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This chapter should be cited as follows:
Tanner H, Barrett HL, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.414103

The Continuous Textbook of Women’s Medicine SeriesObstetrics Module

Volume 8

Maternal medical health and disorders in pregnancy

Volume Editor: Clinical Associate Professor Sandra Lowe, University of New South Wales, Australia

Chapter

Subclinical Thyroid Disease in Pregnancy

First published: August 2021

AUTHORS

Dr Helen Tanner
Director of Obstetric Medicine, Royal Brisbane and Women’s Hospital, Herston; and Senior Lecturer, School of Medicine, University of Queensland, Herston, Queensland, Australia
Dr Helen L Barrett
Director of Endocrinology, Mater Misericordiae Ltd, South Brisbane; and Senior Research Fellow, Mater Research Institute – The University of Queensland, South Brisbane, Queensland, Australia

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INTRODUCTION

Thyroid dysfunction is common in pregnancy with an estimated prevalence of up to 15%, with the majority of patients having subclinical disease.1 Overt thyroid disease is discussed in the Endocrine Diseases in Pregnancy chapter of the Global Library of Women’s Medicine (GLOWM).2 This chapter discusses the following clinical scenarios:

  • Iodine deficiency;
  • Isolated hypothyroxinemia;
  • Subclinical hyperthyroidism;
  • Subclinical hypothyroidism;
  • Euthyroid with thyroid peroxidase antibody positivity.

Subclinical thyroid dysfunction is the presence of an abnormal serum thyroid-stimulating hormone (TSH) level with a normal free thyroxine (FT4) and triiodothyronine level (FT3). The precise definition of what constitutes subclinical thyroid disease in pregnancy has been variable across studies as there is no consensus opinion on the definitive upper and lower limits of TSH in pregnancy. We include for reference a list of recent guidelines in Box 1 below. Universal screening of pregnant women for abnormal TSH is controversial and at present the American Thyroid Association recommends there is insufficient evidence to either recommend or discourage this practice.3,5 

Box 1 List of recent guidelines

Guidelines

Iodine supplementation:

  • WHO Guideline: Fortification of food-grade salt with iodine for the prevention and control of iodine deficiency disorders, 20144
  • WHO Guideline: Iodine supplementation in pregnant and lactating women

Management of thyroid disease in pregnancy:

  • American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum5

Physiology

During pregnancy, there is a significant increase in the size of the maternal thyroid gland by 10% in iodine-replete areas and by up to 20–40% in areas with iodine deficiency. In addition, production of thyroid hormones, thyroxine (T4) and triiodothyronine (T3) increases, renal iodine excretion increases and thyroxine binding proteins increase. For these reasons, thyroid function test results differ in pregnant women as compared with the non-pregnant population.

TSH falls in the first trimester, secondary to increasing human chorionic gonadotropin (hCG) levels which have a ‘thyrotropin-like’ effect on the thyroid gland causing production of T4.6 This fall does not usually occur until week 7 of pregnancy and is most pronounced at 7–12 weeks' gestation.7 For this reason, it is the opinion of the American Thyroid Association (ATA), that pregnancy-specific reference ranges be applied from gestation week 7 onwards.5 There are multiple factors that influence the TSH level in the first trimester, including geographical location, body mass index (BMI) and ethnicity.5 The serum measurement of FT4 in pregnancy can be difficult due to increased levels of circulating T4-binding globulin and decreased albumin, both of which affect the reliability of the immunoassay.

The fetal thyroid is not fully functional until gestational week 16–18, so prior to this the fetus relies solely on the mother for T4.8 T3 is not able to cross the placenta meaning the fetus relies solely on maternal T4 with both the placenta and the fetus able to convert T4 to T3.

IODINE DEFICIENCY

Iodine requirements increase in pregnancy, due to increased maternal thyroid hormone production, urinary excretion and fetal requirements as described above.5 Additionally, iodine is secreted in breast milk, meaning that the increased requirements continue throughout lactation. Iodine deficiency can result in maternal and fetal hypothyroidism and has been associated with miscarriage, stillbirth and poor infant outcomes.9 Iodine is also important in cognitive development of the child, and iodine deficiency is the primary global cause of preventable intellectual impairment. More mild maternal iodine deficiency has been associated with attention deficit and hyperactivity (ADHD) in children, as well as poorer intellectual outcomes.9,10,11

The World Health Organization recommended iodine intake is 250 μg/day for pregnant or lactating women.12 Of note, urinary iodine measurement has high variability in concentration day to day, meaning that it is not recommended as an individual clinical marker, but is more useful on the population level.13,14 Population iodine sufficiency varies globally and Global Fortification Data Exchange and Iodine Global Network publications contain data on iodine status and food fortification of countries worldwide (Table 1).15,16

1

Iodine sufficiency status and food fortification.16

Country

Fortification standard15

Median UIC (ug/L)16

Iodine intake16

Afghanistan

Mandatory fortification of salt, voluntary fortification of wheat flour and oil

171

Adequate

Australia

Mandatory fortification of salt and wheat flour, voluntary fortification of oil

177

Adequate

Korea – DPR of

Status unknown

97

Insufficient

Korea, Republic of

Status unknown

432

Excessive

South Sudan

Voluntary fortification of oil

94

Insufficient

United Kingdom

Mandatory fortification of wheat flour

138

Adequate

Sample data from the Global Fortification data exchange15 and the global scorecard of iodine nutrition in 2019.16

Normal Reference Ranges

TSH levels vary across ethnicities, and geographical location. A recent study from Korea found the 97.5th centile for TSH in healthy, thyroid-antibody negative women to be 4.24 mIU/L, 4.84 mIU/L and 5.57 mIU/L in the first, second and third trimesters respectively.17 This contrasts with a similar study from Spain which found the 97.5th centiles to be 2.63 mIU/L, 2.59 mIU/L and 3.48 mIU/L for trimester 1, 2 and 3, respectively.18 Studies from Switzerland and the United States have found results similar to Spain, whereas studies in India and China are comparable with the Korean findings.17

Ideally the reference range for TSH should be defined in the local setting, using local typical patients without known thyroid disease. The ATA recommends that the local range be set using “healthy thyroid peroxidase antibody (TPOAb) negative women with optimal iodine intake and without thyroid illness”. The minimum number of healthy volunteers from which to derive a reference range has been set at 120.19 If this is not possible, the ATA recommends using the range from a similar population, using similar TSH assays and, in addition, if those are not available, then using an upper reference limit of 4.0 mIU/L.5 Table 2 is adapted from the ATA guidelines (Table 4 of that document) and shows median TSH and FT4 in pregnancy for studies excluding women with positive TPOAb and including >500 participants.

Measurement of FT4 concentration in pregnancy can be problematic, due to an increase in thyroid binding globulin, higher non-esterified fatty acid concentrations and lower albumin.20 Classical equilibrium dialysis and ultrafiltration assays are not widely available and most clinical measurement is performed using indirect immunoassay. The mass spectrometry methods (LC-MS/MS) determined FT4 reference interval falls gradually with gestational age.21,22 The LC-MS/MS methods are not widely available. Automated immunoassays are most commonly used in clinical practice and can be affected by the increase in thyroid binding globulin and fall in albumin seen during pregnancy and need a method specific and trimester specific reference range.23 There are some small comparison studies of different manufacturers that show variable results.24,25 There are ongoing efforts toward standardization of thyroid function testing.22,26 The ATA recommends that assay method specific and trimester specific pregnancy ranges should be applied.5

2

Gestational TSH and FT4. Adapted from the ATA guidelines – Table 4.5 The studies had >500 participants and excluded thyroid peroxidase antibody positive women. 

Study

Gestational age (weeks)

Median TSH (mU/L)

Median FT4 (pmol/L)

Number of subjects

Bestwick et al., Italy27

<16

1.07

9.3

5505

Bestwick et al., UK27

<16

1.11

13.9

16334

Bocos-Terraz et al., Spain18

<14

0.94

13.9

481

Gilbert et al., Australia28

9–13

0.74

13.5

1817

Lambert-Messerlian et al., USA29

T1

1.00

14.2

8351

T2

1.19

13.0

8415

La’ulu et al., USA30,31

10–13

0.94

14.7

2172

14–20

1.14

12.0

2683

Li et al., China7

7–12

1.47

15.8

640

Mannisto et al., Finland32


T1

1.11

15.3

4333

T2

1.37

14.6

747

Medici et al., The Netherlands33

8–18

1.30

14.7

5186

Pearce et al., USA34

<14

1.1

2.1

585

Quinn et al., Russia35

Trimester 1

1.66

380

Trimester 2

2.00

549

Springer et al., Czech Republic36

9–11

1.21

4337

Stricker et al., Switzerland37

6–12

0.95

13.9

575

Trimester 2

1.02

12.2

528

Vaidya et al., UK38

<12

1.08

14.6

1089

SUBCLINICAL HYPERTHYROIDISM

Definition

  • TSH below the lower limit of normal, with normal FT4 and FT3.
    • If pregnancy-specific population-based reference ranges for TSH are available then these should be used to determine the lower limit of TSH.
    • If population-based reference ranges do not exist, the TSH lower limit is 0.4 mU/L below the non-pregnant reference range.5 This limit should be applied from week 7 of pregnancy with a gradual return towards the non-pregnant reference range in FT4 and FT3.5

A reduction in the lower reference range for TSH compared to non-pregnancy ranges is seen in pregnancy in almost all studies. A TSH below 0.1 mU/L may be seen in as many as 5–18% of pregnant women in the first trimester, and likely reflects elevated hCG levels.39 When hCG levels are over 200,000 IU/L, TSH is suppressed in 67% of samples and when hCG levels are over 400,000 IU/L, TSH is suppressed in 100% of samples.40 Clinical scenarios where this is more common include hyperemesis gravidarum, multiple pregnancy and gestational trophoblastic disease.

One important consideration with subclinical hyperthyroidism, is recognizing when there is another cause of low TSH that may require management, such as Grave’s disease.

Practice point

When assessing patients with subclinical hyperthyroidism, undertake a review for a personal or family history of thyroid dysfunction and/or examination findings (e.g. goiter, nodules or eye signs) suggestive of thyroid disease. This may require further investigation and management.

Pregnancy and Neonatal Outcomes

Studies evaluating pregnancy outcomes in the setting of subclinical hyperthyroidism are scarce and those that do report on it have found inconsistent results. Two large studies found no association with adverse pregnancy outcomes including birth weight, gestation at delivery, congenital abnormalities, perinatal mortality, APGAR scores and placental abruption.41,42 In one of these studies, women with subclinical hyperthyroidism were less likely to develop pre-eclampsia.41 However, a recent study from China found that subclinical hyperthyroidism was associated with a higher risk of pre-eclampsia (OR 5.143; 95% CI 1.46–18.1, p = 0.011) and placental abruption (OR 4.68; 95% CI 1.12–21.51, p = 0.048).43 No associations were found with gestation at delivery and birth weight. In terms of positive pregnancy outcomes, the Chinese study found a reduction in the rate of miscarriage (OR 0.206, 95% CI 0.05–0.84, p = 0.028).44 The authors postulate that this effect is due to the higher levels of hCG in these women.

Overt hyperthyroidism has previously been found to be associated with pre-eclampsia45 and interestingly treatment of subclinical hypothyroidism with thyroxine has also been found to be associated with an increased risk of pre-eclampsia.46

There is an increased incidence of suppressed TSH in women with hyperemesis gravidarum.47 The exact cause of this is unclear; however, it is known that TSH levels fall in line with rising hCG levels in the first trimester.48 Several hypotheses exist for the relationship between TSH and hyperemesis including excessive levels of hCG, an excess of specific isoforms of hCG that stimulate the TSH receptor and ‘hypersensitive‘ TSH receptors that may be more easily stimulated by hCG. Hyperemesis gravidarum usually resolves by 20 weeks' gestation49 and with this there is a gradual return of the TSH back to normal levels.50 No specific treatment of the suppressed TSH is required, although hyperemesis gravidarum should be managed actively.51

Management of subclinical hyperthyroidism in pregnancy

There is no high quality evidence to guide management of subclinical hyperthyroidism which might include repeat measurement or assessment of thyroid hormone levels, thyroid imaging, measurement of antibodies or pharmacotherapy.

We suggest the following, while taking into account the particular patient and setting:

  • Assess the patient including:
    • a personal or family history of thyroid dysfunction;
    • examination findings such as goiter or Grave’s eye disease.
  • If any of these features are present, perform TSH receptor antibodies.
  • If there are no features suggestive of underlying thyroid disease, repeat TSH, FT4 and FT3 in 4 weeks. If normal, no further testing is required.
  • If TSH still remains low, perform TSH receptor antibodies.
    • If TSH receptor antibodies are positive, manage the patient as per Grave’s disease.
    • If TSH receptor antibodies are negative, continue to monitor the TSH, FT4 and FT3 every 4–6 weeks or until normalized. If abnormalities persist, the patient will require consideration of other diagnoses such as toxic nodules.
  • If FT4 or FT3 become elevated, manage as per overt hyperthyroidism. Ongoing assessment postpartum will also be required.
  • Subclinical hyperthyroidism should not be treated in pregnancy.

ISOLATED HYPOTHYROXINEMIA

Definition

  • Normal TSH with a FT4 below the normal reference range, i.e. below the 2.5th centile of a given population.

There are studies that show a correlation between isolated hypothyroxinemia and adverse childhood outcomes, particularly reduced childhood cognition.5,52 A recent meta-analysis from 2018 evaluated 11 studies and found that maternal hypothyroxinemia was significantly associated with signs of intellectual impairment in the offspring (OR 1.63, 95% CI 1.03–2.56, -0.04). However, when only the four studies reporting an odds ratio were included in the meta-analysis, no association was found (OR 2.11, 95% CI 0.92–4.83).53 Of note, two randomized-controlled trials evaluating the use of thyroxine in pregnant women with isolated hypothyroxinemia failed to show any benefit on childhood cognition.54,55

Data on isolated hypothyroxinemia and other pregnancy outcomes are limited. A meta-analysis looking only at preterm birth, found that isolated hypothyroxinemia was associated with preterm birth when compared with euthyroid women (absolute risk difference, 1.2% (95% CI 0.4–2.5%).56

Management

Given the lack of benefit, there is international consensus that isolated hypothyroxinemia should not be treated with thyroxine in pregnancy.5 Some experts believe that iodine deficiency may play a role in isolated hypothyroxinemia57 and for this reason it is important to ensure women are receiving adequate (but not excessive) iodine supplementation. There is a lack of evidence-based guidance on how frequently to repeat thyroid function tests in these women. We recommend testing every trimester or until the FT4 normalizes.

SUBCLINICAL HYPOTHYROIDISM

The definition of subclinical hypothyroidism is a TSH above the reference range with a normal FT4 and FT3. However, there is no consensus agreement on what the upper limit of TSH in pregnancy is (see Section on reference ranges above). The ATA published guidelines in 2017 on the definition and management of subclinical hypothyroidism in pregnancy.5 The definition attempts to deal with the current challenges around the assessment of TSH normal range, which leaves a broad scope for local clinical decision making.

For the purposes of this text, we have elected to propose an absolute definition whilst recognizing issues with variability of reference ranges. This definition was recently accepted as a consensus agreement of endocrinologists in Melbourne, a major center of Australia.58

Definition of subclinical hypothyroidism in pregnancy

  • TSH above the upper limit of normal but less than 10 mU/L, with normal FT4 and FT3.
    • If pregnancy specific population-based reference ranges for TSH are available, then these should be used to determine the upper limit of the TSH.
    • If population-based reference ranges do not exist, a TSH >4 mU/L should be used.
    • TSH ≥10 mU/L is consistent with overt hypothyroidism regardless of FT4 and FT3 level.5

Subclinical hypothyroidism and fertility

A large retrospective Danish study found that subclinical hypothyroidism with a TSH >3.7 mIU/L was associated with an increased risk of not having children and/or not getting pregnant.59 In contrast, a subsequent prospective study found that in women with one or two previous pregnancy losses and no history of infertility, TSH >2.5 mIU/L was not associated with time to pregnancy, pregnancy loss or live birth.60 In addition, secondary analysis of two large randomized controlled trials of infertility, found that a TSH >2.5 mIU/L was not associated with cumulative conception, clinical pregnancy, miscarriage and live birth rates.61 With regards specifically to in vitro fertilization (IVF), a recent retrospective study from China found a TSH >2.5 mIU/L did not affect pregnancy rate or miscarriage rate in women undergoing IVF or ICSI.62

Subclinical hypothyroidism and pregnancy outcome

Studies assessing the relationship between subclinical hypothyroidism and pregnancy outcomes have found conflicting results.63 A systematic review from 2016 found that subclinical hypothyroidism was associated with multiple adverse maternal and neonatal outcomes, including pregnancy loss (RR 2.01, 95% CI 1.66–2.44), placental abruption (RR 2.14, 95% CI 1.23–3.7), premature rupture of membranes (RR 1.43, 95% CI 1.04–1.95) and neonatal death (RR2.58, 95% CI 1.41–4.73).64 However, no association was found with gestational diabetes, preterm labor, preterm delivery, gestational hypertension, pre-eclampsia, placenta previa, cesarean delivery, intrauterine growth restriction (IUGR), low birth weight, low Apgar scores or small for gestational age. In contrast, systematic reviews looking at IUGR, preterm birth and gestational diabetes, did find associations with subclinical hypothyroidism.65,66,67

Treatment of subclinical hypothyroidism and pregnancy outcomes

Studies evaluating the effect of treatment of subclinical hypothyroidism on pregnancy outcomes are limited. One observational study in 2017 found that treatment of subclinical hypothyroidism was associated with a lower risk of pregnancy loss; however, subgroup analysis found this effect only occurred in women with a TSH >4.0 mU/L.46 Interestingly treatment was associated with a higher risk of pre-eclampsia, premature delivery and gestational diabetes highlighting the fact that treatment may cause harm. A recent meta-analysis showed that when compared with placebo, treatment of subclinical hypothyroidism with thyroxine reduced the risk of pregnancy loss (OR 0.78, 95% CI 0.66–0.94) and increased the likelihood of live birth (OR 2.72, 95% CI 1.44–5.11). When compared with euthyroid women, treatment with thyroxine increased the likelihood of preterm labor (OR 1.82, CI 1.14–2.91). Further studies are needed to clarify whether treatment with thyroxine improves pregnancy outcomes, and specifically which pregnancy outcomes.68

Subclinical hypothyroidism and childhood neurocognitive outcomes

A large meta-analysis performed in 2018 showed that maternal subclinical hypothyroidism was associated with increased risk for intellectual impairment in children (OR 2.14, 95%CI 1.20–3.83, p = 0.01).53 No association was found between maternal hypothyroidism and autism or ADHD. When only studies reporting odds ratios (six studies) were included, no association was found and when only studies measuring TSH prior to 12 weeks were included, no association was found. The authors attribute this to the smaller sample sizes. In contrast with these findings, a large prospective study in the United Kingdom found no association between maternal subclinical hypothyroidism in the first trimester and child performance at school or educational achievement.69

Treatment of subclinical hypothyroidism and childhood neurocognitive outcomes

Two randomized trials of treatment with thyroxine for subclinical hypothyroidism did not show any reduction in the incidence of low intelligence quotient (IQ) in children when tested at age 3 in one study54 and age 5 in the other.55 This finding remained when these two trials were combined in a meta-analysis (OR 0.95, 95% CI 0.74–1.23, -0.71).53 The main criticism of these trials was that thyroxine was generally started after the first trimester. Overall, studies assessing the association of subclinical hypothyroidism and childhood neurocognitive outcomes have produced inconsistent results. There is no current evidence that treatment of subclinical hypothyroidism impacts on childhood IQ.

A summary of subclinical hypothyroidism and pregnancy and childhood outcomes is shown in Table 3.

3

Associations reported between subclinical hypothyroidism and pregnancy outcomes. In all categories, findings are not consistent.

Maternal5,70,71,72,73,74,75

Fetal63,64,65,75

Childhood53,56,69,76,77,78,79,80,81,82,83,84

↑Pregnancy loss

Excessive pregnancy weight gain

Impaired glucose tolerance

Hypertensive disorders of pregnancy

Placenta previa

Preterm delivery

↑Pregnancy loss

Placenta previa

Preterm delivery

Large for gestational age

Intrauterine growth restriction

Increased metabolic syndrome

Increased overweight/obesity

Lower global neurocognitive development

ADHD, autism

No risk of intellectual impairment

Management of subclinical hypothyroidism in pregnancy

Given the conflicting findings between subclinical hypothyroidism and adverse outcomes, the following management plan was devised by consensus agreement of Melbourne hospital endocrinologists.58 These recommendations are based on the lack of evidence of benefit of treatment with thyroxine and limits its use to women with a TSH >4 mIU/L, regardless of thyroid antibody status. The question of antibody status as a confounding factor is difficult as some studies suggest benefit only in those with positive thyroid antibodies,85 while others only for the subset of women with TSH >4 mIU/L.86,87 A similar definition and management plan has previously been published in the British Medicine Journal and addresses the same concerns regarding the uncertainties of treatment benefit.88

  • Repeat the test if TSH is only borderline elevated;
  • Initiate levothyroxine at 50 μg per day;
  • Test for anti-TPO antibodies to help guide postpartum management (risk of postpartum thyroiditis and Hashimoto’s disease);
  • Test TSH and FT4 6-weekly throughout the pregnancy. Target range for TSH once on levothyroxine is 0.1–2.5 mU/L. If the TSH is in the target range at 30 weeks' gestation, no further testing is required;
  • Cease levothyroxine in all women after delivery except:
    • TSH >10 mU/L at diagnosis;
    • Strongly positive anti-TPO antibodies at least 3 times the upper limit of normal;
    • Women contemplating a pregnancy within the next 12 months;
    • Women attempting to conceive again with a history of unexplained spontaneous abortion.

EUTHYROID WITH THYROID PEROXIDASE (TPO) ANTIBODY POSITIVITY

Definition

  • Thyroid antibody positivity with normal thyroid hormone levels. This is considered a form of subclinical thyroid disease, although it is better thought of as potential thyroid disease.

Fertility

While the presence of TPO antibodies has been associated with miscarriage, there is little evidence that supplementing with thyroxine is of assistance. A small randomized control trial of 72 women with positive TPO antibodies randomized to levothyroxine or placebo during fertility treatment reported no difference in pregnancy rate between treatment and placebo.89 A recent Cochrane review found that in women who were euthyroid but had positive TPO antibodies, the studies would suggest a live birth rate of 31% for those with no treatment or placebo and 26%-40% for those on thyroxine and the evidence was of low quality.90 The more recent TABLET randomized controlled trial was designed to answer this question. It enrolled 952 women to receive either levothyroxine 50 μg/day or placebo. These women were positive for TPO antibodies and aged 16–41 years and trying to conceive. There was no difference in live birth rates (37% levothyroxine compared with 38% placebo).91

Pregnancy outcomes

Studies evaluating the association of thyroid peroxidase antibodies in euthyroid women and pregnancy outcomes have been conflicting. In 2006 Negro et al. found that euthyroid women with anti-TPO positivity were more likely to suffer miscarriage and premature deliveries and that treatment with thyroxine appeared to reduce the risk of these adverse outcomes.92 However, a more recent study from 2019 randomly assigned euthyroid women with TPO antibodies who were actively trying to conceive or undergo assisted conception, to receive 50 μg thyroxine daily or placebo.93 The study recruited 952 women, with 476 in both arms. There was no difference in the rate of live birth after 34 weeks' gestation (thyroxine 37.4% vs. placebo 37.9%; RR 0.97, CI 0.83–1.14). There was also no difference in the rate of miscarriage (thyroxine 28.2%, placebo 29.6%; RR, 0.95; 95% CI, 0.73–1.23).

Management of TPO antibody positive, euthyroid women in pregnancy

We do not recommend treating euthyroid women with TPO antibody positivity with thyroxine in pregnancy or when trying to conceive, even in the setting of assisted reproduction.

PRACTICE RECOMMENDATIONS

  • Ensure iodine sufficiency in all women prior to conception, during pregnancy and lactation:5
    • recommended intake of 250 μg/day iodine.5
  • Use appropriate reference ranges for thyroid hormone levels in pregnancy.
  • Do not treat subclinical hyperthyroidism in pregnancy.
  • Do not treat isolated hypothyroxinemia in pregnancy.
  • Treat subclinical hypothyroidism if TSH >4.0 mU/L irrespective of antibody status.
  • Do not treat thyroid antibody positive euthyroid women.
  • Await the outcome of further trials in this area.

CONFLICTS OF INTEREST

The authors of this chapter declare that they have no interests that conflict with the contents of the chapter.


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