NODULAR THYROID DISEASE

Thyroid nodule growth during pregnancy

Thyroid nodules are common in young women and medical care provided during pregnancy may present the first opportunity for a thyroid nodule to be clinically recognized 416, 417. A few studies have evaluated the incidence of thyroid nodules and nodule changes associated with pregnancy, in areas with borderline iodine sufficiency or mild iodine deficiency. In a prospective study performed in Brussels, thyroid nodules were diagnosed by ultrasound at initial presentation during early gestation in 3% of a cohort of normal pregnancies 176. Repeat ultrasound performed within a week after delivery revealed a 60% increase in the size of the known nodules and detection of new nodules in 20% of these women. In another study in Northern Germany, the presence of thyroid nodules was shown to be significantly greater in women with prior pregnancies compared to nulliparous women (25% versus 9%). Furthermore, women with three or more pregnancies had a higher percentage of thyroid nodules, compared with women who had one or two prior pregnancies (34% versus 21%) 418. Finally in a study from Southern China, women were evaluated in the 3 trimesters of pregnancy and early postpartum 419. Thyroid nodules were detected in 15% of women in 1st trimester, and there was a significant increase in their volume, as well as new nodule formation during pregnancy. Thus, in areas with mild iodine insufficiency, pre-existing nodules are prone to increase in size during pregnancy. Furthermore during the course of pregnancy, new nodules will be detected in approximately 15% of women. Unfortunately, data on nodule growth and formation in iodine- sufficient areas are not available.

Diagnostic evaluation of a thyroid nodule in pregnancy

Diagnostic evaluation of thyroid nodules discovered during pregnancy should be similar to that of non-pregnant patients, but the ongoing pregnancy raises an additional concern regarding timing of surgical management 420-424. The diagnosis and decision-making for overall management of a nodule diagnosed in pregnancy relies primarily on the results of thyroid ultrasound and fine needle aspiration biopsy (FNAB). Despite the fact that a minority of nodules are potentially malignant, the fear of cancer may be accentuated in pregnant women. Therefore, diagnostic investigation using FNAB is recommended in most pregnant women. A number of studies have suggested that a delay in the work-up of a nodule until after delivery causes no change in final prognosis as compared with surgical resection of a malignant lesion in the second trimester 422, 425. Knowing the diagnosis via FNAB cytology is, however, often helpful to the mother in planning the postpartum period, including decisions regarding breast-feeding and the potential need for adjunctive therapy with radioiodine after surgical removal of a cancer. Furthermore, a delay in surgical treatment of thyroid cancer beyond a one-year period is not recommended because of increased likelihood of cancer complications 421.

Thyroid ultrasonography is useful to characterize the dominant lesion (solid versus cystic), identify other non-palpable nodules within a nodular goiter, monitor nodule growth, etc. Thyroid ultrasound is also a useful adjunct to guiding the FNAB procedure. FNAB is safe and diagnostically reliable and should be routinely performed when any single or dominant thyroid nodule greater than 1 cm has been discovered 1, 417. In the particular context of a nodule identified during pregnancy, and because of the potential therapeutic implications, it is highly important that FNAB be carried out and analyzed by experienced teams.

Management

Subsequent management depends on results of FNAB cytology. Most nodular lesions are cytologically benign and do not require surgery. If cytology is suspicious or positive for thyroid cancer, treatment decision-making must take into account the gestational age, the apparent tumor stage and the personal inclination of the patient. If FNAB cytology is highly suggestive of papillary, follicular, or medullary carcinoma, surgery is offered in the 2nd trimester, before fetal viability 426. Surgery for papillary cancer may be postponed until after delivery because there is no evidence that pregnancy worsens the prognosis or that waiting until postpartum alters the long term prognosis of a well-differentiated thyroid cancer 420, 422, 425, 427. When cytology is highly suggestive of a follicular neoplasm, the risk of malignancy is 10%-15% and thyroid surgery can be delayed, if preferred, until a short time after delivery. In patients who need to be reassured or when there is significant growth of the nodule before mid-gestation, surgery is a valid option and should be carried out during the second trimester. For follicular neoplasms with Hurthle cell features (i.e. oncocytes), the patient should be encouraged to have surgery during pregnancy, given the more aggressive behavior of Hurthle cell carcinoma 428. Finally, when a nodule is discovered in the third trimester, further work-up and treatment can be delayed until after delivery 429, 430.

Overall, most experts in the field agree that pregnancy does not worsen the prognosis of differentiated thyroid carcinoma and there is, therefore, no justification to recommend interrupting the pregnancy. In a recent study, the long-term outcome of a large grop of women diagnosed with thyroid cancer was evaluated 431. The authors observed no significant difference in the outcome, compared with an age-matched non pregnant cohort. Furthermore, there was no adverse effect of surgery performed during pregnancy on the outcome of pregnancy.

One frequently asked question concerns the risk of a pregnancy in thyroid cancer survivors. Recent data have indicated that pregnancy is unlikely to cause clinically significant disease recurrence in women treated previously for differentiated thyroid cancer who are considered free of residual disease 432. However occasionally, pregnancy can be associated with progression of known metastatic lesions 433.

Recommendations and "take home" messages

Fine needle aspiration (FNA) cytology should be performed for all thyroid nodules greater than 1 cm, discovered in pregnancy. Ultrasound guided FNA may have an advantage for minimizing inadequate sampling.

When nodules are discovered in the 1st or early 2nd trimester to be malignant on cytological analysis or exhibit rapid growth, pregnancy should not be interrupted but surgery offered in the 2nd trimester, before fetal viability. Women with cytology indicative of papillary cancer or follicular neoplasm without evidence of advanced disease, and who prefer to wait until the postpartum period for definitive surgery, may be reassured that most well differentiated thyroid cancers are slow growing and that surgical treatment soon after delivery is unlikely to change prognosis.

Thyroid hormone administration is justified to achieve a slightly suppressed (but detectable) serum TSH in pregnant women with an FNAB positive for or suspicious for cancer and who elect to delay surgical treatment until postpartum.

SCREENING FOR THYROID DISORDERS ASSOCIATED WITH PREGNANCY

Prerequisites for screening in primary prevention

In primary prevention, screening is defined as testing for a disease when there are no signs or symptoms, with the aim of improving health outcomes by early diagnosis followed by treatment (when required) or monitoring. In order to justify systematic screening for primary prevention in medicine, a number of prerequisites has, ideally, to be met:

Prevalence of disease must be high enough to justify screening.

Laboratory techniques must be available to reliably detect disease, and these techniques must have high positive and negative predictive values.

Screening procedures must be safe (i.e. with very low co-morbidity).

Adequate medical intervention (such as medication) must be available, so that a given diagnosis can be followed by adapted therapy.

Benefits of medical intervention should outweigh potential risks of secondary negative side effects of both screening and therapy.

Evidence-based medicine should ideally have clearly established the usefulness of screening. This issue obviously also implies health policy and cost-benefit considerations, although the latter will always remain controversial since cost-benefit evaluations are highly variable from country to country and depend primarily upon applicable national social security systems and health insurance policies.

Evidence-based medicine must show decreased morbidity and/or improved health status when treating conditions detected by screening procedures.

When trying to assess whether such prerequisites have been met (completely or partially) for thyroid disorders associated with pregnancy, what can we conclude?

Concerning the prevalence of thyroid disorders, many studies have shown that 5-15% of pregnant women have thyroid autoantibodies, 2-3% of them have undiagnosed hypothyroidism, and 0.3-0.5% undiagnosed hyperthyroidism 1, 212, 434. Based on our own pregnancy studies in Belgium, Figure 14-20 shows the different thyroid conditions that were observed in successive prospective cohort studies involving altogether ~2.400 women. The data indicate clearly that the overall prevalence of thyroid disorders associated with pregnancy is sufficiently high to warrant screening.

With regard to the laboratory techniques (reliability & safety), the two main candidates for screening are serum TSH and detection of TPO-Ab. More complete testing should also include detection of Tg-Ab and serum free T4 measurement. Preliminary results from an ongoing prospective study in Wales, (the "CATS study" or Controlled Antenatal Thyroid Screening study), utilizing both serum TSH and free T4 measurements to diagnose thyroid function abnormalities, indicate that the abnormalities tend to cluster around two main pregnant subpopulations 435. In about half the women with abnormalities, an isolated low serum free T4 level was found (defined as in the lowest 2.5th centile of normals) and an equal number of women having an isolated high serum TSH (defined as above the 97.5th centile of normals), with relatively few of them having both low T4 and high TSH.

Concerning the financial burden of thyroid testing, the latest calculations made for my country (Belgium) indicate that measuring TSH, free T4 and TPO-Ab amounts to a total cost of 38.40 € (i.e. ~50 US $). Patients who are covered by the national social security system (almost 100% of the population) would have to contribute 8.70 €, and the state would reimburse the difference to the laboratory (i.e. 29.70 €). When considering the average medical "cost" of an uncomplicated pregnancy in our country (~2.500 €), the inclusion of thyroid screening would only add 1.5% to the overall cost.

Concerning the screening procedures, several schemes can be proposed, although all encompass advantages and disadvantages that need to be carefully considered. The optimal timing of screening has not been determined, although there are good arguments to favor early screening. Immune suppression of autoantibody production points to the necessity to check the presence of TPO-Ab as early as possible during gestation 208, 212. On the other hand, the normal physiologic (transient) blunting in serum TSH near the end of 1st trimester makes the delineation of the optimal timing for TSH screening more complex. Therefore, nomograms or trimester-specific references for normality have been proposed by some authors to facilitate the interpretation of TSH changes during pregnancy 72-75. Measurements of serum free T4 can also be altered artefactually during pregnancy and this needs to be considered as well, as it might perhaps be minimized by using laboratory-specific or assay-specific or trimester-specific serum free T4 reference norms, that need to be locally established 66, 70, 72.

Concerning benefits of treatment with regard to obstetrical outcome and fetal development, there is good evidence that they outweigh largely the risks associated with absence of treatment for overt hypothyroidism & hyperthyroidism (related mainly to GD) (see Table 14-16). Concerning subclinical hypothyroidism and thyroid autoimmunity features in women who have a normal thyroid function in early pregnancy, studies have now convincingly shown that early treatment with thyroxine was advantageous by restoring and/or maintaining euthyroidism throughout gestation 202, 225. Concerning subclinical hyperthyroidism (related mainly to gestational hCG-induced hyperthyroidism), advantages of treatment have not been demonstrated so far, except in severe cases with hyperemesis gravidarum. After screening, and notwithstanding the decision to treat a thyroid condition or monitor thyroid function, it is important to note that diagnosing chronic autoimmune thyroiditis also allows for delineating a group of women who are at risk of developing thyroid dysfunction during the postpartum period and hypothyroidism later in life 205.

A recent publication by Dosiou et al. proposed the first cost-effectiveness analysis of screening pregnant women for thyroid autoimmunity and dysfunction 436. In this model, the authors evaluated three options: no screening, screening with TPO-Ab, or screening with TSH. The index case on which the model was based was a 25 year-old woman screened once in the 1st trimester. After initial screening, the authors selected various "strategy" tracks in order to include serum re-testing, visits with an endocrinologist, follow-up and treatment when appropriate. Using available probabilities of thyroid function abnormalities and evaluation of financial costs implied by such procedures, the authors derived from their probabilistic approach a plausible evaluation of cost-effectiveness and concluded that screening in the 1st trimester was indeed cost-affective compared with not screening.

Besides the evident issues of cost, practicality, or feasibility of systematic screening in pregnancy, some potential disadvantages must also be considered. For instance, the results of screening might induce unnecessary anxiety. Also, finding a low serum TSH (without hyperthyroidism) might be followed by the administration of antithyroid drugs, even when such treatment is not justified. Finally, there are also legal aspects to consider in this matter. If universal screening should become mandatory, then obstetric care providers may face the risk that any deviation from accepted guidelines might constitute a cause for legal suits.

Policy considerations for systematic screening during pregnancy

Policy considerations concerning universal routine thyroid screening before and/or during pregnancy remain controversial and are subject of heated debates, especially in the United States.

Between 2000 & 2004, the American College of Obstetricians and Gynecologists (ACOG), the American Thyroid Association (ATA), and a consensus panel including the American Association of Clinical Endocrinologists (AACE), ATA, and The Endocrine Society (TES) has not endorsed the recommendation for routine screening of thyroid disorders in pregnancy. In their conclusions, the panel wrote that “there is insufficient evidence to recommend routine thyroid screening in pregnancy (or in women desiring pregnancy)” 437-439. Subsequently, the leadership of AACE, ATA, and ES has invited a second group to determine whether there were areas of legitimate and significant disagreement with the conclusions of the consensus panel. This group concluded their work “in favor of routine screening for subclinical thyroid dysfunction in adults, including pregnant women and those contemplating pregnancy” 440.

In 2005, an international ad hoc committee was established under the auspices of the American Endocrine Society to review the best available evidence for thyroid disorders associated with pregnancy and develop evidence-based guidelines for clinical practice. Members of the ten-person task force (chaired by Leslie DeGroot) included representatives of TES, ATA, ETA, LATS, AOTA, AACE & ACOG. The issue of “universal screening” was hotly debated in this task force. One major consideration among the task force members was that negative outcomes had clearly been linked to thyroid function abnormalities associated with pregnancy and it was felt, therefore, that renewed attention should be focused on screening for thyroid dysfunction in the peri-partum period.

Specifically, the association of infertility with thyroid autoimmunity and dysfunction, the association of an increased risk of miscarriage with thyroid abnormalities, the association of a poorer obstetrical outcome with thyroid dysfunction, the association of a decreased IQ in the offspring of mothers with subtle degrees of thyroid dysfunction, and finally the association of postpartum thyroid disorders with thyroid autoimmunity, contributed all to the apparent merit of universal screening. However after reviewing the available evidence, force was to admit that the overall lack of carefully conducted studies evaluating the impact of medical intervention on the negative outcomes associated with thyroid abnormalities during pregnancy and the postpartum precluded a recommendation for universal screening. As already alluded to above, individual members of the committee considered that there were enough valid arguments to believe that the evidence (albeit incomplete or indirect) was sufficient to justify screening before/during pregnancy. Finally, the task force came to the conclusion that “since it was not possible to recommend universal screening, an acceptable compromise is aggressive case finding; targeted case finding in high risk population may provide an appropriate balance between inaction and screening entire populations” (see Table 14-12) 1. More details can be found in the Section on "primary hypothyroidism".

On a more personal note, it is regrettable that ACOG did not, eventually, endorse the recommendations of the international guidelines committee. In a press release by ACOG in October 2007, their representatives wrote that “there is no evidence that identifying and treating pregnant women with subclinical hypothyroidism improves either maternal or infants outcomes” 441. We certainly agree that it can be argued that the high frequency of thyroid hormone and TSH determinations that are out of the "normal" range, but normal for pregnancy, could constitute an adverse effect of systematic screening by health care providers other than endocrinologists 442. Such values could wrongly be misinterpreted by non-endocrine providers and result in unnecessary anxiety, referral, and even undue treatments for the pregnant woman. Alternatively and as already elaborated earlier, there are good arguments to advise that routine screening for thyroid disorders is warranted in the general population, and especially in pregnant women 440. In an editorial by the Editor of the Journal "Thyroid", Terry Davies wrote that “to list so many reasons for testing women in a case-finding approach such that almost all women would be included is less satisfactory that leading and stating clearly that it is not appropriate to let pregnant women proceed without thyroid function testing. I doubt a single physician present at the Endocrine Society presentation would fail to screen a pregnant woman for thyroid disease. And that means that every obstetrician should be doing the same thing” 443.

Present situation concerning screening

An interesting study was recently conducted in the New Jersey/New York metropolitan area, with the objective to determine the level of knowledge of endocrinologists, obstetrician/gynecologists, internists, and finally family physicians in regard to thyroid disease and pregnancy 444. In this 16-item questionnaire, the questions asked concerned topics such as hypothyroidism and GD in pregnancy, thyroid autoimmunity and pregnancy, postpartum thyroiditis, risk of IQ impairment in the progeny of mothers with thyroid disorders, etc. A total of 412 physicians completed the questionnaire. Among them, percentages of physicians who treated pregnant women were 94% for the endocrinologists, 90% for the obstetricians/gynecologists, 58% for the internists and 68% for the family physicians. The main findings indicated a "disturbingly" low level of knowledge in physicians across all disciplines. Knowledge gaps were mainly related to areas of relatively recent scientific new acquisitions, but also to facts that have been known for decades. Endocrinologists scored highest with 77% of correct responses to the questionnaire. Two questions, for instance, dealt with Graves' disease (on the natural course of the disease and the goal of treatment with antithyroid drugs). Correct response rates to these questions were 71% for the endocrinologists, but only less than 50% for the obstetricians/gynecologists and also less than 40% for the family physicians. The overall low scores may be attributed to a lack of adequate education on thyroid disease during pregnancy, lack of exposure to women during pregnancy, or the inability to translate research information into clinical practice. Thus when discussing the pros and cons of systematic screening during pregnancy, one must take into account that the main challenge is to translate new research-derived information into clinical practice, and this goal can only be achieved through education of the various medical professions involved with the care of pregnant women.

Irrespective of the opinions of some scientific societies, the practice of screening pregnant women for thyroid disorders has already been adopted in many university hospital centers, mainly (but not only) in Europe. A survey by Haddow et al. indicates, for instance, that many practitioners in Maine have also instituted routine TSH testing in pregnancy, in spite of a lack of consensus among professional organizations 445.

Is a case-finding approach sufficient? This question has been recently evaluated by Vaidya et al. in the UK in a study wherein screening pregnant women classified as "high-risk" was evaluated 446. High-risk women were defined on the following criteria: a personal history of thyroid disorders including women with thyroid treatment, a personal history of type 1 diabetes and/or other autoimmune disorders, and finally a family history of thyroid disorders. The authors showed that the use of high-risk criteria allowed only for the detection of 70% of women with hypothyroidism, while high-risk criteria were no better than low-risk criteria for the identification of women with a suppressed serum TSH (see Figure 14-21).

In summary from the few studies available, it seems reasonable to conclude that there are obvious shortcomings in a targeted approach to screening. Therefore, such strategies should remain considered as partial solutions, at least until more data become known to us in order to fine-tune benefits of universal screening of women for thyroid disorders during pregnancy 1, 434, 447.

FINAL CONCLUSIONS

Pregnancy has profound effects on the regulation of thyroid function in healthy women and patients with thyroid disorders. These effects need to be recognized, precisely assessed, clearly interpreted, and correctly managed. For healthy pregnant women who reside in areas with a restricted iodine intake, relative hypothyroxinemia & goitrogenesis occur frequently, indicating that pregnancy constitutes a challenge for the thyroidal economy.

Overt thyroid dysfunction occurs in 2-3% of pregnancies, but subclinical thyroid dysfunction (both hyper- & hypothyroidism) is probably more prevalent and frequently remains undiagnosed, unless specific screening programs are initiated to disclose thyroid function abnormalities in early gestation. Maternal alterations of thyroid function due to iodine deficiency, hypothyroidism and hyperthyroidism have important implications for fetal/neonatal outcome. In recent years, particular attention has been focused on potential developmental risks for the fetuses of women with hypothyroxinemia during early gestation.

Pregnancy increases the metabolic rate, blood flow, heart rate, and cardiac output, and various subjective sensations such as fatigue and heat intolerance that may suggest the possibility of coexistent thyrotoxicosis. Other metabolic changes which also impact the hypothalamic pituitary thyroid system are the potential direct stimulation of the maternal thyroid by hCG, as well as the accelerated metabolism of thyroxine, presumably due to increased placental deiodination enzymes.

In patients with hypothyroidism, it is important to recognize that therapeutic requirements for exogenous thyroxine are increased by 50% on average during pregnancy. This should be taken into account in the management of such patients.

Main causes of thyrotoxicosis in pregnancy include Graves' disease (uncommon, but potentially pregnancy-threatening) and gestational non autoimmune transient hyperthyroidism (more common, but remaining mild usually). The natural history of Graves' disease is altered during pregnancy, with a tendency for exacerbation in 1st trimester, amelioration during 2nd & 3rd trimesters, and typically a rebound during the postpartum period. These changes are the consequences of partial immune suppression during gestation with a rebound during the postpartum period. This must be kept in mind when treating thyrotoxic patients, since all ATD cross the placenta and may affect fetal thyroid function.

Fetal and neonatal hyperthyroidism is due to the transplacental transfer of maternal stimulating TSH-receptor antibodies (TRAb). The diagnosis of fetal (and neonatal) hyperthyroidism is usually made on the basis of fetal tachycardia, accelerated bone age, and intrauterine growth retardation. It may occur in infants born to women with active Graves' disease, but also to women who have had prior definitive cure of their disease by surgery or radioactive iodine, but maintain high titers of TRAb. The proper management of pregnant patients with Graves' disease remains a difficult challenge in clinical endocrinology.

Thyroid nodules discovered during pregnancy should be aspirated for cytological diagnosis. If a malignancy is diagnosed, surgery should be performed during pregnancy or shortly thereafter. Pregnancy by itself does not adversely affect the natural history of differentiated thyroid carcinoma.

During the postpartum period, particular attention should be given to women with thyroid autoimmunity, since hypothyroidism and hyperthyroidism are frequently exacerbated in the months following the delivery.