**3.2 Pregnancy and clinical/subclinical hypothyroidism**

The need for iodine increases in pregnancy (daily requirement of iodine −150–200 μg/day, 250 μg/day in pregnancy) leading to an iodine deficient status if not adequately supplemented. Apart from iodine deficiency, the other most common factor for thyroid hormone deficiency has been attributed to anti-TPO antibodies. Hypothyroidism is registered to be more prevalent in Asian countries compared to their Western counterparts. As such thyroid disorders have wide geographical variations attributed to dietary factors, level of various goitrogens in diet and their consumption level, deficiencies of micronutrients like selenium, iron and most importantly iodine. Autoimmune thyroid diseases are also more prevalent in Asian countries and accumulating literatures suggest it to be more substantial in Indian population with greater prevalence of anti TPO antibody positivity.

High TSH level with normal T4 level is known as subclinical hypothyroidism (SCH). Subclinical hypothyroidism is one of the most common type of thyroid dysfunction that is found to be associated with pregnancy [38, 39]. The increased need of thyroid hormones to meet the extra demand by the growing fetus in the first 12 weeks of gestation is dealt by hCG due to its thyrotrophic action as discussed earlier and also via hypothalamus-pituitary-thyroid axis regulation which usually results in small painless enlargement, i.e., goiter formation in pregnant women [1]. This also results in increased need of iodine in pregnancy.

Hence, endemic areas of iodine deficiency have shown a higher prevalence of clinical or subclinical hypothyroidism in general and in particular in pregnant women. Because of increased thyroid hormone production, increased renal iodine excretion, and fetal iodine requirements, dietary iodine requirements are higher in pregnancy than they are for non-pregnant adults. The requirement of iodine is 250 μg/day in pregnancy. Recommendation by American Thyroid Association (ATA) is women who are planning pregnancy or currently pregnant, should supplement their diet with a daily oral supplement that contains 150μg of iodine in the form of potassium iodide [40]. This should optimally start 3 months in advance of planned pregnancy.

### **3.3 Hypothyroidism and autoimmunity in pregnancy**

However, apart from iodine deficiency, the other most significant cause of hypothyroidism in recent times is presence of anti thyroperoxidase antibody, i.e., anti TPO antibody and anti Tg (anti thyroglobulin) antibody in the serum. The thyroperoxidase enzyme as described above is highly essential for oxidation of trapped iodine and its incorporation into tyrosine molecule for synthesis of thyroxin. Anti TPO antibody destroys the thyroperoxidase enzyme and hence prevents the iodination of tyrosine molecule and overall synthesis of thyroxin is hampered resulting in hypothyroidism. This autoimmune basis of hypothyroidism is now more relevant after iodine deficiency has been tackled by fortification of food products with iodine/with iodine supplementation as potassium iodide. In pregnancy, immune regulatory cytokines and cells are present in the mother's circulatory system and accumulate in the decidua and can modify autoimmune responses influencing the symptoms of autoimmune disease [41].

Presence of anti-TPO antibody is a major risk factor for progression to overt hypothyroidism. Various studies reveal a prevalence of 2–17% of euthyroid pregnant women being anti-TPO antibody positive. Still data from Indian scenario is extremely limited. TPO antibodies are able to cross the placenta. At the time of delivery, cord blood anti TPO Ab levels strongly correlate with third-trimester

maternal anti TPO antibody concentrations [8]. However, concrete documentation of maternal passage of either anti TPO antibodies or anti Tg antibodies affecting the fetal thyroid function is still debatable [9–12].

It has been documented that euthyroid pregnant women who are positive for thyroid peroxidase autoantibody (anti TPO antibody) also are at increased risk of various complications of pregnancy including miscarriage, preterm birth, pregnancy-induced hypertension (PIH), intrauterine death (IUD), and intrauterine growth retardation (IUGR) [42, 43].

A number of etiologies have been hypothesized as the cause of the relationship between various pregnancy related complications like miscarriage, IUGR, preeclampsia, pre term delivery and autoimmune thyroid antibodies. To enumerate a few: (a) prior presence of a restrained degree of hypothyroidism, (b) thyroid antibodies reflecting an immunological imbalance inclining towards auto immunity in the pregnant female, (c) direct effects of thyroid autoantibodies on the placenta or the fertilized ovum. The above hypotheses have been corroborated by the observation of higher levels of TSH within the normal range noted in various meta-analysis studies indicating a milder degree of thyroid failure in euthyroid pregnant women with thyroid auto antibodies positivity [41, 44–46].

#### **3.4 Autoimmune hypothyroidism and development of goiter in pregnancy**

Pregnancy is considered to be a goitrogenic status, particularly in the Iodine deficiency scenario. Increased need of thyroid hormones, TSH simulating actions of beta HCG with super added iodine deficiency actually leads to volumetric increase in the gland and not just vascular engorgement which also has been biochemically corroborated by observations of high serum Thyroglobulin levels, more T3 secretion and small rise in basal TSH level at delivery. Studies supports that there is actual goiter formation in pregnancy which can be tackled to a measurable extent by adequate iodine supplementation [47].

Presence of anti TPO antibodies is mostly associated with Hashimoto's thyroiditis, Graves' disease, nodular goiter and thyroid carcinoma [1]. Anti TPO antibody positivity in pregnancy is mostly associated with overt or subclinical hypothyroidism during pregnancy sometimes associated with a goiter which is often painless. Post-delivery, there are incidences of postpartum thyroiditis with a milder form of Graves' disease lacking the typical symptomatic features which after a few months, changes to hypothyroidism and development of small painless goiter [1, 48, 49].

#### **4. Reference limits for diagnosis of hypothyroidism in pregnancy**

It is important to know the burden of anti-TPO antibody associated SCH cases due to their differences in management. This is even more important in case of pregnant women as presence of anti TPO antibody makes them more vulnerable to clinical hypothyroidism and hence its detection at early pregnancy helps in its better management. The management for pregnant women with subclinical hypothyroidism with anti TPO Ab positive and negative differs from each other.

Setting the reference limits for thyroid hormones and TSH in pregnancy is a debatable fact due to different laboratories giving different values and there is gross geographical variation too. Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease during Pregnancy and Postpartum (ATA 2011) recommends a trimester specific range of TSH in pregnancy which is lower than in normal adult, i.e., first trimester: 0.1–2.5 mIU/L, second trimester: 0.2–3.0 mIU/L, third trimester: 0.3–3.0 mIU/L [40]. However, the recent guidelines

**21**

*Autoimmune Basis of Sub Clinical Hypothyroidism in Pregnancy*

**TSH value T4/T3 Anti** 

2 TSH >10.0 mU/L Normal Negative Strong

**TPO**

Normal Positive Strong

Normal Negative Not recommended

Normal Positive Weak recommendation

Normal Negative Weak recommendation

**Therapy with LT4**

recommendation

recommendation

of ATA recommend "When available, population- and trimester-specific reference ranges for serum TSH during pregnancy should be defined by a provider's institute or laboratory and should represent the typical population for whom care is provided. Reference ranges should be defined in healthy anti TPO Ab-negative pregnant women with optimal iodine intake and without thyroid illness. If internal or transferable pregnancy-specific TSH reference ranges are not available, an upper reference limit of ∼4.0 mIU/L may be used" (ATA-2017) [50]. In the absence of accredited trimester specific reference ranges for thyroid hormones and TSH levels in pregnancy in India, the current practice is to use the reference limits set by ATA

*Recommendations by ATA 2017 guidelines regarding management of sub clinical hypothyroidism in pregnancy [50].*

**4.1 Management of overt and subclinical hypothyroidism in pregnancy**

**5. Thyroid auto antibodies and assisted fertilization**

Recent guidelines of ATA recommends regular monitoring of thyroid status in women with overt and subclinical hypothyroidism (treated or untreated) or those at risk for hypothyroidism (e.g., patients who are euthyroid but anti TPO antibody or anti Tg antibody positive, post-hemithyroidectomy, or treated with radioactive iodine) with a serum TSH measurement approximately every 4 weeks until completion of second trimester and at least once near 30 weeks gestation [50]. Sub clinical hypothyroidism in anti TPO antibody negative and positive cases in pregnancy are differently managed with levothyroxine (LT4) as per the recommendations of ATA

Recently, some researchers speculated that assisted conception in women positive for anti-thyroid antibodies had poor outcome of *in vitro* fertilization, even if they were euthyroid. Studies do document that anti thyroid antibodies positive patients had low fertilization rate, implantation rate, and pregnancy rate and high abortion rate. Regarding the question how these antibodies interfered with fertilization, embryo development as well as implantation potential still remains unanswered. The hypothesis is that the antibodies may bind to either the surface of the egg and/or embryo and interfere with fertilization and subsequent embryo

*DOI: http://dx.doi.org/10.5772/intechopen.88508*

1 Within the pregnancy-specific reference range or <4.0 mIU/L (if specific reference

3 TSH >2.5 mU/L and below the upper limit of the pregnancy-specific reference range

reference range or >4.0mIU/L (if specific

4 TSH greater than the upper limit of the pregnancy-specific reference range but

5 TSH greater than pregnancy-specific

reference range unavailable)

range unavailable)

below 10.0 mU/L

**Table 2.**

as per 2017 guidelines [50].

2017 guidelines [50] (**Table 2**).

*Autoimmune Basis of Sub Clinical Hypothyroidism in Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.88508*


#### **Table 2.**

*Goiter - Causes and Treatment*

fetal thyroid function is still debatable [9–12].

with thyroid auto antibodies positivity [41, 44–46].

by adequate iodine supplementation [47].

growth retardation (IUGR) [42, 43].

maternal anti TPO antibody concentrations [8]. However, concrete documentation of maternal passage of either anti TPO antibodies or anti Tg antibodies affecting the

It has been documented that euthyroid pregnant women who are positive for thyroid peroxidase autoantibody (anti TPO antibody) also are at increased risk of various complications of pregnancy including miscarriage, preterm birth, pregnancy-induced hypertension (PIH), intrauterine death (IUD), and intrauterine

A number of etiologies have been hypothesized as the cause of the relationship between various pregnancy related complications like miscarriage, IUGR, preeclampsia, pre term delivery and autoimmune thyroid antibodies. To enumerate a few: (a) prior presence of a restrained degree of hypothyroidism, (b) thyroid antibodies reflecting an immunological imbalance inclining towards auto immunity in the pregnant female, (c) direct effects of thyroid autoantibodies on the placenta or the fertilized ovum. The above hypotheses have been corroborated by the observation of higher levels of TSH within the normal range noted in various meta-analysis studies indicating a milder degree of thyroid failure in euthyroid pregnant women

**3.4 Autoimmune hypothyroidism and development of goiter in pregnancy**

Pregnancy is considered to be a goitrogenic status, particularly in the Iodine deficiency scenario. Increased need of thyroid hormones, TSH simulating actions of beta HCG with super added iodine deficiency actually leads to volumetric increase in the gland and not just vascular engorgement which also has been biochemically corroborated by observations of high serum Thyroglobulin levels, more T3 secretion and small rise in basal TSH level at delivery. Studies supports that there is actual goiter formation in pregnancy which can be tackled to a measurable extent

Presence of anti TPO antibodies is mostly associated with Hashimoto's thyroiditis, Graves' disease, nodular goiter and thyroid carcinoma [1]. Anti TPO antibody positivity in pregnancy is mostly associated with overt or subclinical hypothyroidism during pregnancy sometimes associated with a goiter which is often painless. Post-delivery, there are incidences of postpartum thyroiditis with a milder form of Graves' disease lacking the typical symptomatic features which after a few months, changes to hypothyroidism and development of small painless goiter [1, 48, 49].

**4. Reference limits for diagnosis of hypothyroidism in pregnancy**

ism with anti TPO Ab positive and negative differs from each other.

It is important to know the burden of anti-TPO antibody associated SCH cases due to their differences in management. This is even more important in case of pregnant women as presence of anti TPO antibody makes them more vulnerable to clinical hypothyroidism and hence its detection at early pregnancy helps in its better management. The management for pregnant women with subclinical hypothyroid-

Setting the reference limits for thyroid hormones and TSH in pregnancy is a debatable fact due to different laboratories giving different values and there is gross geographical variation too. Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease during Pregnancy and Postpartum (ATA 2011) recommends a trimester specific range of TSH in pregnancy which is lower than in normal adult, i.e., first trimester: 0.1–2.5 mIU/L, second trimester: 0.2–3.0 mIU/L, third trimester: 0.3–3.0 mIU/L [40]. However, the recent guidelines

**20**

*Recommendations by ATA 2017 guidelines regarding management of sub clinical hypothyroidism in pregnancy [50].*

of ATA recommend "When available, population- and trimester-specific reference ranges for serum TSH during pregnancy should be defined by a provider's institute or laboratory and should represent the typical population for whom care is provided. Reference ranges should be defined in healthy anti TPO Ab-negative pregnant women with optimal iodine intake and without thyroid illness. If internal or transferable pregnancy-specific TSH reference ranges are not available, an upper reference limit of ∼4.0 mIU/L may be used" (ATA-2017) [50]. In the absence of accredited trimester specific reference ranges for thyroid hormones and TSH levels in pregnancy in India, the current practice is to use the reference limits set by ATA as per 2017 guidelines [50].

#### **4.1 Management of overt and subclinical hypothyroidism in pregnancy**

Recent guidelines of ATA recommends regular monitoring of thyroid status in women with overt and subclinical hypothyroidism (treated or untreated) or those at risk for hypothyroidism (e.g., patients who are euthyroid but anti TPO antibody or anti Tg antibody positive, post-hemithyroidectomy, or treated with radioactive iodine) with a serum TSH measurement approximately every 4 weeks until completion of second trimester and at least once near 30 weeks gestation [50]. Sub clinical hypothyroidism in anti TPO antibody negative and positive cases in pregnancy are differently managed with levothyroxine (LT4) as per the recommendations of ATA 2017 guidelines [50] (**Table 2**).

### **5. Thyroid auto antibodies and assisted fertilization**

Recently, some researchers speculated that assisted conception in women positive for anti-thyroid antibodies had poor outcome of *in vitro* fertilization, even if they were euthyroid. Studies do document that anti thyroid antibodies positive patients had low fertilization rate, implantation rate, and pregnancy rate and high abortion rate. Regarding the question how these antibodies interfered with fertilization, embryo development as well as implantation potential still remains unanswered. The hypothesis is that the antibodies may bind to either the surface of the egg and/or embryo and interfere with fertilization and subsequent embryo

development. Alternatively, the presence of the auto antibodies in the endometrial tissue may exert detrimental effect on embryo implantation leading to early pregnancy loss [51–54].
