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Department of Pathology and
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Division of Endocrinology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110. Clinical Chemistry Case Conferences of the Division of Laboratory Medicine, Washington University School of Medicine, Saint Louis, MO 63110.
a Address correspondence to this author at: Department of Pathology, Washington University School of Medicine, Box 8118, Saint Louis, MO 63110. Fax 314-362-1461; e-mail gronowski{at}pathology.wustl.edu
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Abstract |
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 Top Abstract IntroductionPresentation of the CaseDiscussionSummaryReferences |
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Case: A woman in the 18th week of pregnancy presented with tachycardia, increased blood pressure, severe vomiting, increased total and free thyroid hormone concentrations, a thyroid-stimulating hormone (TSH) concentration within the reference interval, and an increased human chorionic gonadotropin (hCG) ß-subunit concentration.
Issues: During pregnancy, normal thyroid activity undergoes significant changes, including a two- to threefold increase in thyroxine-binding globulin concentrations, a 30–100% increase in total triiodothyronine and thyroxine concentrations, increased serum thyroglobulin, and increased renal iodide clearance. Furthermore, hCG has mild thyroid stimulating activity. Pregnancy produces an overall increase in thyroid activity, which allows the healthy individual to remain in a net euthyroid state. However, both hyper- and hypothyroidism can occur in pregnant patients. In addition, two pregnancy-specific conditions, hyperemesis gravidarum and gestational trophoblastic disease, can lead to clinical hyperthyroidism. The normal changes in thyroid activity and the association of pregnancy with conditions that can cause hyperthyroidism necessitates careful interpretation of thyroid function tests during pregnancy.
Conclusion: Assessment of thyroid function during pregnancy should be done with a careful clinical evaluation of the patient’s symptoms as well as measurement of TSH and free, not total, thyroid hormones. Measurement of thyroid autoantibodies may also be useful in selected cases to detect maternal Graves disease or Hashimoto thyroiditis and to assess risk of fetal or neonatal consequences of maternal thyroid dysfunction.
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Introduction |
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TopAbstractIntroductionPresentation of the CaseDiscussionSummaryReferences |
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Presentation of the Case |
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TopAbstractIntroductionPresentation of the CaseDiscussionSummaryReferences |
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Pertinent laboratory data included (reference values in parenthesis) were as follows: alkaline phosphatase, 170 U/L (38–126 U/L); total bilirubin, 18 mg/L (2–13 mg/L ); thyroxine (T4),1 387 µg/L (45–120 µg/L); percentage of uptake, 41.3% (21–32%); free T4 index, 15.98 (1.2–3.6); thyroid-stimulating hormone (TSH), 0.8 mIU/L (0.4–6.2 mIU/L); total triiodothyronine (T3), 5420 ng/L (800–2000 ng/L); and ß-subunit of human chorionic gonadotropin (ßhCG), 59 952 IU/L (3000–50 000 IU/L for second trimester). Stool and emesis were guaiac positive.
The patient was admitted to the hospital and treated with intravenous fluids, propranolol, propylthiouracil, and prochlorperazine. She responded to supportive measures and was discharged 1 week later when she tolerated a regular diet, her resting pulse was 80–90, and her blood pressure 110–140/40–60 mmHg. The clinical diagnosis at discharge was hyperthyroidism associated with hyperemesis gravidarum.
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Discussion |
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TopAbstractIntroductionPresentation of the CaseDiscussionSummaryReferences |
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) (4). The mechanism for this increase in TBG
involves both an increase in hepatic synthesis of TBG and an
estrogen-induced increase in sialylation, which increases the half-life
of TBG [from 15 min to 3 days for fully sialylated TBG
(2)(3)(5)]. A summary of changes in
thyroid tests during pregnancy is shown in Table 1
.
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Increases in total T4 and T3.
Plasma
concentrations of total T4 and
T3 are also increased during pregnancy, often
outside the health-related reference interval. Total
T4 and total T3
concentrations increase sharply in early pregnancy and plateau early in
the second trimester at concentrations 30–100% greater than
prepregnancy values (4)(6). The etiology of this
increase in total circulating thyroid hormones involves, primarily,
increased concentrations of plasma TBG
(3)(4)(6). Another proposed
mechanism for this increase in total thyroid hormone concentrations is
production of type III deiodinase from the placenta (3).
This enzyme, which converts T4 to reverse
T3, and T3 to
diiodotyrosine (T2), has extremely high activity
during fetal life (7)(8). Increased demand for
T4 and T3 has been
suggested to increase production of these hormones with, ultimately,
increased concentrations in the circulation (3). The
increase in T4 and T3
concentrations is less than would be expected by the increase in TBG.
Glinoer (3) refers to this as a "relative
hypothyroxinemia". As discussed below, this is reflected by a
decrease in free T4 concentrations as well as a
progressively decreasing T4/TBG ratio during
pregnancy (9).
Changes in free T4 and T3 concentrations during pregnancy have been controversial. Some authors have reported a decrease in free hormones (10)(11), whereas others have reported no change or even an increase (6)(12)(13)(14). These discrepancies may have been attributable to the techniques used for free hormone measurement. Roti et al. (15) demonstrated variability in serum free thyroid hormones in pregnant women at term among 10 commercially available methods. Regardless of the method, however, pregnant women, on average, had lower free hormone concentrations at term than nonpregnant women. Other studies have confirmed that serum free T4 and T3 are ~25% lower in women at delivery than nonpregnant subjects (9)(16). However, most pregnant women (>78%) remain within the same reference interval as nonpregnant women (9).
Thyroid stimulation by hCG.
hCG has mild thyrotropic activity
(17)(18)(19)(20)(21)(22). During the first trimester of pregnancy, when hCG
is at its greatest concentration, serum TSH concentrations drop,
creating the inverse image of hCG (Fig. 2
). In most pregnancies, this decrease in TSH remains within the
health-related reference interval (16). Under pathological
conditions in which hCG concentrations are markedly increased for
extended periods, significant hCG-induced thyroid stimulation can
occur, decreasing TSH and increasing free hormone concentrations (see
below).
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Members of the glycoprotein hormone family of luteinizing hormone,
follicle-stimulating hormone, TSH, and hCG contain a common 
-subunit
and a hormone-specific ß-subunit. Because the hCG and TSH
ß-subunits share 85% sequence homology in the first 114 amino acids
and contain 12 cysteine residues at highly conserved positions, it is
likely that their tertiary structures are very similar
(17)(18). Purified hCG, like TSH, has been shown
to (a) increase iodide uptake and cAMP production in FRTL-5
rat thyroid cells; (b) increase cAMP production
dose-dependently and displace binding of
125I-labeled TSH in Chinese hamster ovary cells
stably transfected with human TSH receptor; and (c)
stimulate iodide uptake, organification, and T3
secretion in cultured human thyroid follicles
(17)(18). Glinoer (3) has estimated
that a 10 000 IU/L increment in circulating hCG corresponds to a mean
free T4 increment in serum of 0.6 pmol/L (0.1
ng/dL) and in turn, to a lowering of serum TSH of 0.1 mIU/L. Hence, he
predicts that an increase in serum free T4 during
the first trimester will be observed only when hCG concentrations
>50 000–75 000 IU/L are maintained for >1 week.
Some patients may be oversensitive to circulating hCG. Recently, Rodien et al. (23) described two patients, a mother and her daughter, with recurrent gestational hyperthyroidism and severe nausea, despite serum hCG concentrations within the health-related reference interval. Both women were heterozygous for a missense mutation in the extracellular domain of the thyrotropin receptor. The mutation, a substitution of guanine for adenine at codon 183, led to the replacement of a lysine residue with an arginine (K183R). When expressed in COS-7 cells, the mutant receptor was ~30-fold more sensitive than the wild-type receptor to hCG, as measured by cAMP production. The mutation thereby could account for the occurrence of hyperthyroidism in these two women despite the presence of hCG concentrations within the reference interval. Further studies are needed to determine the incidence of this mutation in the general population.
Increase in renal iodide clearance.
In pregnancy, the renal
clearance of iodide increases substantially because of an increased
glomerular filtration rate (3). The iodide loss lowers the
circulating concentrations of iodide and produces a compensatory
increase in thyroidal iodide clearance. In areas of the world where
iodine intake is sufficient, such as the US, the iodide losses in the
urine are not clinically important. In other areas of the world,
however, iodine deficiency during pregnancy can lead to hypothyroidism
and goiter and poses a serious public health issue. Approximately 500
million people live in areas of overt iodine deficiency (3).
In the nonpregnant condition, adequate iodine intake is estimated to be
100–150 µg/day. The World Health Organization recommends that during
pregnancy, iodine intake be increased to at least 200 µg/day
(3).
Increase in serum thyroglobulin.
Although thyroglobulin lacks
specific hormonal activity, it can indicate the activity status of, or
injury to, the thyroid gland (24). Thyroglobulin frequently
is increased during pregnancy, reflecting the increased activity of the
thyroid gland during pregnancy (3). The increase in
thyroglobulin can be seen as early as the first trimester, but it is
more pronounced in the latter part of pregnancy (3).
Increased serum thyroglobulin concentrations are also associated with
an increase in thyroid volume. Despite this, goiter, as defined by
thyroid volume >23 mL, occurs in only 5–15% of women at term in the
US (16)(25). This low incidence is likely
attributable to adequate intake of dietary iodine.
hyperthyroidism during pregnancy
The incidence of hyperthyroidism in pregnant women has been
estimated at 0.2% (25). Most women have symptoms before
pregnancy, but some will demonstrate symptoms for the first time during
pregnancy. Causes of hyperthyroidism during pregnancy are listed in
Table 2
. The most common cause is Graves disease, which accounts for
85–90% of all cases (25)(26). Diagnosis of
hyperthyroidism during pregnancy is important because untreated or
poorly treated hyperthyroidism can lead to adverse obstetrical
outcomes. These include first-trimester spontaneous abortions, high
rates of still births and neonatal deaths, two- to threefold increases
in the frequency of low birth weight infants, preterm delivery, fetal
or neonatal hyperthyroidism, and intrauterine growth retardation
(25)(27). Diagnosis of Graves disease can be
difficult because healthy pregnant women may exhibit tachycardia,
palpitations, mild heat intolerance, emotional lability, diaphoresis,
and warm, moist skin. For these reasons, diagnosis of hyperthyroidism
during pregnancy needs to be made on careful clinical observations and
well-conceived laboratory testing.
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Diagnosis of hyperthyroidism.
Clinical symptoms such as weight
loss or inappropriately low weight gain for gestational age, goiter,
lid lag, muscle weakness, heart rate >100, and onycholysis may help to
differentiate symptoms of hyperthyroidism from the hypermetabolic
effects of pregnancy (25). Laboratory testing is
similar to that for nonpregnant women in that it should
include measurement of serum TSH. Evaluation should not include total
T4 or T3 because these will
be increased in healthy pregnant women, and should instead include an
assessment of free hormone values either directly or via a calculated
index (Fig. 3
). Routine
laboratory tests in hyperthyroid patients may show mild leukopenia,
hypercalcemia (<10% of patients), increased alkaline phosphatase, and
occasional mild increases in other liver enzymes (25).
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Thyroid autoantibodies.
Thyroid anti-microsomal antibodies
(also known as thyroid peroxidase antibodies or TPO antibodies) are
increased in most (80–90%) patients with Graves disease, and thyroid
hormone receptor antibodies (TRAbs) are increased in ~80% or more of
patients (25)(28). Therefore, measurement of
these antibodies can be useful in establishing a diagnosis of Graves
disease. Although the presence of TPO antibodies favors a diagnosis of
autoimmune hyperthyroidism over other etiologies, the presence of TRAbs
is more specific for Graves disease. In addition, the TRAbs have
prognostic implications for fetal and neonatal hyperthyroidism, as
discussed later. It is important to note that the natural course of
Graves disease is altered during pregnancy, with an aggravation in the
first trimester because of increased thyroid activity, amelioration in
the second half of pregnancy because of immune suppression, and
aggravation in the postpartum period as the immune system rebounds
(29).
There are two types of assays for measuring TRAbs. The first, called either thyroid-stimulating immunoglobulin (TSI or TSIG) or thyroid growth-stimulating immunoglobulin (TGI), measures the ability of antibodies in the sera of patients to actually stimulate a biological response in cells expressing the TSH receptor. The TSI assay most commonly utilizes the rat thyroid cell line, FRTL-5, but it can also utilize a cell line that is transfected with the human TSH receptor (30)(31). The patient immunoglobulin is added to the cultured cells, and if thyroid-stimulating antibodies are present, the cells are stimulated to produce cAMP. The cAMP is then measured by radioimmunoassay. Normal is considered anything <130% of basal activity. Alternatively, the TGI assay measures growth of the thyroid cells by incorporation of 1 H into DNA (30).
The second assay is called thyroid-binding inhibitory immunoglobulin. This assay measures the ability of patient antibody to interfere with TSH binding to its receptor. It does not distinguish whether the interfering antibodies are stimulatory or inhibitory in nature. This assay is performed by incubating the TSH receptor with 125I-labeled TSH and patient sample. After incubation, the receptor-bound 125I-TSH is separated from unbound using polyethylene glycol. Normal is <10% inhibition, whereas Graves disease is indicated by 10–100% inhibition (30). The TSI and TGI tests are more expensive and technically more difficult to perform but provide important information regarding the nature of the antibody. There are commercial assays available for the determination of thyroid-binding inhibitory immunoglobulin. This assay correlates well with the bioassay in patients with Graves disease and is less costly. For these reasons, it is the most commonly used worldwide (25).
TRAbs can cross the placenta and, at high enough concentrations, can bind to TSH receptors and stimulate the fetal thyroid. High titers of TRAbs in maternal serum during the third trimester are predictive of fetal or neonatal dysfunction. Therefore, it has been suggested that TRAbs be measured early in pregnancy and again in the last trimester. Values >500% of baseline are considered high and are a predictor of fetal or neonatal disease (25). In addition, a study by Glinoer et al. (32) demonstrated that women with anti-TPO antibodies or anti-thyroglobulin antibodies were fourfold more likely to have spontaneous abortions than healthy controls (13.3% vs 3.3%).
pregnancy-specific conditions that lead to hyperthyroidism
There are two pregnancy-specific conditions, hyperemesis
gravidarum and trophoblastic disease, that can lead to hyperthyroidism.
These conditions need to be identified as soon as possible because
treatment of the underlying disease will resolve the hyperthyroidism.
Hyperemesis gravidarum.
The syndrome of transient
hyperthyroidism of hyperemesis gravidarum should be considered in any
woman presenting in early pregnancy with weight loss, tachycardia, and
vomiting and manifesting biochemical evidence of hyperthyroidism.
Hyperemesis gravidarum is characterized by severe vomiting, which
begins at ~6–9 weeks of gestation and usually resolves spontaneously
by 18–20 weeks. This disorder occurs in ~0.2% of pregnancies
(33). Of patients with hyperemesis gravidarum, as many as
60% exhibit hyperthyroidism (34). They have no history of
thyroid illness preceding pregnancy, goiter is usually absent, and
thyroid antibodies are negative. On laboratory examination, the serum
free T4 is more frequently increased compared
with the serum free T3 concentration. In
addition, when hyperthyroidism is present, patients are more likely to
have abnormal electrolytes and liver function tests. Interestingly,
more severe vomiting is associated with a greater degree of thyroid
stimulation and higher concentration of hCG (Fig. 4
) (35).
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The etiology of transient hyperthyroidism of hyperemesis gravidarum is unclear. Some have argued that the hyperthyroidism is the cause of the hyperemesis, whereas others have argued the reverse. Mestman et al. (25) discuss this controversy in more detail, but there is little evidence to weigh in favor of one theory over another. The recent report by Rodien et al. (23), describing two patients with hyperemesis and hyperthyroidism attributable to hCG-hypersensitive thyrotropin receptors, suggests that hyperemesis can be directly related to the overactive thyroid and not necessarily to the effects of excess hCG. Treatment for transient hyperthyroidism of hyperemesis gravidarum involves rest, a controlled diet, and antiemetic therapy. The hyperthyroidism generally resolves with the cessation of vomiting.
Gestational trophoblastic disease.
Hyperthyroidism can also
occur in women with gestational trophoblastic disease (GTD). GTD is a
general term that includes benign and malignant conditions of
hydatidiform mole (both complete and partial) as well as
choriocarcinomas. The frequency of hydatidiform mole is approximately 1
in 1500–2000 pregnancies and that of choriocarcinoma is 1 in
40–60 000 (36)(37)(38). The frequency of hyperthyroidism in
GTD has been estimated as anywhere from 5% to 64%
(17)(36). The etiology of the hyperthyroidism is
thought to be related to the increased concentrations of serum hCG in
these patients, which can be as high as 1000-fold higher than reference
values (26). As mentioned previously, prolonged increases in
serum hCG can clearly cause a significant increase in thyroid function
(3).
Hyperthyroidism attributable to GTD should be suspected in patients who demonstrate increased free T4 and T3 concentrations, decreased TSH, and significantly increased hCG. Although free T4 and T3 concentrations can be increased with hCG concentrations >50 000 IU/L, in patients with trophoblastic tumors, serum hCG usually exceeds 300 000 IU/L and always exceeds 100 000 IU/L (18). Thyrotoxic patients also have a higher serum T4-to-T3 ratio than patients with Graves hyperthyroidism, a characteristic of hCG-induced thyroid stimulation (18). The thyroid gland is either not enlarged or only slightly enlarged, rarely to more than twice normal size, and ophthalmopathy is absent. Complete surgical removal of the GTD rapidly cures the hyperthyroidism.
hypothyroidism during pregnancy
The incidence of hypothyroidism in pregnant women has been
estimated to be 0.3–0.7% (3). There is a known association
between hypothyroidism and decreased fertility (39)(40)(41). For
this reason, the frequency of hypothyroidism in pregnancy is actually
lower than the 0.6–1.4% frequency in the general population
(3). Causes of hypothyroidism during pregnancy are listed in
Table 3
. Autoimmune thyroid disease (Hashimoto thyroiditis) and
postthyroid ablation therapy are the most common causes of
hypothyroidism (25). Hypothyroidism during pregnancy has
been associated with pregnancy-induced hypertension, placenta abruptio,
postpartum hemorrhage, and an increase in the frequency of low
birth-weight infants (25).
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Recently, Haddow et al. (42) reported that untreated hypothyroidism during pregnancy may cause a significant decrease in the IQ of children. In this study, the authors measured thyroid hormone concentrations in 25 216 pregnant women. Thyroid deficiency was undetected at the time of pregnancy in 48 of 62 women with low thyroid hormone concentrations. The IQ scores of children born to these women were, on average, seven points lower than those of children born to women with thyroid values within the appropriate reference intervals. Approximately 20% of these children had IQ levels of 85 or lower. This study suggests that TSH should be measured before or early in pregnancy to allow adequate treatment of the mother. Further research is required to determine when screening should take place, and treatment guidelines.
Diagnosis of hypothyroidism.
As with the assessment of
hyperthyroidism, laboratory evaluation of hypothyroidism should be made
using TSH and an assessment of free hormone values, either directly or
via a calculated index (Fig. 5
). Total T4 and T3
measurements should be considered unreliable because of the increase in
TBG concentrations. Anti-TPO antibodies and anti-thyroglobulin
antibodies are increased in most patients with Hashimoto thyroiditis
and therefore may be useful in establishing this diagnosis. It is
important to note that the natural course of Hashimoto thyroiditis is
altered in pregnancy, with amelioration in the second half of pregnancy
and aggravation in the postpartum period (29). In addition,
pregnant women who are on thyroid replacement therapy require larger
doses compared with nonpregnant patients because of increases in the
TBG concentration and increased type III deiodinases from the placenta
(3)(25). TSH should be monitored closely, and
the dose of thyroid replacement should be adjusted to maintain TSH in
the reference interval. Doses of thyroid replacement therapy can be
lowered to prepregnancy levels at parturition.
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postpartum thyroid dysfunction
Although this review is focused on thyroid function
during pregnancy, a few words should be said about
postpartum thyroid dysfunction. Postpartum thyroid dysfunction occurs
within the first year after delivery and can manifest itself as hyper-
or hypothyroidism (Table 4
). Postpartum thyroiditis (PPT) is the most common cause of
postpartum thyroid dysfunction (43), and is the only form of
postpartum thyroid dysfunction to be covered here. For more detail, the
reader is directed to several excellent reviews that cover this topic
in greater detail (44)(45)(46).
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PPT is characterized by a brief thyrotoxic phase (1–3 months postpartum) followed by a more long-lasting hypothyroid phase (3–8 months postpartum) (44)(45). More than 80% of patients with PPT are euthyroid within 12 months of delivery (47). The incidence of this syndrome has been estimated at anywhere from 1.9% to 21% (44)(45). The great variability in this estimate may be attributable to differences in the diagnostic criteria between studies (48). Symptoms during both the thyrotoxic and hypothyroid phases are often mild and nonspecific, leading to underdiagnosis. Fatigue, which is the predominant complaint in many patients, is often attributed to the postpartum state itself. Diagnosis should be considered in women who have delivered within the last 9 months if they present with a goiter or the nonspecific physical or emotional symptoms seen in hyper- or hypothyroidism, such as emotional lability, depression, fatigue, or palpitations. Serum TSH is a good screening test. If it is abnormal, a free T4 (direct or calculated) should be performed. The thyrotoxic phase of PPT is characterized by a low radioactive iodine or technetium uptake in the thyroid, which distinguishes it from postpartum Graves disease. Treatment of the thyrotoxic phase of PPT often is not required unless symptoms are severe. If severe, a short course of ß-blockers can be instituted. Antithyroid drugs are not useful in PPT because thyrotoxicosis is secondary to thyroid hormone release from the damaged gland and is not a result of increased synthesis. Similarly, because the hypothyroid phase of PPT is transient and minimally symptomatic, thyroxine replacement is not always necessary (44). Patients who have recovered from PPT should have serum TSH values monitored at yearly intervals or sooner if they become pregnant again or develop symptoms of thyroid dysfunction.
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Summary |
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TopAbstractIntroductionPresentation of the CaseDiscussionSummaryReferences |
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In the case presented here, the patient showed signs of hyperemesis gravidarum. The patient denied tremor and palpitations, had a normal-sized thyroid, had no exophthalmos, and had no history of thyroid disease before pregnancy, which is consistent with hyperemesis gravidarum rather than Graves disease. TSAb measurement is recommended in this case to confirm a diagnosis of Graves disease because antithyroid drugs, which were started at an outside hospital, usually are not indicated in hyperthyroidism attributable to hyperemesis. Close monitoring of thyroid function during both the latter half of pregnancy and postpartum are also suggested because her hyperthyroidism may have been the result of or aggravated by the hyperemesis gravidarum.
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Footnotes |
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References |
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The following articles in journals at HighWire Press have cited this article:
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  M. Qatanani, J. Zhang, and D. D. Moore Role of the Constitutive Androstane Receptor in Xenobiotic-Induced Thyroid Hormone Metabolism Endocrinology, March 1, 2005; 146(3): 995 - 1002. [Abstract] [Full Text] [PDF]
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 R. Sapin and M. d'Herbomez Free Thyroxine Measured by Equilibrium Dialysis and Nine Immunoassays in Sera with Various Serum Thyroxine-binding Capacities Clin. Chem., September 1, 2003; 49(9): 1531 - 1535. [Full Text] [PDF]
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 N K Kuscu and F Koyuncu Hyperemesis gravidarum: current concepts and management Postgrad. Med. J., February 1, 2002; 78(916): 76 - 79. [Abstract] [Full Text] [PDF]
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P Shankar, A Kilvert, and C Fox Changing thyroid status related to pregnancy Postgrad. Med. J., September 1, 2001; 77(911): 591 - 592. [Abstract] [Full Text] [PDF]
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N. Amino, H. Tada, Y. Hidaka, and Y. Izumi Thyroid Function during Pregnancy Clin. Chem., July 1, 2000; 46(7): 1015 - 1016. [Full Text] [PDF]
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R. Swaminathan, A. M. Gronowski, S. Dagogo-Jack, C. R. Fantz, and J. H. Ladenson Thyroid Function during Pregnancy The authors of the Case Conference cited in the previous two letters respond: Clin. Chem., July 1, 2000; 46(7): 1016 - 1017. [Full Text] [PDF]
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, decreased; 
,
increased.
