Levothyroxine For Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy


Roy Davenport, Mercer University College of Pharmacy

Conditions such as subclinical hypothyroidism and hypothyroxinemia may develop in pregnancy and can have major or fatal effects on the outcome of the fetus.  Cognitive dysfunction may occur in the offspring due to thyroid hormone deficiency, especially in the first trimester.  Clinical data was considered to be limited on the implementation of thyroid hormone replacement therapy during early stages of pregnancy would result in increased cognitive functioning in the offspring. [1]


Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy [2]
Design Two multicenter, randomized, placebo-controlled trials; N= 1,203
Objective To determine if levothyroxine treatment in pregnant patients with hypothyroidism or hypothyroxinemia improves cognitive function in their children
Study Groups Pregnant women before 20 weeks of gestation: hypothyroidism (n= 677) and hypothyroxinemia (n= 526)
Child I.Q assessments (n= 323)
Methods Eligible women were screened for subclinical hypothyroidism (thyrotropin levels greater than or equal to 4.00 mU/L and normal  free thyroxine levels [T4] of 0.86 – 1.90 ng/dL) and hypothyroxinemia (normal thyrotropin levels of 0.08 – 3.99 mU/L and free thyroxine levels less than 0.86 ng/dL).  Women were given a 7 day supply of placebo and those subjects that took 50% or more of the capsules and returned within two weeks were randomized into either the hypothyroidism or hypoproteinemia trial.  
Subjects in the hypothyroidism trial began taking 100 ug of levothyroxine daily while those in the hypothyroxinemia trial took 50 ug of levothyroxine daily.  Each trial was compared to a placebo.  Every month blood samples were taken within both trials and adjusted to produce a goal thyrotropin level of 2.5 mU/L in the hypothyroidism group and a goal of normal free T4 levels in the hypothyroxinemia group.  The maximum dose of levothyroxine for both trials was 200 ug.
A full-scale IQ was assessed in offspring at age 5 with Wechsler Preschool and Primary Scale of Intelligence III and Wechsler Preschool (WPPSI-II).  The Differential Ability Scales-II (DAS) was used at 3 years of age or death before age 3.  Analysis was performed via the Wilcox test with the intention-to-treat principle.
Duration 5 years
Primary Outcome Measure IQ score of offspring at 5 years of age
Baseline Characteristics
Subclinical Hypothyroidism Hypothyroxinemia
Levothyroxine Placebo Levothyroxine Placebo
Mean age, yrs ± SD 27.7 ± 5.7 27.3 ± 5.7 27.8 ± 5.7 28.0 ± 5.8
Race, n (%)
Black 27 (8) 25 (7) 61 (23) 65 (25)
Hispanic 195 (58) 185 (55) 131 (49) 125 (48)
White 109 (32) 117 (35) 69 (26) 69 (26)
BMI, kg/m2 ±SD 28.1 ± 6.4 28.2 ± 6.4 30.3 ± 6.4 30.2 ± 7.1
Thyrotropin, mU/liter
Median 4.5 4.3 1.5 1.4
95% CI 4.4-4.7 4.2-4.5 1.4-1.6 1.3-1.5
Free thyroxine, ng/dL
Median 1.01 1.02 0.83 0.83
95% CI 1.00-1.02 1.01-1.04 0.82-0.83 0.82-0.83
Gestation, wks ± SD 16.6 ± 3.0 16.7 ± 3.0 18.0 ± 2.8 17.7 ± 2.9
Offspring, n Median I.Q score, n (95% Cl) p value
Subclinical Hypothyroidism
Levothyroxine 323 97 (94-99) 0.71
Placebo 326 94 (92-96)
Levothyroxine 254 94 (91-95) 0.30
Placebo 253 91 (89-93)
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: death, subclinical hypothyroidism trial (n= 1 child)
Percentage that Discontinued due to Adverse Events: Subclinical hypothyroidism trial; 0.4%
Study Author Conclusions Neurodevelopmental outcomes in children whose mothers received levothyroxine treatment for subclinical hypothyroidism or hypothyroxinemia during pregnancy showed no difference than in children whose mothers did not receive such treatment.

   The fetal thyroid begins development and producing hormones between 10 to 12 weeks of gestation.  The study included women in stage of gestation of 16 to 18 weeks (post first trimester), which may have altered optimal effects from thyroxine therapy. Thyroid hormone therapy may have been more beneficial prior to conception or within the first trimester for those women with subclinical hypothyroidism.  Only thyroxine was administered in this study, and cognitive behavior may still turn out to be affected by other thyroid hormone replacements.   


[1] Tudosa R, Vartej P, Horhoianu I, Ghica C, Mateescu S, Dumitrache I. Maternal and fetal complications of the hypothyroidism-related pregnancy. Maedica (Buchar). 2010;5(2):116-23.

[2] Casey BM, Thom EA, Peaceman AM, et al. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med. 2017;376(9):815-825.



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