Should All Women Be Screened for Thyroid Dysfunction in Pregnancy?

Abstract

The subject of universal thyroid screening in pregnancy generates impassioned debate. Thyroid dysfunction is common, has significant adverse implications for fetal and maternal well-being, is readily detectable and can be effectively and inexpensively treated. Furthermore, the currently recommended case-finding strategy does not identify a substantially proportion of women with thyroid dysfunction thus favoring universal screening. On the other hand subclinical thyroid dysfunction forms the bulk of gestational thyroid disorders and the paucity of high-level evidence to support correction of these asymptomatic biochemical abnormalities weighs against universal screening. This review critically appraises the literature, examines the pros and cons of universal thyroid screening in pregnancy, highlighting the now strong case for implementing universal screening and explores strategies for its implementation.

Keywords

child neurodevelopment hyperthyroidism hypothyroidism isolated hypothyroxinemia levothyroxine pregnancy screening subclinical hypothyroidism

Thyroid hormones have fundamental but diverse physiological roles and are essential for normal adult health and childhood development [1]. Because thyroid disorders are common in women of reproductive age thyroid dysfunction is frequently encountered in pregnancy [2]. The prevalence of hyperthyroidism in pregnancy is 0.5%, while subclinical hypothyroidism is present in about 4–8% of women of child bearing age and overt hypothyroidism occurs in 0.5% of pregnant women [2 –4]. In iodine-replete populations the bulk of thyroid disorders are due to the autoimmune thyroid disorders, namely Hashimoto's thyroiditis and Graves' disease, although iodine deficiency is the most common cause of gestational thyroid dysfunction worldwide [2]. Uncorrected thyroid dysfunction carries significant morbidity affecting virtually every system in the body, and in extreme cases, culminating in life threatening catastrophic emergencies [5,6]. In addition there is growing recognition that even mild degrees of thyroid dysfunction or variations in thyroid function within the normal reference range may carry adverse cardiovascular and metabolic consequences [7,8].

Recent decades have seen an increasing appreciation of the critical role of thyroid hormones in fetal neurodevelopment together with the detrimental effects of overt thyroid dysfunction on fetal and maternal well-being [1,2]. Furthermore, substantial progress has been made in understanding the intricate changes in thyroid hormone economy that accompany pregnancy and there is now a growing emphasis on the value of gestation specific laboratory reference ranges in assessing thyroid status in pregnancy [9,10]. Thus, given the importance of thyroid hormones for optimal pregnancy outcomes, the availability of sensitive diagnostic tests, coupled with accessible and established cost–effective therapies for thyroid dysfunction, there has been considerable often impassioned debate as to whether all women should be screened for thyroid disease in pregnancy [11,12]. In this review we examine the case for universal thyroid screening in pregnancy and scrutinize this against established criteria for screening.

Criteria for screening

Screening is a strategy used to systematically identify whether an individual has a disease in the absence of apparent clinical signs and symptoms. In order for a screening test for a disease to be justified it should meet key criteria first laid down by Wilson and Jungner (Box 1) [13]. In essence the disease should be serious and common with a detectable preclinical phase, the screening test should be sensitive and specific as well as acceptable to patients and the treatment should be safe, effective and able to modify disease progression. At present there is no clear consensus regarding universal thyroid screening in pregnancy. Most international endocrine societies recommend screening only in women with the highest risk of thyroid dysfunction, the so called case-finding strategy [9,10]. However, some regional endocrine societies, most notably the Spanish Society of Endocrinology, [14,15] now advocate screening. In addition a number of experts in the field [16 –18], including a significant proportion of practicing endocrinologists [19], also favor universal thyroid screening.

Public health impact of thyroid dysfunction in pregnancy

The public health importance of thyroid dysfunction in pregnancy is determined by its prevalence together with its severity and its impact on fetal and maternal outcomes. The spectrum of gestational thyroid dysfunction includes hyperthyroidism, hypothyroidism and isolated hypothyroxinemia. Individuals who are biochemically euthyroid but who have thyroid autoimmunity may also be at risk of adverse outcomes. Subclinical thyroid disease is characterized by normal thyroid hormones, FT4 and FT3, in the presence of abnormal TSH while in overt disease FT4 or FT3 are abnormal along with abnormal thyroid-stimulating hormone (TSH) [20,21]. The potential for adverse obstetric outcomes in women with positive thyroid antibodies and normal thyroid function (euthyroid thyroid autoimmunity) or low FT4 and normal TSH levels (isolated hypothyroxinemia, IH) have also attracted recent interest [10,21–22]. Furthermore, iodine nutrition is a key determinant of thyroid function and iodine deficiency may complicate pregnancy by exacerbating potential adverse feto-maternal effects of thyroid dysfunction [23]. In this section, we will consider the health implications of each of these conditions individually.

Box 1.

Points to consider for a screening test to be justified.

Is the condition an important health problem?

Is there an accepted treatment for patients with recognized disease?

Are facilities for diagnosis and treatment available?

Is there should a recognizable latent or early symptomatic stage?

Is there should a suitable test or examination?

Is the test acceptable to the population?

Is the natural history of the condition, including development from latent to declared disease adequately understood?

Is there should an agreed policy on whom to treat as patients?

Is the cost of case finding (including diagnosis and treatment of patients diagnosed) economically balanced in relation to possible expenditure on medical care as a whole?

Case finding should be a continuing process and not a “once and for all” project

Adapted from Wilson J, Jungner G: Principles and practice of screening for disease. Geneva: World Health Organization, 1968. Public health papers 34, (2011) [13].

Hypothyroidism

Hypothyroidism affects about 4–10% of women including a substantial proportion of women who are of reproductive age [24,25]. In pregnancy the prevalence of overt and subclinical hypothyroidism is estimated at 0.5 and 4–8%, respectively [2,4] although higher rates are reported when the gestational upper TSH limits recommended by international guidelines are applied [9–10,26–27]. Observational studies consistently report an increased risk of adverse obstetric outcomes in association with overt hypothyroidism including miscarriage, premature birth, gestational hypertension, placental abruption and postpartum hemorrhage [28,29] Similar but less pronounced negative pregnancy outcomes are reported for women with subclinical hypothyroidism [1,22,30 –32].

Subclinical hypothyroidism during pregnancy is also associated with an increased incidence of adverse pregnancy outcomes including preterm delivery, placental abruption, respiratory distress, early pregnancy loss and admissions to the intensive care unit [33 –37]. These effects can be substantial, in 9403 singleton pregnancies, pregnant women with a TSH in the second trimester higher than 6.0 mU/l had increased odds of fetal death odds ratio (OR) = 4.4, (95% CI: 1.9–9.5) compared with women with a TSH less than 6.0 mU/l [38]. Furthermore Benhadi et al., in a study of 2497 pregnant Dutch women, reported a 60% increase (95% CI: 1.04, 2.47) in the rate of fetal loss for each doubling of maternal TSH within the normal range [39].

This negative impact of borderline thyroid function on pregnancy outcomes is not simply due to TPO antibody positivity as a large study of 4129 antibody negative Italian women, showed that a TSH level of 2.5–5.0 mU/l was associated with a 60% increase in the risk of miscarriage compared with TSH <2.5 mU/l [40]. However despite these compelling observational data there is a paucity of intervention trials to support the benefits of correcting subclinical hypothyroidism in pregnancy. One controlled trial by Negro et al. showed that treatment of low-risk women with gestational subclinical hypothyroidism (TSH >2.5 mU/l) carried a significantly reduced risk of adverse pregnancy events compared with no treatment at all (OR: 0.43; 95% CI: 0.26–0.70) [37].

The deleterious impact of gestational hypothyroidism may also extend beyond pregnancy to affect the subsequent neuro-intellectual performance of the child [41 –43]. The study by Haddow and colleagues showed that children born to mothers with untreated hypothyroidism had a seven point IQ deficit compared with the children of mothers with normal thyroid function [41]. Other studies have since observed similar findings in the offspring of women with hypothyroxinemia. Pop et al. reported an 8–10-point reduction in IQ in the children of mothers who had hypothyroxinemia at 12 weeks gestation compared with the children of euthyroid control mothers [42]. More recently a large population based study involving 3659 mother–child pairs also confirmed an association between maternal hypothyroxinemia and cognitive impairment, specifically expressive language and nonverbal delays [43].

In contrast the only randomized controlled trial on the subject to date, the controlled antenatal thyroid screening trial by Lazarus et al. found no significant differences in IQ in the children of mothers who were treated with levothyroxine for gestational subclinical hypothyroidism or IH compared with the children of untreated mothers [44]. The interpretation of this study must however bear in mind that intervention was started at the end of the first trimester which may have been too late for beneficial effects to be apparent. The fetal thyroid gland does not become fully functional until about 14 weeks gestation and up till this point the foetus is wholly dependent on maternal thyroxine sources [1,32]. Treatment started at the end of the first trimester may thus have missed the critical early neurodevelopmental phase. A second consideration is that the children in the controlled antenatal thyroid screening trial underwent psychometric testing at age three, a time which could have been too early in life for cognitive differences to be exposed. Thus pending further studies the effect of levothyroxine in subclinical hypothyroidism remains unresolved.

Hyperthyroidism

Hyperthyroidism is less common than hypothyroidism, occurring in approximately 0.1–1.0% of pregnancies [1,2]. Graves ‘disease accounts for at least 80% of these cases while other causes include solitary or multiple autonomous nodules [32]. Overt hyperthyroidism (high FT4 and low TSH) in pregnancy is a serious condition, resulting in increased risk of adverse obstetric outcomes including miscarriage, stillbirth, pre-term birth and intra-uterine growth restriction [1]. Fetal hyperthyroidism with fetal tachycardia, goitre and hydrops is a potential cause of pregnancy loss [32]. Furthermore, 1–5% of neonates born to mothers with Graves ‘disease develop neonatal hyperthyroidism due to the transplacental transfer of thyroid-stimulating TSH receptor antibodies from the mother's circulation to the newborn. Although this condition is typically self-limiting it may cause significant neonatal morbidity and is occasionally fatal [32]. In the absence of thyroid testing recognition of neonatal hyperthyroidism may prove challenging especially in the infants of mothers with undiagnosed hyperthyroidism.

Estrogen mediated increases in thyroid binding globulins together with the weak thyroid-stimulating actions of human chorionic gonadotrophins (HCG) lead to a rise in total thyroid hormones which is accompanied by a corresponding fall in TSH [32]. While biochemically similar to Graves, there are no antibodies against the TSH receptor, goitre, abnormal thyroid texture on ultrasound or the presence of ophtalmopathy [45]. This transient thyrotoxicosis presents in the first trimester of pregnancy at the time of peak levels of HCG. and occurs in 1.7–3.0% of pregnant women. It is not associated with adverse obstetric or offspring outcomes [46,47] probably because the fetus is protected from marginal excess FT₄ through the inactivating effect of placental type 3 deiodinase [48]. Thus specific therapy is not indicated for this condition.

Thyroid autoimmunity in euthyroid individuals

Thyroid antibodies are the hallmark of autoimmune thyroid disease but about 10% of pregnant women will test positive for thyroid peroxidize antibodies (TPOAb) or thyroglobulin antibodies (TgAb) with normal thyroid function [1]. A number of studies have suggested that the presence of these antibodies may have adverse effects on obstetric or child neurointellectual performance independent of thyroid function [49 –54]. A prospective randomized intervention trial showed that euthyroid antibody positive women had a higher risk of miscarriages and premature deliveries which was reduced with levothyroxine treatment [55]. A meta-analysis of 31 studies involving 12,126 women confirmed this association, and also found a significant increase in the risk of preterm birth in women with thyroid antibodies [56]. The mechanism of this association is unclear and there is no evidence that thyroid antibodies per se are harmful to the fetus. Proposed explanations include the possibility of subtle subclinical thyroid dysfunction in antibody positive women, co-existence of a diffuse autoimmune process which deters fetal survival, or a noncausal association arising from confounding factors such as the older age of thyroid antibody-positive women [54].

Isolated hypothyroxinemia

IH may be considered as a form of thyroid failure in which the FT4 is low in the presence of a normal TSH, however its pathological significance is unclear [57]. It is also unknown why in some individuals there is no rise in TSH in response to lower levels of FT4, although iodine deficiency as well as auto-immune disease may be a factor [58]. Interpreting the evidence regarding IH is challenging as the limits of the low FT4 has been variously defined as below the 2.5th, 5th or 10th centile of the pregnancy related reference range and as such highly discrepant prevalence rates ranging from 1 to 26% have been reported [57,59]. Casey et al. [60] identified IH (FT4 <0.86 ng/dl) in 233 of 17,298 pregnant women (1.3%) but observed no excessive adverse pregnancy outcomes. Korevaar et al. [22] noted that 1.4% of pregnant women were hypothyroxinemic (FT4 <2.5th percentile) and had a 2.5-fold increased risk of premature delivery and a 3.6-fold increased risk of very premature delivery. Similar results were obtained when all FT4 levels were analyzed irrespective of their TSH, as well as after exclusion of TPO antibody positive women or those with other comorbidities. In a study of 10,990 pregnant women first trimester hypothyroxinemia was associated with increased odds of preterm labor OR = 1.62 (95% CI: 1.00–2.62) and macrosomia OR = 1.97 (95% CI: 1.37–2.83), whereas second trimester hypothyroxinemia was associated with gestational diabetes OR = 1.70 (95% CI: 1.02–2.84) [61]. Finally the median free thyroxine was lower in women with preterm delivery compared with controls (0.94 vs 0.99) p <0.001.

Maternal IH has been linked with lower IQ in the offspring [41–42,62] and attention deficit hyperactivity disorders in observational data [63]. In addition some studies have showed an association with adverse obstetric outcomes including preterm delivery while others have shown no adverse perinatal effects [60]. Therefore the pathological significance of IH remains unresolved and further studies are needed to clarify its impact on pregnancy outcomes.

Iodine deficiency

Iodine is an integral component of thyroid hormones essential for normal neurological and physical development. The iodine deficiency disorders include goitre, hypothyroidism, subfertility, impaired childhood development and mental deficiency amongst other conditions [64]. In pregnancy a combination of renal iodide losses, increased placental iodine delivery and the extra demands on thyroxine production from fetal needs, all serve to increase susceptibility to iodine deficiency [65]. Routine prenatal iodine supplementation is recommended by professional bodies in both North America [66] and Europe [67] but it appears unlikely that this adhered to in many European countries where gestational iodine status remains inadequate [68 –70]. An estimated two billion people worldwide are at risk of iodine deficiency and the problem is particularly prevalent in Europe where approximately, 44% of school-age children still have insufficient iodine intake with countries such as the UK, Italy and parts of Spain are now moderately iodine deficient [71 –78] In the UK, this is exacerbated due to low levels of commercial salt iodization [71]. Australia and New Zealand were also recently identified to be mildly iodine deficient although effective treatment strategies such as iodization of bread have been employed [79 –81].

An observational study from England recently reported an association between maternal iodine deficiency and deficiencies in verbal IQ, reading accuracy and comprehension in the offspring [82]. A systematic review and meta-analysis on the health consequences of mild to moderate iodine deficiency concluded that even correction of mild iodine deficiency improved maternal thyroid indices and benefited aspects of cognitive function in school-age children [83]. Thus the current levels of iodine nutrition would dictate a need for an effective approach to ensuring adequate iodine nutrition as well as thyroid status in pregnancy.

Screening tests for thyroid dysfunction in pregnancy

The diagnosis of thyroid dysfunction is based on clinical assessment, guided by the measurement of serum FT₄ and TSH and relevant antibodies. Thyroid function testing based on venous blood sampling is standard and acceptable practice and in one study 18% of all adults had their thyroid function tested in a year [84]. Many laboratories now offer low-cost automated modern assays for FT₄ and TSH with rapid assay turnaround times. The inverse logarithmic relationship between FT₄ and TSH means that small variations in T₄ are reflected in large changes in TSH, making TSH the most sensitive and specific indicator of thyroid status in overt and subclinical thyroid dysfunction [85]. During pregnancy estrogen mediated increases in thyroid binding globulins combined with the action of HCG lead to a rise in total thyroid hormones which is accompanied by a corresponding fall in TSH [32]. Thus the normal reference ranges in pregnancy differ from the nonpregnant range necessitating the use of trimester-specific gestation reference ranges for accurate assessment of thyroid status in pregnancy [86]. A number of studies have shown that both the normal lower and upper TSH limits are lower in pregnancy than in the nonpregnant range [86 –89] In contrast a recent study in China [90] demonstrated a significantly higher TSH reference range for each trimester. In this study the first trimester reference range was 0.12–5.08 mIU/l and as a consequence, using the suggested 0.1–2.5 mIU/l as reference range would classify about 28% of the pregnant women in China as suffering from hypothyroidism, compared with 4% when using ethnic specific reference range [4,20 –22]. Data from Europe from the Generation R cohort highlighted that a comparison of disease prevalence between a population-based versus an ethnicity-specific reference range changed the diagnosis for 18% of women who were initially diagnosed as having an abnormal thyroid function test result [91]. Each laboratory is therefore advised to derive its own reference ranges based on local normative pregnancy values. Where such data are unavailable an upper TSH limit of 2.5 mU/l is recommended in the first trimester with a limit of 3.0 mU/l in subsequent trimesters [9,10].

Unlike TSH, FT₄ assays during pregnancy may be beset by problems of interference from the presence of pregnancy-modified plasma proteins. Equilibrium dialysis is the gold standard of FT₄ measurement in pregnancy but is technically challenging to undertake and not routinely available in most laboratories. An alternative strategy is to measure total T₄ which may give a more practical pregnancy reference-range but stands the risk of spurious results from variations in thyroid binding globulin, the complexities and implications of this are summarized here [92]. Some modern FT₄ assays have been proven to correlate well with equilibrium dialysis [93] and the use of TSH as a first-line approach complemented with a sensitive FT₄ assay would allow a pragmatic and reliable protocol for detecting thyroid disease in pregnancy.

Management of thyroid dysfunction in pregnancy

Hypothyroidism is rewarding to treat. Levothyroxine is the treatment of choice and is safe, effective, cheap and easy to monitor [10,94]. Recent years have seen an increase in levothyroxine prescription in the UK although up to a third of levothyroxine users are sub optimally treated [95,96]. Thus the management of hypothyroidism in pregnancy should ideally start before conception and it is important that women already on levothyroxine have their dose adjusted to achieve TSH levels <2.5 mU/l although this is often not achieved [97]. On conception additional adjustments are required to maintain TSH <2.5 mU/l in the first trimester and <3.0 mU/l in subsequent trimesters [10]. These adjustments are necessary since up to a third of women receiving levothyroxine embark on pregnancy with abnormal thyroid status [98,99]. We recently analyzed a large primary care database of levothyroxine treated women in pregnancy which revealed that TSH levels above 2.5 mU/l in the first trimester was associated with an increased odds of miscarriage (p = 0.008). In comparison to women with TSH within the reference range of 0.2–2.5 mU/l, the risk of miscarriage was almost double in women with first trimester TSH between 4.5 and 10.0 mU/l and nearly fourfold in women with TSH >10 mU/l [100].

The management of overt hyperthyroidism in pregnancy is more complex. The antithyroid drugs, carbimazole or propylthiouracil, are the mainstay of treatment. Radio-iodine is absolutely contraindicated [9,101] and while thyroidectomy may be used in pregnancy it is associated with increased morbidity [102] and may also be associated with a higher risk of subsequent fetal thyrotoxicosis compared with antithyroid drug treatment [103]. Propylthiouracil is advised in the first trimester of pregnancy since there is a small risk of embryopathy associated with carbimazole use at this stage. However, because propylthiouracil is in turn associated with potentially serious liver dysfunction, it is recommended that a switch is made from propylthiouracil to carbimazole after the first trimester of pregnancy [32,104]. The risks of these side effects are low and clearly outweighed by the need for early control of hyperthyroidism in order to reduce the risks of miscarriage and other adverse pregnancy outcomes seen with uncontrolled hyperthyroidism [1,105].

There are as yet no recommendations to support treatments for IH or for euthyroid thyroid antibody positive women in pregnancy [9]. Thus if these conditions are detected in screening sensitive counseling will be required to allay anxiety. The bulk of data would support treatment in patients with overt hypothyroidism and overt hyperthyroidism [9–10,106–107]. As highlighted in a recent Cochrane review however, the existing data are inconclusive regarding the benefits of levothyroxine therapy in women with gestational subclinical hypothyroidism [108]. Besides many important adverse pregnancy outcomes associated with clinical and subclinical hypothyroidism have never been evaluated in intervention trials. A decision to offer treatment to women with subclinical hypothyroidism should therefore be individualized. However it is worth highlighting that many clinicians do treat subclinical hypothyroidism in pregnancy as there is some evidence it reduces the risk of miscarriage and other adverse obstetric outcomes, particularly in TPO antibody positive women [37,109]. Recent ETA guidelines have also endorsed that subclinical hypothyroidisim arising before conception or during gestation should be treated with levothyroxine with the aim of normalizing maternal serum TSH values within the trimester-specific pregnancy reference range [21].

Universal screening versus targeted case finding

There is as yet no agreement among endocrinologists regarding the optimal screening strategy for thyroid dysfunction in pregnancy (Table 1). A questionnaire study of members of the European Thyroid Association identified that 42% of respondents screen all women in pregnancy, 43% perform targeted high-risk case finding, while 17% do not perform screening [19]. The Endocrine Society task force on thyroid disease management in pregnancy failed to reach a consensus on the issue of screening with some members in support of universal screening and others proposing a case -finding approach [10]. A selective screening approach of high-risk women, focusing particularly on women with fertility problems is efficient at identifying women with thyroid disease [110]. However, focusing exclusively on high-risk pregnancies could leave over two-thirds of women with subclinical hypothyroidism undiagnosed [98,111]. The American Thyroid Association currently recommends targeted screening for thyroid disease using a set of revised more comprehensive criteria (Box 2). This comprehensive case-finding strategy is in essence an endorsement for universal screening since the risk bracket is so wide that a high proportion of women would qualify for screening.

Table 1.

Key viewpoints regarding thyroid screening in pregnancy from society guidelines.

Society issuing guideline	Defined TSH in first trimester	High-risk screening	Universal screening	Thyroid antibody screening	Ref.
ACOG 2007	No	Recommended	Not recommended	Not addressed	[106]
ATA 2011	Trimester specific. If unavailable use 0.1–2.5 mU/l	Recommended	Insufficient evidence for recommendation	Insufficient evidence for recommendation
Endocrine Society 2012	0.1–2.5 mU/l	Recommended	No consensus	Not recommended	[10]
AACE 2012	Trimester specific. If unavailable use upper limit of 2.5 mU/l	Not addressed	Not recommended	Only for evaluating subclinical hypothyroidism	[107]

AACE American Association of Clinical Endocrinologists; ACOG: American Congress of Obstetricians and Gynecologists; ATA: American Thyroid Association; TSH: Tyroid-stimulating hormone.

Cost–effectiveness of universal screening

A cost–effective analysis by Dosiou et al. compared three screening strategies using a state transition Markov model: universal screening for thyroid disease in pregnancy, screening high-risk women and no screening [112]. Risk based screening and universal screening were cost effective compared with no screening at all. In addition universal screening was cost–effective compared with risk-based screening, with an incremental cost effective ratio of 7258 USD per quality-adjusted life year (QALY). Importantly universal screening remained cost–effective assuming that only overt hypothyroidism had adverse effects on obstetric or child intelligence. In another study Thung and colleagues used a decision model to compare the cost benefits of screening versus no screening for subclinical hyperthyroidism in pregnancy [113]. Their model which was based on the assumption that levothyroxine could reduce the frequency of low IQ in the children of women with subclinical hypothyroidism predicted that 8,356,383 USD was saved and 589.3 QALYs were gained for every 100,000 pregnant women screened. It should however be noted that a beneficial effect of levothyroxine on child IQ is yet to be proven for subclinical hypothyroidism. Negro and co-workers in their randomized controlled trial of screening versus case finding derived that 40 women were needed to be screened to prevent a single outcome.

Box 2.

Women with high risk of thyroid disease.

Women with a history of thyroid dysfunction and/or thyroid surgery

Women with a family history of thyroid disease

Women with a goitre

Women with positive thyroid antibodies

Women with symptoms or clinical signs suggestive of hypothyroidism

Women with Type I diabetes

Women with a history of miscarriage or preterm delivery

Women with other autoimmune disorders frequently associated with autoimmune thyroid dysfunction, including vitiligo, adrenal insufficiency, hypoparathyroidism, atrophic gastritis, pernicious anemia, systemic sclerosis, systemic lupus erythematosus (SLE) and Sjögren's syndrome

Women with infertility

Women with prior therapeutic head or neck irradiation

Women with morbid obesity

Women age 30 years or older

Women treated with amiodarone

Women treated with lithium

Women with a recent exposure to iodinated radiological contrast agents

Data taken from the Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum [66].

The case against universal screening

The main argument against universal screening is the lack of interventional studies to support benefit in subclinical hypothyroidism that constitutes the bulk of thyroid disorders in pregnancy. Furthermore, the significance of these asymptomatic borderline biochemical abnormalities is far from settled with some studies showing high rates of reversal to normal in the general population [84]. On this basis it could be argued that universal screening does not meet key criteria for an acceptable screening test. Screening all pregnancies will involve a monumental cost. In one study up to a quarter of pregnant women were classified as abnormal by using the currently recommended TSH upper limits [114]. This will generate a level of anxiety which may conceivably extend into the developmental years of the progeny with the risk of child labeling based on minor deviations from the reference range. Treatment of mild or borderline states also carries a small risk of over-treatment especially in the hands of inexperienced or overenthusiastic practitioners. Lastly, the practicalities of universal screening remain vague and do not appear to have received detailed consideration. For example at what stage of pregnancy will women be screened, which caregivers will be responsible for screening, where will screening take place and who will act on the results of abnormal tests? Thus, it could be argued that universal screening could potentially do more harm than good and is not wholly supported by the current level of evidence. More robust systems may also need to be put in place for titrating levothyroxine during pregnancy as many women established on levothyroxine do not attain the trimester specific reference-range for TSH [97].

The case for universal screening

The case for universal thyroid screening in pregnancy is compelling. Thyroid dysfunction is common in pregnancy, is easily detectable with a simple blood test and may be treated efficiently, safely and inexpensively. Universal screening of pregnant women in the first trimester for autoimmune thyroid disease is cost–effective in comparison to targeted screening or no screening at all [112]. Furthermore, there is a need to detect and treat overt hypothyroidism during pregnancy, as this alone has been shown to be cost–effective [112]. Also the argument that screening will not benefit women with subclinical hypothyroidism becomes tenuous considering that thyroid function represents a continuum and the threshold at which treatment becomes beneficial is still in flux, a situation no different from some other conditions with established screening programs such as hypertension.

A pragmatic screening algorithm is to measure TSH preconception in women planning pregnancy or as early as possible on conception, with a reflex FT₄ undertaken if TSH is outside the pregnancy and trimester specific reference-range. All women with identified overt hyperthyroidism or hypothyroidism should be treated immediately while a decision regarding treatment of subclinical hypothyroidism and other thyroid abnormalities should be arrived at jointly by the clinician and patient following a discussion of the risks and benefits of therapeutic intervention. The management of abnormal results and training of frontline staff should involve experienced clinicians and arrangements will vary according to the facilities in place.

Although most endocrine societies recommend targeted screening over universal screening targeted screening will miss a third of women with thyroid dysfunction including a proportion of women with overt thyroid dysfunction [98]. In particular universal screening will reduce the risk of adverse pregnancy effects in the so-called low-risk women [37]. Furthermore, there are significant discrepancies as to the definition of thyroid disease risk and the current recommendations do not take into account the role of additional factors which may affect thyroid function such as the iodine nutrition status of the population or the genetic determinants of intracellular thyroid hormone delivery. As iodine nutrition status in countries like the UK is now mild-moderate deficiency it would seem reasonable to have a systematic approach to both iodine supplementation and thyroid function in pregnancy. In practice some clinicians are now moving toward near-universal screening, which lends further support to the need for a formal universal screening program [111].

Conclusion

Close examination of the criteria for screening (Box 1) provides a persuasive case for universal thyroid screening in pregnancy. From the evidence we have presented it is clear that thyroid dysfunction is an important health problem (criteria 1), resulting in adverse obstetric and offspring outcomes. This still holds true even if only overt hypothyroidism and overt hyperthyroidism are considered. Treatment of both hypothyroidism and hyperthyroidism results in improved outcomes and is cost–effective and acceptable to patients (criteria 2); however, the TSH threshold for initiation of levothyroxine during pregnancy is less clear. Facilities for both diagnosis and treatment are readily available (criteria 3). For hypothyroidism in particular there is also a well-recognized asymptomatic stage (criteria 4). Clinical assessment of thyroid status and thyroid function testing are both commonplace and are already readily acceptable to the general population (criteria 5 + 6). The natural history of subclinical thyroid dysfunction leading to overt hypothyroidism/hyperthyroidism is well understood, however it needs highlighting that many women with subclinical hypothyroidism would not progress to overt hypothyroidism if left untreated (criteria 7). The costs of case finding are also economically balanced even if only overt thyroid disease is considered (criteria 9). The nature of thyroid screening in pregnancy ensures a continuing process and not a ‘once and for all’ project (criteria 10). Realistically only criteria 8 ‘there should be an agreed policy on whom to treat as patients’ is not satisfied as more data on the benefits of levothyroxine therapy in women with subclinical hypothyroidism, IH and euthyroid autoimmunity are needed. Given there is widespread variation in current practice at present so this criteria alone should not prevent the implementation of universal screening. In practice, any attempt to introduce universal screening will need careful thought and planning regarding the practicalities of implementation within existing health service structures in order to ensure that the proposed benefits of a screening program will be realized. It is also worth highlighting that obstetricians, in general, are much more cautious in their acceptance of thyroid screening and ongoing close liaison between endocrinologists and obstetricians is essential. Further clarification of who to treat will arise from trials outlined below, but only become fully apparent once universal thyroid screening is implemented.

Future perspective

A major critique of universal screening has been the lack of intervention data on benefits from levothyroxine in gestational subclinical hypothyroidism. While this indicates insufficient evidence to endorse either position on screening it should not be interpreted as evidence for lack of benefit. Instead the knowledge gap should spur researchers, funders and policy makers alike to support future trials, arduous as it may seem. High-quality randomized controlled trial data are particularly needed on the benefits of levothyroxine on pregnancy and child developmental outcomes in subclinical hypothyroidism, IH and euthyroid autoimmunity.

In this regard two trials are currently in progress. A randomized controlled trial of the effect of levothyroxine therapy for maternal subclinical hypothyroidism or hypothyroxinemia on subsequent childhood cognitive function is being conducted under the auspices of the National Institute of Child Health and Human Development [115]. In this study women have been recruited from <20 weeks gestation with psychometric testing of the offspring undertaken at 5 years of age. Another large multicenter study in Birmingham, UK, is presently investigating the benefits of levothyroxine on obstetric outcomes in euthyroid antibody positive women (TABLET trial) [116]. In this large double-blind placebo-controlled trial euthyroid thyroid peroxidase antibody positive women with a history of infertility or miscarriages are being recruited before and during pregnancy and randomized to receive treatment with 50 mcg of thyroxine or placebo for one year with the occurrence of preterm delivery in subsequent pregnancies as outcomes [116].

The opposition to universal screening has also stemmed from the lack of clarity regarding aspects of screening such as the choice and timing of screening tests. However the onus is on the advocates of screening to propose concise evidence-based algorithms to support an effective strategy. Additional data comparing the performance and cost–effectiveness of different screening tests such as FT4, TSH and TPOAb, will be useful. Audits of existing screening practices in routine pregnancy care will provide a more realistic picture of clinician preferences and practices and will guide in the planning and implementation of future screening programs. Such surveys need not be restricted to endocrine or specialist obstetric units but should involve practices run by generalists, community midwives and obstetricians who provide the greater part of routine pregnancy care. Furthermore, it is important to clarify whether in the absence of universal screening we can reliably predict which woman will develop thyroid dysfunction in pregnancy. To this end the sensitivity of the more comprehensive case-finding stratifications should be evaluated in real world settings.

Lastly, it is arguable whether in the light of the proven benefits of correcting overt hypothyroidism it is justifiable to continue to await future intervention data in subclinical hypothyroidism before adopting a universal screening policy. Levothyroxine intervention trials in pregnancy are enormously challenging to undertake, often span many years and face major obstacles in recruiting trial participants from early gestation due to the fact that many pregnancies are unplanned or unnoticed in the early phase. Thus there is no guarantee that future trials will be free of the limitations of past studies. Meanwhile there is increasing public awareness of the potential associations between thyroid dysfunction and adverse pregnancy outcomes and a growing proportion of clinicians now opt for universal screening in pregnancy. In a single academic center in Boston, for example, 85% of women underwent thyroid testing under routine care settings and of these 80% of women with thyroid dysfunction would have been missed if a case-finding approach had been adopted [111]. Thus with the current trend it is not inconceivable that future ethical committees may struggle to justify withholding therapy in the control arm of subsequent trials.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Thyroid disorders are common in pregnant women and may be asymptomatic.

Thyroid function tests are largely reliable in determining thyroid status. However, trimester and population specific reference ranges should be used where possible.

Maternal thyroid hormone status in pregnancy impacts on both obstetric and offspring outcomes.

Both gestational hypothyroidism and hyperthyroidism are easily treatable with well-established therapies.

Correction of overt thyroid disease improves fetal and maternal outcomes but there is a paucity of high-quality data to support therapeutic benefits in subclinical thyroid dysfunction.

Further research is needed relating to the benefits of screening for subclinical hypothyroidism, isolated hypothyroxinemia and euthyroid autoimmunity.

Targeted antenatal screening of thyroid function while efficient will miss a substantial proportion of women with thyroid dysfunction.

Cost-benefit analysis favors universal thyroid above targeted screening or no screening at all.

Universal thyroid screening would pose key challenges to implement and careful planning is necessary to ensure that the proposed benefits will be realized.

References

Papers of special note have been highlighted as:

of considerable interest

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12.

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13.

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37.

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38.

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39.

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41.

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42.

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43.

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44.

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45.

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49.

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50.

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51.

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52.

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53.

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54.

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56.

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57.

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58.

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59.

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60.

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61.

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67.

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69.

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70.

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71.

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72.

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73.

Summarizes current evidence and rationale for current practice.

74.

Zimmermann

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76.

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78.

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79.

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80.

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81.

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82.

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83.

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84.

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86.

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90.

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95.

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100.

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104.

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105.

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109.

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