**1. Introduction**

Subclinical hypothyroidism (SCH), frequently observed in pregnancy is defined as high TSH with normal T4 and T3 level. The growing fetus is entirely dependent on mother thyroid hormones in the first 12 weeks; hence, any abnormalities during this period should be detected early and preventive measures initiated as decreased thyroid hormones is known to affect the mother and the fetus adversely.

Presence of anti-TPO antibody is a major risk factor for progression to overt hypothyroidism. After widespread use of fortified Iodine rich food and extra supplementation of iodine in pregnancy, the knowledge and prevalence of autoimmune clinical and subclinical hypothyroidism with presence of various antibodies against thyroid tissues and metabolic factors gains more importance. Adverse obstetric and fetal outcomes particularly attributed to anti TPO antibodies makes its study even more clinically relevant. It is important to know the burden of anti-TPO antibody associated SCH cases due to their differences in management.


**Table 1.**

*Normal levels of thyroid hormones and TSH in pregnancy [1].*

## **1.1 Anatomical, physiological and biochemical adaption of thyroid gland to pregnancy**

A palpable increase in size of the thyroid gland is observed in normal pregnancy which is also associated with a bruit [1]. There is an established increased renal clearance of iodide leading to increased thyroid iodide clearance with associated raised uptake of 131Iodide by the thyroid glands during pregnancy. This results in a relative iodine deficient status in the pregnant mother. There is also an increase in TBG (thyroid hormone binding globulin) for which total thyroxine exhibits a raised value but free thyroxine and free triiodothyronine (fT3) is mostly normal (**Table 1**).

#### **1.2 Regulation of synthesis of thyroid hormones in pregnancy**

The synthesis of thyroid hormones is regulated by HPT axis, i.e., hypothalamuspituitary-thyroid axis. The TRH released from hypothalamus acts positively on pituitary gland which releases TSH [1]. The TSH in turn stimulates the thyroid gland to synthesize and release T4 and T3. The thyroid gland gives negative feedback signal to hypothalamus and pituitary and thus excess of its synthesis is controlled and regulated. During pregnancy, in addition to the normal regulatory mechanisms, hCG also plays a significant role in regulation of thyroid hormone synthesis. hCG mostly the asialo-hCG fraction secreted from the placenta is known to have weak TSH simulating action and this plays an important role in maintaining the thyroid hormone levels, whose demand is increased in pregnancy due to fetal dependency on mother's thyroid hormones almost exclusively up to 12 weeks of gestation and hCG acts by contributing to thyrotropic action of placenta. This also results in mild hyperthyroidism status in early pregnancy.

### **2. Anti-thyroid antibodies to thyroid antigens**

#### **2.1 Anti TPO antibody**

Polyclonal antibodies directed against some epitopes of thyroperoxidase molecule are present in the blood of some healthy individuals and patients having auto immune thyroid disorders [1–3]. Anti-TPO antibodies from auto immune thyroid patients act as competitive inhibitors of enzymatic activity though those from healthy subjects are not seen to block thyroperoxidase [4, 5]. These antibodies mostly belong to IgG class, more often IgG1and IgG4 subtypes [6]. Prevalence of anti-TPO antibodies are more common than other anti-thyroid antibodies and more symbolic for thyroid hormone imbalance. Excess of oxidative stress markers in blood are seen with anti-TPO antibodies indicating it to be an inducer of oxidative

**17**

*Autoimmune Basis of Sub Clinical Hypothyroidism in Pregnancy*

stress [7]. Apart from hypothyroid patients, anti-TPO antibodies are also detected in Graves' disease patients. These antibodies possess the potential of crossing the placenta barrier to variable extent [8], though its effect on the neonate is debatable. Few studies document that children born to anti TPO antibody positive pregnant women supposedly suffer from compromised motor and neuropsychological development [9]. There can be behavioral problems, attention deficit disorders in the off springs associated with raised titers of anti TPO antibody in the mothers during pregnancy [10]. Couple of literatures substantiate that children of anti TPO antibody positive mothers have lower brain to body mass ratio, decreased weight of brain and smaller head circumference compared to those of anti TPO antibody

As the influence and outcome on off springs of increased anti TPO antibody concentration during pregnancy is of greater significance, longer follow up studies is required to gather more data on this important clinical aspect of neuropsycho-

Polyclonal anti thyroglobulin (Tg) antibodies are found in the serum of healthy subjects whereas oligoclonal antibodies are seen in patients having auto immune thyroid disorders. It has been hypothesized that normal blood levels of Tg induce self-tolerance in T cells as low levels of antigens are usually responsible for development of self-tolerance. But this self-tolerance is not seen in case of B cell activity resulting in healthy individuals having very low levels of anti-Tg antibodies which is usually below detection limits. Higher levels of Tg following tissue damage, or due to conformation alteration of the Tg molecule in presence of high iodine levels, or in presence of very high TSH levels, there is alteration in the titers of the anti-Tg antibody. The anti-Tg antibodies are predominantly of IgG4 though minor proportions of IgA and IgM class are also seen. The functional consequence of anti-Tg antibodies is hitherto not known. Circulating antibodies were detected in healthy young subjects and in people >60 years of age to an extent of 10–15%. Presence of anti-Tg antibodies have been documented in auto immune thyroid disorders, Graves' disease and in patients with non-thyroid immune disorders. These antibodies like anti TPO antibodies can cross the placenta barrier but its effects are not very

These antibodies bind to thyroid cell membrane at/near TSH receptor and mimics the action of TSH as "occupied" receptor. This leads to excess thyroxin synthesis by the gland which escapes feedback control mechanisms. It is demonstrated frequently in Grave's disease-also known as long acting thyroid stimulator (LATS)

Excess of synthesis of thyroid hormones is known as hyperthyroidism and deficiency leads to hypothyroidism. Both the conditions are associated with deleterious

Thyroid hormones T4 and T3 affect almost every metabolic processes of the body. Pregnancy is considered to be a physiologically altered state of metabolism as the body tries to cater to the needs of the growing fetus. There is an increased need

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

negative mothers [11, 12].

substantially known [1].

antibodies.

**2.3 Thyroid hormone receptor antibodies**

effects to various metabolic processes of the body [1].

**3. Thyroid hormones and pregnancy**

logical development of the children.

**2.2 Anti-thyroglobulin antibody**

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

stress [7]. Apart from hypothyroid patients, anti-TPO antibodies are also detected in Graves' disease patients. These antibodies possess the potential of crossing the placenta barrier to variable extent [8], though its effect on the neonate is debatable.

Few studies document that children born to anti TPO antibody positive pregnant women supposedly suffer from compromised motor and neuropsychological development [9]. There can be behavioral problems, attention deficit disorders in the off springs associated with raised titers of anti TPO antibody in the mothers during pregnancy [10]. Couple of literatures substantiate that children of anti TPO antibody positive mothers have lower brain to body mass ratio, decreased weight of brain and smaller head circumference compared to those of anti TPO antibody negative mothers [11, 12].

As the influence and outcome on off springs of increased anti TPO antibody concentration during pregnancy is of greater significance, longer follow up studies is required to gather more data on this important clinical aspect of neuropsychological development of the children.
