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 Table of Contents  
INVITED REVIEW
Year : 2018  |  Volume : 16  |  Issue : 2  |  Page : 48-51

Thyroid disorders in pregnancy


Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication20-Jun-2018

Correspondence Address:
Dr. Riddhi Das Gupta
Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_23_18

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  Abstract 

There are significant changes that occur in the thyroid gland and its function during pregnancy, thus making the assessment of thyroid functions in pregnancy substantially important. Normal pregnancy is associated with an increase in renal iodine excretion, an increase in T4 binding proteins, an increase in thyroid hormone production, and thyroid stimulatory effects of human chorionic gonadotropin (hCG), and the treatment targets are different from women who are not pregnant. Both hypothyroidism and hyperthyroidism are associated with significant impact on the fetomaternal unit and pregnancy outcomes. Evidence appears to support an association between overt thyroid dysfunction and an increased risk of infertility, and there is strong evidence to recommend treatment for overt hypothyroidism in pregnancy. The recommended treatment of maternal hypothyroidism is the administration of oral LT4.

Keywords: Hypothyroidism, thyroid autoantibodies, thyroid dysfunction, thyroid hormones


How to cite this article:
Gupta RD. Thyroid disorders in pregnancy. Curr Med Issues 2018;16:48-51

How to cite this URL:
Gupta RD. Thyroid disorders in pregnancy. Curr Med Issues [serial online] 2018 [cited 2018 Jul 19];16:48-51. Available from: http://www.cmijournal.org/text.asp?2018/16/2/48/234833


  Introduction Top


Pregnancy has a significant impact on the thyroid gland and its function. During pregnancy, the thyroid gland increases in size by 10% in iodine-replete countries but by 20%–40% in areas of iodine deficiency. The production of the thyroid hormones, thyroxine (T4), and triiodothyronine (T3), increases by nearly 50%, in conjunction with a separate 50% increase in the daily iodine requirement. In healthy women, these changes happen smoothly, while in specific pathological conditions, there can be profound dysfunction of the normal metabolic milieu. There is a wide spectrum of thyroid disorders that affect the pregnant mother, thus making the assessment of thyroid functions in pregnancy substantially important.

Thyroid hormone changes in normal pregnancy

Normal pregnancy is associated with an increase in renal iodine excretion, an increase in T4 binding proteins, an increase in thyroid hormone production, and thyroid stimulatory effects of human chorionic gonadotropin (hCG). All of these factors influence thyroid function tests in the pregnant patient. The healthy thyroid adapts to these alterations through changes in thyroid hormone metabolism, iodine uptake, and the regulation of the hypothalamic–pituitary–thyroid axis. During pregnancy, women have lower serum thyroid stimulating hormone (TSH) concentrations than before pregnancy, and a TSH below the nonpregnant lower limit of 0.4 mU/L is observed in as many as 15% of healthy women during the first trimester of pregnancy. The use of population-based, trimester-specific reference ranges remains the best way to interpret thyroid functions in pregnancy.

Thyroid autoantibodies in pregnancy

Anti-TPO or anti-Tg thyroid autoantibodies are present in 2%–17% of unselected pregnant women through the prevalence of antibodies varies with ethnicity. Studies have shown that TPOAb and TgAb were present in 8% of women, while 5% demonstrated isolated Tg antibodies and 4% demonstrated isolated TPOAb concentrations with higher serum TSH being seen in those with thyroid autoimmunity. Because of the increased risk of TSH elevation in this population, euthyroid pregnant women who are TPOAb or TgAb positive should have measurement of serum TSH concentration performed at the time of pregnancy confirmation and every 4 weeks through midpregnancy. Although insufficient evidence exists to definitely identify decreased risk of pregnancy loss with LT4 therapy in TPOAb-positive euthyroid women who are newly pregnant, it may be beneficial to administer LT4 25–50 μg once daily to TPOAb-positive euthyroid pregnant women with a prior history of pregnancy loss.

Thyroid dysfunction in infertility and assisted reproduction

Although direct causality between overt hypothyroidism and primary infertility remains contentious, the majority of evidence appears to support an association between overt thyroid dysfunction and an increased risk of infertility.

Thyroid dysfunction being reversible and treatment being generally safe, it is reasonable to treat overt thyroid dysfunction in infertile women, with the goal of normalizing thyroid function. The evaluation of serum TSH concentration is recommended for all women seeking care for infertility. LT4 treatment is recommended for infertile women with overt hypothyroidism who desire pregnancy and may be recommended in subclinically hypothyroid, thyroid autoantibody-negative women who are attempting natural conception (not undergoing assisted reproductive technology) but not recommended in nonpregnant, thyroid autoantibody-positive euthyroid women attempting the same. Subclinically hypothyroid women undergoing in vitro fertilization intracytoplasmic sperm injection should be treated with LT4 to achieve a TSH concentration <2.5 mU/L.

Hypothyroidism and pregnancy

In the setting of pregnancy, maternal hypothyroidism is defined as a TSH concentration elevated beyond the upper limit of the pregnancy-specific reference range. If pregnancy-specific TSH reference ranges are not available, an upper reference limit of 4.0 mU/L may be used. Overt hypothyroidism is associated with significant fetal and maternal morbidities. Specific adverse outcomes associated with overt maternal hypothyroidism include increased risks of premature birth, low birth weight, pregnancy loss, and lower offspring IQ. Increased risk of fetal loss and gestational hypertension has also been demonstrated. The risk to the fetomaternal unit with subclinical hypothyroidism remains a matter of intense research. Overall, studies indicate an increased risk of pregnancy loss and preterm delivery, in relation to elevated maternal TSH concentrations. Importantly, however, this effect is exacerbated by the presence of elevated TPOAb, especially when TSH exceeds 2.5 mU/L. As such, all pregnant women with TSH >2.5 should be evaluated for TPOAb status.

Treatment indications

There is strong evidence to recommend treatment for overt hypothyroidism in pregnancy.

Subclinical hypothyroidism in pregnancy should be treated as follows:

  1. LT4 therapy is recommended for


    • TPOAb-positive women with a TSH greater than the pregnancy-specific reference range
    • TPOAb-negative women with a TSH >10.0 mU/L


  2. LT4 therapy may be considered for


    • TPOAb-positive women with TSH concentrations >2.5 mU/L and below the upper limit of the pregnancy-specific reference range
    • TPOAb-negative women and TPOAb-negative women with TSH concentrations greater than the pregnancy-specific reference range and below 10.0 mU/L


  3. LT4 therapy is not recommended for


    • TPOAb-negative women with a normal TSH (TSH within the pregnancy-specific reference range or <4.0 mU/L if unavailable).



  Monitoring Top


The recommended treatment of maternal hypothyroidism is the administration of oral LT4.

For optimal treatment, it is reasonable to target a TSH in the lower half of the trimester-specific reference range. When this is not available, it is reasonable to target maternal TSH concentrations below 2.5 mU/L. Women with overt and subclinical hypothyroidism (treated or untreated) or those at risk for hypothyroidism (e.g., patients who are euthyroid but TPOAb or TgAb positive, posthemithyroidectomy, or treated with radioactive iodine) should be monitored with a serum TSH measurement approximately every 4 weeks until midgestation and at least once near 30-week gestation.

Dose adjustment during pregnancy and preconception targets

Treated hypothyroid women of reproductive age should be counseled regarding the likelihood of increased demand for LT4 during pregnancy. Such women should also be counseled to contact their caregiver immediately on a confirmed or suspected pregnancy. In hypothyroid women treated with LT4 who are planning pregnancy, serum TSH should be evaluated preconception, and LT4 dose adjusted to achieve a TSH value between the lower reference limit and 2.5 mU/L. Hypothyroid patients receiving LT4 treatment with a suspected or confirmed pregnancy (e.g., positive home pregnancy test) should independently increase their dose of LT4 by 20%–30% and immediately contact their caregiver. Following delivery, LT4 should be reduced to the patient's preconception dose and repeat thyroid function testing should be performed at approximately 6 weeks' postpartum.

Thyrotoxicosis in pregnancy

The most common cause of thyrotoxicosis is hyperfunction of the thyroid gland (hyperthyroidism), and the most common cause of hyperthyroidism in women of childbearing age is autoimmune Graves' disease (GD) occurring in approximately 0.2% during pregnancy. Less common nonautoimmune causes of hyperthyroidism in pregnancy include toxic multinodular goiter and toxic adenoma. Subacute painful or painless thyroiditis are less common causes of thyrotoxicosis in pregnancy, More frequent than GD as the cause of hyperthyroxinemia is “gestational transient thyrotoxicosis,” which is limited to the first half of the pregnancy. This condition, characterized by elevated FT4 and suppressed serum TSH, is diagnosed in about 1%–3% of pregnancies and is secondary to elevated hCG levels. Often it is associated with hyperemesis gravidarum, defined as severe nausea and vomiting in early pregnancy with more than 5% weight loss, dehydration, and ketonuria. Other conditions associated with hCG-induced thyrotoxicosis include multiple gestation, hydatidiform mole, and choriocarcinoma.

Serum TSH may decrease in the first trimester of normal pregnancy as a physiological response to the stimulating effect of hCG on the TSH receptor, especially within the first 11 weeks of pregnancy. Any subnormal serum TSH value should be evaluated in conjunction with serum total or free T4 and T3 values. The biochemical diagnosis of overt hyperthyroidism is confirmed in the presence of a suppressed or undetectable serum TSH and inappropriately elevated serum total/free t4.

Differentiating Graves' disease from gestational thyrotoxicosis

In early pregnancy, the differential diagnosis in the majority of cases is between GD and gestational transient thyrotoxicosis. In both situations, common clinical manifestations include palpitations, anxiety, tremor, and heat intolerance.

A careful history and physical examination are of utmost importance in establishing the etiology. The findings of no prior history of thyroid disease, no stigmata of GD (goiter, orbitopathy), a self-limited mild disorder, and symptoms of emesis favor the diagnosis of gestational transient thyrotoxicosis. When a suppressed serum TSH is detected in the first trimester (TSH less than the reference range), a medical history, physical examination, and measurement of maternal serum FT4 or total T4 concentrations should be performed. Measurement of TSH receptor antibodies (TRAb) and maternal total T3 may prove helpful in clarifying the etiology of thyrotoxicosis. However, radionuclide scintigraphy or radioiodine uptake determination should not be performed during pregnancy.

Treatment strategies

Gestational thyrotoxicosis

The appropriate management of abnormal maternal thyroid tests attributable to gestational transient thyrotoxicosis and/or hyperemesis gravidarum includes supportive therapy, management of dehydration, and hospitalization if needed. ATDs are not recommended, though beta-blockers may be considered.

Graves' disease

Untreated GD during pregnancy has significant fetal and maternal complications. Poor control of thyrotoxicosis is associated with pregnancy loss, pregnancy-induced hypertension, prematurity, low birth weight, intrauterine growth restriction, stillbirth, thyroid storm, and maternal congestive heart failure. Moreover, some studies suggest fetal exposure to excessive levels of maternal thyroid hormone may lead to seizure disorders and neurobehavioral disorders in the offspring in later life.

Thionamide antithyroid drugs (methimazole [MMI], carbimazole [CM], and propylthiouracil [PTU]) are the mainstays of treatment for hyperthyroidism during pregnancy. The initial doses during pregnancy are as follows: MMI, 5–30 mg/d (typical dose in average patient 10–20 mg); CM, 10–40 mg/d; and PTU, 100–600 mg/d (typical PTU dose in average patient 200–400 mg/d). The equivalent potency of MMI to PTU is approximately 1:20 (e.g., 5 mg MMI = 100 mg of PTU). Ten milligrams of CM is rapidly metabolized to approximately 6 mg of MMI. Owing to the hepatotoxicity associated with PTU, it was initially recommended to limit the use of PTU to the first trimester of pregnancy. However, the greatest risk surrounding the use of antithyroid drugs in pregnancy is related to their potential teratogenic effects. A “syndrome of MMI/CM embryopathy” which also includes dysmorphic facies, aplasia cutis, choanal or esophageal atresia, various types of abdominal wall defects and eye, urinary system, and ventricular septal defects. Beta-adrenergic blocking agents such as propranolol 10–40 mg every 6–8 h may be used for controlling hypermetabolic symptoms until patients have become euthyroid. Long-term treatment with beta-blockers has been associated with intrauterine growth restriction, fetal bradycardia, and neonatal hypoglycemia.

In a newly pregnant woman with GD, who is euthyroid on a low dose of MMI (5–10 mg/d) or PTU (100–200 mg/d), all antithyroid medication should be discontinued given potential teratogenic effects. Following the cessation of antithyroid medication, maternal thyroid function testing (TSH, and FT4 or TT4) and clinical examination should be performed every 1–2 weeks to assess maternal and fetal thyroid status. If the pregnant woman remains clinically and biochemically euthyroid, test intervals may be extended to 2–4 weeks during the second and third trimester.

In pregnant women with a high risk of developing thyrotoxicosis if antithyroid drugs were to be discontinued, continued antithyroid medication may be necessary. Factors predicting high clinical risk include being currently hyperthyroid, or requirement of >5–10 mg/d MMI or >100–200 mg/d PTU to maintain a euthyroid state.

In such cases:

  1. PTU is recommended for the treatment of maternal hyperthyroidism through 16 weeks of pregnancy
  2. Pregnant women receiving MMI who are in need of continuing therapy during pregnancy should be switched to PTU as early as possible
  3. When shifting from MMI to PTU, a dose ratio of approximately 1:20 should be used (e.g., MMI 5 mg/d = PTU 50 mg twice daily)
  4. If ATD therapy is required after 16-week gestation, either MMI or PTU can be continued, and there is no recommendation for switching drugs.


A combination regimen of LT4 and an ATD should not be used in pregnancy, except in the rare situation of isolated fetal hyperthyroidism.

Monitoring and dose adjustments

In women being treated with antithyroid drugs in pregnancy, FT4/Total T4 and TSH should be monitored approximately every 4 weeks, and maternal serum FT4/Total T4 at the upper limit or moderately above the reference range should be targeted.

Surgery for Graves' disease

Thyroidectomy for GD during pregnancy should be electively postponed after until after delivery. Otherwise, nonurgent surgery should be performed in the second trimester in specific scenarios.

Indications for estimating thyroid stimulating hormone receptor antibodies levels in pregnancy

  • If the patient has a history of GD treated with ablation (radioiodine or surgery), a maternal serum determination of TRAb is recommended at initial thyroid function testing during early pregnancy
  • If maternal TRAb concentration is elevated in early pregnancy, repeat testing should occur at weeks 18–22
  • If maternal TRAb is undetectable or low in early pregnancy, no further TRAb testing is needed
  • If a patient is taking antithyroid drugs for the treatment of Graves' hyperthyroidism when pregnancy is confirmed, a maternal serum determination of TRAb is recommended
  • If the patient requires treatment with ATDs for GD through midpregnancy, a repeat determination of TRAb is again recommended at weeks 18–22
  • If elevated TRAb is detected at weeks 18–22 or the mother is taking ATD in the third trimester, a TRAb measurement should again be performed in late pregnancy (weeks 30–34).


Fetal surveillance in maternal hyperthyroidism

Fetal surveillance should be performed in women who have uncontrolled hyperthyroidism in the second half of the pregnancy, and in women with high TRAb levels detected at any time during pregnancy (>3 times the upper limit of normal).

Monitoring should include ultrasound to assess heart rate, growth, amniotic fluid volume, and the presence of fetal goiter.

Treatment for toxic nodules

A low dose of antithyroid drugs should be administered with the goal of maternal FT4 or TT4 concentration at the upper limit or moderately above the reference range.

Thyroid dysfunction and lactation

As maternal hypothyroidism can adversely impact lactation, women experiencing poor lactation without other identified causes should have TSH measured to assess for thyroid dysfunction. Subclinical and overt hypothyroidism should be treated in lactating women seeking to breastfeed. However, there is no sufficient evidence to treat maternal hyperthyroidism on the grounds of improving lactation.

When antithyroid medication is indicated for women who are lactating, both MMI (up to maximal dose of 20 mg/d) and PTU (up to maximal dose of 450 mg/d) can be administered.

The use of I-131 is contraindicated during lactation. If required, I-123 can be used if breast-milk is pumped and discarded for 3–4 days before breastfeeding is resumed.

Breastfed children of women who are treated with antithyroid drugs should be monitored for appropriate growth and development during routine pediatric health and wellness evaluations but routine thyroid function assessment in the child is not recommended.


  Conclusion Top


Both hypothyroidism and hyperthyroidism are associated with significant impact on the fetomaternal unit and pregnancy outcomes. Early detection, rational therapy, and evidence-based treatment protocols are paramount to achieving wellbeing of the mother and newborn. Alterations of thyroid hormone levels in physiological conditions during pregnancy should always be kept in mind before initiation of detailed evaluation and treatment. The role of thyroid dysfunction in infertility and women opting for assisted reproduction need special consideration.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.




 

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