When considering the importance of thyroid function in pregnancy, it is also essential to consider iodine, which is an integral component of thyroid hormone. It has been long established that severe maternal iodine deficiency has a profound deleterious impact on offspring neurodevelopment (1). Infants or children with an intelligence quotient (IQ) of 40 or less, a condition known as “cretinism”, were commonly reported in severely iodine deficient areas worldwide; thanks to the introduction of iodine supplementation before and during early pregnancy, this condition can now be prevented (2).
In the last 20 years there has been a substantial increase in our understanding of the importance of thyroid hormones for maintaining a successful pregnancy and foetal development, especially with regard to its neurological development (3-8). In particular, there has been a growing appreciation that maternal thyroid hormone levels are especially important in the first half of pregnancy whilst the foetal thyroid is developing.
Thyroid disorders are common globally in women of child-bearing age (9); furthermore, pregnancy increases the demands on the hypothalamic-pituitary-thyroid axis. As a result thyroid dysfunction, particularly borderline thyroid abnormalities, are frequently encountered during pregnancy. Correction of both overt hypothyroidism and hyperthyroidism dramatically reduces the risk of adverse obstetric outcomes including foetal loss and preterm birth (3,6). Currently all endocrine, thyroid, and obstetrical societies recommend initiating treatment for overt thyroid disease detected in pregnancy. However, the benefits of treating more marginal thyroid function such as subclinical hypothyroidism (ScHypo) and isolated hypothyroxinemia (IH) are less clear, therefore the need of a universal screening program of thyroid function in pregnancy is still a major debate in thyroidology. Furthermore many women are established on levothyroxine either prior to or during pregnancy (10).
Thyroid physiology in pregnancy
Our understanding of the appreciable effects of pregnancy on thyroid economy has had notable advances in the last 20 years (4). Pregnancy determines an increase of urinary iodine excretion and thyroxine-binding globulin (TBG) levels, and a rise in thyroid hormone degradation by placental type III deiodinase; furthermore, the foetus utilizes maternal thyroid hormones. Thus the demands on maternal thyroid axis are increased, and as a consequence the maternal thyroid hormone production rises (3). This scenario induces compensatory mechanisms such as an increased thyroidal production of free-thyroxine (FT4) and free tri-iodothyronine (FT3) triggered by the placental secretion of human chorionic gonadotrophin (hCG) (11). Furthermore it is well known that pregnancy induces a condition of general immunosuppression for all its duration (12). As a consequence, the activity of autoimmune disorders is reduced during gestation, including thyroid autoimmunity and leading to additional changes in thyroid hormones levels.
Table 1 summarizes the significant, but reversible, changes in thyroid function occurring in pregnancy (3,5). During gestation, plasma volume and glomerular filtration rate increase significantly, with consequent augmented excretion of iodine in the urine (13). Thus the reduced serum iodine concentration exacerbates iodine deficiency, and may be causative of goitre and reduced levels of maternal thyroxine (T4), especially in areas of endemic cretinism (14). An augmented thyroid volume has been observed even in areas of mild-moderate iodine deficiency (15,16), but not in iodine sufficient regions (15). This is of particular relevance to the UK which is iodine deficient (17) and data from the UK has shown mild-moderate iodine deficiency in pregnancy is associated with a lower child IQ (18). A daily iodine intake of 250 µg in pregnancy is recommended by several different authorities (19,20), however it is not always achieved even in developed parts of the world (9,21). Endocrine disruptors may exacerbate iodine deficiency and may also have a deleterious effect on offspring neurodevelopment (22,23). Thus, to prevent foetal brain damage additional iodine supplementation in pregnancy may be required in areas of suboptimal iodine nutrition. Ideally iodine sufficiency should be attained prior to conception by either universal salt iodisation or targeting women of child-bearing age (24).
During pregnancy the levels of thyroid hormone transport proteins rise, especially TBG, due to oestrogen-induced increase in TBG sialylation with consequent reduced degradation and increased half-life, as well as enhanced hepatic synthesis (25,26). As a consequence, total T4 and total T3 levels rise.
The hCG glycoprotein hormone shares a common alpha subunit with thyroid stimulating hormone (TSH) but has a unique beta subunit, which confers specificity; the amount and type of hCG secretion by placenta seems to be somewhat dependent on ethnicity (27). In vitro studies on thyroid tissue and on eukaryotic cells stably expressing the human TSH receptor (TSHR) showed that hCG acts as a TSH agonist (28); however others showed limitations of such in vitro assays, therefore this topic is still object of controversy (29).
The incidence of gestational transient hyperthyroxinemia caused by elevated hCG levels and therefore not treated was 0.285% in a study screening more than 23,000 pregnant women (30). There is good evidence that hyperemesis gravidarum (severe nausea and vomiting), which sometimes requires hospitalisation for the management of its potential complications including dehydration and ketosis, may be associated with hyperthyroidism due to excess hCG stimulation (31). Furthermore, both the hCG secreted in the first trimester of pregnancy and that produced by hydatidiform mole tissue, have a high thyroid stimulating specific activity (32). The sensitivity of TSHR to hCG has also been demonstrated by a few isolated case reports of familial gestational hyperthyroidism caused by mutant TSHR (missense mutation) which was more sensitive to hCG than the wild type receptor (33-35). Recent data suggests that women with positive autoantibodies to thyroid peroxidase (TPOAb) may have an impaired response to hCG (36) and therefore may not be able meet the extra demands placed on the thyroid. This may be a key factor in why TPOAb positivity is associated with adverse outcomes.
In this complex scenario the precise mechanisms leading to a decline in free thyroid hormones have not been elucidated, however the interaction of oestrogens, hCG, TSH and thyroid binding proteins is crucial. In iodine deficient areas (including marginal iodine deficiency) the pregnant woman may become significantly hypothyroxinaemic with preferential T3 secretion, especially if iron deficient (37). As a general rule, FT4 transiently rises in the first trimester due to the relatively high circulating hCG concentration, while FT4 decreases in the second and third trimester, albeit still within the normal reference range (3). Changes in FT3 concentration are also seen in which they broadly parallel the FT4, again within the normal range (3). The thyroidal ‘stress’ is also evidenced by a rise in the median TSH and serum thyroglobulin; in particular TSH levels have a specular trend compared with hCG, therefore lower in the first trimester and higher in the second and third trimesters (4,38).
Thyroid function assessment during pregnancy
The profound changes that occur during pregnancy have consequences for thyroid hormone serum concentrations and the assessment of thyroid function. There is a significant overlap between the signs and symptoms of the hypermetabolic state typical of normal euthyroid pregnant women, and those due to thyroid dysfunction. Therefore, a differential diagnosis can be challenging to make, and the availability of reliable accurate tests for gestational thyroid function is crucial to this purpose. However, the notable underlying physiological changes occurring during pregnancy also cause many difficulties with the laboratory measurements of thyroid function. The diagnosis of maternal gestational thyroid dysfunction is of clinical importance for both maternal and foetal health (39,40), and therefore requires (I) specialised assays measuring thyroid hormones with high specificity and sensitivity; (II) normal and reliable intervals for comparison during pregnancy; and (III) appropriate treatment regimen. To this purpose dedicated guidelines have been published by several organizations (41,42).
Several factors influence thyroid status in pregnancy, including iodine status (16), hCG levels (11), ethnicity (27,43), body mass index (44), parity (44) and male foetal sex (44). A population of pregnant women not biased by such key factors is required to calculate more precise gestational-related reference ranges for thyroid hormones, essential to make a correct diagnosis. Therefore, centres should assess their normal thyroid reference-range excluding women with thyroid dysfunction and/or positivity for TPOAb, using medications altering thyroid function, resident in areas of iodine deficiency. Equally, women who have undergone in vitro fertilization or are expecting twins, since both conditions are characterised by higher hCG levels (45). The current American Thyroid Association guidelines recommend the use of pregnancy specific, local population-based reference ranges where possible (46). Furthermore, normal thyroid status changes over pregnancy, therefore the accurate assessment of thyroid function in pregnant women requires the use of different gestational age (trimester-specific) reference intervals (47).
Two guidelines provided by the Endocrine Society (42) and the National Academy of Clinical Biochemistry (41) detailed the strengths and limitations of currently available thyroid function tests. TSH has been traditionally the primary marker of thyroid status during pregnancy, however the measurement of T4 levels is essential in differentiating between overt and subclinical thyroid disease, and the assessment of thyroid hormones during pregnancy has several weaknesses. In particular the free hormone assays based on measuring the concentrations of thyroid hormone binding-proteins are known to be method-dependent, and therefore are at risk of providing inaccurate FT4 and FT3 values during gestation. Direct FT4/FT3 assays based on equilibrium dialysis are more reliable however less available since expensive and time-consuming (48). Finally, most laboratories still do not use pregnancy-specific reference intervals for thyroid function tests.
In some cases, serum TPOAb and autoantibodies to thyroglobulin (TgAb) and/or to TSHR (TRAb) can provide other information. TPOAb can predict the risk of hypothyroidism; low TSH levels in pregnant women are accompanied by TRAb in 60–70% of the cases, and need to be monitored since may cause foetal and neonatal hyperthyroidism (46).
Since TSH and FT4 are linked by a log-linear relationship, very small changes in T4 levels will determine a much larger variation in serum TSH concentrations (49,50). For this reason serum TSH levels represent the first biochemical indicator checked in the suspect of thyroid dysfunction. However during gestation thyroid and pituitary functions undergo notable variations; for example during early pregnancy the significant rise in hCG concentrations determines a suppression of TSH levels by 20–50% by week 10 (51). Therefore, the measurement of only serum TSH in women treated for thyroid dysfunction during gestation has several limitations since can result in maternal under-replacement with levothyroxine, or overtreatment with anti-thyroid drugs (ATD), both scenarios causing maternal hypothyroidism with consequent increased risk for impaired foetal brain development. The biochemical evaluation of the hypermetabolic symptoms presented by women with reduced TSH but still normal FT4 levels may include the measurement of FT3 and FT3 index (FT3I).
Total and free thyroid hormone measurements
T4 and T3 circulates >99% bound to plasma transport proteins, mainly to TBG and to a lesser extent to transthyretin and albumin; the free- and protein-bound hormones are at equilibrium (52). The highly concentrated (nanomolar) protein-bound hormone fractions act as a storage reservoir and prevent thyroid hormones from entering cells where they exert their biological effects. The biologically active form of thyroid hormones is that free from protein-binding, and present at much lower concentrations (picomolar) (53).
Assays for total thyroid hormones have been much easier to develop compared with their free component, due to their increased serum concentrations, and are considered more accurate and valid compared with free hormone assays. In particular total T4 assays generally agree quite well, and are characterised by better defined reference intervals in adults (54). However, in pregnancy oestrogens cause an increase of TBG levels and therefore a consequent increase of total T4 concentrations (up to 1.5-fold in the second trimester), thus gestation-specific reference intervals for total thyroid hormones are necessary for accuracy (6). Due to the influence of thyroid hormone binding proteins, in most clinical laboratories FT4 assays have replaced the total T4 testing.
The measurement of the free quote of thyroid hormones allows taking into account the biologically active form only, and this is a clear advantage. However, this approach has significant challenges compared with the total thyroid hormone assays due to: (I) the lower concentration of analyte; (II) the risk to disturb the equilibrium between the free and protein-bound hormone quotes; (III) the potential interference of the much higher concentrations of the protein-bound hormone quote. In fact due to the changes in the TBG concentrations during pregnancy, concern has been raised regarding the accuracy of FT4 assays (54). It has to be noted that such interference is maximum in the third trimester, while minimal in the first trimester, which is the most important time-point for thyroid dysfunction screening. Furthermore, variation in FT4 as opposed to T4 levels is more robustly associated with adverse obstetric and offspring outcomes (55,56).
The first step in the measurement of the free hormones is their physical separation from the protein bound hormones by specific techniques (i.e., equilibrium dialysis or ultrafiltration), followed by immunoassay, or more recently using isotope dilution mass spectrometry (MS) (57-59). The immunoassay methodologies are more prone to interference by thyroxine binding protein abnormalities or immunoglobulins (i.e., heterophilic antibodies and antibodies to thyroid hormones) (60-62). Possible strategies to overcome this limitation are: (I) to measure the total hormone concentrations (T3 and T4) correcting for the increased binding proteins, i.e., directly measuring the TBG levels to provide T4/TBG or T3/TBG ratios; (II) to perform a T3 or T4 uptake test to estimate free thyroid hormone indices (63-67).
More recently free thyroid hormones have been measured by tandem MS which provides more accurate, specific, fast and simple measurements (68-70). Further development was achieved coupling MS with high performance liquid chromatography (62).
These assays are complex and laborious, therefore often not routinely employed in clinical practice and limited to specialized laboratories. In fact, clinical laboratories prefer to use commercially available immunoassays for FT4 and FT3 only estimating the concentration of the free thyroid hormone quote, since not physical separating that from the protein-bound hormone quote (71). Surprisingly, one of the commercially available FT4 assays resulted to correlate more closely to total T4 assays than to FT4 measured following physical separation of the free-quote from binding proteins (72). However the physiological increase in TBG levels occurring during gestation has been showed to influence at various extents the results obtained with commercial FT4 immunoassays (73). This explains why a significant method-dependent variation exists when measuring gestational FT4 levels, with different groups reporting serum concentration of thyroid hormones to be decreased, increased or unchanged during pregnancy depending on the assays used; thus it is challenging to establish universal gestation-related FT4 reference intervals (60,61).
Considering the differences in thyroid hormones related to the laboratory method used and the gestation period, the use of method- and gestation-specific reference intervals is recommended for the correct interpretation of thyroid function in pregnant women (71). Method- and gestation-specific reference intervals for FT4 should be derived in the appropriate reference populations. To this purpose both the iodine and thyroid autoimmunity status should be evaluated when selecting the reference population; only iodine sufficient subjects should be taken into account (41,42). Unfortunately, very few FT4 immunoassay manufacturers include appropriate method-specific normal pregnancy-related reference intervals, and most clinical laboratory reports only provide reference intervals not adjusted for gestation, making challenging the interpretation of laboratory results during pregnancy. In cases where a clear diagnosis is difficult to reach, the integration of both free and total thyroid hormone assays, and/or reanalysis of the samples on a different platform are possible options to consider.
Trimester- and method-specific reference intervals
In order to reduce the global variability of thyroid hormone assessments, numerous trimester-specific population-based reference intervals have been derived. In 2010 Lazarus et al. provided a comprehensive summary of some trimester-specific reference ranges for different populations worldwide (5). In 2017 Korevaar et al. reported additional updated worldwide reference ranges for early pregnancy in their supplementary Table S1 (8).
Current T4 and TSH levels are affected worldwide by iodine deficiency, ranging from mild to moderate and still present in some geographical areas despite the national policies of iodine implementation using mandatory iodized salt. Furthermore, the overall iodine intake may be significantly different due to the variable content of natural iodine within the local food and water, or the presence of variable individual responses to supplementation (5). In the first trimester we assist to an increase of total thyroid hormone concentration, with consequent decrease of both FT4 and TSH. In areas of iodine sufficiency the second and third trimesters are characterised by increased TSH levels, while FT4 and FT3 levels decrease; this is not the case in iodine deficient populations due to the TSH stimulation (5). As previously highlighted the interpretation of gestational FT4 values needs caution to avoid misinterpretation, since the results of FT4 laboratory assays are characterised by significant variability even within the same population (60,61).
It should be noted that the measurements by different methods in distinct populations did provide very dissimilar ranges; furthermore slightly divergent results were produced even in the same population in case of different ethnicities, and the same method applied to different populations provided significantly different results (5). As additional point, the population-based reference ranges did not take into account the various genetic set-points specific for every subject (74,75). Similarly, gestational specific reference intervals may be more affected by intra-individual changes than specific single measurements. In fact the use of gestation- and method-specific reference intervals, even if determining a crucial reduction in results variability and risk of misinterpretation, should not prevent from considering also the intra-individual variability (5).
In conclusion, a correct interpretation and comparison of gestation-specific results should always consider the assay analysis methods used, the size of the group evaluated, the subject inclusion and exclusion criteria including the iodine, ethnicity, age and singleton pregnancy status, the study design (cross-sectional or longitudinal) and the statistical methods used for data analysis.
Epidemiology of thyroid disease in pregnancy
Overt maternal hypothyroidism—elevated TSH and low maternal FT4 concentrations—occurs in approximately 0.2–0.6% of pregnant women (76,77), whereas ScHypo—elevated TSH and normal FT4 concentrations—can occur in up to 18% of pregnancies depending on the precise definition and TSH cut-point used (8,46). IH is defined as a normal TSH with FT4 below the 2.5 percentile, and was originally considered to be a pregnancy specific condition possibly arising as a consequence of mild iodine deficiency. This concept has been more recently challenged as it occurs in iodine sufficient areas and does not typically resolve with iodine supplementation (78,79). Other factors including elevated BMI, older age, iron status and placental angiogenic factors have all been identified as likely risk factors for IH (80-82).
Pathological overt hyperthyroidism, usually due to Graves’ disease, occurs with a frequency of approximately 0.2% (83), however previously treated maternal Graves’ disease prior to pregnancy is more common and can occur prior to 1% of pregnancies (83). New onset pathological hyperthyroidism during pregnancy is much rarer with a prevalence of 0.05% for Graves’ disease (83). Gestational thyrotoxicosis (suppressed TSH and elevated FT4) mainly through excess hCG and usually associated with hyperemesis gravidarum, occurs in up to 3% of pregnancies (83). Subclinical hyperthyroidism (ScHyper) most commonly occurs as a result of peak hCG levels (44) although may occur due to pathological thyroid disease. Owing to this dual cause of ScHyper its true consequences and prevalence are poorly studied.
Consequences of maternal thyroid dysfunction
Overt hypothyroidism has been repeatedly associated with a higher risk of adverse obstetric outcomes including foetal loss, premature delivery, low birth weight and preeclampsia (76,85). Effects have been observed on foetal neurodevelopment; a large case-control study demonstrated children born to women with untreated hypothyroidism had a 7-point lower IQ than women with normal thyroid function (86).
ScHypo is also associated with similar adverse obstetric outcomes as overt hypothyroidism, albeit with a more modest effect. Studies have demonstrated an increased incidence of adverse pregnancy outcomes including preterm delivery, placental abruption, respiratory distress, early pregnancy loss and admissions to the intensive care unit (87-91) but it has not been associated with impaired development of offspring (92-94).
Although IH is also regarded as a mild form of thyroid failure, it has been found to be associated with impaired offspring developmental outcomes (7), but not obstetric outcomes in stark contrast to ScHypo. In particular, adverse consequences have been observed regarding offspring verbal delay (95). The relationship between maternal FT4 and offspring IQ appears to be “U” shaped with individuals with hypothyroxinemia having lower IQ, and lower grey matter and cortical volume (7). Maternal IH has also been shown to be associated with offspring autism (96) and attention-deficit/hyperactivity disorder (ADHD) (97,98).
TPOAb positivity is a major risk factor for ScHypo (99). However, the combination of ScHypo and TPOAb positivity appears to have a synergistically adverse outcome. In particular, adverse synergistic associations occur for miscarriage, premature delivery and gestational diabetes mellitus (100). It also appears to be a risk factor in its own right for miscarriage and pre-term delivery (101).
Pathological hyperthyroidism is a condition independent from hCG levels, and usually determined by Graves’ disease or, more rarely, by an autonomous production of thyroid hormones (i.e., toxic goitre or adenoma). It is associated with increased risk of maternal heart failure, preeclampsia, foetal loss, pre-term birth and low birth weight (83,102,103).
Given that all endocrine and obstetric guidelines endorse the treatment of pathological thyroid dysfunction, it is difficult to ascertain from current studies which of these negative outcomes are secondary to the maternal thyroid dysfunction itself, or foetal hyperthyroidism (due to TRAb crossing the placenta), or consequences of treating the maternal thyrotoxicosis, including ATD side effects or induced foetal hypothyroidism (8).
Gestational hyperthyroidism and ScHyper
Gestational hyperthyroidism is a usually transient condition caused by increased hCG levels during the first trimester of pregnancy, determining an augmentation of thyroid hormone production. It is usually responsible for the majority of ScHyper cases diagnosed in pregnancy and is considered to be a non-pathological condition (8).
There is a current lack of data investigating the effects of pathological ScHyper on adverse pregnancy, maternal, foetal and neonatal outcomes; one first difficulty is to reliably distinguish cases of pathological versus non-pathological (gestational) ScHyper (8). This step is crucial, since recent findings showed that increased levels of thyroid hormones did not represent a risk factor for preeclampsia if associated with high hCG levels (indicating gestational hyperthyroidism), while a 3.4–11.1-fold higher risk of such adverse outcome was present if they were associated with low hCG levels (indicating pathological hyperthyroidism) (104). A combined measurement of thyroid function and hCG would therefore help in distinguishing these two forms of ScHyper in pregnancy.
Benefits of treatment of maternal thyroid dysfunction
Treatment of overt hypothyroidism
Although no randomised controlled trials of levothyroxine for overt hypothyroidism in pregnancy have been conducted, the wealth of data regarding the adverse consequences of overt hypothyroidism with pregnancy effects mean performing such studies would be unethical. However, all endocrine and obstetric society guidelines recommend treatment of overt hypothyroidism in pregnancy; in women established on levothyroxine prior to pregnancy dose adjustments are often needed to cope with the increased thyroidal demand (8,46).
Despite this, many women on levothyroxine have sub-optimal thyroid function during pregnancy and in those with TSH levels >4.5 mU/L an increased risk of foetal loss has been described (105). The “U” shaped response seen with maternal thyroid function and IQ (7) and the CATS II study (94,106) also shows that caution should be taken in not over-treating patients with hypothyroidism or ScHypo. This is particularly important in treating women with milder thyroid abnormalities as the residual function in the thyroid gland may be readily responsive to hCG resulting in over-treatment if injudicious doses of levothyroxine are given.
Treatment of ScHypo and IH
To date three large randomized controlled trials have investigated the effects of screening and treating borderline low thyroid function in pregnancy: the controlled antenatal thyroid screening (CATS) study (92), a study by Casey et al. (93), and a recent study by Nazarpour et al. (107), summarized in Table 3.
In terms of offspring benefits, neither CATS nor Casey study showed any beneficial effects of treatment on children IQ. Reasons for negative findings might include relatively late initiation of treatment (particularly in the Casey study) (93) and early age of IQ assessment (particularly in the CATS study) (92). Follow on analysis of the CATS study (CATS II) confirmed no apparent benefit of treatment at age 9 (94) although identified levothyroxine over-treatment may increase the risk of ADHD (106).
In terms of pregnancy outcomes, no benefit was observed with levothyroxine on obstetric outcomes in both the Casey (93) and the Nazarpour study (107), as well as in a meta-analysis of the two studies considering five obstetrical and neonatal outcomes: preterm delivery <37 weeks gestation, gestational age at delivery, placental abruption, neonatal intensive care admission and head circumference (108). A more recent analysis using data linkage and the majority of the CATS cohort identified that levothyroxine treatment significantly reduced the risk of miscarriage/still birth (109). This was in agreement with previous findings from another prospective study identifying that levothyroxine reduced the risk of miscarriage and pre-term birth (110).
Treatment of pathological hyperthyroidism
The treatment of hyperthyroidism in pregnancy is imperative due to its important negative effects on pregnancy outcome and both mother and foetus health (83,102,103). Thus no randomized controlled trials have been conducted in pregnant hyperthyroid women comparing ATD interventions with no interventions (111).
ATD are the preferred treatment during pregnancy (46,112) since radioiodine is absolutely contra-indicated due to deleterious effects on foetal thyroid gland and teratogenicity (113-115), and thyroidectomy in pregnancy results in increased morbidity compared to non-pregnant women (116). Thyroidectomy can be considered in special circumstances during pregnancy, such as allergy/contraindications to ATD or if euthyroidism cannot be achieved despite high doses. Thyroidectomy if required should be performed in the second trimester.
All ATD cross the placenta and therefore the lowest possible dose to control hyperthyroidism is recommended (46,76). The most used ATD are carbimazole (CBZ)/methimazole (MMI) and propylthiouracil (PTU), and it is still unclear whether there is a substantial difference in placental transfer between them; the choice of ATD used is therefore based on side effects. CBZ/MMI have been considered for years to be associated with an increased risk of embryopathy than PTU (113). Thus considering that the teratogenic risk is greater in early pregnancy, and that PTU is associated with increased risk of maternal hepatotoxicity (117), guidelines advise to use PTU in the first trimester, and then switch to CBZ/MMI (42,118). However more recent evidence suggests a similar rate of malformations occurring with both CBZ/MMI and PTU, even if slightly lower with PTU, and no benefits derived from switching from CBZ/MMI to PTU during the first trimester (119). These observations therefore question the clinical utility of drug switch in early pregnancy, and underline the necessity to identify new ATD drugs with reduced or absent side effects.
To reduce unnecessary exposure to ATD in early pregnancy ideally all potentially fertile women should be given written instructions to (I) perform a pregnancy test within a few days after the 1st day of a missed (or atypical week) menstrual period, if pregnancy is a possibility; (II) if the pregnancy test is positive promptly contact physician/specialist nurse and do not take further ATD until advice given. Considering the risks of hyperthyroidism on one side, and those derived from ATD interventions to the other, some authors suggest that fertile women affected with hyperthyroidism and seeking pregnancy should plan thyroid surgery or radioactive iodine before the plan to become pregnant (111,118).
TRAb can cross the placenta especially during the second half of pregnancy, therefore can trigger foetal and neonatal hyperthyroidism, with deleterious consequences including but not limited to intrauterine growth retardation, craniosynostosis and death (120). Thus, women affected with Graves’ disease (both current and past) and women previously treated by either thyroid surgery or radioiodine should have their serum TRAb levels measured early in pregnancy to mitigate foetal and neonatal morbidity and mortality (46). If positive, and especially if elevated, TRAb should be measured again at weeks 18–22 and in the last trimester (30–34 weeks); if still positive, appropriate neonatal and postnatal monitoring should be performed, and ATD treatment given if necessary.
The management of pathological hyperthyroidism secondary to Graves’ disease is summarized in Box 2.
Treatment of transient gestational thyrotoxicosis and ScHyper
Transient gestational thyrotoxicosis usually occurs during the first trimester of pregnancy, and spontaneously resolves when hCG levels decrease, therefore ATD interventions are not indicated, while beta-blockers may be considered in symptomatic cases (111,121). Similarly, no ATD treatment is required for women with hyperemesis gravidarum; however, they need careful electrolyte monitoring and may require intravenous fluids, especially in severe forms.
ScHyper during pregnancy is usually determined by transient gestational thyrotoxicosis, therefore non-pathological and not requiring ATD treatment. Due to the difficulty to distinguish between pathological and gestational ScHyper, so far, no studies have investigated and compared the benefits, as well as the potential arms due to the drugs’ side effects, of treating pathological ScHyper with ATD (8). Even a mild increase of maternal FT4 levels during pregnancy was found to be associated with preeclampsia (104), reduced birth weight (8), reduced child neurocognition (7) and increased ADHD disorder (106), however it is unlikely that the benefits of ATD treatment would overcome its risks (8).
The consequences of thyroid disease and benefits of treatment are summarized in Table 4.
Universal thyroid screening in pregnancy
Universal thyroid screening in pregnancy is a key debate in thyroidology. As we have indicated thyroid dysfunction is common in pregnancy and has substantial adverse implications. Furthermore, it is readily detectable and can be inexpensively treated. However, as subclinical thyroid disease and IH represent the vast majority of the thyroid abnormalities, and the benefits of treatment here are less clear, screening is therefore contentious. Nevertheless universal thyroid screening in pregnancy appears to be very cost-effective; screening solely for overt hypothyroidism also had a cost-effectiveness ratio of $6,776/QALY (quality adjusted life-year) (122) which is favourable compared to gestational diabetes mellitus screening ($12,078/QALY) and is well below the $50,000/QALY figure used in the United States as a criteria for screening decisions.
Taken together, it is widely accepted that thyroid dysfunction is an important health problem especially in pregnancy (123). Accepted, effective and well-established treatments are available, as is the ability to readily and easily make a diagnosis. Furthermore, thyroid function testing is universally suitable to patients. For hypothyroidism, but to a lesser extent hyperthyroidism, there is a well-recognised asymptomatic stage. The natural history of subclinical thyroid dysfunction leading to overt disease is well understood, although many women with ScHypo will not progress to overt hypothyroidism if left untreated. Universal thyroid screening is cost effective even if only overt thyroid disease is considered and the nature of screening in pregnancy ensures it will be a continuous process. Thus universal thyroid screening in pregnancy meets almost all the criterion laid out by Wilson and Jungner (124). A key criterion is not resolved as there is not an agreed policy on whom to treat given the debate regarding management and treatment thresholds of IH and subclinical thyroid dysfunction. This can only be resolved by further appropriately powered randomised controlled trials.
In the last decade in particular, our knowledge regarding the diagnosis and treatment of thyroid disease in pregnancy has been revolutionised by substantial advances. In particular we reached a better understanding of the thyroid hormone physiology during pregnancy and the gestational-derived stress on the thyroid, which is exacerbated in areas of iodine deficiency. Furthermore, new developments have been achieved in the technology for thyroid hormone analysis, and progress has been made in defining pregnancy-specific reference intervals for thyroid hormones. In fact, the variation in assay methodology, and other determinants of thyroid function, indicated the necessity of establishing normative gestational-related (trimester-specific) reference ranges for thyroid hormones which are locally derived, namely method- and instrument-specific for the particular laboratory where samples were tested, and generated in iodine sufficient populations excluding women positive for TPOAb. This is crucial to prevent misinterpretation of thyroid function test results during pregnancy.
There is growing evidence that TPOAb positivity and higher TSH levels synergistically interact to increase the risk of adverse pregnancy outcomes. Even modest abnormalities in FT4 levels as seen in IH are also associated with adverse neurological development in offspring further supporting the role of thyroid hormone in foetal neurodevelopment. These findings would support the use of thyroid screening in pregnancy, although more data are needed.
Hypothyroidism is common in pregnancy and should be appropriately treated to reduce obstetric and foetal complications. Given foetal brain development requires adequate thyroxine delivery to foetal neurones, it also seems reasonable to treat mothers with hypothyroidism with levothyroxine to prevent IQ decrement as well as for obstetric reasons. Women already receiving levothyroxine require an increase in dose during gestation aiming for the top of the FT4 reference-range, however caution is needed to avoid over-treatment and potentially modest deleterious effects on behaviour.
Hyperthyroidism in pregnancy, usually due to Graves’ disease, is uncommon but has deleterious effects on mother and foetus and requires therapy. Especially in early pregnancy treatment with ATD may increase the risk of foetal abnormalities, although treatment is safer than uncontrolled thyrotoxicosis. Use of the lowest dose of ATD possible, including consideration of temporary cessation of treatment during critical periods of organogenesis with close monitoring, will mitigate this risk. Subclinical and mild forms of hyperthyroidism are usually caused by gestational thyrotoxicosis, a non-pathological condition usually self-limiting and not requiring treatment with ATD.
Further prospective trials of early screening of thyroid function in pregnancy with both obstetric and developmental outcomes are still required to clarify whether universal thyroid screening in pregnancy is necessary. In the meantime, the correction of worldwide iodine deficiency continues to be required and monitored, and the impact of endocrine disruptors needs further exploration.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- McCarrison R. Observations on Endemic Cretinism in the Chitral and Gilgit Valleys. Ind Med Gaz 1908;43:441-9. [PubMed]
- Delange F. The disorders induced by iodine deficiency. Thyroid 1994;4:107-28. [Crossref] [PubMed]
- Brent GA. Maternal thyroid function: interpretation of thyroid function tests in pregnancy. Clin Obstet Gynecol 1997;40:3-15. [Crossref] [PubMed]
- Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-33. [Crossref] [PubMed]
- Lazarus J, Soldin OP, Evans C. Assessing Thyroid Function in Pregnancy. In: Brent G. editor. Thyroid Function Testing. Boston, MA: Springer, 2010:209-33.
- Lazarus JH. Thyroid function in pregnancy. Br Med Bull 2011;97:137-48. [Crossref] [PubMed]
- Korevaar TI, Muetzel R, Medici M, et al. Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol 2016;4:35-43. [Crossref] [PubMed]
- Korevaar TIM, Medici M, Visser TJ, et al. Thyroid disease in pregnancy: new insights in diagnosis and clinical management. Nat Rev Endocrinol 2017;13:610-22. [Crossref] [PubMed]
- Taylor PN, Albrecht D, Scholz A, et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol 2018;14:301-16. [Crossref] [PubMed]
- Velasco I, Taylor P. Identifying and treating subclinical thyroid dysfunction in pregnancy: emerging controversies. Eur J Endocrinol 2018;178:D1-12. [Crossref] [PubMed]
- Hershman JM. The role of human chorionic gonadotropin as a thyroid stimulator in normal pregnancy. J Clin Endocrinol Metab 2008;93:3305-6. [Crossref] [PubMed]
- Hegde UC. Immunomodulation of the mother during pregnancy. Med Hypotheses 1991;35:159-64. [Crossref] [PubMed]
- Glinoer D. Pregnancy and iodine. Thyroid 2001;11:471-81. [Crossref] [PubMed]
- Berghout A, Wiersinga W. Thyroid size and thyroid function during pregnancy: an analysis. Eur J Endocrinol 1998;138:536-42. [Crossref] [PubMed]
- Smyth PP, Hetherton AM, Smith DF, et al. Maternal iodine status and thyroid volume during pregnancy: correlation with neonatal iodine intake. J Clin Endocrinol Metab 1997;82:2840-3. [Crossref] [PubMed]
- Taylor PN, Okosieme OE, Dayan CM, et al. Therapy of endocrine disease: Impact of iodine supplementation in mild-to-moderate iodine deficiency: systematic review and meta-analysis. Eur J Endocrinol 2014;170:R1-15. [Crossref] [PubMed]
- Vanderpump MP, Lazarus JH, Smyth PP, et al. Iodine status of UK schoolgirls: a cross-sectional survey. Lancet 2011;377:2007-12. [Crossref] [PubMed]
- Bath SC, Steer CD, Golding J, et al. Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet 2013;382:331-7. [Crossref] [PubMed]
- Li M, Eastman CJ. Neonatal TSH screening: is it a sensitive and reliable tool for monitoring iodine status in populations? Best Pract Res Clin Endocrinol Metab 2010;24:63-75. [Crossref] [PubMed]
- Caldwell KL, Miller GA, Wang RY, et al. Iodine status of the U.S. population, National Health and Nutrition Examination Survey 2003-2004. Thyroid 2008;18:1207-14. [Crossref] [PubMed]
- Vermiglio F, Lo Presti VP, Scaffidi Argentina G, et al. Maternal hypothyroxinaemia during the first half of gestation in an iodine deficient area with endemic cretinism and related disorders. Clin Endocrinol (Oxf) 1995;42:409-15. [Crossref] [PubMed]
- Bellanger M, Demeneix B, Grandjean P, et al. Neurobehavioral deficits, diseases, and associated costs of exposure to endocrine-disrupting chemicals in the European Union. J Clin Endocrinol Metab 2015;100:1256-66. [Crossref] [PubMed]
- Taylor PN, Okosieme OE, Murphy R, et al. Maternal perchlorate levels in women with borderline thyroid function during pregnancy and the cognitive development of their offspring: data from the Controlled Antenatal Thyroid Study. J Clin Endocrinol Metab 2014;99:4291-8. [Crossref] [PubMed]
- Zimmermann MB. Iodine deficiency. Endocr Rev 2009;30:376-408. [Crossref] [PubMed]
- Fantz CR, Dagogo-Jack S, Ladenson JH, et al. Thyroid function during pregnancy. Clin Chem 1999;45:2250-8. [PubMed]
- Glinoer D. What happens to the normal thyroid during pregnancy? Thyroid 1999;9:631-5. [Crossref] [PubMed]
- Price A, Davies R, Heller SR, et al. Asian women are at increased risk of gestational thyrotoxicosis. J Clin Endocrinol Metab 1996;81:1160-3. [PubMed]
- Yoshimura M, Nishikawa M, Yoshikawa N, et al. Mechanism of thyroid stimulation by human chorionic gonadotropin in sera of normal pregnant women. Acta Endocrinol (Copenh) 1991;124:173-8. [Crossref] [PubMed]
- Hoermann R, Poertl S, Liss I, et al. Variation in the thyrotropic activity of human chorionic gonadotropin in Chinese hamster ovary cells arises from differential expression of the human thyrotropin receptor and microheterogeneity of the hormone. J Clin Endocrinol Metab 1995;80:1605-10. [PubMed]
- Tanaka S, Yamada H, Kato EH, et al. Gestational transient hyperthyroxinaemia (GTH): screening for thyroid function in 23,163 pregnant women using dried blood spots. Clin Endocrinol (Oxf) 1998;49:325-9. [Crossref] [PubMed]
- Kimura M, Amino N, Tamaki H, et al. Gestational thyrotoxicosis and hyperemesis gravidarum: possible role of hCG with higher stimulating activity. Clin Endocrinol (Oxf) 1993;38:345-50. [Crossref] [PubMed]
- Yoshimura M, Pekary AE, Pang XP, et al. Thyrotropic activity of basic isoelectric forms of human chorionic gonadotropin extracted from hydatidiform mole tissues. J Clin Endocrinol Metab 1994;78:862-6. [PubMed]
- Rodien P, Bremont C, Sanson ML, et al. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 1998;339:1823-6. [Crossref] [PubMed]
- Coulon AL, Savagner F, Briet C, et al. Prolonged and Severe Gestational Thyrotoxicosis Due to Enhanced hCG Sensitivity of a Mutant Thyrotropin Receptor. J Clin Endocrinol Metab 2016;101:10-1. [Crossref] [PubMed]
- Caron P, Susini M, Savagner F, et al. Familial Gestational Hyperthyroidism Caused by Val597ile Mutant of TSH Receptor Gene with Human Chorionic Gonadotropin Hypersensitivity. 41st ETA Annual Meeting; Newcastle (UK), 2018:1-118.
- Korevaar TI, Steegers EA, Pop VJ, et al. Thyroid Autoimmunity Impairs the Thyroidal Response to Human Chorionic Gonadotropin: Two Population-Based Prospective Cohort Studies. J Clin Endocrinol Metab 2017;102:69-77. [PubMed]
- Teng X, Shan Z, Li C, et al. Iron Deficiency May Predict Greater Risk for Hypothyroxinemia: A Retrospective Cohort Study of Pregnant Women in China. Thyroid 2018;28:968-75. [Crossref] [PubMed]
- Yoshimura M, Hershman JM, Pang XP, et al. Activation of the thyrotropin (TSH) receptor by human chorionic gonadotropin and luteinizing hormone in Chinese hamster ovary cells expressing functional human TSH receptors. J Clin Endocrinol Metab 1993;77:1009-13. [PubMed]
- Dashe JS, Casey BM, Wells CE, et al. Thyroid-stimulating hormone in singleton and twin pregnancy: importance of gestational age-specific reference ranges. Obstet Gynecol 2005;106:753-7. [Crossref] [PubMed]
- Casey BM, Leveno KJ. Thyroid disease in pregnancy. Obstet Gynecol 2006;108:1283-92. [Crossref] [PubMed]
- Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13:3-126. [Crossref] [PubMed]
- Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92:S1-47. [Crossref] [PubMed]
- Korevaar TI, Medici M, de Rijke YB, et al. Ethnic differences in maternal thyroid parameters during pregnancy: the Generation R study. J Clin Endocrinol Metab 2013;98:3678-86. [Crossref] [PubMed]
- Korevaar TI, de Rijke YB, Chaker L, et al. Stimulation of Thyroid Function by Human Chorionic Gonadotropin During Pregnancy: A Risk Factor for Thyroid Disease and a Mechanism for Known Risk Factors. Thyroid 2017;27:440-50. [Crossref] [PubMed]
- Korevaar TI, Steegers EA, de Rijke YB, et al. Reference ranges and determinants of total hCG levels during pregnancy: the Generation R Study. Eur J Epidemiol 2015;30:1057-66. [Crossref] [PubMed]
- Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid 2017;27:315-89. [Crossref] [PubMed]
- Stricker R, Echenard M, Eberhart R, et al. Evaluation of maternal thyroid function during pregnancy: the importance of using gestational age-specific reference intervals. Eur J Endocrinol 2007;157:509-14. [Crossref] [PubMed]
- Kung AW, Jones BM. A change from stimulatory to blocking antibody activity in Graves' disease during pregnancy. J Clin Endocrinol Metab 1998;83:514-8. [PubMed]
- Wehmann RE, Nisula BC. Radioimmunoassay of human thyrotropin: analytical and clinical developments. Crit Rev Clin Lab Sci 1984;20:243-83. [Crossref] [PubMed]
- Rothacker KM, Brown SJ, Hadlow NC, et al. Reconciling the Log-Linear and Non-Log-Linear Nature of the TSH-Free T4 Relationship: Intra-Individual Analysis of a Large Population. J Clin Endocrinol Metab 2016;101:1151-8. [Crossref] [PubMed]
- Casey BM, Dashe JS, Spong CY, et al. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 2007;109:1129-35. [Crossref] [PubMed]
- Bartalena L, Robbins J. Thyroid hormone transport proteins. Clin Lab Med 1993;13:583-98. [Crossref] [PubMed]
- Larsen PR, Davies TF, Hay ID. The thyroid gland. In: Wilson JD, Foster DW, Kronenberg HM, et al. editors. Williams textbook of endocrinology. 9th ed. Philadelphia: WB Saunders, 1998:389-515.
- Lee RH, Spencer CA, Mestman JH, et al. Free T4 immunoassays are flawed during pregnancy. Am J Obstet Gynecol 2009;200:260.e1-6. [Crossref] [PubMed]
- Korevaar TI, Chaker L, Medici M, et al. Maternal total T4 during the first half of pregnancy: physiologic aspects and the risk of adverse outcomes in comparison with free T4. Clin Endocrinol (Oxf) 2016;85:757-63. [Crossref] [PubMed]
- Oken E, Braverman LE, Platek D, et al. Neonatal thyroxine, maternal thyroid function, and child cognition. J Clin Endocrinol Metab 2009;94:497-503. [Crossref] [PubMed]
- Soldin OP, Hilakivi-Clarke L, Weiderpass E, et al. Trimester-specific reference intervals for thyroxine and triiodothyronine in pregnancy in iodine-sufficient women using isotope dilution tandem mass spectrometry and immunoassays. Clin Chim Acta 2004;349:181-9. [Crossref] [PubMed]
- Fabian HM, Radestad IJ, Waldenstrom U. Characteristics of Swedish women who do not attend childbirth and parenthood education classes during pregnancy. Midwifery 2004;20:226-35. [Crossref] [PubMed]
- Gu J, Soldin OP, Soldin SJ. Simultaneous quantification of free triiodothyronine and free thyroxine by isotope dilution tandem mass spectrometry. Clin Biochem 2007;40:1386-91. [Crossref] [PubMed]
- d'Herbomez M, Forzy G, Gasser F, et al. Clinical evaluation of nine free thyroxine assays: persistent problems in particular populations. Clin Chem Lab Med 2003;41:942-7. [Crossref] [PubMed]
- Sapin R, d'Herbomez M. Free thyroxine measured by equilibrium dialysis and nine immunoassays in sera with various serum thyroxine-binding capacities. Clin Chem 2003;49:1531-5. [Crossref] [PubMed]
- Soldin OP, Soldin SJ. Thyroid hormone testing by tandem mass spectrometry. Clin Biochem 2011;44:89-94. [Crossref] [PubMed]
- Nelson JC, Tomei RT. Dependence of the thyroxin/thyroxin-binding globulin (TBG) ratio and the free thyroxin index on TBG concentrations. Clin Chem 1989;35:541-4. [PubMed]
- Stockigt JR. Free thyroid hormone measurement. A critical appraisal. Endocrinol Metab Clin North Am 2001;30:265-89. [Crossref] [PubMed]
- Roberts RF, La'ulu SL, Roberts WL. Performance characteristics of seven automated thyroxine and T-uptake methods. Clin Chim Acta 2007;377:248-55. [Crossref] [PubMed]
- Thienpont LM, Van Uytfanghe K, Poppe K, et al. Determination of free thyroid hormones. Best Pract Res Clin Endocrinol Metab 2013;27:689-700. [Crossref] [PubMed]
- Faix JD. Principles and pitfalls of free hormone measurements. Best Pract Res Clin Endocrinol Metab 2013;27:631-45. [Crossref] [PubMed]
- Soldin OP, Tractenberg RE, Hollowell JG, et al. Trimester-specific changes in maternal thyroid hormone, thyrotropin, and thyroglobulin concentrations during gestation: trends and associations across trimesters in iodine sufficiency. Thyroid 2004;14:1084-90. [Crossref] [PubMed]
- Kahric-Janicic N, Soldin SJ, Soldin OP, et al. Tandem mass spectrometry improves the accuracy of free thyroxine measurements during pregnancy. Thyroid 2007;17:303-11. [Crossref] [PubMed]
- Soldin SJ, Soukhova N, Janicic N, et al. The measurement of free thyroxine by isotope dilution tandem mass spectrometry. Clin Chim Acta 2005;358:113-8. [Crossref] [PubMed]
- Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf) 2003;58:138-40. [Crossref] [PubMed]
- Fritz KS, Wilcox RB, Nelson JC. A direct free thyroxine (T4) immunoassay with the characteristics of a total T4 immunoassay. Clin Chem 2007;53:911-5. [Crossref] [PubMed]
- Wang R, Nelson JC, Weiss RM, et al. Accuracy of free thyroxine measurements across natural ranges of thyroxine binding to serum proteins. Thyroid 2000;10:31-9. [Crossref] [PubMed]
- Feldt-Rasmussen U, Hyltoft Petersen P, Blaabjerg O, et al. Long-term variability in serum thyroglobulin and thyroid related hormones in healthy subjects. Acta Endocrinol (Copenh) 1980;95:328-34. [Crossref] [PubMed]
- Andersen S, Pedersen KM, Bruun NH, et al. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab 2002;87:1068-72. [Crossref] [PubMed]
- Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev 2010;31:702-55. [Crossref] [PubMed]
- Medici M, Korevaar TI, Visser WE, et al. Thyroid function in pregnancy: what is normal? Clin Chem 2015;61:704-13. [Crossref] [PubMed]
- Negro R, Soldin OP, Obregon MJ, et al. Hypothyroxinemia and pregnancy. Endocr Pract 2011;17:422-9. [Crossref] [PubMed]
- Zimmermann MB, Gizak M, Abbott K, et al. Iodine deficiency in pregnant women in Europe. Lancet Diabetes Endocrinol 2015;3:672-4. [Crossref] [PubMed]
- Shi X, Han C, Li C, et al. Optimal and safe upper limits of iodine intake for early pregnancy in iodine-sufficient regions: a cross-sectional study of 7190 pregnant women in China. J Clin Endocrinol Metab 2015;100:1630-8. [Crossref] [PubMed]
- Knight BA, Shields BM, Hattersley AT, et al. Maternal hypothyroxinaemia in pregnancy is associated with obesity and adverse maternal metabolic parameters. Eur J Endocrinol 2016;174:51-7. [Crossref] [PubMed]
- Korevaar TI, Steegers EA, de Rijke YB, et al. Placental Angiogenic Factors Are Associated With Maternal Thyroid Function and Modify hCG-Mediated FT4 Stimulation. J Clin Endocrinol Metab 2015;100:E1328-34. [Crossref] [PubMed]
- Cooper DS, Laurberg P. Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol 2013;1:238-49. [Crossref] [PubMed]
- Lazarus J. Iodine and brain function. In: Lieberman HR, Kanarek RB, Prasad C. editors. Nutritional Neuroscience. Bosa Raton, FL: CRC Press, 2005:261-74.
- van den Boogaard E, Vissenberg R, Land JA, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update 2011;17:605-19. [Crossref] [PubMed]
- 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;341:549-55. [Crossref] [PubMed]
- Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105:239-45. [Crossref] [PubMed]
- Glinoer D, Soto MF, Bourdoux P, et al. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions. J Clin Endocrinol Metab 1991;73:421-7. [Crossref] [PubMed]
- Williams GR. Neurodevelopmental and neurophysiological actions of thyroid hormone. J Neuroendocrinol 2008;20:784-94. [Crossref] [PubMed]
- Li Y, Shan Z, Teng W, et al. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25-30 months. Clin Endocrinol (Oxf) 2010;72:825-9. [Crossref] [PubMed]
- Negro R, Schwartz A, Gismondi R, et al. Universal screening versus case finding for detection and treatment of thyroid hormonal dysfunction during pregnancy. J Clin Endocrinol Metab 2010;95:1699-707. [Crossref] [PubMed]
- Lazarus JH, Bestwick JP, Channon S, et al. Antenatal thyroid screening and childhood cognitive function. N Engl J Med 2012;366:493-501. [Crossref] [PubMed]
- Casey BM, Thom EA, Peaceman AM, et al. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med 2017;376:815-25. [Crossref] [PubMed]
- Hales C, Taylor PN, Channon S, et al. Controlled Antenatal Thyroid Screening II: Effect of Treating Maternal Suboptimal Thyroid Function on Child Cognition. J Clin Endocrinol Metab 2018;103:1583-91. [Crossref] [PubMed]
- Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 2010;95:4227-34. [Crossref] [PubMed]
- Roman GC, Ghassabian A, Bongers-Schokking JJ, et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol 2013;74:733-42. [Crossref] [PubMed]
- Vermiglio F, Lo Presti VP, Moleti M, et al. Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries. J Clin Endocrinol Metab 2004;89:6054-60. [Crossref] [PubMed]
- Modesto T, Tiemeier H, Peeters RP, et al. Maternal Mild Thyroid Hormone Insufficiency in Early Pregnancy and Attention-Deficit/Hyperactivity Disorder Symptoms in Children. JAMA Pediatr 2015;169:838-45. [Crossref] [PubMed]
- Medici M, de Rijke YB, Peeters RP, et al. Maternal early pregnancy and newborn thyroid hormone parameters: the Generation R study. J Clin Endocrinol Metab 2012;97:646-52. [Crossref] [PubMed]
- Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, et al. Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study. J Clin Endocrinol Metab 2013;98:4382-90. [Crossref] [PubMed]
- Thangaratinam S, Tan A, Knox E, et al. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ 2011;342:d2616. [Crossref] [PubMed]
- Sheffield JS, Cunningham FG. Thyrotoxicosis and heart failure that complicate pregnancy. Am J Obstet Gynecol 2004;190:211-7. [Crossref] [PubMed]
- Sahu MT, Das V, Mittal S, et al. Overt and subclinical thyroid dysfunction among Indian pregnant women and its effect on maternal and fetal outcome. Arch Gynecol Obstet 2010;281:215-20. [Crossref] [PubMed]
- Korevaar TI, Steegers EA, Chaker L, et al. The Risk of Preeclampsia According to High Thyroid Function in Pregnancy Differs by hCG Concentration. J Clin Endocrinol Metab 2016;101:5037-43. [Crossref] [PubMed]
- Taylor PN, Minassian C, Rehman A, et al. TSH levels and risk of miscarriage in women on long-term levothyroxine: a community-based study. J Clin Endocrinol Metab 2014;99:3895-902. [Crossref] [PubMed]
- Hales C, Taylor PN, Channon S, et al. Controlled Antenatal Thyroid Screening (CATS) Study II; (i) Effect of treatment of suboptimal gestational thyroid function (SGTF) on children's behaviour at age 9. Thyroid Research - Meeting abstracts from the 64th British Thyroid Association Annual Meeting 2017;10:2.
- Nazarpour S, Ramezani Tehrani F, Simbar M, et al. Effects of Levothyroxine on Pregnant Women With Subclinical Hypothyroidism, Negative for Thyroid Peroxidase Antibodies. J Clin Endocrinol Metab 2018;103:926-35. [Crossref] [PubMed]
- Yamamoto JM, Benham JL, Nerenberg KA, et al. Impact of levothyroxine therapy on obstetric, neonatal and childhood outcomes in women with subclinical hypothyroidism diagnosed in pregnancy: a systematic review and meta-analysis of randomised controlled trials. BMJ Open 2018;8. [Crossref] [PubMed]
- Taylor PN, Lacey A, Thayer D, et al. Controlled Antenatal Thyroid Study: Obstetric Outcomes. Thyroid Research - Meeting abstracts from the 64th British Thyroid Association Annual Meeting 2017;10:2.
- Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 2006;91:2587-91. [Crossref] [PubMed]
- Earl R, Crowther CA, Middleton P. Interventions for preventing and treating hyperthyroidism in pregnancy. Cochrane Database Syst Rev 2010. [PubMed]
- Taylor PN, Vaidya B. Side effects of anti-thyroid drugs and their impact on the choice of treatment for thyrotoxicosis in pregnancy. Eur Thyroid J 2012;1:176-85. [Crossref] [PubMed]
- Marx H, Amin P, Lazarus JH. Hyperthyroidism and pregnancy. BMJ 2008;336:663-7. [Crossref] [PubMed]
- Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081-125. [Crossref] [PubMed]
- American Thyroid Association Taskforce On Radioiodine Safety, Sisson JC, Freitas J, et al. Radiation safety in the treatment of patients with thyroid diseases by radioiodine 131I: practice recommendations of the American Thyroid Association. Thyroid 2011;21:335-46. [Crossref] [PubMed]
- Kuy S, Roman SA, Desai R, et al. Outcomes following thyroid and parathyroid surgery in pregnant women. Arch Surg 2009;144:399-406; discussion 406. [Crossref] [PubMed]
- Taylor P, Bhatt S, Gouni R, et al. A Case of Propylthiouracil-Induced Hepatitis during Pregnancy. Eur Thyroid J 2012;1:41-4. [Crossref] [PubMed]
- Cooper DS, Rivkees SA. Putting propylthiouracil in perspective. J Clin Endocrinol Metab 2009;94:1881-2. [Crossref] [PubMed]
- Andersen SL, Olsen J, Wu CS, et al. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab 2013;98:4373-81. [Crossref] [PubMed]
- Zimmerman D. Fetal and neonatal hyperthyroidism. Thyroid 1999;9:727-33. [Crossref] [PubMed]
- LeBeau SO, Mandel SJ. Thyroid disorders during pregnancy. Endocrinol Metab Clin North Am 2006;35:117-36. vii. [Crossref] [PubMed]
- Dosiou C, Barnes J, Schwartz A, et al. Cost-effectiveness of universal and risk-based screening for autoimmune thyroid disease in pregnant women. J Clin Endocrinol Metab 2012;97:1536-46. [Crossref] [PubMed]
- Taylor PN, Okosieme OE, Premawardhana L, et al. Should all women be screened for thyroid dysfunction in pregnancy? Womens Health (Lond) 2015;11:295-307. [Crossref] [PubMed]
- Wilson JM, Jungner YG. Principles and practice of mass screening for disease. Bol Oficina Sanit Panam 1968;65:281-393. [PubMed]
Cite this article as: Muller I, Taylor PN, Lazarus JH. Thyroid function in pregnancy. Ann Thyroid 2018;3:27.