Hypothyroidism in Pregnancy

Review Article

HYPOTHYROIDISM IN PREGNANCY Geeta Chadha * and Mamta Goel ** *Senior Consultant,** Registrar, Department of Obstetrics & Gynaecology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr Geeta Chadha, Senior Consultant, Department of Obstetrics & Gynaecology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Due to pregnancy thyroid economy is affected with changes in iodine metabolism, TBG and development of maternal goiter. The incidence of hypothyroidism in pregnancy is quite common with autoimmune hypothyroidism being the most important cause. Overt as well as subclinical hypothyroidism has a varied impact on maternal and neonatal outcome. After multiple studies also, routine screening in pregnancy for hypothyroidism can still not be recommended. Management mainly comprises of dosage adjustments as soon as pregnancy is diagnosed based on results of thyroid function tests. The aim should be to keep FT4 at the upper end of normal range. Key words: Hypothyroidism in pregnancy, Physiology, Pregnancy outcome, Screening, Management.

PHYSIOLOGY Changes in pregnancy occur in thyroid gland due to (a) Pregnancy induces a marked increase in circulating levels of major thyroxine transport protein, thyroxine binding globulin, in response to high estrogen levels, (b) Several thyroidal stimulatory factors of placental origin are produced in excess, (c) Pregnancy is accompanied by a decreased availability of iodide for the maternal thyroid. This occurs due to increased renal clearance and excretion that results in a relative iodine deficiency state (Table 1). Moderate thyroid enlargements occur due to glandular hyperplasia and increase in vascularity. Thyroid volume determined ultrasonographically increases although its echostructures and echogenecity remains unchanged [1]. These enlargements are not pathological and normal pregnancy does not typically cause significant thyromegaly, thus, any goiter should be investigated. A clinically apparent goiter suggests iodine deficiency or pathology [2]. In early pregnancy, thyrotropin activity decreases because of thyroid stimulation from the weak crossover activity of chorionic gonadotrophin (Fig.1) [3]. Fetal physiology The pituitary thyroid system is functional by the end of first trimester. The thyroid gland is able to synthesize hormones by 10-12 weeks, and TSH, thyroxine and thyroxine binding globulin (TBG) have been detected in Apollo Medicine, Vol. 6, No. 4, December 2009

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fetal serum as early as 11 weeks [4]. The placenta actively concentrates iodide on the fetal side, and by 12 weeks and throughout pregnancy, the fetal thyroid concentrates iodide more avidly than does the maternal thyroid. Thus, maternal administration of either radioiodide or appreciable amounts of ordinary iodide is hazardous after this time. Immediately after birth, there are major changes in thyroid function and metabolism. Atmospheric cooling evokes sudden and marked increase in thyrotropin secretion, which in term causes a progressive increase in serum T4 levels that are maximal 24 to 36 hours after birth. INCIDENCE The incidence of hypothyroidism is approximately 1 %. Thyroid disease is the second most common cause of endocrine dysfunction in women of childbearing age (diabetes is the first). In a study [5], the overall incidence of hypothyroidism was 2.5 %; overt thyroid deficiency was 1.8 per 1000 and subclinical cases 23 per 1000. CLASSIFICATION Clinical or overt hypothyroidism is diagnosed when an abnormally high serum thyrotropin levels is accompanied by an abnormally low thyroxine levels. Subclinical hypothyroidism is defined by an elevated serum thyrotropin level with normal serum thyroxine.

Review Article

Table 1. Physiological changes in pregnancy Physiological change

TFT’s

Increased TBG

Increased total T3, T4

First trimester increase in hCG

Increased FT4 & decreased TSH

Increased plasma volume

Increased T3, T4, pool size

Increased type III, 5- deiodinase due to increased placental mass

Increased T4, T3, degradation

Increased iodine clearance

Decreased hormone production in iodine deficient areas.

subacute de Quervain’s thyroiditis or post partum thyroiditis. CLINICAL FEATURES Many symptoms occur as in normal pregnancy; discriminatory symptoms are cold intolerance, slow heart rate and delayed relaxation of deep tendon reflexes, particularly those of the ankle. Pregnancy outcome with subclinical hypothyroidism (Table 2) Abnormalities in maternal thyroid function can adversely affect the fetus directly by the way of the transplacental passage of abnormal maternal hormone concentration, thyroid stimulating hormone(TSH) receptor antibodies, or prescribed antithyroid medication and indirectly by way of the altered maternal gravid physiology [6].

Fig.1 TSH and hCG during gestation.

Severe hypothyroidism with pregnancy is uncommon, probably because it is often associated with infertility and increased miscarriage rates. CAUSES (i)

Atrophic (autoimmune) hypothyroidism – Most common cause is autoimmune associated with thyroid peroxidase autoantibodies, leading to destruction of the gland, lymphoid infiltration and eventual atrophy and fibrosis. Antibodies blocking TSH receptor are also present in some cases.

(ii) Hashimotos thyroiditis – It is differentiated form of thyroiditis, also with thyroid peroxidase (microsomal) autoantibodies, often at high titer. However, atrophic changes occur with regeneration and result in goiter formation. (iii) Iatrogenic like after treatment with Lithium, amiodarone or antithyroid drugs. (iv) Transient occurring as a part of the disease course in

Studies show that hypothyroidism may impair fetal neuropsychological development. Studies show that children born to uncontrolled hypothyroid mothers are at increased risk of psychomotor development and diminished school performance, reaching recognition and IQ scores. Pregnancy with hypothyroidism is associated with higher incidence of maternal complications like PIH and GDM as seen in a study [7]. Pregnancy outcome with overt hypothyroidism (Table 3) The most serious consequence of hypothyroidism is myxedema coma but it is extremely rare. Cretinism (deaf mutism, spastic motor disorder, and hypothyroidism) is a distinct and severe form, of brain damage caused by severe maternal iodine deficiency. Overt hypothyroidism causes subfertility,and the presence of thyroid autoantibodies,even if the mother is euthyroid,is associated with an increased risk of miscarriage

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Table 2. Pregnancy outcomes in women with untreated subclinical hypothyroidism Outcome

Euthyroid controls (n = 15,689)

Subclinical hypothyroidism (n = 404)

Hypertension (%)

P value

9

11

0.39

0.3

1.0

0.026

d 36 weeks

6.0

7.0

0.390

d 34 weeks

2.5

4.0

0.011

d 32 weeks

1.0

2.5

0.068

Mean birth weight (g)

3367 ± 567

3317 ± 599

0.081

RDS – ventilator (%)

1.5

3.0

0.048

Neonatal intensive care (%)

2.0

4.0

0.019

Placental abruption (%) Gestational age delivered (%)

RDS = Respiratory distress syndrome; Data from Casey and colleagues (2005) [5]

A study [10] reported a higher cesarean section rates in the study group (28.7%) compared with the institutional rate (18%). In hypothyroidism there are placental hypoxic changes. This may be responsible for thick meconium stained liquor and/or fetal distress.

Table 3 Pregnancy complications in 112 women with hypothyroidism Complications

Hypothyroidism (%) Overt (n=49)

Subclinical (n=63)

Preeclampsia

31

16

Abruptio placentae

8

0

Cardiac dysfunction

3

2

Birthweight less than 2000 g

3

19

Stillbirths

8

2

DIAGNOSIS Normal values for Thyroid Function Tests during pregnancy are given in Table 4 [11]. SCREENING IN PREGNANCY

Modified from Abalovich (2002) [8] Davis (1988), and Leung (1993), and all their associates.

that was quantified as having an odds ratio of 2.3% (95% CI,1.8 – 2.95) in a recent meta analysis [9].According to guidelines although a positive association exists between the presence of thyroid antibodies and pregnancy loss, universal screening for antithyroid antibodies and possible treatment cannot be recommended at this time. As of this date, only one adequately designed intervention trial has demonstrated decrease in the miscarriage in thyroid antibody positive euthyroid women.

Routine screening for hypothyroidism is still controversial. One school of thought is that thyroid testing during pregnancy should be performed on symptomatic women or those with a personal history of thyroid disease. ACOG [12] had recommended against implantation of screening until further studies were done to validate or refute the findings of association of adverse neuropsychological development with subclinical hypothyroidism. However, many studies on delayed neurological development in babies born to hypothyroid women have been published in recent years, and have advocated routine, prepregnancy, and early pregnancy screening [13].

Table 4. Normal values for thyroid function test Test

Non pregnant

First trimester

Second trimester

Free T4 (pmol/L)

11-23

10-24

9-19

Free T3 (pmol/L)

4-9

4-8

4-7

3-5

TSH(mu/L)

<4

0-1.6

1-1.8

7-7.3

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Third trimester 7-17

Review Article

One major concern is that it seems unlikely that treatment given after the period of early cerebral development would be totally efficacious to prevent neurological damage [14]. This is further strengthened by the January 2005 statement of The American Thyroid Association and The American Association of Clinical Endocrinologists recommending routine TSH measurement during prepregnancy evaluation or as soon as pregnancy is diagnosed [15]. IODINE DEFICIENCY Adequate iodine is requisite for normal fetal neurological development beginning soon after conception. The WHO estimated in 1990 that 20 million people worldwide have varying degree of preventable brain damage due to fetal iodide deficiency [16]. Iodide supplementation before pregnancy prevents neurological morbidity from severe deficiency. Addition of supplemental iodine to pre-natal vitamins has been proposed. CONGENITAL HYPOTHYROIDISM Because the clinical diagnosis of hypothyroidism in neonates is usually missed, newborn mass screening was introduced in 1974 and is now required by law. Early and aggressive thyroxine replacement is critical for these infants. Except in those with severe congenital hypothyroidism, sequalae including intellectual impairment are typically preventable [17]. Preterm Infants Transient hypothyroxinemia is common in preterm infants, and it has been assumed that treatment with thyroxine is not necessary.

dosage adjustments are required. Suggested mechanisms for this increased requirement include an elevated extrathyroidal pool of T4; the need to saturate large quantities of thyroid-binding globulin; increased degradation of T4; reduced absorption of T4, especially if taken with iron supplements; and increased transfer of T4 from mother to fetus. Because a similar increased requirement is seen in post menopausal women, with hypothyroidism who are given estrogen replacement, this increased demand in pregnancy may be caused by increased estrogen production [18]. A study shows that thyroxine requirement increases in majority of patients as early as fifth week of pregnancy and the authors propose that the hypothyroid women should increase their levothyroxine dose by approximately 30% as soon as pregnancy is diagnosed [19]. However it was also generally believed that hypothyroid women on maintenance dose rarely require an increase in dosage during pregnancy. A recent study shows that none of the women who had stable doses of thyroxine during pregnancy had required recent pre-pregnancy changes in dose or needed postnatal changes [20]. Baseline thyroid function test should be performed as soon as possible. They should be performed every 3 months and more frequently if dosage adjustments are made. The adjustment should be made based on results of thyroid function tests. Thyroxine replacement should be done to a dose that insures that thyroid function test are normal with FT4 at the upper end of normal range for each trimester of pregnancy and serum TSH should be < 2.5 m U/L. Exception is women who have had a thyroidectomy for thyroid cancer as it is necessary to suppress TSH secretion. Thyroxine absorption is decreased by certain drugs including iron and calcium supplement. Thyroxine is best taken on an empty stomach and four hours apart from iron or other supplements or soy products.

MANAGEMENT Pre-pregnancy Consider diagnosis of hypothyroidism in patients with infertility or menstrual disorders and medical therapy should be optimized and pregnancy to be delayed until good control is achieved. Pre-natal In a newly diagnosed hypothyroid patient, a full replacement thyroxine dose should be instituted immediately, assuming there are no abnormalities in cardiac function. Treatment should be initiated with a dose of 100 – 150 microgm/day or titrated according to body weight (2.0 – 2.4 micrograms/kg body weight/day). In diagnosed cases, as thyroxine requirements increase,

Some studies show that the etiology of hypothyroidism plays a pivotal role in determining the timing and magnitude of thyroid hormone adjustments during pregnancy. For example patients with primary hypothyroidism required smaller cumulative dose increases whereas patients with treated Graves disease required largest cumulative increases in LT [4] dosage. Labour and delivery When adequate control is achieved, no specific measures are needed for labour and delivery. However, when large goiter causes respiratory compromise, anaesthetic or surgical advice may be required.

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Review Article 8. Abalovich M, Gutierrez S, Alcaraz G, et al. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002; 12: 63.

Post-Natal Women should resume their prepregnancy levothyroxine dosage immediately after delivery and have their serum TSH level re-evaluated after 6 weeks. Thyroid peroxidase auto antibodies are significantly associated with postpartum thyroiditis and postpartum depression. Post Partum thyroiditis Transient autoimmune thyroiditis has consistently been found in 5 to 10 percent of women during the first year after childbirth [21].Yet there are insufficient data to recommend screening of all women for postpartum thyroiditis.The propensity for thyroiditis antedates pregnancy and is directly related to increasing serum levels of thyroid autoantibodies.Women with high antibody titers in early pregnancy commonly are affected [22].Women known to be thyroid peroxidase antibody positive should have a TSH performed at 3 and 6 months postpartum.Upto 25% of women with type 1 diabetes develop postpartum thyroid dysfunction [23].Women who experience postpartum thryoiditis have about 30% risk of developing permanent hypothyroidism [24]. Asymptomatic women with PPT who have a TSH above the reference range but below 10 PU/mL and who are not planning a subsequent pregnancy do not necessarily require intervention, but should, if untreated, be re-monitored in 4-8 weeks. Symptomatic women and women with a TSH above normal and who are attempting pregnancy should be treated with levothyroxine. REFERENCES 1. Rasmussen NG, Horness PJ, Hegedius L. Ultrasonographically determined thyroid size in pregnancy and postpartum; The goitrogenic effect of pregnancy. Am J Obstet Gynecol 1989; 160: 1216. 2. Glinoer D. Pregnancy and iodine; Thyroid 2001; 11: 471-481. 3. Grossman M, Weintraus BD, Szkudlinski MW. Novel insights into the molecular mechanisms of human thyrotropin action: Structural, physiological and therapeutic implications for the glycoprotein hormone family.Endocr Rev 1997 18: 476 . 4. Ballabio M, Nicoloni V, Jowett T, et al. Maturation of thyroid function normal human fetuses.Clin Endocrinol 1989; 31: 505. 5. Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism pregnancy outcomes.Obstet Gynecol 2005; 105: 38. 6. Le Beau SO, Mandal SJ. Thyroid disorders during pregnancy. Endocrinol Metab Clin N Am 2006; 35: 117-136. 7. Kumar A, Singh R, Prasad S. Hypothyroidism during pregnancy. Int J Gynaecol Obstet 2004; 84: 252253.

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9. Prummel MF, Wiersinga WM. Thyroid autoimmunity and miscarriage. Eur J Endocrinol 2004; 150(6),751-755. 10. Idris I, Srinivasan R, Simm A, et al. Maternal hypothyroidism in early and late gestation: effects on neonatal and obstetric outcome. Clin Endocrinol (Oxf) 2005; 63: 560-565. 11. Adapted from (a) Chan BY, Swaminathan R. Serum thyrotropin concentration measured by sensitive assays in normal pregnancy: BJOG 1988; 95:1332-1334 (b) Parker JH. Amerlex free triidothyronine and free thyroxine levels in normal pregnancy. BJOG 1985; 92: 1234-1238 ¤ Girling JC. Thyroid disorders in pregnancy. Curr Obstet Gynaecol 2003; 13: 45-51. 12. Thyroid disease in pregnancy. Practice Bulletin no. 37, 2002. American College of Obstetricians and gynecologists. 13. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341: 549-555. 14. Utiger RD, Maternal hypothyroidism development. Eng J Med 1999; 341: 601.

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15. Gharib H, Tuttle MR, Baskin J, et al. Subclinical thyroid dysfunction: A joint statement on management from the American Association of Clinical Endocrinologists, American Thyroid Association and the Endocrine Society. Endocer Pract Metab 2004; 90: 497-501. 16. Hazel BS. Iodine deficiency and fetal brain damage. N Engl J Med 1994; 331: 1270. 17. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function.N Eng J Med 1994; 331: 1072. 18. Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy.N Engl J Med 2001; 344: 1743. 19. Erik K, Marqusee E, Laurens J, Jarolin P, Fischer GA, Larsen PR. Timing and magnitude of increases in Levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004; 351: 241-249. 20. Kothari A, Girling J. Hypothyroidism in pregnancy: pre pregnancy thyroid status influences gestational thyroxine requirements. BJOG 2008; 115(13):1704-1708. 21. Amino N, Tada H, Hidaka Y, et al: Postpartum autoimmune thyroid syndrome.Endocr J 2000; 47: 645. 22. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003; 348: 2646. 23. Alavarez Marfany M, Roman SH, Drexler AJ, et al. Longterm prospective study of postpartum thyroid dysfunction in women with insulin dependent diabetes mellitus.J Clin Endocrinol Metab 1994; 79:10. 24. Muller AF, Drexhage HA, Berghout A. Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: Recent insights and consequences for antenatal and postnatal care.Endocr Rev 2001; 22: 605.

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