Original Article
Increased Need for Thyroxine during Pregnancy in Women with Primary Hypothyroidism
N Engl J Med 1990; 323:91-96July 12, 1990
- Abstract
- Abstract
Background and Methods.
Women with hypothyroidism have been thought not to require an increase in thyroxine replacement during pregnancy. To evaluate the effects of pregnancy on thyroxine requirements, we retrospectively reviewed the thyroid function of 12 women receiving treatment for primary hypothyroidism before, during, and after pregnancy.
Results.
In all patients, the serum thyrotropin level increased during pregnancy. The mean (±SE) serum freethyroxine index decreased from 111.0±5.8 before pregnancy to 86.5±5.2 during pregnancy (normal, 64 to 142; P<0.05), and the mean serum thyrotropin level increased from 2.0±0.5 mU per liter before pregnancy to 13.5±3.3 mU per liter during pregnancy (normal, 0.5 to 5.0 mU per liter; P<0.01). Because of high thyrotropin levels, the thyroxine dose was increased in 9 of the 12 patients. Among the three patients who did not require an increased thyroxine dose were two with low serum thyrotropin levels before pregnancy, suggesting excessive replacement at that time. The mean thyroxine dose before pregnancy was 0.102±0.009 mg per day; it was increased to 0.148±0.015 mg per day during pregnancy (P<0.01).
The mean postpartum serum free-thyroxine index was 136.6±11.4 (P<0.05 as compared with values before and during pregnancy), and the mean postpartum serum thyrotropin level was 1.4±0.4 mU per liter (P<0.01 as compared with levels during pregnancy), demonstrating a decrease in the thyroxine requirement. The mean postpartum thyroxine dose was decreased to 0.117±0.011 mg per day (P<0.01 as compared with the dose during pregnancy).
Conclusions.
Our results indicate that the need for thyroxine increases in many women with primary hypothyroidism when they are pregnant, as reflected by an increase in serum thyrotropin concentrations. Although the effects of this modest level of hypothyroidism are not known, we think it prudent to monitor thyroid function throughout gestation and after delivery and to adjust the thyroxine dose to maintain a normal serum thyrotropin level. (N Engl J Med 1990; 323:91–6.)
Article Activity
- Article
THE consensus has been that women with hypothyroidism who are taking a maintenance dose of thyroxine rarely require an increase in the dose during pregnancy.1 , 2 This view is supported by reports that despite an increase in the serum concentration of total thyroxine during pregnancy, its fractional degradation decreases, so that daily production remains constant.3 Inadequate treatment of patients with moderate-to-severe hypothyroidism during pregnancy has been reported to result in increased maternal and fetal morbidity, however,4 , 5 and this raises questions about the appropriate thyroxine replacement dose for pregnant women with even mild hypothyroidism. In 1984 Pekonen et al. suggested that some pregnant women with hypothyroidism may need to have their thyroxine dose adjusted.6 The results of thyroid-function tests before pregnancy were not reported, and the patients were not followed post partum.6
In our clinical practice, we observed an apparent increase in the thyroxine requirement in a number of pregnant women with hypothyroidism. This led us to review thyroid function retrospectively in women with preexisting primary hypothyroidism who were followed during pregnancy by our group. We also prospectively followed patients identified during the course of this review. All such patients had increases in their serum thyrotropin concentrations, and most had decreases in their serum free-thyroxine indexes, indicating the need for increased doses of thyroxine.
Methods
Patients
Women with primary hypothyroidism seen in the private thyroid and endocrine clinics of Brigham and Women's Hospital who were pregnant or who had been followed during an earlier pregnancy were identified through interviews with our staff. From a review of their records, we selected all women with a diagnosis of hypothyroidism who were receiving a maintenance dose of thyroxine before and during the first months after conception and whose thyroxine dose and thyroid function were monitored regularly before, on at least two occasions during, and after pregnancy. The diagnosis of primary hypothyroidism in these patients had been made on the basis of clinical manifestations, decreased serum free-thyroxine indexes, and increased serum thyrotropin concentrations before the initiation of therapy. Women who were given a diagnosis of hypothyroidism during pregnancy were excluded.
Among 21 pregnant women with hypothyroidism who were seen from 1982 to 1990, 12 met the criteria for inclusion in the study. Nine were excluded because of incomplete results of thyroid-function tests or inadequate documentation of their thyroxine dose before, during, or after pregnancy. Although the patients were cared for by several endocrinologists, the thyroxine dose in all patients was adjusted when serum thyrotropin levels exceeded the normal range (0.5 to 5.0 mU per liter) during pregnancy.
For this analysis, the results before the pregnancy were considered to be those recorded at the time of the patient's last visit before conception. Subsequently, the changes in thyroid function and the thyroxine dose and the gestational week in which the changes occurred were recorded. The maximal levels of serum thyrotropin during pregnancy and corresponding values for the serum free-thyroxine index were used for analysis. The frequency of thyroid testing during pregnancy varied among the patients; the mean number of measurements was four (range, two to seven).
The results of the first set of postpartum thyroid-function tests were used for analysis. At that time, 11 patients were taking the same dose of thyroxine as during their pregnancy. In the case of one patient (Patient 9), the daily thyroxine dose had been lowered from 0.2 mg to 0.125 mg immediately after delivery. Her postpartum thyroid studies were performed while she was receiving this reduced dose. The postpartum dose of thyroid hormone was adjusted according to the results of the postpartum thyroid-function tests.
This study was approved by the human subjects committee of Brigham and Women's Hospital.
Serum Hormone Measurements
All hormonal measurements were made in the Endocrinology—Hypertension Laboratory of Brigham and Women's Hospital. Serum thyroxine was measured by radioimmunoassay (RIA) kits obtained from Diagnostic Products (Los Angeles) and Baxter Travenol Diagnostics (Cambridge, Mass.). Before January 1987, serum thyrotropin was measured by RIA (Becton Dickinson Immunodiagnostics, Salt Lake City). The sensitivity of this assay was 2.5 mU per liter, Undetectable values were assigned this value for the calculation of group mean values. Subsequent assays were done with the Allegro TSH kit (Nichols Institute, San Juan Capistrano, Calif.), an immunoradiometric assay (IRMA) with a sensitivity of 0.1 mU per liter. For this assay, the intraassay and interassay coefficients of variation were 3.4 percent and 4.0 percent, respectively. An assessment of the concentration of unoccupied binding sites for thyroxine-binding globulin was performed with use of a solid-phase [l25I]triiodothyronine-uptake test (Coat-A-Count kit, Diagnostic Products). The thyroid hormone—binding ratio was the patient's uptake normalized to that of a reference serum value.7 Serum free-thyroxine indexes were calculated as the products of the total hormone concentration and the thyroid hormone—binding ratio.7 The normal ranges for these values are shown in Table 1Table 1
Thyroxine Dose and Serum Levels of Thyroid Hormone and Thyrotropin in Women with Hypothyroidism before, during, and after Pregnancy.*.Statistical Analysis
The serum free-thyroxine indexes and thyrotropin concentrations during the third trimester and after delivery in seven patients were analyzed with use of the paired t-test and the Wilcoxon signed-rank test, respectively. The serum thyrotropin values were not distributed normally. Analysis of variance by repeated measures was used to analyze all other data, followed by the Student—Newman—Keuls test, with the use of the Statistical Analysis Systems software package.8 The results are presented as the mean values, with the standard error of the mean as the index of dispersion.
Results
Characteristics of the Study Population
The mean age of the patients studied was 30.6 years (range, 24 to 38), and the mean duration of hypothyroidism before pregnancy was 50 months (range, 3 to 168). The causes of the hypothyroidism in the 12 women were Hashimoto's thyroiditis (8 patients), subtotal thyroidectomy for thyrotoxicosis due to Graves' disease (2), and iodine-131 therapy for thyrotoxicosis due to Graves' disease (2). The weights of 10 of the 12 patients before pregnancy were known. For these women, the mean thyroxine dose before conception was 1.75 μg per kilogram of body weight (range, 0.7 to 3.0). None of the patients were taking any drugs known to alter thyroid function, nor did they have other medical conditions. All the pregnancies were uncomplicated. Compliance was monitored by periodic history taking.
Thyroid Function and Thyroxine Dose before Pregnancy
The last tests of thyroid function in these women before pregnancy had been done an average of 7.5 months (range, 1 to 23) before pregnancy. The mean (±SE) serum thyrotropin level was 2.0±0.5 mU per liter, and the mean serum free-thyroxine index was 111.0±5.8. At that time, the mean thyroxine dose was 0.102±0.009 mg per day (range, 0.05 to 0.175) (Table 1). The mean duration of therapy with this dose was 36 months (range, 2 to 168), and the mean total duration of therapy was 50 months (range, 3 to 168).
Thyroid Function and Thyroxine Dose during Pregnancy
While receiving the same thyroxine doses as they received before pregnancy, the 12 women had a significant decrease in their mean serum free-thyroxine index during pregnancy (from 111.0±5.8 to 86.5±5.2; P<0.05), but in only 1 patient (Patient 1, Table 1) did the level fall below the normal range. All had a concomitant increase in serum thyrotropin levels (the level was considered to have increased in Patient 11 because her serum level was undetectable when measured by RIA before pregnancy and detectable when measured by IRMA during pregnancy). The mean maximal serum thyrotropin level— 13.5±3.3 mU per liter — was significantly higher (P<0.01) than the level before pregnancy (Table 1). Figure 1Figure 1
Representative Patterns of Changes in Thyroid Function and Thyroxine Dose during Pregnancy in Women with Hypothyroidism. shows the chronologic relation between serum thyrotropin levels and the free-thyroxine index in three patients, all of whom had tests of thyroid function during the first trimester.Because thyroid function was measured at various intervals after conception, the earliest demonstrable decrease in the serum free-thyroxine index and increase in the serum thyrotropin level are not known. However, serum thyrotropin levels increased in all seven patients studied during the first trimester, and it increased in the second trimester in the remaining five patients who were first tested at that time.
Among the 12 women, 9 (Patients 1 through 9; 75 percent) had an increase in serum thyrotropin levels to more than 5.0 mU per liter during pregnancy and therefore subsequently received more thyroxine. The remaining three (Patients 10 through 12) continued to receive the same dose as before pregnancy throughout gestation. The mean maximal thyroxine dose taken by all 12 patients during pregnancy — 0.148±0.015 mg per day — was significantly higher than that taken before pregnancy (P<0.01).
Of the three patients who did not require an increase in the thyroxine dose, two (Patients 10 and 11) were probably receiving excessive doses before pregnancy, since their serum thyrotropin concentrations at that time were low (0.2 mU per liter by IRMA; <2.5 mU per liter by RIA). Patient 10 had a sevenfold increase in the serum thyrotropin level, from 0.2 to 1.5 mU per liter, during pregnancy. The absolute magnitude of the increase could not be calculated in Patient 11, although her serum thyrotropin level did become measurable (1.2 mU per liter by IRMA) during pregnancy. The third patient (Patient 12) in whom the thyroxine dose was not increased had serum thyrotropin values of 1.4 mU per liter before pregnancy and 3.6 mU per liter during the eighth week of pregnancy (Fig. 1, right-hand panel). Two of these three patients (Patients 11 and 12) had their serum thyrotropin measured during all three trimesters. In both, the peak serum thyrotropin level occurred in the first trimester. Thus, although serum thyrotropin values were within the normal range throughout pregnancy in all three women, the levels increased during pregnancy.
Postpartum Thyroid Function and Thyroxine Dose
The serum free-thyroxine index and thyrotropin values were determined a mean of 3.1 months after delivery (range, 1 to 7) in 11 patients while they were receiving the same dose of thyroxine that they had received during the latter part of their pregnancies and in 1 patient (Patient 9) in whom the dose was decreased at the time of delivery. For these 12 women, the mean serum free-thyroxine index after delivery — 136.6±11.4 — was significantly higher (P<0.05) than that before and during pregnancy (Table 1). The mean serum thyrotropin concentration (1.4±0.4 mU per liter) was significantly lower than that during pregnancy (13.5±3.3 mU per liter; P<0.01), but not significantly different from the value before pregnancy (2.0±0.5 mU per liter) (Table 1). In the seven patients (Patients 1, 2, 3, 5, 7, 10, and 12) in whom serum thyrotropin levels were measured with the sensitive IRMA in the third trimester and after delivery while they were taking the thyroxine dose prescribed during pregnancy, the mean serum free-thyroxine index (145.4±15.4) was significantly higher after delivery than in the third trimester (101.7±6.4; P<0.05) (Fig. 2Figure 2
Individual Serum Free-Thyroxine Indexes and Thyrotropin Concentrations during the Third Trimester and post Partum in Women with Hypothyroidism.). Conversely, the mean serum thyrotropin level was significantly lower after delivery than in the third trimester (0.3±0.2 vs. 4.2±1.7 mU per liter; P<0.05).For all 12 patients, the mean thyroxine dose (0.117±0.011 mg per day) after the first postpartum visit was significantly lower than that during pregnancy (0.148±0.015 mg per day; P<0.01), but it was similar to the mean dose before pregnancy. All nine patients who required an increased thyroxine dose during pregnancy needed a decrease in dose after delivery. Among the three patients who did not require an increase in the thyroxine dose during pregnancy, one had a low postpartum serum thyrotropin value (0.1 mU per liter) that necessitated a decrease in the thyroxine dose (Patient 12, Fig. 1, right-hand panel). Her serum thyrotropin level before pregnancy was 1.4 mU per liter. The other two patients (Patients 10 and 11), who initially had low serum thyrotropin levels before pregnancy (0.2 and <2.5 mU per liter, respectively), continued to receive the same thyroxine dose post partum as during pregnancy, although their serum thyrotropin values had increased ( 1.4 and 2.0 mU per liter).
Discussion
In all 12 patients being treated for primary hypothyroidism, pregnancy induced an increase in serum thyrotropin concentrations, an exquisitely sensitive indicator of thyroid status (Fig. 1). The magnitude of the increase was independent of the cause of the patient's hypothyroidism and led to an increase in the thyroxine dose in 9 of the 12 patients. The mean dose increment was 45 percent. The increased need for thyroxine appeared in the first trimester and persisted throughout pregnancy, but returned to pregestational levels within a few months after delivery.
The mild hypothyroidism in our patients during pregnancy, manifested only as an increase in the serum thyrotropin concentrations, is unlikely to have been the result of noncompliance. The patients had had hypothyroidism for a mean of 50 months before pregnancy and had normal serum thyroid hormone and thyrotropin levels while receiving a maintenance dose of thyroxine. During pregnancy, there was an appropriate decrease in serum thyrotropin as their dose was increased, and their serum thyrotropin levels fell after delivery while they continued to take this increased thyroxine dose.
Two questions are raised by these results: Why was the need for an increase in thyroxine not recognized in earlier studies (for example, the study by Pekonen et al.6), and why does this increase occur? The recognition of the need for increased doses of thyroxine during pregnancy is probably a consequence of the reduction in the recommended thyroxine replacement doses for all patients with hypothyroidism in recent years. This reduction is largely due to the recent availability of a sensitive IRMA for serum thyrotropin that can readily quantitate the lower limit of the normal range (0.5 mU per liter), thus facilitating the recognition of a supraphysiologic dose. Before this test became available, many patients were treated with excessive doses of thyroxine, since it was not possible to distinguish subnormal from normal serum thyrotropin concentrations.9 In such patients, serum thyrotropin concentrations could increase as much as sevenfold during pregnancy and still be normal, as we found in Patients 10 and 11.
There are several possible explanations for an increased need for thyroxine during pregnancy. Since the rise in serum thyrotropin concentrations was associated with a decrease in serum free-thyroxine indexes, we can eliminate an alteration in hypothalamic—pituitary—thyroid relations as a cause. The absorption and distribution of thyroxine may be altered by the gravid uterus, changes in the distribution of cardiac output, and the effect of the mass of the fetal—placental unit. Because the increased need for thyroxine occurs relatively early in gestation, it is unlikely that these physiologic changes cause it. Thyroxine metabolism by the fetal—placental unit could contribute to an increased need for thyroxine in the later phases of pregnancy and to the decrease in the need after delivery.
The appearance of the increased need for thyroxine during the first trimester suggests an explanation related to alterations in thyroid physiology during normal pregnancy that cannot occur in women with hypothyroidism. In healthy women, serum concentrations of total triiodothyronine and thyroxine rise during the first three months of pregnancy and plateau either late in the second or early in the third trimester.10 , 11 These increases are due to increases in serum concentrations of thyroxine-binding globulin that are a consequence of an estrogen-induced increase in the glycosylation of thyroxine-binding globulin and lead to decreased hepatic clearance of this protein.12 Earlier analyses suggested that as serum concentrations of thyroxine-binding globulin rose, daily production of thyroxine remained constant,3 whereas the serum free-thyroxine concentration and the thyroxine-degradation rate decreased, allowing a slow increase in serum concentrations of total thyroxine until serum concentrations of free thyroxine returned to normal.13 However, recent studies indicate that serum free-thyroxine concentrations are higher during the first trimester than during the second or third trimesters10 , 11 , 14 or in normal nonpregnant women and men.10 This increase in serum free-thyroxine levels occurs when chorionic gonadotropin levels are maximal10 , 14 and is probably due to its weak thyrotropic effect.14 The serum thyrotropin levels during the first trimester of pregnancy are lower than those in nonpregnant women, although they are not usually less than 0.5 mU per liter. Serum thyrotropin concentrations then gradually increase in the second and third trimesters, although they remain within the normal range for nonpregnant women and for men.11 , 14 These results suggest that although there is an increase in thyroxine production during the first trimester of pregnancy, it is transient and not dependent on thyrotropin. In addition, it must be more than sufficient to satisfy the need for increased amounts of thyroxine caused by the increase in serum concentrations of thyroxine-binding globulin. The extent to which the normal production of chorionic gonadotropin contributes to thyroxine production later in pregnancy is not known, but it is presumed to be minimal.
Because the thyroxine requirements increased so uniformly in the first trimester in these pregnant women with hypothyroidism, it seems clear that the transient chorionic gonadotropin—induced elevation of the thyroxine-production rate in normal pregnancy obscures an augmented rate of thyroxine production that would otherwise be compensated for by the hypothalamic—pituitary—thyroid axis. Since these women have thyroid glands that cannot respond either to thyrotropin or to chorionic gonadotropin, the increased need for thyroxine is not met and the serum thyrotropin level rises. Our finding that these women needed more thyroxine throughout pregnancy, rather than transiently (Fig. 1), also implies that there is a sustained increase in thyroxine production throughout gestation. The alternative explanation — that these women have a persistent acceleration in thyroxine metabolism — seems very unlikely.
Inadequate treatment of moderate-to-severe hypothyroidism during pregnancy may be associated with increased maternal and fetal morbidity.4 , 5 , 15 Such complications would not be expected to result from the mild hypothyroidism we observed, but we are not aware of studies evaluating this possibility. Recently, Vulsma et al.16 demonstrated transplacental passage of maternal thyroxine, which may have a critical role in ensuring normal development of the fetal brain in infants with congenital hypothyroidism.16 , 17 A normal serum level of free thyroxine in the mother would be especially critical during such pregnancies.
Whatever the explanation, we found that many women with primary hypothyroidism have a decrease in the serum free-thyroxine index and an increase in serum thyrotropin levels during pregnancy. Although the effects of this mild hypothyroidism on pregnancy and fetal development are not known, they could be deleterious and can be avoided. We therefore recommend close monitoring of thyroid function in women with hypothyroidism throughout gestation and after delivery. The dose of thyroxine should be adjusted to maintain a normal serum thyrotropin level.
Supported in part by grants (5 T32 HL07609 and DK 36256) from the National Institutes of Health and a Physician-Scientist Award (5 K12 AM01401). Data management and statistical analyses were performed in a CLINFO facility supported by a grant (RR 02635) from the Division of Research Resources. Dr. Larson is an Investigator of the Howard Hughes Medical Institute.
We are indebted to Drs. Ghada El-Hajj Suleihan, Meryl LeBoff, and Thomas Moore for providing records for their patients and to Dr. Ray Gleason for providing valuable assistance in performing the statistical analyses.
Source Information
From the Thyroid Diagnostic Center and Endocrine—Hypertension Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston. Address reprint requests to Dr. Brent at the Thyroid Diagnostic Center, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.
- References
References
1
Longcope C. The male and female reproductive systems. In: Ingbar SH, Braverman LR, eds. Werner's the thyroid: a fundamental and clinical text. 5th ed. Philadelphia: J.B. Lippincott, 1986:1194–9.
2
Burrow GN. Thyroid diseases in pregnancy. In: Burrow GN, Oppenheimer JE, Volpe R, eds. Thyroid function and disease. Philadelphia: W.B. Saunders, 1989:292–323.
3
Dowling
CrossRef | Web of Science | Medline4
Man
Web of Science | Medline5
Davis
Web of Science | Medline6
Pekonen
Web of Science | Medline7
Larsen
CrossRef | Web of Science | Medline8
SAS Institute Inc. SAS user's guide: statistics, version 5 edition. Cary, N.C.: SAS Institute, 1985:956.
9
Ross
CrossRef | Web of Science | Medline10
Guillaume
CrossRef | Web of Science | Medline11
Weeke
Medline12
Ain
CrossRef | Web of Science | Medline13
Ingbar SH. The thyroid gland. In: Wilson JD, Foster DW, eds. Williams textbook of endocrinology. 7th ed. Philadelphia: W.B. Saunders, 1985:682–815.
14
Yoshikawa
CrossRef | Web of Science | Medline15
Montoro
Web of Science | Medline16
Vulsma
Full Text | Web of Science | Medline17
Larsen
Full Text | Web of Science | Medline
- Citing Articles (92)
Citing Articles
1
Clarisa R. Gracia, Christopher B. Morse, Grace Chan, Samantha Schilling, Maureen Prewitt, Mary D. Sammel, Susan J. Mandel. (2012) Thyroid function during controlled ovarian hyperstimulation as part of in vitro fertilization. Fertility and Sterility
CrossRef2
Blaz Krhin, Nikola Besic. (2012) Effectiveness of L-thyroxine treatment on TSH suppression during pregnancy in patients with a history of thyroid carcinoma after total thyroidectomy and radioiodine ablation. Radiology and Oncology 1:-1, 1-6
CrossRef3
Alex Stagnaro-Green, Marcos Abalovich, Erik Alexander, Fereidoun Azizi, Jorge Mestman, Roberto Negro, Angelita Nixon, Elizabeth N. Pearce, Offie P. Soldin, Scott Sullivan, Wilmar Wiersinga. (2011) Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum. Thyroid 21:10, 1081-1125
CrossRef4
A. Dal Lago, E. Vaquero, P. Pasqualetti, N. Lazzarin, C. De Carolis, R. Perricone, C. Moretti. (2011) Prediction of early pregnancy maternal thyroid impairment in women affected with unexplained recurrent miscarriage. Human Reproduction 26:6, 1324-1330
CrossRef5
Jaume Arroyo Bros, Pilar Gil Lluís, Gemma Llauradó Cabot, Assumpta Caixàs Pedragós. (2011) Hipotiroidismo primario: consideraciones para una buena utilización del tratamiento con levotiroxina. Medicina Clínica 136:5, 207-214
CrossRef6
Offie P Soldin, Steven J Soldin, Alexander A Vinks, Islam Younis, Helain J Landy. (2010) Longitudinal Comparison of Thyroxine Pharmacokinetics Between Pregnant and Nonpregnant Women: A Stable Isotope Study. Therapeutic Drug Monitoring 32:6, 767-773
CrossRef7
Marcos Abalovich, Graciela Alcaraz, Jessica Kleiman-Rubinsztein, María Magdalena Pavlove, Cecilia Cornelio, Oscar Levalle, Silvia Gutierrez. (2010) The Relationship of Preconception Thyrotropin Levels to Requirements for Increasing the Levothyroxine Dose During Pregnancy in Women with Primary Hypothyroidism. Thyroid 20:10, 1175-1178
CrossRef8
Carey Winkler, Fred Coleman. 2010. Endocrine Emergencies. , 425-437.
CrossRef9
Mark E. Molitch, Alan Peaceman. 2010. Pituitary and Adrenal Disease in Pregnancy. , 335-351.
CrossRef10
Megan R. Haymart, Max A. Cayo, Herbert Chen. (2010) Thyroid Hormone Replacement in Women of Reproductive Age: Is Surgeon Knowledge Related to Operative Volume?. Thyroid 20:6, 627-631
CrossRef11
Offie P Soldin. (2010) Therapeutic Drug Monitoring During Pregnancy and Lactation: Thyroid Function Assessment in Pregnancy-Challenges and Solutions. Therapeutic Drug Monitoring 32:3, 265-268
CrossRef12
Johanna Mayr, Susanne Kohlfürst, Hans-Jürgen Gallowitsch, Peter Lind, Peter Mikosch. (2010) Schilddrüse und Schwangerschaft. Wiener Medizinische Wochenschrift 160:7-8, 186-193
CrossRef13
Megan Rist Haymart. (2010) The Role of Clinical Guidelines in Patient Care: Thyroid Hormone Replacement in Women of Reproductive Age. Thyroid 20:3, 301-307
CrossRef14
Matthew Kim. 2010. Thyroid Disorders and Pregnancy. , 694-706.
CrossRef15
Rundsarah Tahboub, Baha M. Arafah. (2009) Sex steroids and the thyroid. Best Practice & Research Clinical Endocrinology & Metabolism 23:6, 769-780
CrossRef16
David M. Haas, Mary F. Hebert, Offie P. Soldin, David A. Flockhart, Parvaz Madadi, James J. Nocon, Christina D. Chambers, Gary D. Hankins, Shannon Clark, Katherine L. Wisner, Lang Li, Jamie L. Renbarger, Lee A. Learman. (2009) Pharmacotherapy and Pregnancy: Highlights from the Second International Conference for Individualized Pharmacotherapy in Pregnancy. Clinical and Translational Science 2:6, 439-443
CrossRef17
B. Harbeck, H. Lehnert, H. Mönig. (2009) Schilddrüsenentzündungen in Schwangerschaft und Stillzeit. Gynäkologische Endokrinologie 7:4, 224-230
CrossRef18
Juan C. Galofre, Terry F. Davies. (2009) Autoimmune Thyroid Disease in Pregnancy: A Review. Journal of Women's Health 18:11, 1847-1856
CrossRef19
Erik K. Alexander. (2009) Thyroid function: The complexity of maternal hypothyroidism during pregnancy. Nature Reviews Endocrinology 5:9, 480-481
CrossRef20
O.E. Janßen. (2009) Sterilität und Schilddrüse. Der Gynäkologe 42:8, 639-646
CrossRef21
Bengt Hallengren, Mikael Lantz, Bengt Andreasson, Lars Grennert. (2009) Pregnant Women on Thyroxine Substitution Are Often Dysregulated in Early Pregnancy. Thyroid 19:4, 391-394
CrossRef22
Jennifer A. Loh, Leonard Wartofsky, Jacqueline Jonklaas, Kenneth D. Burman. (2009) The Magnitude of Increased Levothyroxine Requirements in Hypothyroid Pregnant Women Depends upon the Etiology of the Hypothyroidism. Thyroid 19:3, 269-275
CrossRef23
Linda A. Barbour. 2009. Thyroid Disease in Pregnancy. , 328-341.
CrossRef24
Christian De Geyter, Sabine Steimann, Beat Müller, Marius E. Kränzlin, Christian Meier. (2009) Pattern of Thyroid Function During Early Pregnancy in Women Diagnosed with Subclinical Hypothyroidism and Treated with
l -Thyroxine Is Similar to That in Euthyroid Controls. Thyroid 19:1, 53-59
CrossRef25
Stephen F. Thung, Errol R. Norwitz. 2009. Endocrine Diseases of Pregnancy. , 615-658.
CrossRef26
Monica R. McClain, Geralyn Lambert-Messerlian, James E. Haddow, Glenn E. Palomaki, Jacob A. Canick, Jane Cleary-Goldman, Fergal D. Malone, T. Flint Porter, David A. Nyberg, Peter Bernstein, Mary E. D'Alton. (2008) Sequential first- and second-trimester TSH, free thyroxine, and thyroid antibody measurements in women with known hypothyroidism: a FaSTER trial study. American Journal of Obstetrics and Gynecology 199:2, 129.e1-129.e6
CrossRef27
Christina Cotzias, Sarah-Jane Wong, Erica Taylor, Paul Seed, Joanna Girling. (2008) A study to establish gestation-specific reference intervals for thyroid function tests in normal singleton pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology 137:1, 61-66
CrossRef28
Roberto Negro. (2008) Thyroid insufficiency during pregnancy: complications and implications for screening. Expert Review of Endocrinology & Metabolism 3:2, 137-146
CrossRef29
E. Livadariu, H. Valdes-Socin, M.-C. Burlacu, C. Vulpoi, A.-F. Daly, A. Beckers. (2007) Pseudomalabsorption of thyroid hormones: case report and review of the literature. Annales d'Endocrinologie 68:6, 460-463
CrossRef30
Jayne A Franklyn. (2006) Does impaired secretion of gastric acid reduce absorption of levothyroxine?. Nature Clinical Practice Endocrinology & Metabolism 2:10, 542-543
CrossRef31
Stephen LaFranchi. (2006) Thyroid hormone in hypopituitarism, Graves’ disease, congenital hypothyroidism, and maternal thyroid disease during pregnancy. Growth Hormone & IGF Research 16, 20-24
CrossRef32
Thien-Giang Bach-Huynh, Jacqueline Jonklaas. (2006) Thyroid Medications During Pregnancy. Therapeutic Drug Monitoring 28:3, 431-441
CrossRef33
Iskandar Idris, Ramalingam Srinivasan, Andrew Simm, Renee C. Page. (2005) Maternal hypothyroidism in early and late gestation: effects on neonatal and obstetric outcome. Clinical Endocrinology 63:5, 560-565
CrossRef34
2005. Hypertension (High Blood Pressure). .
CrossRef35
2005. Thyroid Gland. .
CrossRef36
Rui Lu, Kenneth D. Burman, Jacqueline Jonklaas. (2005) Transient Graves' Hyperthyroidism During Pregnancy in a Patient with Hashimoto's Hypothyroidism. Thyroid 15:7, 725-729
CrossRef37
Lyndal R. HARBORNE, Claire E. ALEXANDER, Andrew J. THOMSON, Denis St J. O'REILLY, Ian A. GREER. (2005) Outcomes of pregnancy complicated by thyroid disease. The Australian and New Zealand Journal of Obstetrics and Gynaecology 45:3, 239-242
CrossRef38
Susan J. Mandel, Carole A. Spencer, Joseph G. Hollowell. (2005) Are Detection and Treatment of Thyroid Insufficiency in Pregnancy Feasible?. Thyroid 15:1, 44-53
CrossRef39
Robert C. Smallridge, Daniel Glinoer, Joseph G. Hollowell, Gregory Brent. (2005) Thyroid Function Inside and Outside of Pregnancy: What Do We Know and What Don't We Know?. Thyroid 15:1, 54-59
CrossRef40
O.P. Soldin, R.E. Tractenberg, J.G. Hollowell, J. Jonklaas, N. Janicic, S.J. Soldin. (2004) Trimester-Specific Changes in Maternal Thyroid Hormone, Thyrotropin, and Thyroglobulin Concentrations During Gestation: Trends and Associations Across Trimesters in Iodine Sufficiency. Thyroid 14:12, 1084-1090
CrossRef41
Nilgun O. Turhan, Muhammet C. Kockar, Ilknur Inegol. (2004) Myxedematous coma in a laboring woman suggested a pre-eclamptic coma: a case report. Acta Obstetricia et Gynecologica Scandinavica 83:11, 1089-1091
CrossRef42
Alexander, Erik K., Marqusee, Ellen, Lawrence, Jennifer, Jarolim, Petr, Fischer, George A., Larsen, P. Reed, . (2004) Timing and Magnitude of Increases in Levothyroxine Requirements during Pregnancy in Women with Hypothyroidism. New England Journal of Medicine 351:3, 241-249
Full Text43
Toft, Anthony, . (2004) Increased Levothyroxine Requirements in Pregnancy — Why, When, and How Much?. New England Journal of Medicine 351:3, 292-294
Full Text44
Susan J. Mandel. (2004) Hypothyroidism and chronic autoimmune thyroiditis in the pregnant state: maternal aspects. Best Practice & Research Clinical Endocrinology & Metabolism 18:2, 213-224
CrossRef45
Daniel Glinoer. (2004) Increased TBG During Pregnancy and Increased Hormonal Requirements. Thyroid 14:6, 479-480
CrossRef46
Gabriella Morreale de Escobar, Marı́a Jesús Obregón, Francisco Escobar del Rey. (2004) Maternal thyroid hormones early in pregnancy and fetal brain development. Best Practice & Research Clinical Endocrinology & Metabolism 18:2, 225-248
CrossRef47
Jeffrey M. Zigman. (2004) Authors' Response. Thyroid 14:6, 480-481
CrossRef48
Jorge H. Mestman. (2004) Hyperthyroidism in pregnancy. Best Practice & Research Clinical Endocrinology & Metabolism 18:2, 267-288
CrossRef49
Michael T. McDermott. (2004) Thyroid Disease and Reproductive Health. Thyroid 14:supplement 1, 1-3
CrossRef50
Norman A. Mazer. (2004) Interaction of Estrogen Therapy and Thyroid Hormone Replacement in Postmenopausal Women. Thyroid 14:supplement 1, 27-34
CrossRef51
Caroline GP Roberts, Paul W Ladenson. (2004) Hypothyroidism. The Lancet 363:9411, 793-803
CrossRef52
Graziano Ceresini, Simonetta Morganti, Isabella Rebecchi, Luca Bertone, Gian Paolo Ceda, Alberto Bacchi-Modena, Mariapaola Sgarabotto, Monica Baldini, Fabrizio Ablondi, Giorgio Valenti, Lewis E. Braverman. (2004) A one-year follow-up on the effects of raloxifene on thyroid function in postmenopausal women. Menopause 11:2, 176-179
CrossRef53
Nick Clarke, Udaya M Kabadi. (2004) Optimizing Treatment of Hypothyroidism. Treatments in Endocrinology 3:4, 217-221
CrossRef54
Irwin Klein, Sara Danzi. (2003) Evaluation of the Therapeutic Efficacy of Different Levothyroxine Preparations in the Treatment of Human Thyroid Disease. Thyroid 13:12, 1127-1132
CrossRef55
Jeffrey M. Zigman, Shmuel E. Cohen, Jeffrey R. Garber. (2003) Impact of Thyroxine-Binding Globulin on Thyroid Hormone Economy During Pregnancy. Thyroid 13:12, 1169-1175
CrossRef56
James V. Hennessey. (2003) Precise Thyroxine Dosing: Clinical Requirements. The Endocrinologist 13:6, 479-487
CrossRef57
Daniel Glinoer. (2003) Management of hypo- and hyperthyroidism during pregnancy. Growth Hormone & IGF Research 13, S45-S54
CrossRef58
(2003) References. Thyroid 13:1, 104-126
CrossRef59
Robert C. Smallridge. (2002) Hypothyroidism and Pregnancy. The Endocrinologist 12:5, 454-464
CrossRef60
Marcy A. Adlersberg, Gerard N. Burrow. (2002) Focus on Primary Care Thyroid Function and Dysfunction in Women. Obstetrical & Gynecological Survey 57:Supplement, S1-S7
CrossRef61
M. Abalovich, S. Gutierrez, G. Alcaraz, G. Maccallini, A. Garcia, O. Levalle. (2002) Overt and Subclinical Hypothyroidism Complicating Pregnancy. Thyroid 12:1, 63-68
CrossRef62
Arafah, Baha M., . (2001) Increased Need for Thyroxine in Women with Hypothyroidism during Estrogen Therapy. New England Journal of Medicine 344:23, 1743-1749
Full Text63
Daniel Glinoer, François Delange. (2000) The Potential Repercussions of Maternal, Fetal, and Neonatal Hypothyroxinemia on the Progeny. Thyroid 10:10, 871-887
CrossRef64
Nadia Badawi, Jennifer J. Kurinczuk, Claire L. Mackenzie, John M. Keogh, Paul R. Burton, Patrick J. Pemberton, Fiona J. Stanley. (2000) Maternal thyroid disease: a risk factor for newborn encephalopathy in term infants. BJOG: An International Journal of Obstetrics and Gynaecology 107:6, 798-801
CrossRef65
MARIO ROTONDI, CIRO CACCAVALE, CARMINE DI SERIO, ANDREA DEL BUONO, FRANCESCA SORVILLO, DANIEL GLINOER, ANTONIO BELLASTELLA, CARLO CARELLA. (1999) Successful Outcome of Pregnancy in a Thyroidectomized-Parathyroidectomized Young Woman Affected by Severe Hypothyroidism. Thyroid 9:10, 1037-1040
CrossRef66
Haddow, James E., Palomaki, Glenn E., Allan, Walter C., Williams, Josephine R.Knight, George J., Gagnon, June, O'Heir, Cheryl E., Mitchell, Marvin L., Hermos, Rosalie J., Waisbren, Susan E., Faix, James D., Klein, Robert Z., . (1999) Maternal Thyroid Deficiency during Pregnancy and Subsequent Neuropsychological Development of the Child. New England Journal of Medicine 341:8, 549-555
Full Text67
GREGORY A. BRENT. (1999) Maternal Hypothyroidism: Recognition and Management. Thyroid 9:7, 661-665
CrossRef68
F. VERMIGLIO, V.P. LO PRESTI, M.G. CASTAGNA, M.A. VIOLI, M. MOLETI, M.D. FINOCCHIARO, F. MATTINA, A. ARTEMISIA, F. TRIMARCHI. (1999) Increased Risk of Maternal Thyroid Failure with Pregnancy Progression in an Iodine Deficient Area with Major Iodine Deficiency Disorders. Thyroid 9:1, 19-24
CrossRef69
R. H. Mortimer. (1998) Thyroid disease and pregnancy. Australian and New Zealand Journal of Medicine 28:5, 647-653
CrossRef70
Claire J. Mooney, Diane A. James, Cathy R. Kessenich. (1998) Diagnosis and Management of Hypothyroidism in Pregnancy. Journal of Obstetric, Gynecologic, <html_ent glyph="@amp;" ascii="&"/> Neonatal Nursing 27:4, 374-380
CrossRef71
BEATRIZ R. OLSON. (1998) Facets of Thyroid Disease in Women: Four Case Reports. Journal of Women's Health 7:1, 85-91
CrossRef72
Jean E. Mulder. (1998) THYROID DISEASE IN WOMEN. Medical Clinics of North America 82:1, 103-125
CrossRef73
C. D. KARABINAS, G. J. TOLIS. (1998) Thyroid disorders and pregnancy. Journal of Obstetrics & Gynaecology 18:6, 509-515
CrossRef74
J ECKER, T MUSCI. (1997) TREATMENT OF THYROID DISEASE IN PREGNANCY. Obstetrics and Gynecology Clinics of North America 24:3, 575-589
CrossRef75
MARTÍN N. MONTORO. (1997) Management of Hypothyroidism During Pregnancy. Clinical Obstetrics and Gynecology 40:1, 65-80
CrossRef76
Ernest L. Mazzaferri. (1997) Evaluation and management of common thyroid disorders in women. American Journal of Obstetrics and Gynecology 176:3, 507-514
CrossRef77
Robert S Lindsay, Anthony D Toft. (1997) Hypothyroidism. The Lancet 349:9049, 413-417
CrossRef78
Wood, Alastair J.J., , Surks, Martin I., Sievert, Rubens, . (1995) Drugs and Thyroid Function. New England Journal of Medicine 333:25, 1688-1694
Full Text79
Reg Hall. (1995) Pregnancy and autoimmune endocrine disease. Baillière's Clinical Endocrinology and Metabolism 9:1, 137-155
CrossRef80
Epstein, Franklin H., , Burrow, Gerard N.Fisher, Delbert A.Larsen, P. Reed. (1994) Maternal and Fetal Thyroid Function. New England Journal of Medicine 331:16, 1072-1078
Full Text81
Wood, Alastair J.J., , Toft, Anthony D.. (1994) Thyroxine Therapy. New England Journal of Medicine 331:3, 174-180
Full Text82
J. C. Girling, M. Swiet. (1994) The thyroid and pregnancy. BJOG: An International Journal of Obstetrics and Gynaecology 101:2, 180-180
CrossRef83
R. Hall, J. H. Lazarus. (1994) Authors' reply. BJOG: An International Journal of Obstetrics and Gynaecology 101:2, 181-181
CrossRef84
R. Hall, C. J. Richards, J. H. Lazarus. (1993) The thyroid and pregnancy. BJOG: An International Journal of Obstetrics and Gynaecology 100:6, 512-515
CrossRef85
STEVEN C. BOYAGES, JEAN-PIERRE HALPERN. (1993) Endemic Cretinism: Toward a Unifying Hypothesis. Thyroid 3:1, 59-69
CrossRef86
JOANNA C. GIRLING, MICHAEL SWIET. (1992) Thyroxine dosage during pregnancy in women with primary hypothyroidism. BJOG: An International Journal of Obstetrics and Gynaecology 99:5, 368-370
CrossRef87
J.R. STOCKIGT. (1992) Assessment of Thyroid Function During Pregnancy: Comment. Thyroid 2:1, 63-64
CrossRef88
DANIEL GLINOER, MARC LEMONE. (1992) Goiter and Pregnancy: A New Insight into an Old Problem. Thyroid 2:1, 65-70
CrossRef89
MICHAEL M. KAPLAN. (1992) Assessment of Thyroid Function During Pregnancy. Thyroid 2:1, 57-61
CrossRef90
P. REED LARSEN. (1992) Commentary: Monitoring Thyroxine Treatment During Pregnancy. Thyroid 2:2, 153-154
CrossRef91
MICHAEL M. KAPLAN. (1992) Monitoring Thyroxine Treatment During Pregnancy. Thyroid 2:2, 147-152
CrossRef92
(1990) Therapy of Hypothyroidism. New England Journal of Medicine 323:2, 126-127
Full Text
