Unnikrishnan AG
Department of Endocrinology, Amrita Institute of Medical Sciences, Cochin

Corresponding Author: Dr. Unnikrishnan AG, MD, DM, DNB, MNAMS; Endocrinologist, Amrita Institute of Medical Sciences, Cochin. Phone: 09846005343. E-mail:unnikrishnanag@aims.amrita.edu

ABSTRACT

The occurrence of hypothyroidism in pregnancy can have adverse effects on the mother and the fetus. In  addition, recent research has indicated that  in  the  first  half  of  pregnancy, an adequate thyroid hormone level  could   play  an important  role in fetal brain development. Clinical signs of hypothyroidism in pregnancy are not very specific and sensitive. Therefore, serum TSH estimation is the best way to  make  a diagnosis. Hypothyroidism in pregnancy, whether overt or subclinical, requires therapy with  levothyroxine. Frequent monitoring and precise dose titration are required. The aim of therapy  is to achieve  a TSH value  <2.5 mu/L. This is important to ensure a successful pregnancy outcome.

Maternal Hypothyroidism: An Introduction

The occurrence of  hypothyroidism during pregnancy poses a challenge to the treating clinician. The diagnosis is made by a TSH that is greater than normal, and during pregnancy, this situation deserves therapy. Research over the years has shown that maternal thyroid hormones are very important in pregnancy.1-3 Importantly, emerging data seems to suggest that thyroid hormones are important for fetal brain development, especially during early pregnancy.4 This article  will focus on the clinical  approach  to hypothyroidism in a pregnant woman.

Pregnancy and alterations in thyroid physiology

Table 1. Important Physiological thyroid alterations in pregnancy

Table 1. Important Physiological thyroid alterations in pregnancy

Pregnancy can  cause several physiological changes  in thyroid function  tests (Table 1).5-9 The requirement for thyroid hormones is increased during pregnancy, and  this is achieved  by  an  increased thyroid gland function. The thyroid gland of subjects with pre-existing hypothyroidism lacks the functional reserve to increase thyroxine secretion appropriately. This results in a 25-47% increase in levothyroxine dose requirement during pregnancy.5

Lack of adequate iodine intake is another factor that can compromise thyroid function in pregnancy, especially in iodine-deficient zones.6,7 HCG too is an important  factor  confounding thyroid  function tests. HCG has a structure that is similar to TSH­ thus HCG too can stimulate the thyroid gland. This causes  transient suppression of TSH  in the  first trimester.8 Finally, the estrogenic milieu of pregnancy results in increased sialic acid content of thyroid binding globulin (TBG); this reduces the clearance of TBG  and  prolongs  its circulation time.9 This increase in TBG (which binds to thyroid hormones) can result in a falsely high thyroid hormone (especially T4) levels during pregnancy. However adaptation mechanisms  ensure  that the free or active thyroid hormone levels are  kept  normal. Though these changes affect both the thyroid  hormones (T3 and T4), T4 is the more appropriate hormone to measure, and it has been suggested that, free T4 hormones be measured in pregnancy. In case total T4 is being used as a measuring  tool,  recent reports  suggest  that a different cut-off be used: it has been reported that the normal upper limit of total T4 level is 1.5 times the upper  limit in  non-pregnant adults. Postpartum thyroiditis is an important  pregnancy-related thyroid disease. Autoimmune thyroid disorders remit during pregnancy as a part of the immunosuppressive effects of pregnancy. Classically, there is a post-partum period of exacerbation. A key finding associated with thyroid autoimmunity  is that patients who are euthyroid  but positive for  antibody have  an increased rate  of miscarriage.10 The  reason for  this  is not  well understood.

The clinical importance

Hypothyroidism, as defined by a raised TSH level, affects 2.5% of all pregnancies.11 Thus,  about  40 patients need to be screened to detect one case. In iodine-sufficient areas, the most common cause is Hashimoto’s thyroiditis. The issue of universal screening during pregnancy for this common, serious and easily treatable disease definitely merits consideration, but is a hotly debated controversy.

The diagnosis of maternal hypothyroidism is important because of its implications on both maternal and fetal outcomes (Table 2).2,12 This is even true with subclinical hypothyroidism.13 In addition, it is well known  that untreated hypothyroidism can cause infertility.14

Emerging evidence in the last decade has linked thyroid hormones with fetal brain development Classic studies on neurological cretinism had earlier shown that iodine deficiency caused fetal brain damage.15 This occurs presumably by reducing thyroid hormone synthesis, as iodine is an integral component  of both T3 and T4. However, in addition to iodine deficiency, any cause of maternal hypothyroidism in early pregnancy can cause fetal brain damage.

Table 2. Negative outcomes associated with maternal hypothyroidism

Table 2. Negative outcomes associated with maternal hypothyroidism

Thyroid gland develops in the fetus only after 3weeks. This thyroid gland can trap iodine and synthesize thyroid hormones only after about 3 months. Till this time, the mother gives thyroid hormones to her fetus through placental diffusion. Even after 3 months, maternal T4 transfer continues.12 In order to know whether this transfer was significant, Vulsma et al studied 25 neonates with complete inability to produce thyroid hormones.16 T4 levels in the cord serum of affected neonates ranged from 35 to 70 nmol per liter. The authors concluded that this level purely  accrued  from maternal thyroxine  (T4)  transfer, and  that  this indicated substantial maternal-fetal thyroxine transfer during the  first trimester. Do these transferred hormones serve any important function? In animal studies, thyroid hormones regulate neuronal proliferation, migration of neurons, synapse formation and myelination.17-19 It has been hypothesized that T4 gets converted to tri-iodothyronine  (T3) in the cerebral  cortex, which binds to specific nuclear receptor isoforms to carry out   these functions.  Hypothyroidism as a result low maternal T4 may be overt or mild, presenting with very subtle neurological defects, like learning disabilities or a low intelligence quotient.17-19 However, the evidence linking hypothyroidism with poor obstetrical outcome is much stronger than that linking it to neurological outcomes. To summarize published evidence suggests that maternal hypothyroidism is common, and that it is of crucial significance during both early and late pregnancy.

Making the diagnosis of maternal hypothyroidism

It is difficult to detect hypothyroidism during pregnancy based on symptoms and signs alone. Thus, the diagnosis is made by serum TSH estimation. Trimester-specific normative TSH data are important in this regard, but need to be validated.20 A TSH value that is more than the upper limit of normal (i.e.>4mU/L) should alert the clinician to the diagnosis. Recent studies have suggested that either a total or free T4 must also be simultaneously tested during screening.21 This is because a low T4, even with a normal TSH, is now considered abnormal (especially in iodine deficient zones), and this deserves therapy.21 Thus, the focus seems to be shifting towards maternal hypothyroxinemia  rather than hypothyroidism.21

In  general, free T4  estimation is  important in pregnancy. However, the total T4 is increasingly being used nowadays, given fallibilities in the free T4 assay. Normal levels of total T4 in pregnancy can be decided by multiplying non-pregnant levels by a factor of 1.5 for pregnant women.5 Antithyroid antibody testing is not mandatory, but may can be useful because it identifies an underlying autoimmune basis. Also, high antithyroid antibody titers are associated with infertility and pregnancy losses.22

Management of maternal hypothyroidism

Levothyroxine  (LT4) is the treatment  of choice. In subjects with florid, overt hypothyroidism, the dose required is 2 ug/kg/day.5 This higher dose is important to  cover for  higher thyroxine demand during pregnancy. In subjects with subclinical hypothyroidism and in subjects with a TSH <10 mU/L, the starting dose of LT4 is usually 50-100ugf day. Considerations are different in subjects with ‘’pre­gestational” hypothyroidism i.e. in subjects who have become pregnant while  already taking LT4  for hypothyroidism.  These subjects require a 25-47% increase in dosage. This excess need is because of excess TBG, increased distribution of T4 as well as the placental transport of thyroid hormones. It has been recommended that when a hypothyroid woman taking LT4 becomes pregnant,  the dose should  be increased by about 25-50 ug as soon as pregnancy is diagnosed.23  Usually, the dosage required is stable and plateaus beyond the 20th week. Thus, after this time, very frequent  monitoring  is not needed.23,24  Women taking iron or calcium tablets should not take them simultaneously with LT4. These tablets may be taken about 4 hours after taking LT4. Iodine intake is important in pregnancy.25

Monitoring and therapeutic targets

In the first half of pregnancy, it is best to monitor with free T4 and TSH every 4 weeks. But later on, the monitoring may  be done every  6 weeks.  The target TSH level in pregnancy is <2.5 mU/L.5  In subclinical hypothyroidism, the dose may be increased by about 50ug at a time. However, in cases where the TSH is high (>10 mU/L), the dosage may need to be increased by 50-75 ug at a time. Where TSH is> 20 mU/L the dose may need to be increased by75-100 ug at a time. Post-delivery, the dose must be reduced to the  pre-pregnancy dosage. Thyroid functions may be re-checked when 6 weeks have elapsed following delivery.

Isolated  anti-thyroid antibody positivity

Pregnancy loss  has   been   linked to  thyroid autoimmunity.26 The reasons are hypothetical: firstly, antithyroid antibodies may  only  be  a marker of generalized  autoimmunity, which could explain the high occurrence of miscarriages.22 It is also possible that anti-TPO  (anti-thyroid peroxidase) antibodies, a marker  of autoimmune thyroid  disease  (AITD) could pick out groups of subjects with subtle damage to the thyroid gland. These subjects might be at risk of developing  hypothyroidism because the thyroid gland that is damaged via autoimmune mechanisms is unable to adjust to the physiological loads that are imposed on  it during pregnancy.22   The  third hypotheses suggests that both anti-TPO positivity as well as miscarriages  are common in older women: thus  the link between  thyroid  autoimmunity and pregnancy loss is a statistical aberration  that is due to the confounding  effect of age.22  None of these hypotheses have been proved or disproved, despite several  studies  on the issue. In a recent  study, the authors reported that  LT4 therapy in  euthyroid TPO+ve pregnancies could improve miscarriage rate by 75% and premature deliveries by 69%.27 This study implies, but cannot conclude with certainty, that the judicious  use of levothyroxine could  improve outcomes, especially in pregnant, anti-TPO positive subjects  with  a high-normal TSH.  Future  studies looking into this emerging area are needed before clinical recommendations can be made.

Summary

The presence of hypothyroidism during pregnancy is common, and can have serious  consequences on obstetrical  and fetal outcomes. Diagnosis is based on serum TSH  estimation.  Levothyroxine is  the therapy of choice. Frequent monitoring every 4-6 weeks and dose titration are important. Indeed, a recent guideline suggests that thyroid functions (T4 and  TSH)  should  be  normalized “ as rapidly  as possible” when hypothyroidism complicates pregnancy.28  These  guidelines  recommend target TSH values that are <2.5 mu/L in the first trimester, and < 3 mu/L in the 2nd and 3rd trimesters.28  When T4 measurements are used, the guidelines suggest  that total T4 could  be a very reliable test, and  advise caution while interpreting free  T4 measurements.28    It seems  likely  that the  focused treatment of hypothyroidism during pregnancy will become more important in the years to come.

End Note

Author Information

Dr. Unnikrishnan AG, MD, DM, DNB, MNAMS;
Endocrinologist, Amrita Institute of Medical Sciences, Cochin.
E-mail: unnikrishnanag@aims.amrita.edu
Phone: 09846005343

Conflict of Interest: None declared

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