up to 50 percent) in the levothyroxine dose peaks midway through pregnancy and remains constant thereafter, until delivery. Surveillance of thyroid function can therefore be more relaxed after the 20th week of gestation, during which time one additional test is probably sufficient.
A raised serum thyrotropin concentration, in excess of 6 μU per milliliter, has been reported in 2.5 percent of all pregnant women, with overt hypothyroidism in more than 10 percent of that group.13 Although the debate continues about the wisdom of screening women of childbearing age by measuring serum thyroxine, thyrotropin, or both in order to detect unrecognized thyroid failure in advance of pregnancy, the evidence is beginning to stack up in favor of doing so. If screening is not to be performed universally, it would be reasonable to test those under the age of 35 years who already have one or more of the organ-specific autoimmune diseases, such as type 1 diabetes mellitus, or who have a strong family history of thyroid disease.
Source Information
From the Royal Infirmary, Edinburgh, Scotland.
References
Surks MI, Chopra IJ, Mariash CN, Nicoloff JT, Solomon DH. American Thyroid Association guidelines for use of laboratory tests in thyroid disorders. JAMA 1990;263:1529-1532.
Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf) 2003;58:138-140.
Toft AD, Beckett GJ. Thyroid function tests and hypothyroidism. BMJ 2003;326:295-296.
Hennemann G, Docter R, Visser TJ, Postema PT, Krenning EP. Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid 2004;14:271-275.
Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 2000;85:3975-3987.
Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-433.
Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004;351:241-249.
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.
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.
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.
Davis LE, Leveno KJ, Cunningham FG. Hypothyroidism complicating pregnancy. Obstet Gynecol 1988;72:108-112.
Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific reviews and guidelines for diagnosis and management. JAMA 2004;291:228-238.
Klein RZ, Haddow JE, Faix JD, et al. Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol (Oxf) 1991;35:41-46.(Anthony Toft, M.D.)