The present study compares, for the first time, current clinical practices in the management of thyroid disease in pregnancy, between endocrinologists and generalists of East Asia. Generally, there was a high degree of consistency between clinical practices of East Asian physicians and the ATA and ES guidelines (
3,
4), conforming more closely to the practices of endocrinologists than generalists. In all issues, except one, there were significant differences in clinical approaches between generalists and specialists.
Maternal hyperthyroidism, diagnosed in pregnancy, must be corrected, because it has detrimental effects on both mother and fetal health (
8,
9). Concerning probability of PTU hepatotoxicity (
10) which limits its use as the first line treatment of hyperthyroidism and the teratogenic effect of MMI (
11), ATA and ES recommend PTU during the first trimester, followed by MMI from the second trimester. In the present survey, although most responders follow the guidelines, there is significant discrepancy between subspecialists and generalists, especially regarding shifting therapy from PTU to MMI after the first trimester, which may be due to their own clinical concerns in switching drugs based on the ES suggestions.
For preconception counseling of a Graves’ patient, ATA (
3) recommends the use of MMI/CMZ and change to PTU, once the pregnancy is confirmed (
3). However, whether this approach would prevent MMI/CMZ associated embryopathy is not clear. Despite the significant differences to this approach, between generalists and subspecialists, most responders suggest drug therapy. Nevertheless, the majority of responders in both groups, especially generalists, would prefer to start with PTU.
Almost half of the responders monitor antithyroid drug treatment with TSH and FT
4 and one third with TSH, FT
4 and FT
3, with no significant difference between the two groups. In addition, most endocrinologists target low TSH and FT
4 (or TT
4) in the normal range, during such therapy, which is also considered as good practice, since guidelines recommend TSH and FT
4, as the main tests for such monitoring and advise to aim for FT
4 in the upper end of the normal range, during antithyroid therapy in pregnancy (
3,
4). However, it is distressing that 22% of endocrinologists and 53% of generalists target normal range for serum TSH and FT
4 concentrations, since this approach may increase the chance of fetal goiter and hypothyroidism (
12).
During the first half of pregnancy, differentiation of Graves’ disease and gestational thyrotoxicosis may be difficult. The presence of clinical evidence of autoimmunity, typical goiter and elevated TRAb support the diagnosis of Graves’ disease, while severe nausea, vomiting, weight loss and palpitation, along with negative thyroid antibodies favor gestational thyrotoxicosis (
13). In most cases of gestational thyrotoxicosis, no treatment is indicated, and this approach is followed only by 16% of endocrinologists and 15% of generalists, most of whom, unfortunately, preferred treatment with antithyroid medications, with significant discrepancy between the two groups (
Table 3). In a recent survey, 40% of East Asian endocrinologists just followed the pregnant women without intervention and 55% chose antithyroid therapies, with PTU preference (
6).
Routine measurement of TRAb, in a pregnant hyperthyroid woman under antithyroid drug therapy, is recommended by major professional endocrine organizations (
3,
4). Increased serum TRAb, detected in up to 95% of hyperthyroid pregnant women, is a risk for fetal and neonatal hyperthyroidism and lack of treatment will increase fetal and neonatal morbidity and mortality (
14). However, 46% of endocrinologists and 41% of generalists indicated that they do not routinely check TRAb, mainly due to lack of availability of this test.
There are also significant differences in the management of hyperthyroidism in a postpartum lactating woman, between generalists and specialists. The ATA and ES both recommend treating a lactating hyperthyroid woman with MMI, due to PTU hepatotoxicity (
15). It has been shown that MMI therapy, up to 30 mg daily, does not cause any alterations in thyroid function or the mental or physical development of infants, breast-fed by lactating hyperthyroid mothers (
16,
17). It is unfortunate that 15% of endocrinologists and 23% of generalists recommend stopping lactation during treatment with antithyroid drugs. The results of the recent survey, on the management of hyperthyroidism in pregnancy, by East Asian endocrinologists, were similar to opinions of endocrinologists in the current survey, except for the targeted thyroid hormone value during antithyroid treatment, as previously mentioned (
6).
Universal screening for thyroid dysfunction in pregnant women has been intensely debated in recent years (
18,
19). Although several studies have shown that the targeted case-finding approach misses a significant proportion of pregnant women with thyroid dysfunction (
19,
20), both the ATA and ES recommended targeted screening in pregnancy (
3,
4). The association of mild maternal thyroid hormone deficiency in pregnancy with impaired neuropsychological development of the offspring (
21) and adverse obstetric outcomes has been reported (
22). Only one randomized controlled trial suggests that identification of mild thyroid hormone deficiency in low-risk pregnant women, by screening and treatment with L-T
4, may reduce obstetric complications (
18). In the present survey, most endocrinologists and half of the generalists, or their institutions, perform targeted screening of only the high-risk group, in accordance with ATA and ES recommendations. It is, however, unfortunate that 21% of generalists and 11% of endocrinologists do not carry out any systematic screening. In addition, endocrinologists were more familiar with risk factors for targeted screening than generalists.
Half of the generalists and 54% of endocrinologists reported that they screened thyroid function during the first antenatal visit, and 23% and 28%, respectively, would do so during the first pre-pregnancy visit. One could argue that the identification and treatment of hypothyroidism in the first antenatal visit may be too late to prevent any associated adverse effects. However, implementing systemic screening of thyroid function in all women planning pregnancy would be an enormous challenge, especially for the developing countries of Asia.
Maternal hypothyroidism diagnosed in pregnancy should be treated (
3,
4), because maternal thyroid hormones play an important role in early fetal neurological development (
21). In this survey, most endocrinologists initiated full replacement dose of L-T
4 for pregnant women newly diagnosed with overt hypothyroidism; however, 53% of generalists started on a small dose of L-T
4. It is unfortunate that 7% of endocrinologists and 13% of generalists would recommend the option of abortion in overt hypothyroid patients, despite the absence of any published study to support such a practice. It has been reported that IQs of children, whose mothers had been hypothyroid during early pregnancy, were normal and similar to those of their siblings, who had not been exposed to maternal hypothyroidism in utero (
23). In another study, treatment of maternal hypothyroidism did not improve IQ or impaired cognitive function in 3-year-old offspring (
24).
Most hypothyroid women need an increased dose of L-T
4, from very early pregnancy (
25,
26). Indeed, about 25% of women on L-T4 replacement, at their first antenatal visit, show biochemical evidence of under replacement (
19), which may be prevented by optimizing the L-T
4 dose before pregnancy (
27). In the present study, 48% of endocrinologists (and only 20% of generalists) would advise women to increase the dose of L-T
4, either by 30% - 50% or by two tablets per week, as soon as pregnancy is confirmed, according to previous recommendations (
3,
4,
28). The rest of the responders would check thyroid function, as soon as pregnancy is confirmed.
Regarding the targeted thyroid function for pregnant hypothyroid women, 89% of endocrinologists and 77% of generalists aimed to achieve TSH and FT
4 within the trimester-specific reference range or TSH < 2.5 mU/L in the first trimester and < 3 mU/L in later trimesters, as recommended by current guidelines (
3,
4).
More endocrinologists than generalists would treat TPOAb positivity, with TSH between 2.5 - 5.0 mU/L. Roughly, half of the two groups of physicians would treat isolated TPOAb positivity. There is growing evidence on the association between thyroid autoimmunity and adverse obstetric outcomes, such as miscarriage (
29), recurrent pregnancy loss (
30), preterm delivery and low birth weight (
31). Almost half of endocrinologists and 11% of generalists treat TPOAb negative with TSH 2.5 - 5 mU/L, a practice not in line with guidelines, which do not recommend L-T
4 for these pregnant women (
3,
4), underlining the need for further studies.
There is a lack of consensus on the definition and management of isolated maternal hypothyroxinemia (
32). A large observational study has failed to show an association between maternal hypothyroxinemia and adverse obstetric outcomes (
33). However, the prospective, nonrandomized Generation R study reported increased risk of lower communication development in children, born to women with isolated hypothyroxinemia (
34). Although the majority of the responders practice in accordance with guidelines recommending, against the treatment of maternal hypothyroxinemia in pregnancy, it is remarkable that nearly 43% of endocrinologists reported that they would treat isolated maternal hypothyroxinemia.
In the published surveys on the management of thyroid dysfunction in pregnancy (
5,
6), the investigations were performed in endocrinologists, either by internet or during AFES 2013, in Jakarta and in 21 countries from different Asian regions. The current survey presents a comparison of protocols between endocrinologists and generalists and covers physicians from eight eastern and southern Asian countries, revealing wide differences in the practice of specialists and generalists. The practices of Asian endocrinologists, in both surveys, were similar.
The present study, which provides a snapshot of current practices among endocrinologists and generalists in the management of thyroid disease during pregnancy in East-Asia, is unique in demonstrating potentially important differences between the views of sub specialists and generalists on this issue. Similar studies, in other countries, were conducted only among specialists, without any comparison with generalists, as the first line medical care providence. Previous studies have also reported differences in clinical approaches between generalists and specialists, with regard to treating several common conditions (
35-
38). The results emphasize that many clinicians, in particular generalists, do not adhere to up to date clinical practice guidelines, an important issue that should be considered in continuing education of professional societies.
This study has several limitations. First, the number of participants in this study is small. Second, the responders may not represent all physicians of East-Asian countries and hence, the results are not generalizable, because of the possible selection bias of those who chose to respond, although we could not calculate response rate. Third, variation in the prevailing clinical practices in different countries could have influenced the overall results of the survey. Also, within each group, especially generalists, different backgrounds, age and age of graduation or other confounders have not been considered. It is also not clear whether the results reflect the physicians’ actual practices or are influenced by selective recall, or their desire to give the “correct” answer, as previous studies have highlighted the substantial discrepancies between physicians’ self-reported practices and actual performance (
35,
39). Finally, it is necessary to emphasize that this study did not compare patient outcomes, or any measure of cost-effectiveness between generalists and specialists, limiting only to their self-described practices, however this is beyond the scope of this study.
These results indicate that, for optimal management of patients with certain diseases, for which practices are evolving rapidly, especially in high risk groups, such as pregnant women, it would be better to include consultation or continuing involvement of specialists. However, in the current climate of aggressive cost reduction, surveying improvements in outcomes and cost-effectiveness are definitely required to support this conclusion. It is also necessary to develop and implement strategies that will increase physician knowledge on thyroid and pregnancy among generalists and subspecialists, so that their practice patterns would adhere more closely to the published guidelines.