|Year : 2015 | Volume
| Issue : 2 | Page : 57-61
Study for optimal dose determination of levothyroxine in subclinical hypothyroidism in pregnancy
Semanti Chakraborty1, Jayanta Chakraborty1, Ankan Bandopadhay2
1 Department of Medicine and Endocrinology, Vivekananda Institute of Medical Sciences, Kolkata, West Bengal, India
2 RG Kar Medical College, Kolkata, West Bengal, India
|Date of Web Publication||8-May-2015|
Department of Medicine and Endocrinologist, Vivekananda Institute of Medical Sciences, 516 Jodhpur Park, 99 Sarat Bose Road, Kolkata - 700 068
Source of Support: None, Conflict of Interest: None
Context: Subclinical thyroid dysfunction has been associated with pregnancy complications and affects both maternal and fetal outcomes such as impaired neuropsychological development in offspring and adverse obstetric outcomes-including miscarriage, premature birth, gestational hypertension, placental abruption, and fetal death. Endocrine Society guidelines recommend that all pregnant women with subclinical hypothyroidism be treated with Levothyroxine. The American Thyroid Association guidelines recommend that pregnant women with subclinical hypothyroidism and detectable thyroid-peroxidase antibodies receive Levothyroxine. But till date no authority has given any guideline about the initial dose of Levothyroxine. Aims: To formulate a dosage regime of levothyroxine which is optimal for urgent correction of hypothyroid state in pregnancy. Settings and Design: Prospective (longitudinal) study. Subjects and Methods: A total of 42 apparently normal pregnant women, with known last-menstrual period, with no known metabolic or hypertensive disorder who presented to the clinic had thyroid screening using a standardized method. Women with thyroid stimulating hormone (TSH) value in the range to be diagnosed as subclinical hypothyroidism were included in the study. All patients were followed-up till the time of delivery for the obstetric outcome. Levothyroxine was the mainstay of treatment. Levothyroxine dose were adjusted every trimester on the basis of thyroid function tests (TFTs) including free thyroxine (FT4) and TSH values. Anthropometric measurements included height and body weight at baseline. Statistical Analysis Used: Significance is assessed at 5% level of significance. Pearson and Spearmen correlation test used to find out correlation among normally and non-normally distributed data respectively. Analysis of variance (ANOVA) and Kruskal-wallis with distribution free multiple comparison test used to find the significance of study parameters between three or more groups of patients for normally distributed data and non-normally distributed data. Results: 81.25% of subjects achieved euthyroidism in third trimester. The mean levothyroxine dose used in the first trimester was 40.18 ± 13.78 μg. The mean levothyroxine dose used in the third trimester was 58.25 ± 18.57 μg. Significant increase in the mean dose of levothyroxine required in the third trimester (58.25 ± 18.57 μg) as compared to the first trimester (40.18 ± 13.78 μg, P = 0.0012). Conclusions: Significant improvement in the thyroid function as indicated by higher proportion of patients achieving normal TSH values with significant increase in the mean levothyroxine dose used during the course of treatment gives us guideline about the initial starting doses of levothyroxine.
Keywords: Levothyroxine, pregnancy, subclinical hypothyroidism, thyroid function
|How to cite this article:|
Chakraborty S, Chakraborty J, Bandopadhay A. Study for optimal dose determination of levothyroxine in subclinical hypothyroidism in pregnancy. Thyroid Res Pract 2015;12:57-61
|How to cite this URL:|
Chakraborty S, Chakraborty J, Bandopadhay A. Study for optimal dose determination of levothyroxine in subclinical hypothyroidism in pregnancy. Thyroid Res Pract [serial online] 2015 [cited 2020 Aug 8];12:57-61. Available from: http://www.thetrp.net/text.asp?2015/12/2/57/156727
| Introduction|| |
The recognition of abnormality in thyroid function tests during pregnancy is important for the well-being of both the mother as well as the fetus  Thyroid dysfunction has been associated with pregnancy complications such as preterm birth, hypertension, low birth weight, placental abruption, and fetal death.  The studies identifying the cause-effect relationship between subclinical hypothyroidism and pregnancy outcome has not been well documented. We have undertaken this prospective study to assess optimal dose determination of levothyroxine and pregnancy outcomes in women with subclinical hypothyroidism.
Pregnancy has an intense impact on the thyroid gland and thyroid function. There have been reports of thyroid gland enlargement by or more than 10% in iodine deficient countries during pregnancy.  The production of thyroid hormones and iodine requirement each increases by approximately 50% during pregnancy.  Pregnancy is a stressful condition for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency. Maternal thyroxine specifically have been found to play an important role, particularly in early pregnancy because the fetal thyroid gland is unable to synthesize iodothyronines until after 10 weeks of gestation. From 10 weeks onward, maternal as well as fetal thyroid hormones are necessary for normal neurodevelopment.  The infant can develop intense neurologic impairment and mental retardation as a result of severe iodine deficiency. , Overt maternal hypothyroidism resulting from glandular failure in the first trimester, is also associated with intellectual impairment during childhood as well as pregnancy complications that comprises of preeclampsia, placental abruption, preterm birth, low birth weight, and foetal death. , The effects of mild maternal thyroid deficiency with a normally functioning foetal thyroid gland are still blurred in scientific vision. This is of paramount importance because the spectrum of thyroid deficiency begins with subclinical hypothyroidism characterized by an elevated serum thyroid stimulating hormone (TSH) concentration but a normal serum free thyroxine (FT4) level. ,
Moreover, the signs and symptoms of hypothyroidism do not have any fixed pattern, often transient, and sometimes mistaken for pregnancy-related changes. Patients may report fatigue, constipation, weight gain, cold intolerance, and hair and skin changes to varying degrees. Goitre is unusual, but thyroid enlargement may occur in special circumstances as discussed above. Among patients with Subclinical Hypothyroidism (SCH), approximately 13-24% report one or more of these symptoms.  In most cases, SCH is a laboratory diagnosis because patients are usually asymptomatic. Risk factors include personal or family history of thyroid dysfunction, advanced maternal age, diabetes, other autoimmune disorders, and possibly morbid obesity.  Relying on symptoms and risk factors alone for detection may lead to missing as many as 30% of SCH cases. 
In addition, the diagnosis of thyroid dysfunction during pregnancy is challenging due to number of changes in thyroid physiology. Thyroid binding globulin (TBG) and total T4 levels increase rapidly and remain elevated throughout pregnancy. FT4 and triiodothyronine (T3) levels generally stay the same or are slightly decreased.  The overall production of T3 and T4 has to increase to offset the increase in binding to TBG. TSH shares a subunit with human chorionic gonadotropin (hCG), and is therefore suppressed until the second trimester by rapid increases in hCG. The thyroid takes up iodine more rapidly and renal excretion increases, so more intake is required to maintain homeostasis.
| Subjects and methods|| |
A total of 42 apparently normal pregnant women, with known last-menstrual period, with no known metabolic or hypertensive disorder who presented to the clinic had thyroid screening using a standardized method. Women with TSH value in the range to be diagnosed as subclinical hypothyroidism and who gave a written consent were included in the study. All patients were subjected to detailed history and clinical examination using a predesigned pro forma. Blood samples were collected in out-patient department (OPD) setting between 0800 and 1100 hours. The serum urea, creatinine, bilirubin, aspartate aminotransferase, and alanine aminotransferase levels were checked to assess liver and renal function
All patients were followed-up till the time of delivery for the obstetric outcome. Levothyroxine was the mainstay of treatment. Levothyroxine dose were adjusted every trimester on the basis of thyroid function tests (TFTs) including T4 and TSH values. Anthropometric measurements included height and body weight at baseline [Table 1].
Descriptive statistical analysis has been carried out in the present study. Results on continuous measurements/quantitative data are presented on Mean ± SD (Min-Max) and results on categorical measurements are presented in number (%). Significance is assessed at 5% level of significance. The analysis was carried out according to trimester at the time of enrolment of the subjects. Normality of the distribution of data was determined using Anderson Darling test. Pearson correlation test would be used to find out correlation among normally distributed data and Spearmen correlation test would be used to find out correlation among non-normally distributed data. Analysis of variance (ANOVA) would be used to find the significance of study parameters between three or more groups of patients for normally distributed data and Kruskal-wallis with distribution free multiple comparison test would be used to find the significance of study parameters between three or more groups of patients for non-normally distributed.
The data was analyzed by employing SAS (version 9.1) software.
| Results|| |
In the 42 women studied, mean age was 27.66 ± 6.40, mean weight was 59.26 ± 9.26 kg and mean body mass index BMI was 24.97 ± 3.87 kg/m2 (based on 39 patient's data) [Table 4].
|Table 2: Proportion of patients with normal and elevated TSH values at 2nd Trimester |
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|Table 3: Proportion of patients with normal and abnormal TSH values at 3rd trimester |
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The mean levothyroxine dose used in the first trimester was 40.18 ± 13.78 μg. The minimum and maximum dose used being 25 and 75 μg respectively. [Table 2] shows the frequency and percentage of patients with normal and abnormal TSH value in the second trimester.
Eighteen (72.00%) out of 25 patients in the second trimester were having normal TSH value (<=3 mIU/L) and the remaining 7 patients (28.00%) were having abnormal TSH value (>3 mIU/L). The mean levothyroxine dose used in the second trimester was 50.29 ± 17.469 μg. The minimum and maximum dose used being 25 and 75 μg respectively. [Table 2] shows the frequency and percentage of patients with normal and abnormal TSH value in the second trimester. [Figure 1] shows the percentage of patients with normal and abnormal TSH value in the second trimester.
Thirteen (81.25%) out of 16 patients in the third trimester were having normal TSH value (<=3 mIU/L) and the remaining three patients (18.75%) were having abnormal TSH value (>3 mIU/L). The mean levothyroxine dose used in the third trimester was 58.25 ± 18.57 μg. The minimum and maximum dose used being 25 and 100 μg respectively. [Table 3] shows the frequency and percentage of patients with normal and abnormal TSH value in the third trimester. [Figure 2] shows the percentage of patients with normal and abnormal TSH value in the sthird trimester.
Significant increase in the mean dose of levothyroxine required in the third trimester (58.25 ± 18.57 μg) as compared to the first trimester (40.18 ± 13.78 μg, P = 0.0012), as determined by kruskal-wallis test and distribution free Bonferroni multiple comparison method. No significant difference in the mean dose of levothyroxine required in the first trimester (40.18 ± 13.78 μg) and second trimester (50.29 ± 17.469 μg, P = 0.052), as determined by kruskal-wallis test and distribution free Bonferroni multiple comparison method. No Significant difference in the mean dose of levothyroxine required in the second trimester (50.29 ± 17.469 μg) and third trimester (58.25 ± 18.57 μg, P = 0.454), as determined by kruskal-wallis test and distribution free Bonferroni multiple comparison method. No significant correlation between BMI and overall levothyroxine dose in first trimester. (P = 0.208), as determined by Spearmen correlation test. No significant correlation between BMI and overall levothyroxine dose in second trimester (P = 0.401), as determined by Spearmen correlation test. No significant correlation between BMI and overall levothyroxine dose in third trimester. (P = 0.194), as determined by Spearmen correlation test.
| Discussion|| |
Thyroid dysfunction during pregnancy had been an important research area in clinical endocrinology due to the fact that thyroid dysfunction has immense impact on maternal and foetal outcomes. , More importantly, children born to hypothyroid mothers have poor intellectual function during later part of their life.  Haddow and associates had published a study what is perhaps the best-known study evaluating an association between overt and SCH and foetal neurodevelopmental outcomes. From a large perinatal serum screening bank, the authors had identified 62 women with TSH values between the 98-99.7percentiles, out of which 48 had not received thyroid replacement therapy during pregnancy. The subjects' mean FT4 was within the lower limit of the normal trimester-specific reference range (0.71 ng/dL). They had also identified control subjects (n = 124) and their children and compared them with the hypothyroid subjects. The children of the hypothyroid subjects did statistically less well on 2 of 15 developmental tests. When the 48 untreated subjects were analyzed separately, the children's average IQ scores were 7 points lower than those of matched controls (P = 0.005). The incidence of IQs less than or equal to 85 was also significantly elevated in the untreated group (P = 0.007). Among the 14 treated subjects, results more closely mirrored those of the controls. These observations led the authors to conclude that children of women whose TSH levels were elevated during the mid-trimester of pregnancy had a slight but significant reduction in intelligence quotient scores between 7 and 9 years of age when compared with infants of euthyroid women.  The studies conducted separately by Davis and Leung had also made similar observations in the past that subclinical maternal hypothyroidism might be associated with poor pregnancy outcomes such as placental abruption, preterm birth, and low birth weight infants. , Allen et al., also reported that women with TSH values more than 10 mU/L also had significantly more stillborn infants.  A related observation was also reported by Pop and colleagues about a significant association between abnormally low maternal serum FT4 levels at 12 weeks of pregnancy and impaired neurodevelopment in infants at 10 months.  Thus in the present study, which is a pioneer one gives guidelines of the initial and trimester specific levothyroxine doses in SCH in pregnancy [Table 5]. Trimester specific doses of levothyroxine are as follows. (Levothyroxine mcg/kg body weight) First trimester -0.63 + -0.27. second trimester -0.82+ -0.30, Third trimester -0.94 + -0.40 [Figure 3]. This is quite low as compared to non pregnant overt hypothyroid patients.
The early and rapid attainment of euthyroid state by initial optimum dose and trimester specific escalation of the doses of levothyroxine lead to fast acievement of euthyroid status and consequent less complications.
| References|| |
Kumar A, Gupta N, Nath T, Sharma JB, Sharma S. Thyroid function tests in pregnancy. Indian J Med Sci 2003;57:252-8.
Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, et al
. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105:239-45.
van Raaij JM, Vermaat-Miedema SH, Schonk CM, Peek ME, Hautvast JG. Energy requirements of pregnancy in The Netherlands. Lancet 1987;2:953-5.
Glinoer D. The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-33.
Utiger RD. Maternal hypothyroidism and foetal development. N Engl J Med 1999;341:601-2.
Cao XY, Jiang XM, Dou ZH, Rakeman MA, Zhang ML, O'Donnell K, et al
. Timing of vulnerability of the brain to iodine deficiency in endemic cretinism. N Engl J Med 1994;331:1739-44.
DeLong GR, Stanbury JB, Fierro-Benitez R. Neurological signs in congenital iodine-deficiency disorder (endemic cretinism). Dev Med Child Neurol 1985;27:317-24.
Davis LE, Leveno KJ, Cunningham FG. Hypothyroidism complicating pregnancy. Obstet Gynecol 1988;72:108-12.
Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH. Perinatal outcome in hypothyroid pregnancies. Obstet Gynecol 1993;81:349-53.
Cooper DS. Subclinical hypothyroidism. N Engl J Med 2001;345:260-5.
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al
. Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management. JAMA 2004;291:228-38.
Razvi S, Weaver JU, Pearce SH. Subclinical thyroid disorders: Significance and clinical impact. J Clin Pathol 2010;63:379-86.
Rotondi M, Leporati P, La Manna A, Pirali B, Mondello T, Fonte R, et al
. Raised serum TSH levels in patients with morbid obesity: Is it enough to diagnose subclinical hypothyroidism? Eur J Endocrinol 2009;160:403-8.
Vaidya B, Anthony S, Bilous M, Shields B, Drury J, Hutchison S, et al
. Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high-risk case finding? J Clin Endocrinol Metab 2007;92:203-7.
Soldin OP, Tractenburg RE, Hollowell JG, Jonklaas J, Janicic N, Soldin SJ. Trimester-specific changes in maternal thyroid hormone, thyrotropin, and thyroglobulin concentrations during gestation: Trends and associations across trimesters in iodine sufficiency. Thyroid 2004;14:1084-90.
Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al
. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549-55.
Allan WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Hermos RJ, et al
. Maternal thyroid deficiency and pregnancy complications: Implications for population screening. J Med Screen 2000;7:127-30.
Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, et al
. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999;50:149-55.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]