Adverse effects of subclinical hypothyroidism and the role for levothyroxine

Adverse effectEvidence of adverse effectRole for treatment with levothyroxine
Metabolic syndrome, obesity, diabetesAssociations observed, but cause and effect are unclear23,24No evidence to support
DyslipidemiaRelationships observed between thyroid-stimulating hormone (TSH) elevation and altered lipid profiles13,43Associated with improved lipid profiles2,34,4446
Cardiovascular endothelial dysfunctionIncreased risk of myocardial infarction, atherosclerosis, aortic calcification,48 cardiovascular disease and mortality37; increased arterial stiffness and systemic vascular resistance45,53Lessens cardiovascular risk and mortality in patients < 65 years
StrokeConflicting data: no association in patients ≥ 65 years, but some association in those < 65Lessens cardiovascular risk and mortality in patients < 65 years
Psychiatric and cognitive dysfunctionAssociated with worsened preexisting depression and bipolar disease; may affect cognition65May improve mood, anxiety, cognition in older patients35
Neuromuscular dysfunction, exercise intoleranceAssociated with skeletal muscle dysfunction, exercise intolerance71Limited data on treatment; role is unclear75
Bone healthAssociated with increased risk of hip fracture attributed to suppression of bone turnover by elevated TSH18,76,77Too few clinical studies to define a role
Thyroid cancerSome data suggest elevated TSH is associated with higher risk7982More studies needed to understand association
Infertility, recurrent miscarriageInconclusive evidence links subclinical hypothyroidism with infertility86; infertility rate is higher in women who also have positive thyroid peroxidase antibody than in women without autoimmunity87Some studies have shown lower rates of miscarriage with levothyroxine when TSH > 4.0 mlU/L86,9192; insufficient data to support its use in patients with subclinical hypothyroidism and infertility; however, consider in euthyroid patients with positive peroxidase antibody and recurrent miscarriage90
Pregnancy complicationsAssociated with several pregnancy-related complications including preeclampsia, hypertension, placental abruption, and postpartum hemorrhage in some studies,26,96 but not in others; if present, screen for autoimmunityNo recommendations; insufficient evidence to evaluate role of treatment
Preterm delivery, pregnancy lossAssociated with high risk of miscarriage, preterm delivery, pregnancy loss at even mildly elevated TSH levels (2.5-5 mIU/L)99;104107; risk is as high as 60% with TSH levels > 6 mIU/L and higher with positive thyroid peroxidase antibody108110Improves maternal and fetal outcomes, including risk of low birth weight and low Apgar score, in women with subclinical hypothyroidism and TSH 2.5-10 mIU/L93,106; evidence less clear with TSH 2.5-4 mIU/L86; not recommended for the subgroup of pregnant patients with negative thyroid peroxidase antibody and TSH within pregnancy-specific range or < 4 mIU/L