Subclinical hypothyroidism, outcomes and management guidelines: a narrative review and update of recent literature

Figures & data

Table 1. Overview of studies describing the clinical course of thyroid disease in subjects presenting with subclinical hypothyroidism.

Ref	N	Main findings
21	82	10-year incidence of overt HT according to baseline TSH was 0% (TSH 4–6 mIU/L), 42.8% (TSH >6–12 mIU/L), and 76.9% (TSH >12 mIU/L) (p < 0.001 for trend); the presence vs. absence of TPO Ab was associated with greater progression to overt HT (58.5% vs. 23.2%, p < 0.03)
22	3,996	Reversion to euthyroidism at 2 years was more common for TSH 4.5–6.9 vs. 7–9.9 or 10 mIU/L (46%, 10%, 7%, respectively, p < 0.001 among elderly subjects with SCH; the absence vs. presence of TPO Ab was associated with more frequent reversion to euthyroidism (48% vs. 15%, p < 0.001)
23	71	Progression to overt HT was higher for subjects with SCH (7.0%) vs, controls (1.6%) after adjustment for other factors (OR 4.56, p = 0.009); TPO Ab was also a significant multivariate predictor of progression
24	107	Increasing baseline TSH was associated with higher rates of conversion to overt HT (cases of overt HT/100 person-years were 1.76 (TSH 5–9.9 mIU/L), 19.67 (TSH 10–14.9 mIU/L), and 73.47 (TSH 15.0–19.9 mIU/L); TSH was the only significant multivariate predictor of progression
26	68	Optimal cut-off values for predicting overt HT were baseline TSH >2.5 mIU/L (vs. ≤4.0 mIU/L), TPO Abs >29 kIU/L (vs. 35 kIU/L), and Tg Abs >22 kIU/L (vs. 55 kIU/L); for women with TPO Ab or Tg Ab, the prevalence of overt HT after 14 years was 12.0% (baseline TSH ≤ mIU/L), 55.2% (TSH 2.5–4.0 mIU/L), 85.7% (TSH >4.0 mIU/L)

Abbreviations. Ab, antibodies; HT, hypothyroidism; Tg, thyroglobulin; OR, odds ratio; TPO, thyroid peroxidase; SCH, subclinical hypothyroidism; TSH, thyrotropin/thyroid stimulating hormone.

Table 2. Overview of evidence for associations between subclinical hypothyroidism (SCH) and adverse clinical outcomes in adult patients, presented in the 2013–4 European Thyroid Association (ETA) guidelines for the management of SCH^4,5.

Clinical issue	Overview of the extent of evidence presented for an aetiological relationship with SCH
Dyslipidaemia	Observational studies published before 2013 reported inconsistent associations between the level of TSH and effects on the lipid profile. Overall, the evidence at the time supported a modest, though clinically significant, adverse effect of increased TSH on the lipid profile, with elevations of total and LDL-cholesterol. There was a suggestion of more marked adverse effects on lipids effects in women and in older subjects. Randomized evaluations of LT4, and meta-analyses of these studies, supported a reduction in total- and LDL-cholesterol following LT4 therapy, but these effects may have been more marked where TSH was particularly high, possible weakening the association between dyslipidaemia and SCH (as opposed to overt hypothyroidism), as seen in most patients with the condition.
Obesity	Longitudinal studies demonstrated an association between increasing levels of TSH and higher body weight, including following careful adjustment for potential confounders of this relationship, such as age, smoking and menopausal status. Importantly, the relationship was bidirectional – increased TSH was associated with weight gain, and reduction in the TSH level was associated with weight loss.
ASCVD and vascular function	Three observational studies associated SCH with increased aortic or carotid IMT, a validated measure of atherosclerosis, and one of these associated SCH with an increased risk of MI. Three further studies demonstrated an association of SCH with endothelial dysfunction. RCTs demonstrated LT4-mediated improvements in endothelial function (2 studies) IMT (1 study) and cardiac dynamics (2 studies).
Ischaemic heart disease or stroke	Evidence for association of TSH with CHD events was consistent, especially for TSH >10 mIU/L. RCTs (mostly small) of LT4 and observational data suggested a possible, but modest, benefit for LT4 on CV risk. One observational study suggested a lack of association between SCH and stroke.
Diabetes	SCH and overt hypothyroidism coexist frequently with type 1 (autoimmune) diabetes. Hypothyroidism increases insulin resistance which may exacerbate or precipitate type 2 diabetes and metabolic syndrome (see also the sections on obesity and dyslipidaemia).
Heart failure and LV function	Several studies associated SCH with systolic and diastolic LV dysfunction. Some (not all) observational studies suggested a increased risk of heart failure events with increased TSH (including in patients with SCH), but much of this evidence related to TSH >10 mIU/L.
Bone health	The ETA guidelines did not discuss effects of SCH on bone health in adults.
Cancer	Good evidence to support an association between TSH levels (including within the normal range) and thyroid cancer. Encouraging (but not definitive) cross-sectional evidence for reduction of thyroid cancer risk with LT4 in people with nodular goitre.
Pregnancy outcomes^a	Although overt hypothyroidism clearly promotes adverse pregnancy outcomes (including pre-eclampsia, pregnancy loss, devastating developmental impairment of offspring), associations between SCH and adverse pregnancy outcomes (and the effects of LT4) were less clear. However, several studies associated SCH with pregnancy loss, gestational hypertension and pre-eclampsia. SCH was also associated with gestational diabetes. Data on SCH and other pregnancy complications, and on associations between SCH in pregnancy and neuropsychological impairment in offspring, were conflicting.
Psychological outcomes	Multiple placebo-controlled or observational studies demonstrated improvements in mood or psychological function when LT4 was used to control TSH; conversely, mood/psychological function deteriorated when LT4 was withdrawn. This was not demonstrated for TSH <10 mIU/L, however. Heterogeneous study populations and study designs seem to have complicated the interpretation of these data.

References supporting the conclusions from the 2013 guidance can be found within the original article and are not reproduced here for conciseness. Abbreviations. ASCVD, atherosclerotic CV disease; CV, cardiovascular; IMT, intima-media thickness; LV, left ventricle (or ventricular); RCT, randomized, controlled trial; SCH, subclinical hypothyroidism.

^aAll material is from the 2013 ETA guideline for the management of SCH⁴ except for pregnancy outcomes, which was abstracted from the 2014 ETA guideline for the management of SCH in pregnancy and children⁵.

Table 3. Summaries of randomized, controlled trials or observational studies that evaluated the effects of SCH and its treatment on classical cardiovascular risk factors.

Ref/y	Risk factor or outcome	Design	N^a	Overview of key findings
50	Vascular dysfunction	RCT^b	184	18 months of treatment with LT4 vs. placebo did not reduce mean CIMT (mean treatment difference 0.02 mm [95%CI, −0.01 to 0.06], p = 0.30); no difference between groups for proportion of carotid plaque, plaque thickness, and no signal for treatment effect in subgroups defined by age, baseline TSH, or presence/absence of CVD
66	AMI	RCT	95	1 year of LT4 vs. placebo did not affect LVEF significantly vs. placebo (mean difference 0.76% [95%CI −0.93 to 2.46], p = 0.37) in a population with SCH admitted for AMI; secondary endpoints also did not demonstrate differences between treatment groups (LV volumes, infarct size, AE, patient-reported outcomes [health status, HRqOL, depression])
47	Vascular dysfunction	Obs	32^c	Children with SCH (autoimmune thyroiditis) vs. controls had higher atherogenic index (AI), levels of hs-CRP EFT and lower endothelial function (flow-mediated vasodilatation); epicardial fat thickness correlated with TSH, hs-CRP, AI, and endothelial dysfunction
51	Vascular dysfunction	Obs	18^c	CIMT was higher for people with SCH vs. healthy controls; six months of treatment with LT4 was associated with a significant reduction in CIMT after 3 and 6 months of treatment
68	Blood pressure	Obs	3,078	No difference in office BP according to presence vs. absence of SCH but measures of ambulatory BP were higher for SCH vs. euthyroid, with more in the SCH group not displaying a night-time dip in BP; SCH was associated with sustained and masked hypertension.
57	CHF	Obs	54	Subjects with vs. without SCH had lower E/A ratio, higher E/e’ sep. ratio, higher myocardial performance index (MPI), lower global longitudinal strain (GLS), and lower S wave (tissue Doppler imaging); 5 months of LT4 treatment were associated with higher ejection fraction, lower E/e’ sep. ratio, lower MPI, and improved GLS vs. baseline TSH levels correlated negatively with ejection fraction, E/A ratio, GLS, and S/TDI and correlated positively with E/e’ sep., irrespective of thyroid status
58	CHF	Obs	80	LV systolic and diastolic function and RV function were impaired in women with SCH vs. 35 control subjects; LV mass remained higher for SCH vs. controls after LT4 therapy
59	CHF	Obs	38	Lower phosphocreatine:ATP ratio was associated independently with SCH implying impaired cardiac bioenergentics; LT4 treatment improved this parameter so that it did not differ significantly from controls
60	CHF	Obs	20	Cardiac magnetic resonance (CMR) myocardial longitudinal relaxation time (T1) mapping demonstrated diffuse myocardial injury and deficits correlated positively with TSH and negatively with FT4; LV diastolic function was poorer in subjects with vs. without SCH
63	CHF	Obs	1,100	SCH was associated with lower O2 consumption and higher pulmonary artery pressure (no difference for LV function) in patients with pre-existing CHF; SCH significantly predicted increased risk of MACE and mortality
76	MACE	Obs	3,021	Subjects with SCH and TSH in the highest quartile were at increased risk of CV events and death, especially for subjects with high CV risk according to risk factor scoring
77	MACE	Obs	344^d	Elevated TSH predicted increased risk of CV events, but adding TSH to conventional risk factor scoring had little effect on risk prediction
78	MACE	Obs	936	SCH vs. euthyroidism in patients who had undergone coronary revascularization independently predicted increased risk of revascularization, cardiac death and a composite event occurred more frequently in the SCH group than in the euthyroidism; TSH levels predicted the risk of a CV event

^aNumber of subjects enrolled. ^bRCT nested within the Thyroid Hormone Replacement for Subclinical Hypothyroidism trial. ^cPlus the same number of matched control subjects. ^d344 with SCH plus 2,624 euthyroid controls.

Abbreviations. AE, adverse event; ASCVD, atherosclerotic CV disease; CV, cardiovascular; IMTm intima-media thickness; LV, left ventricle (or ventricular); RCT, randomized, controlled trial; AMI, acute myocardial infarction; CHF, congestive heart failure; CIMT, carotid intima-media thickness; CV, cardiovascular; HRqOL, health-related quality of life; LT4, levothyroxine; LV, left ventricular; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular event; Obs, observational study; RCT, randomized, controlled trial; RV, right ventricular; SCH, subclinical hypothyroidism; TSH, thyrotropin/thyroid stimulating hormone. Type 2 diabetes and obesity are not included here as were only meta-analyses were published post-2014 in these areas.

Table 4. SCH and cardiovascular risk factors other than obesity, diabetes, chronic kidney disease or high blood pressure.

Ref/y	Risk factor	Design	N^a	Overview of key findings
72/2016	FGF-19	Obs	99	Significantly decreased fibroblast growth factor-19 (FGF-19) levels, an endocrine factor associated with metabolic regulation, in SCH or overt hypothyroidism vs. euthyroid controls in a cross-sectional study. The presence vs. absence of isolated anti-thyroid antibodies did not affect serum FGF.
73/2015	Haemostasis	Obs	82	SCH was associated with a prothrombotic state vs. healthy controls (high Factor VII, PAI-1, tPA, mean platelet volume, higher platelet aggregability, and low D-dimer). Six months of LT4 improved all of these parameters significantly, except for a non-significant trend to improvement in D-dimer.
74/2022	Haemostasis	MA	12/1,325	People with SCH had a hypercoagulable and hypofibrinolytic haemostatic profile with increased tPA and PAI-1, compared with a control group. No difference for activated partial thromboplastin time (APTT) or D-dimer between groups
75/2020	Homocysteine	MA	12/684	Slight but significant increase in plasma homocysteine, an amino acid associated with higher cardiovascular risk, for people with SCH vs. controls aged 18–65 years.

^aNumber of subjects enrolled (no. of trials/patients for meta-analyses). Abbreviations. MA, meta-analysis; Obs, observational study.

Table 5. Publications on pregnancy outcomes in people with subclinical hypothyroidism (SCH) that have appeared since the publication of the 2014 European Thyroid Association guideline for the management of SCH during pregnancy.

(a) Randomized and observational studies
Ref/y	N^a	Design	Overview of key findings
95/2022	1,736	RCT	LT4 treatment increased the live birth rate and reduced spontaneous pregnancy loss in women who were TPOAb + or who had SCH; no effect of LT4 on women without recurrent pregnancy loss irrespective of TPOAb or thyroid status.
96/2018	573 neonates	RCT	No difference in neonatal TSH according to LT4 use by mothers with hypothyroxinaemia or SCH (pre-specified secondary analysis of data from 2 prior RCTs)
97/2017	677	RCT	No effect of LT4 on neurocognitive outcome of children of mothers treated with LT4 or placebo during gestational weeks 8–20.
98/2016	1,671	RCT	Women screened for thyroid dysfunction in pregnancy reported fewer miscarriages or foetal macrosomia, and more Caesarean sections, than those who were not.
99/2021	1,014	Obs	No significant effect of LT4 vs. control on live birth rates in pregnant women with SCH and a history of pregnancy loss: OR 0.95 (0.23–3.83).
100/2018	534	Obs	No effect of SCH on the risk of subsequent PCOS in obese women: OR 0.984 (0.581–1.667).
101/2017	270	Obs	No difference in clinical pregnancy rate, miscarriage, or live births for groups with TSH in the upper vs. lower part of the reference range in a prospective cohort study of women undergoing first assisted reproduction.
102/2017	5,405	Obs	LT4-treated women with SCH in a large US claims database had lower median TSH (median 3.3 mIU/L) vs. non-treated women with SCH (4.8 mIU/L). The LT4 group had lower ORs for pregnancy loss (0.62 [0.48–0.82]) but higher ORs for preterm delivery (1.60 [1.14–2.24]), gestational diabetes (1.37 [1.05–1.79]), and pre-eclampsia (1.61 [1.10–2.37]); the benefit for pregnancy loss was seen only for pre-treatment TSH of 4.1–10 mIU/L and not for 2.5–4 mIU/L.
103/2016	1,193	Obs	No difference for TSH ≥2.5 mIU/L vs. <2.5 mIU/L in risk ratios for pregnancy loss (1.07 [0.81–1.41]), live births (0.97 [0.88–1.07]) or time to pregnancy (1.09 [0.90–1.31]) in a prospective cohort study
104/2013	286	Obs	No difference in live birth rate between women with SCH or no thyroid dysfunction or between treated or untreated SCH in a cohort of women with a history of pregnancy loss.
(b) Systematic reviews and meta-analyses
Ref/y	N^a	Overview of key findings
105/2022	22/108,831	Pregnant women with SCH had increased risk of hypertensive disorder of pregnancy vs. euthyroid pregnant women (OR 1.54 [1.21–1.96]), with risk increasing with TSH >4 IU/m.
106/2022	6/7,955	Study of women diagnosed with SCH according to 2017 US guidance.^6 Treatment with LT4 vs. a control group was associated with lower OR for pregnancy loss pregnant women with SCH treated with LT4 had a lower risk of pregnancy loss (0.55 [0.43–0.71), preterm birth (0.63 [0.41–0.98]) and gestational hypertension (0.78 [0.63–0.97]).
107/2021	13/7,342	Pregnant women with SCH treated with LT4 vs. controls had lower RR for pregnancy loss (0.79 [0.67–0.93]) and neonatal death (0.35; [0.17–0.72]); no difference for other pregnancy outcomes or cognitive status of offspring.
108/2020	17/–^b	No influence of SCH or LT4 on recurrent pregnancy loss. Thyroid autoimmunity predicts recurrent pregnancy loss.
109/2020	13/11,503	Lower OR for pregnancy loss (0.78 [0.66–0.94) and higher OR for live birth (2.72 [1.44–5.11]), but also higher OR for preterm labour (1.82 [1.14–2.91]) for LT4 treatment vs. placebo in pregnant women with SCH.
110/2019	4/820	No clear conclusions could be drawn concerning the effects of LT4 on fertility outcomes in women with SCH (with or without thyroid autoimmunity) undergoing assisted reproduction (Cochrane review).
111/2019	11/56,055	Increased risk of gestational diabetes in women with SCH and thyroid autoimmunity (OR 3.22 [1.72–6.03]).
112/2018	4787	Decreased miscarriage rate for LT4 vs. placebo -treated women undergoing assisted reproduction who had SCH and thyroid autoimmunity (RR 0.51 [0.32–0.82]); the effect was not significant in women with SCH or thyroid autoimmunity. No effect on live births, preterm births, or clinical pregnancy rate.
113/2018	3/1,837	No effect of LT4 vs. no LT4 on a range of outcomes including miscarriage, gestational hypertension, pre-eclampsia, preterm delivery, mode of delivery, neonatal intensive care unit admission, birth weight, gestational age at delivery, childhood IQ and neurodevelopmental scores.
114/2018	15/1,896	Maternal SCH in pregnancy increased the risk of foetal growth restriction (RR 2.4 [91.56–3.7]) and preterm delivery premature delivery (RR 1.96 [1.34–2.88]). Significant effects of maternal SCH were also reported for foetal distress and postnatal development of the offspring.
115/2017	9/17,931	Higher RR for miscarriage for pregnant women with untreated SCH vs. euthyroid (1.90 [1.59–2.27]) but not for LT4-treated SCH vs. euthyroid (1.14 [0.82–1.58]). Also higher RR for miscarriage for presence vs. absence of thyroid autoimmunity in women with SCH (2.47 [1.77–3.45]) and for SCH without thyroid autoimmunity vs. euthyroid (1.45 [1.07–1.96]).
116/2016	18/3,995	Higher RRs for pregnancy loss (2.01 [1.66–2.44]), placental abruption (2.14 [1.23–3.70]), premature rupture of membranes (RR 1.43 [1.04–1.95]), and neonatal death (2.58 [1.41–4.73]) for presence vs. absence of SCH.
117/2013	3 220	LT4 vs. no LT4 was associated higher RR for delivery rate (2.76 [1.20–6.44]), and lower RR for miscarriage (0.45 [0.24–0.82]), with no effect on clinical pregnancy rate (1.75 [0.90–3.38]) in women undergoing assisted reproduction.

^aNumber of subjects enrolled (no. of trials/patients for meta-analyses). ^bNot given.

Abbreviations. Obs, observational study; OR, odds ratio; PCOS, polycystic ovary syndrome; RCT, randomized, controlled trial; RR, relative risk. Figures in parentheses with ORs or RRs are 95% confidence intervals.

Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2(4):215–228.

 PubMedGoogle Scholar

Lazarus J, Brown RS, Daumerie C, et al. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014;3(2):76–94.

 PubMedGoogle Scholar

Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American thyroid association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(3):315–389.

 PubMed Web of Science ®Google Scholar