TSH elevation associated with pregnancy problems

Preconception TSH and pregnancy outcomesTSH (thyroid stimulating hormone) when elevated even within the ‘normal’ range at preconception, can result in adverse pregnancy outcomes. Further evidence for this was presented in a studyrecently published in Clinical Endocrinology, that examines whether subclinical hypothyroidism (SCH) has negative effects on pregnancy.

“Subclinical hypothyroidism (SCH), defined as elevated TSH and normal free T4 (fT4) levels, with an incidence of 2–13·7%, is the most common thyroid disorder during pregnancy. SCH has also been associated with adverse foeto-maternal outcomes…”

Thyroid hormone levels before pregnancy

Adverse effects of SCH during the first trimester and after have been documented in earlier studies, but there has been much less data for preconception thyroid hormone levels.

“To the best of our knowledge, this study was the first large-scale study to investigate the association between maternal TSH levels within the 6 months before conception and the risk of adverse pregnancy outcomes in a population at low risk. The second aim was to determine whether the first-trimester specific reference range or nonpregnant reference range for TSH should be applied during preconception evaluation.”

This was a large study, with 248,501 pairs of volunteer couples recruited from a free National Pre-pregnancy Checkups Project from 2010 to 2012 in China, out of which 184,611 women who later became pregnant were examined by measuring maternal thyroid stimulating hormone within 6 months before conception.

“Participants were grouped according to TSH: 0·48–2·49 mIU/l (n = 133 232, 72%), 2·50–4·28 mIU/l (n = 44 239, 24%) and 4·29–10·0 mIU/l (n = 7140, 4%). Multivariable logistic regression models were used to study the association between TSH and pregnancy outcomes.”

Preconception TSH elevation increases risk of adverse pregnancy outcomes

Even when within what is often still considered the normal non-pregnant range, thyroid stimulating hormone elevation predicted pregnancy problems.

“The overall incidence of adverse pregnancy outcomes was 28·6%. Compared with TSH 0·48–2·50 mIU/l, TSH 2·50–4·29 mIU/l was associated with spontaneous abortion [aOR: 1·10,], preterm birth (aOR: 1·09) and operative vaginal delivery (aOR: 1·15, 95% CI: 1·09–1·21), while TSH 4·29–10 mIU/l was correlated with spontaneous abortion (aOR: 1·15), stillbirth (aOR: 1·58), preterm birth (aOR: 1·20), caesarean section (aOR: 1·15) and large for gestational age (LGA) infants (aOR: 1·12).”

The authors discuss the implication of these odds ratios that are small yet significant.

“The present study involving 194 154 subjects demonstrated that preconception high TSH was associated with a small but significant increased risk of overall adverse pregnancy outcomes, including spontaneous abortion, preterm birth and LGA infants, regardless of whether we used first-trimester-specific upper limit (2·50 mIU/l) or nonpregnant reference upper limit (4·29 mIU/l). Our data support that women planning a pregnancy within 6 months should be regarded as ‘pregnant status’ and that closer observation may be required once TSH levels exceed 2·50 mIU/l, rather than the nonpregnant reference upper limit.”

Clinicians should also bear in mind:

Borderline TSH elevation has been shown to portend deleterious impacts on various pregnancy outcomes. In the present study, we found that the higher the preconception TSH, the higher the incidence of adverse pregnancy outcomes. This was concordant with other studies, although they measured TSH during pregnancy, rather than before conception. Thyroid hormones themselves directly affect foetal development and utero-placental maturation; hence, maternal hypothyroidism can influence pregnancy outcomes, especially in early gestation.”

Regarding case management, the authors conclude:

“…preconception high TSH levels were associated with a small but significant increased risk of overall adverse events, including preterm birth, CS delivery and LGA infants, even within normal nonpregnant range. TSH <2·5 mIU/l is more suitable for the assessment of women planning a pregnancy in China, but one should not make a hasty decision to initiate treatment at this point without repeating TSH measurement and checking TPO antibody status. Prospective randomized controlled trials examining the role of levothyroxine supplement in mildly hypothyroid prepregnant women are warranted in the future.”

See also Subclinical hypothyroidism in pregnancy.

Subclinical hypothyroidism worsens cardiometabolic profile

Subclinical hypothyroidism and cardiometabolic biomarkersSubclinical hypothyroidism (SCH), poor thyroid effect throughout the body in the presence of ‘normal’ thyroid serum tests, is a widespread yet under-appreciated clinical challenge. A recent study published in the Journal of the Endocrine Society documents adverse cardiometabolic biomarkers in the presence of subclinical hypothyroidism. Additionally, practitioners must bear in mind that more than adequate iodine intake can worsen the condition.

Clarifying the definition of normal thyroid function

The authors note that uncertainty around the definition of normal thyroid function can go beyond contention involving different opinions on laboratory reference ranges by examining the effect of suboptimal thyroid function on the entire organism.

“As thyroid function has multisystemic effects, its derangement could affect a broad range of cardiometabolic pathways potentially related to clinical manifestations. However, the definition of normal thyroid function has been intensely debated, with some experts advocating for lowering the upper limit of normal for thyroid stimulating hormone (TSH) and others for maintaining the current standard. In this regard, thyroid-related risk for incident type 2 diabetes (T2D) and cardiovascular disease (CVD) may impact the definition of TSH normality.”

They note some of the mechanisms by which SCH can adversely affect cardiovascular and metabolic function:

“The potential relationship of thyroid hypofunction with T2D and CVD may be mediated by abnormalities in lipids, lipoprotein subclasses, endothelial function, coagulation, inflammatory pathways, and insulin resistance.”

This hardly exhausts the list of adverse physiological effects since every part of the body, including the brain, requires the stimulus of thyroid hormone to produce energy and function. The public health implications are enormous.

“Detailed assessment of thyroid function effects on these mediators/markers may have high population health implications, especially along the milder hypofunction spectrum within euthyroidism and SCH. Understanding the role of thyroid function in cardiometabolic pathways may guide the clinically relevant definition of thyroid function and unveil potential targets for controlling related morbidity.”

Subclinical hypothyroidism increases cardiometabolic risk

Thus the authors set out to…

“…examine thyroid function across the spectrum of euthyroid to HT in relationship to cardiometabolic pathways represented by lipids, lipoproteins, inflammation, coagulation, glycemic, and insulin resistance biomarkers.”

They examined data for 28,024 apparently healthy middle-aged and older women, and indeed found that cardiometabolic health worsens on a gradient from normal thyroid (euthyroid) function, through subclinical hypothyroidism, to full-blown hypothyroid:

Going from euthyroid to HT, the lipoprotein subclass profiles were indicative of insulin resistance: larger very-low-density lipoprotein size (nm); higher low-density lipoprotein (LDL) particle concentration (nmol/L), and smaller LDL size. There was worsening lipoprotein insulin resistance score from euthyroid to SCH and HT. Of the other biomarkers, SCH and HT were associated with higher high-sensitivity C-reactive protein and hemoglobin A1c. For increasing TSH quintiles, results were overall similar.”

TSH, total and LDL cholesterol not so useful

They note that it was other biomarkers that revealed the actual progressive risk:

“In this population of apparently healthy middle-aged and older women, individuals with SCH and HT had differences in the lipid and lipoprotein subclass profile that indicated worsening insulin resistance and higher cardiometabolic risk compared with euthyroid individuals, despite having similar LDL cholesterol and total cholesterol. Of the other biomarkers, only hs-CRP and HbA1c were associated with SCH and HT. For TSH quintiles mostly within the normal range, lipid and lipoprotein results for TSH quintiles were generally similar but null for other biomarkers. Hence, progressive thyroid hypofunction was associated with insulin-resistant and proatherogenic lipids and lipoproteins profile in a graded manner, with potential clinical consequences.”

Mechanisms

Besides thyroid as a driver of metabolic activity, insulin resistance appears to play a key role. They point out that insulin resistance appears to affect lipoprotein metabolism before glucose metabolism, an observation important for clinicians to bear in mind.

Thyroid hormones act as modulators of cholesterol synthesis and degradation through key enzymes. One of the main mechanisms is the stimulus of thyroid hormones over sterol regulatory element–binding protein 2, which in turn induces LDL receptor gene expression. However, it was shown that the association of HT and higher LDL cholesterol levels is present only in insulin-resistant subjects. Indeed, the lack of LDL cholesterol differences could be explained by our insulin-sensitive study population (low HbA1c levels). HT has also been associated with lower catabolism of lipid-rich lipoproteins by lipoprotein lipase, hepatic lipase, and decreased activity of cholesterol ester transfer proteinthat mediates exchanges of cholesteryl esters of HDL particles with triglyceride-rich LDL and VLDL particles. These mechanisms might explain the relationship of thyroid hypofunction with atherogenic and insulin-resistant lipid and lipoprotein abnormalities. Finally, the milder differences noted in HbA1c compared with LPIR across thyroid categories may be explained by the earlier effects of insulin resistance on lipoprotein metabolism than on glucose metabolism.”

Practitioners should be attentive to the authors’ conclusion:

“In this large population of apparently healthy women, individuals with SCH had differences in their biomarker profile that indicated worsening lipoprotein insulin resistance and higher cardiometabolic risk compared with euthyroid individuals, despite having similar LDL cholesterol and total cholesterol levels. These findings suggest that cardiometabolic risk may increase early in the progression toward SCH and overt HT.

Iodine supplementation reminder

More than adequate iodine increases autoimmune thyroiditisClinicians who may be tempted to reflexively offer iodine supplementation for thyroid disorders including subclinical hypothyroidism should remember the body of evidence showing this can fire up autoimmune thyroiditis. One example by way of a reminder is a study published in the European Journal of Endocrinology showing that more thanequate iodine intake may increase subclinical hypothyroidism and autoimmune thyroiditis. The authors describe their intent:

“With the introduction of iodized salt worldwide, more and more people are exposed to more than adequate iodine intake levels with median urinary iodine excretion (MUI 200–300 μg/l) or excessive iodine intake levels (MUI >300 μg/l). The objective of this study was to explore the associations between more than adequate iodine intake levels and the development of thyroid diseases (e.g. thyroid dysfunction, thyroid autoimmunity, and thyroid structure) in two Chinese populations.”

They examined thyroid hormones, thyroid autoantibodies in serum, iodine levels in urine were measured. and B-mode ultrasonography of the thyroid for 3813 individuals, in two areas with differing levels of iodine exposure. The levels of iodine intake were: Rongxing, MUI 261 μg/l; and Chengshan, MUI 145 μg/l. (MUI =median urinary iodine excretion.) They found a blatant difference in thyroid biomarkers:

“The prevalence of subclinical hypothyroidism was significantly higher for subjects who live in Rongxing than those who live in Chengshan. The prevalence of positive anti-thyroid peroxidase antibody (TPOAb) and positive anti-thyroglobulin antibody (TgAb) was significantly higher for subjects in Rongxing than those in Chengshan. The increase in thyroid antibodies was most pronounced in the high concentrations of TPOAb (TPOAb: ≥500 IU/ml) and low concentrations of TgAb (TgAb: 40–99 IU/ml) in Rongxing.”

Their results suggest there is a discrete window for thyroid intake:

“Compared with the adequate iodine intake level recommended by WHO/UNICEF/ICCIDD MUI (100–200 μg/l), our data indicated that MUI 200–300 μg/l might be related to potentially increased risk of developing subclinical hypothyroidism or autoimmune thyroiditis. This result differs from the WHO’s suggestion that MUI >300 μg/l may increase the risk of developing autoimmune thyroid diseases.”

Practitioners should be cautious with dosing of supplemental iodine in keeping with the authors’ conclusion:

“In conclusion, compared with the population with MUI 145 μg/l in Chengshan, the population with MUI 261 μg/l in Rongxing had a higher risk to develop autoimmune thyroiditis and subclinical hypothyroidism. Thus, more than adequate iodine intake might not be recommended for the general population in terms of keeping a normal function of thyroid.”

Readers may wish to also see the earlier post Hypothyroidism can be provoked by small amounts of supplemental iodine.